>> WE SHOULD PROBABLY GET STARTED. GOOD MORNING, EVERYONE. I'M PATRICK STOVER, AND WILL BE SERVING AS THE CHAIR OF THIS WORKSHOP, SPONSORED BY THE OFFICE OF DIETARY SUPPLEMENTS AT NIH AS WELL AS 10 OTHER FEDERAL CO-SPONSORS. SO TO START, I WOULD REALLY LIKE TO WELCOME ALL OF OUR WORKSHOP SPEAKERS. MEMBERS OF OUR AUDIENCE HERE ON THE NIH CAMPUS, AS WELL AS THOSE WHO ARE VIEWING THE PROGRAM BY WAY OF VIDEOCAST. TODAY WE WILL DISCUSS THE TOPIC OF IRON SCREENING AND SUPPLEMENTATION IN THE CONTEXT OF PREGNANT WOMEN AND YOUNG CHILDREN. ESPECIALLY IN THE CASE OF IRON-REPLETE INDIVIDUALS. THIS IS A COMPLEX AND CHALLENGING ISSUE, AND WE REALLY LOOK FORWARD TO A FRUITFUL DISCUSSION ON THESE TOPICS. IN A FEW MINUTES, WE WILL HEAR ABOUT THE ORGANIZATION AND GOALS OF THE WORKSHOP, BUT BEFORE THAT, I WOULD LIKE TO COVER SEVERAL LOGISTICAL ISSUES FOR THE WORKSHOP. FIRST, WHEN YOU ARRIVED THIS MORNING, YOU SHOULD HAVE RECEIVED A MEETING PACKET LIKE THIS CONTAINING THE AGENDA AS WELL AS INFORMATION ABOUT THE SPEAKERS. IN THE INTEREST OF TIME, WE WILL BE INTRODUCING OUR SPEAKERS BY THEIR NAMES ONLY, AND YOU CAN REFER TO YOUR FOLDERS FOR MORE INFORMATION ABOUT THEIR AFFILIATIONS. THERE WILL BE MORNING AND AFTERNOON BREAK TODAY, AS WELL AS A ONE-HOUR LUNCH BREAK. LUNCH CAN BE OBTAINED IN THE CAFETERIA OP THE UPPER LEVEL OF THIS BUILDING. RESTROOMS CAN BE FOUND ON THIS FLOOR, AS WELL AS ON THE UPPER LEVEL. THE WORKSHOP INCLUDES QUITE A FEW SESSIONS OF OPEN DIALOGUE. FOR THOSE IN THE AUDIENCE, PLEASE COME TO THE MICROPHONES IN THE AISLES TO ASK YOUR QUESTIONS. FOR THOSE OF YOU WATCHING BY VIDEOCAST, INFORMATION ABOUT EMAIL ADDRESSES TO USE FOR YOUR QUESTIONS WILL BE PROJECTED ON THE SCREENS. ALSO FOR THOSE WHO ARE SPEAKERS, PLEASE DO NOT USE THE LASER POINTER AS THAT'S NOT VERY HELPFUL TO THOSE WATCHING BY VIDEOCAST. PLEASE USE THE MOUSE THAT'S PRESENT ON THE PODIUM SCREEN. BUT IT IS IMPORTANT THAT MICROPHONES WILL BE USED AT ALL TIMES, SO THAT EVERYONE CAN HEAR YOU, AND BECAUSE WE ARE RECORDING THIS WORKSHOP. I WANT TO END MY LOGISTICAL DUTIES BY ACKNOWLEDGING CHRISTINE TAYLOR OF THE OFFICE OF DIETARY SUPPLEMENTS AND PATSY BRA NON-OF CORNELL UNIVERSITY, BOTH OF WHOM HAVE WORKED TIRELESSLY IN THE LAST YEAR IN COLLABORATION WITH MANY OTHERS INCLUDING MANY IN THIS ROOM TO DEVELOP THIS WORKSHOP AND MAKE IT A REALITY, SO WE THANK THEM FOR THAT. SO BEFORE WE BEGIN OUR SESSION, WE HAVE SEVERAL SPEAKERS WHO WILL SET THE STAGE FOR THE WORKSHOP. WE WILL MOVE QUICKLY THROUGH THESE BACKGROUND PRESENTATIONS WITHOUT THE OPPORTUNITY FOR QUESTIONS IN THE INTEREST OF TIME BUT ALL SPEAKERS WILL BE AVAILABLE THROUGHOUT THE WORKSHOP AND YOU'LL BE ABLE TO FOLLOW UP WITH THEM IF YOU'D LIKE. SO TO BEGIN, I INVITE PAUL COATES TO COME TO THE PODIUM. >> THANK YOU VERY MUCH, PATRICK, AND GOOD MORNING, EVERYBODY. IT'S A PLEASURE TO SEE ALL OF YOU HERE, AND I WANT TO PAY SPECIAL TRIBUTE TO THE SPEAKERS AND THE PANELISTS WHO WILL BE TAKING PART IN DISCUSSIONS TODAY AND TOMORROW. IT'S BEEN MANY MONTHS OF WORK AND DIALOGUE TO BRING US ALL HERE TODAY AND YOU DON'T KNOW HOW GRATEFUL WE ARE FOR THE EFFORTS THAT YOU'VE PUT INTO THIS. WE'RE ALSO GRATEFUL TO THE CO-SPONSORS, PATRICK MENTIONED THAT WE HAD SEVERAL, AND THIS IS A LISTING OF THEM. SEVERAL AGENCIES WITHIN THE DEPARTMENT OF HEALTH AND HUMAN SERVICES, AS WELL AS THE DEPARTMENT OF AGRICULTURE, AND THE DEPARTMENT OF DEFENSE. AND WE'RE GRATEFUL FOR THEIR INTEREST AND WE HOPE THAT THE OUTCOME OF THIS MEETING WILL BE OF VALUE TO THEM AS WELL. WE ALSO HAVE REPRESENTATIVES WITH US TODAY FROM THE WORLD HEALTH ORGANIZATION, FROM ACADEMIC RESEARCH CENTERS, STATE DEPARTMENTS OF HEALTH, HEALTHCARE PRACTICES AND CENTERS, WIC CLINICS, THE INFANT FORMULA INDUSTRY AS WELL AS THE FOOD AND DIETARY SUPPLEMENT INDUSTRIES, AND IN ADDITION, I'D LIKE TO POINT OUT CHRIS LYNCH, WHO DIDN'T KNOW I WAS GOING TO DO THIS, BUT CHRIS LYNCH IS HERE TODAY. HE'S THE NEW DIRECTOR OF THE OFFICE OF NUTRITION RESEARCH OF THE ANYAND IS CENTRAL -- YOU OUGHT TO GET TO KNOW HIM. IN THIS FINAL SLIDE, I JUST WANTED TO USE THIS AS A FRAME FOR WHAT WE'RE TRYING TO ACCOMPLISH AND YOU'LL HEAR MUCH MORE DETAIL FROM CHRIS AND OTHERS. PU WE DEVELOPED THIS WORKSHOP BECAUSE OUR ORGANIZATION LIKE OTHERS AT THE NIH HAS MADE A COMMITMENT TO HELP CLOSE THE RESEARCH GAPS IDENTIFIED BY THE U.S. PREVENTIVE SERVICES TASK FORCE, AN INDEPENDENT PANEL OF EXPERTS IN PRIMARY CARE AND PREVENTION THAT SYSTEMATICALLY REVIEWS THE EVIDENCE OF EFFECTIVENESS AND DEVELOPS RECOMMENDATIONS FOR CLINICAL PREVENTIVE SERVICES. YOU'LL HEAR ABOUT THEIR CONCLUSIONS IN A BIT FROM DR. KEMPER AND HOW THOSE CONCLUSIONS SERVE AS A JUMPING OFF POINT FOR THIS WORKSHOP. BEFORE I TURN THE PODIUM OVER, THOUGH, I'D LIKE TO HIGHLIGHT THE ODS INTEREST IN THE OUTCOMES OF THIS WORKSHOP, AND WE HAVE SOME EXPERIENCE WITH THIS. I THINK THE ONE THAT PARTICULARLY COMES TO MIND IS OUR EXPERIENCE WITH VITAMIN D, WHERE AS A RESULT OF CONVERSATIONS, MUCH LIKE THOSE THAT WE'LL BE HAVING HERE TODAY, ODS WAS INVOLVED IN COFUNDING RESEARCH ORIGINATING AT THE NIH RELATIVE TO VITAMIN D METABOLISM AND HEALTH OUTCOMES. IT ALSO SERVED AS A PLATFORM FOR ODS TO STIMULATE ACTIVITY IN THE DEVELOPMENT AND VALIDATION OF APPROPRIATE LABORATORY METHODOLOGIES, IN THIS CASE, STANDARDIZATION OF BLOOD MEASURES OF VITAMIN D, AND IT ALSO HAS SUPPORTED TRANSLATIONAL RESEARCH AND SPECIAL STUDIES RELATED TO VITAMIN D. SO JUST SO YOU KNOW, WE, CHRIS TAYLOR, PATSY WR PRA NAN, PATRICK STOVER, CATHY ROSS, OTHERS WILL BE LISTENING TODAY AND TOMORROW TO WHAT THE MANY EXPERTS HERE HAVE TO SAY AND SUGGEST, AND WE ANTICIPATE THAT THE CONVERSATIONS WILL BE BOTH STIMULATING AND USEFUL. THANK YOU, AND WITH THAT, I'D LIKE TO TURN THE PODIUM OVER TO CHRIS TAYLOR. >> THANK YOU VERY MUCH, PAUL, AND WELCOME TO ALL OF YOU. IN THE NEXT FEW MOMENTS, I WILL TALK ABOUT THE REASON AND THE WAYS WE ARRIVED AT THIS WORKSHOP, THE OVERARCHING ISSUES, AS WELL AS HOW THE WORKSHOP IS ORGANIZED. VERY BROADLY SPEAKING, THE WORKSHOP IS INTENDED TO DISCUSS EVIDENCE GAPS AND TO FOSTER DIALOGUE, TO EXPLORE AN EMERGING ISSUE, AND IN THE END, TO SPECIFY NEEDED RESEARCH. THIS IS NOT A WORKSHOP ABOUT REACHING CONSENSUS, BUT RATHER THE GOAL IS INFORM CONCLUSIONS ABOUT WHAT WE NEED TO PURSUE IN ORDER TO MAKE MEANINGFUL PROGRESS. AS PAUL HAS MENTIONED, OUR STARTING POINT IS THE U.S. PREVENTIVE SERVICES TASK FORCE REPORTS, BUT THE WORKSHOP EVOLVED TO EMBRACE ADDITIONAL RELATED ISSUES. THE 2015 REPORT ON IRON TARGETED THE U.S. AND FOCUSED ON SCREENING AND ROUTINE SUPPLEMENTATION AMONG PREGNANT WOMEN AND YOUNG CHILDREN DEFINED BY THE TASK FORCE OF 6 TO 24 MONTHS. AS PAUL MENTIONED ALSO, YOU'LL HEAR FROM DR. KEMPER IN MORE DETAIL ABOUT THESE REPORTS, BUT LET ME JUST MENTION BRIEFLY THAT THE TASK FORCE IDENTIFIED CRITICAL EVIDENCE GAPS AND CON CLOUDED THEY COULD NOT DETERMINE BENEFITS OR HARMS FOR THESE SERVICES. IT IS IMPORTANT TO RECOGNIZE THAT THE CONCLUSIONS DID NOT REFLECT CONCLUSIONS ABOUT THE OVERALL IMPORTANCE OF IRON DEFICIENCY ANEMIA. PLANNING FOR THE WORKSHOP INVOLVED MANY CONVERSATION WITH STAKEHOLDERS, AND IT WAS DETERMINED THAT IN ORDER TO ADDRESS THE EVIDENCE GAPS, TWO FUNDAMENTAL TOPICS NEEDED TO BE EXPLORED. THE BIOLOGICAL MECHANISMS AND THE ACCURACY OF SCREENING AND RISK PREDICTIONS. IN ADDITION, THE WORKSHOP WAS SEEN AS AN OPPORTUNITY TO EXPLORE AN EMERGING ISSUE, SOMETHING THAT HAD BEEN DISCUSSED BUT NOT WELL-DEFINED, AND THAT WAS THE ROUTINE SUPPLEMENTATION OF WHAT ARE LIKELY TO BE IRON-REPLETE INDIVIDUALS. DESPITE THE TASK FORCE FINDING OF HARMS BEING UNLIKELY FROM ROUTINE SUPPLEMENTATION, A NUMBER OF EXPERTS WERE RELUCTANT TO PUT THE ISSUE ASIDE, GIVEN THE NOTABLE LEVELS OF IRON EXPOSURE PARTICULARLY IN THE U.S., AS WELL AS CAUTIONARY STATEMENTS FROM EXPERT GROUPS ABOUT THE LACK OF CLARITY OR THE UNKNOWNS SURROUNDING ROUTINE SUPPLEMENTATION. ROUTINE SUPPLEMENTATION LIKELY REDUCES THE PREVALENCE OF IRON DEFICIENCY ANEMIA, BUT OTHER IMPACTS ARE LESS CLEAR. AND AGAIN, I WANT TO EMPHASIZE THAT OUR INCLUSION OF IRON-REPLETE HERE DOES NOT SIGNAL THAT IRON DEFICIENCY ANEMIA IS NOT A CONCERN IN DEVELOPED COUNTRIES. SO WE ORGANIZED THE WORKSHOP INTO FIVE SESSIONS. THE FIRST THIS MORNING WILL BE BIOLOGICAL UNDERPINNINGS, AND THE QUESTIONS WE ASKED OF THE SPEAKERS ARE: GIVEN IRON HOMEOSTASIS, WHAT'S IMPORTANT, WHAT'S SIGNIFICANT, WHAT'S RELEVANT IN TERMS OF PREGNANCY AND YOUNG CHILD GROWTH FOR THESE DATA GAPS? WE ALSO ARE ASKING WHAT WE NEED TO KNOW ABOUT THE INFLAMMATORY RESPONSE, GIVEN THAT LATER IN THE WORKSHOP, THE EFFECT OF INFORMATION WILL ARISE. WE HAVE ADDITIONAL PRESENTATIONS ON IRON PARTITIONS, ON TARGETS OF IRON EXCESS, ETHNIC AND GENETIC FACTORS, AND THEN GIVEN OUR INTEREST IN FOSTERING DISCUSSION, WE HAVE AN EXTENSIVE PERIOD FOR AN OPEN DIALOGUE. SESSION TWO WORKS FOR MEASUREMENT AND SCREENING, AND I THROW UP THIS IMPOSSIBLE-TO-READ SLIDE ONLY TO MAKE THE SIMPLE POINT THAT MARKER RS OF IRON STATUS ARE VERY COMPLICATED. YOU'VE GOT A LOT OF MARKERS, YOU'VE GOT THEM REFLECTIVE OF DIFFERENT TYPES OF STATUS, AND THEN YOU HAVE CONFOUNDING AND COMPLICATIONS WHEN IT COMES TO THEIR ANALYTICAL MEASURES. GROUPS SUCH AS THE WORLD HEALTH ORGANIZATION AND THEN PROJECTS SUCH AS BON AND BRINDA HAVE BEEN WORKING ON THIS FOR MANY YEARS AND THERE'S STILL YET A LOT OF WORK TO BE DONE. SO THE SPEAKERS IN SESSION 2 WERE ASKED TO CONSIDER THE STRENGTHS AND LIMITATIONS OF THESE MARKERS, BUT THEY WERE ALSO ASKED TO PUT IT IN THE CONTEXT OF HARMONIZATION AND STANDARDIZATION. WE WONDERED IF WE NEEDED A BETTER UNDERSTANDING ABOUT PLASMA VOLUME EXPANSION, AS WELL AS THE EFFECT OF INFLAMMATION. AND OF COURSE THERE ARE ALWAYS QUESTIONS ABOUT THE CHALLENGES SURROUNDING THE CUT POINTS, AND AGAIN, WE'VE ALLOWED TIME FOR OPEN DISCUSSION WITH PEOPLE ABOUT THIS. SESSIONS 3 AND 4 MOVE US IN THE DIRECTION OF THE IRON-REPLETE ISSUE. AND THE QUESTIONS WE ASK ARE IN THE CONTEXT OF DEVELOPED COUNTRIES, PARTICULARLY THE U.S., WHEREAS A GENERAL MATTER, THERE'S A LOWER PREVALENCE OF DEFICIENCY, THERE ARE LIKELY GENEROUS AMOUNTS OF IRON IN THE FOOD SUPPLY, AS WELL AS READY ACCESS TO SUPPLEMENTS. IN ADDITION, IT WOULD APPEAR THAT ROUTINE IRON SUPPLEMENTATION DURING PREGNANCY IS NOT UNCOMMON. SO THIS QUESTION OF IESH IRON EXPOSURE BECAME A BACKGROUND ISSUE FOR WORKSHOP PLANNING AND THERE WAS A GREAT DEAL IN INTEREST IN COMPARING THE U.S. TO EUROPE, GIVEN THAT THE IRON SITUATION IN EUROPE IS SOMEWHAT DIFFERENT THAN THAT IN THE U.S. FOR YOUNG CHILDREN, 6 TO 12 MONTHS AND 12 TO 24 MONTHS, THE REQUIREMENTS, THE REFERENCE VALUES, IN GENERAL BETWEEN THE U.S. AND EUROPE ARE NOT ALL THAT DIFFERENT. YOU HAVE AN RDA OF ABOUT 11 FOR THE YOUNGER GROUP AND 7 FOR THE OLDER GROUP, SOMEWHAT SIMILAR TO THE RANGE OF WHAT YOU SEE IN EUROPE. ON THE OTHER HAND, INFANT FORMULA AS MARKETED, PERHAPS OWING TO TRADITION AS WELL AS LOWER BIOAVAILABILITY OF IRON IN THESE PRODUCTS, THE MARKETED FORMULA IN THE U.S. IS CONSIDERABLY HIGHER THAN THAT IN EUROPE FOR BOTH GROUPS. FOOD FORTIFICATION IS NOT UNHEARD OF IN EUROPE BUT IT IS MUCH MORE PREVALENT IN THE U.S., WITH FOODS COMMONLY CONSUMED BY THE YOUNG CHILD AS HAVING BEEN IRON-FORTIFIED. AND THEN THIS FAR COLUMN ON THE RIGHT, THE HEART OF THE SLIDE, THE MEAN INTAKE COMES WITH AN INCREDIBLE NUMBER OF CAVEATS BECAUSE NATIONALLY REPRESENTATIVE DATA FOR THIS YOUNG AGE GROUP IS VERY DIFFICULT TO OBTAIN. WE DO HAVE AN ANALYSIS FROM RECENT -- 2011, 2012, IN WILLOW INCOME GROUP WAS THE FOCUS AND FROM THERE, WE'RE ABLE TO GET A MEAN INTAKE OF 17 MILLIGRAMS PER DAY FOR THE YOUNGER AND TE 10 FOR THE OLDER. ALSO WE'VE FOUND THAT IT WAS ABOUT 1% OF THE YOUNGER AGE GROUP SURPASSED THE UPPER LEVEL FOR IRON. IN EUROPE THE INTAKE IS ESTIMATED TO BE LOWER, 6 TO 10 FOR THE YOUNGER, 5 TO 9 FOR THE OLDER. JUST AN EXERCISE, WE DID A QUICK CALCULATION FOR AN WILL-YEAR-OLD IN THE U.S. ASSUMING THE EXISTING GUIDELINES WERE FOLLOWED AND WE FOUND THROUGH THIS CALCULATION THAT THROUGH THE FORMULA-FED 8 MONTH OLD, THE INTAKE WOULD BE ABOUT 18.5 MILLIGRAMS FOR THE DAY, FOR THE BREAD-FED, 10.2. WIC WAS ESTIMATING ABOUT 17 MILLIGRAMS A DAY, WHICH IS CONSISTENT HERE WITH THE FORMULA-FED. PREGNANT WOMEN PRESENT A SLIGHTLY DIFFERENT PICTURE. FOR THE U.S. AND FOR CANADA, FOR THAT MATTER, THE INSTITUTE OF MEDICINE HAS DETERMINED THAT PREGNANT WOMEN DO HAVE AN INCREASED NEED FOR IRON, AND HAVE SET A REFERENCE VALUE, RECOMMENDED DIETARY ALLOWANCE OF 27 MILLIGRAMS A DAY. ON THE OTHER HAND, EUROPE, AT LEAST THROUGH THE EUROPEAN FOOD SAFETY AUTHORITY, HAS CONCLUDED PREGNANCY DOES NOT INCLUDE AN INCREASED REQUIREMENT FOR IRON, AND HAS LEFT THEIR REFERENCE VALUE AT 16 MILLIGRAMS A DAY, WHICH IS THE SAME REFERENCE VALUE FOR NON-PREGNANT WOMEN. IN TERMS OF RECOMMENDATIONS FOR SUPPLEMENTATION, THE COMMONLY USED CLINICIAN'S ONLINE REFERENCE CALLED "UP TO DATE" NOTES THE GENERAL ADVICE FOR PREGNANT WOMEN TO INCREASE INTAKE BY 15 MILLIGRAMS A DAY. THE AMERICAN COLLEGE OF OBSTETRICS AND GYNECOLOGY RECOMMENDS SCREENING FIRST AND THEN SUPPLEMENTATION TO FOLLOW IF NEEDED. THE CENTERS FOR DISEASE CONTROL GUIDELINES FROM 1998 ARE STILL WITH US, AND THEY RECOMMEND UNIVERSAL SUPPLEMENTATION FOR PREGNANT WOMEN. I MIGHT JUST ASK KIND OF PARENTHETICALLY THAT WE HAD THE STAFF DO A KIND OF INTERNET SEARCH TO JUST SEE WHAT CHAT ROOMS SAID ABOUT WOMEN BEING ADVISED ON THE INTERNET RELATIVE TO IRON CONSUMPTION, AND ON AVERAGE, IT WAS BETWEEN 30 AND 50 MILLIGRAMS A DAY ADDED SUPPLEMENTATION. IN THE CASE OF EUROPE, ALL OF THE COUNTRIES HAVE THEIR GUIDELINES BUT IN GENERAL, THEY TREND SECH TOWARDS NO ROUTINE SUPPLEMENTATION FOR PREGNANT WOMEN, ONLY IF THEY'RE AT RISK FOR IRON DEFICIENCY ANEMIA. AGAIN THE FAR RIGHT COLUMN BEING A VERY IMPORTANT COLUMN, DIFFICULT TO OBTAIN NATIONALLY REPRESENTATIVE DATA FOR PREGNANT WOMEN. IT'IF NOT IMPOSSIBLE. WE DO HAVE A STUDY CONDUCTED BY COGGSWELL, ET AL. USING THE 1988-1994, 182 PREGNANT WOMEN, AND THEY ESTIMATED THAT THE MEAN INTAKE FOR PREGNANT WOMEN WAS 78 MILLIGRAMS PER DAY. NOW IT IS SKEWED DATA, AND THE MEDIAN WOULD BE 58 MILLIGRAMS A DAY, BUT THIS IS A LOT OF IRON AND AS THE RESEARCHERS POINTED OUT, 7 TO 10% OF THEIR SAMPLES WERE EXCEEDING THE UPPER LEVEL FOR IRON INTAKE. IN ADDITION, BY THE SECOND OR THIRD TRIMESTER OF PREGNANCY, MORE THAN 80% WERE CONSUMING A DIETARY SUPPLEMENT. IT'S TOTALLY INAPPROPRIATE FOR ME TO PUT NON-PREGNANT DATA ON A SLIDE FOR PREGNANT WOMEN BUT I DO HAVE IT HERE BECAUSE I THINK IT PROVIDES THE KIND OF BACKGROUND PRECONDITION FOR PREGNANCY. NON-PREGNANT WOMEN, 19 YEARS OF AGE AND OLDER, IF THEY WERE A SUPPLEMENT USER, WERE CONSUMING 27 MILLIGRAMS PER DAY. IF THEY WERE NOT A SUPPLEMENT USER, 13 MILLIGRAMS A DAY. AGAIN, THESE ARE NON-PREGNANT WOMEN. 2011 TO 2012, ALTHOUGH IT'S ONLY ONE DAY OF DATA, WOMEN 20 YEARS OF AGE AND OLDER WERE CONSUMING ON AVERAGE 17 MILLIGRAMS A DAY. WE DON'T HAVE DATA ON PREGNANT WOMEN FOR EUROPE BUT WE DO HAVE NATIONAL SURVEYS THAT LOOKED AT NON-PREGNANT WOMEN AND THEY ALL TEND TO COALESCE AROUND 10 MILLIGRAMS A DAY, SO A COMPARISON FOR NON-PREGNANT IS 10 EUROPE, 17 U.S. IT WOULD APPEAR THAT THE SALE OF IRON-CONTAINING PRENATAL SUPPLEMENTS IN THE U.S. ARE QUITE ROBUST. TO THE EXTENT THEY CAN BE BELIEVED, THEY WOULD SUGGEST THAT THE TOTAL SALES FOR THESE TYPES OF PRENATAL SUPPLEMENTS EXCEEDS HALF A BILLION DOLLARS A YEAR. IN TERMS OF THE CONTENT OF THESE PRODUCTS, BOTH THE PRESCRIPTION AND OVER THE COUNTER HOVER AROUND 30 MILLIGRAMS. BY GOING THROUGH THIS EXPOSURE DATA, IT ALLOWS SESSION 3 TO SET THE STAGE FOR SESSION 4. WHAT WE ASK FOR THE SPEAKERS IN SESSION 3 IS THAT THEY CONSIDER THE IRON STATUS OF THESE PARTICULAR GROUPS. WE HAVE SPEAKERS WHO WILL TAKE A LOOK AT NHANES, AS WELL AS SOURCES OF DATA FROM THE U.S., CANADA AND EUROPE, AND AGAIN THERE'S TIME FOR OPEN DISCUSSION. BY SESSION 4, WE'RE AT THE QUESTION WHAT ARE THESE CONCERNS FOR ROUTINE SUPPLEMENTATION AND OH DO THEY WARRANT CLOSER EXAMINATION. WE'LL HAVE GROWTH, INFECTION AND DEVELOPMENT, GESTATIONAL DIABETES, THE GUT MICROBIOME AND THE U-SHAPED RISK CURVE. THIS WILL BE FOLLOWED BY PANEL DISCUSSION AND AGAIN, AN OPPORTUNITY FOR OPEN DISCUSSION. SESSION 5 PULLS IT ALL TOGETHER. WE BEGIN WITH A DISCUSSION TO INTEGRATE WHAT'S BEEN HEARD IN SESSION 4. AND THEN THE CHAIR WILL WORK WITH A PANEL THAT HAS BEEN PULLED FROM SPEAKERS AS WELL AS RELEVANT STAKEHOLDERS TO KICK START A DISCUSSION ON RESEARCH NEEDS. THE CHAIR WILL THEN MOVE TO AN OPEN DISCUSSION WITH THE AUDIENCE AND THEN WORK TO SUMMARIZE WHAT HE'S HEARD. I WOULD BE REMISS IF I DIDN'T POINT OUT THE OBVIOUS, WHICH IS THAT IRON IS AN EXTREMELY BROAD TOPIC AND WE COULD NOT WORK EVERYTHING THAT WAS IMPORTANT INTO THIS WORKSHOP. PERHAPS MOST NOTABLY IS WE'RE NOT FOCUSING ON DEVELOPING COUNTRIES. IT WAS FELT THAT MUCH OF THE DISCUSSION THAT WE'LL HEAR TODAY WOULD BE RELEVANT WHETHER IT WAS A DEVELOPED COUNTRY OR A DEVELOPING COUNTRY, BUT CONTEXT IS A FACTOR IN THAT LEVELS OF INFECTIOUS DISEASE, NUTRITIONAL STATUS AND QUALITY OF AVAILABLE HEALTHCARE CAN RESULT IN WHAT SOME HAVE REFERRED TO AS RESPONDERS AND NON-RESPONDERS IN THE SENSE OF AN ACTIVITY CARRIED OUT IN A COUNTRY SUCH AS HONDURAS MAY HAVE A DIFFERENT EFFECT IN A COUNTRY SUCH AS SWEDEN, TO USE AN EXAMPLE FROM AN EXISTING STUDY. WE WILL NOT BE FOCUSING ON TREATING DEFICIENCY OR ON METHODS FOR ESTIMATING IRON INTAKE AND FORTIFICATION THAT IMPACT INTAKE. LAST, WORKSHOP OUTCOMES, WHAT'S GOING TO HAPPEN, DO THESE CONVERSATIONS HAVE LEGS. WE WILL PUBLISH THE PROCEEDINGS WHICH ARE INTENDED TO ADVANCE THE FIELD AND IF DONE APPROPRIATELY, IT SHOULD CREATE AN AWARENESS FOR THE IMPORTANT CONVERSATIONS THAT WE HAVE TODAY IN THE RESEARCH FIELD. PAUL HAS MENTIONED THE OFFICE OF DIETARY SUPPLEMENTS HAS A NUMBER OF PATHWAYS FOR FOLLOW-UP, AND HE'S INCLUDED ALL OF THESE IN HIS EARLIER PRESENTATION. WE CAN CO-FUND RESEARCH FROM THE INSTITUTES AND CENTERS AT NIH, WE CAN SUPPORT TRANSLATIONAL RESEARCH, AND WE CAN DEVELOP COLLABORATIVE ACTIVITIES WITH RELEVANT PARTNERS. SO IN SHORT, WE ARE ANXIOUSLY AWAITING THE CONVERSATIONS WE'LL HAVE TODAY AND WE LOOK FORWARD TO HEARING THEM. THANK YOU VERY MUCH FOR BEING HERE. [APPLAUSE] WE'RE NOW GOING TO HEAR FROM ALEX KEMPER AND THE U.S. PREVENTIVE SERVICES TASK FORCE. >> GOOD MORNING, EVERYUP WITH. ALEX KEMPER. I WANT EVERY ONE TO REMEMBER AS I GO THROUGH MY TALK TODAY THAT I'M A GENERAL PEDIATRICIAN, I'M GOING TO BE TALKING ABOUT IRON FROM THE PERSPECTIVE OF A GENERALIST, AND AGAIN AS A MEMBER OF THE PREVENTIVE SERVICES TASK FORCE, I'M DELIGHTED TO BE HERE AND I'D ALSO LIKE TO ACKNOWLEDGE MY FRIEND AND COLLEAGUE, DR. PHIPPS WHO IS SITTING OVER THERE, OB-GYN AND ALSO SERVES AS A MEMBER OF THE TASK FORCE. SO I GUESS TO START OFF WITH, SPOILER ALERT, THE IRON RECOMMENDATIONS THAT WE'RE GOING TO BE TALKING ABOUT TODAY DID RECEIVE AN I STATEMENT. IF YOU ALL GET ONE THING OUT OF THE NEXT 20 MINUTES, IT WOULD BE WHAT EXACTLY IS MEANT BY AN I STATEMENT, AND I'LL TELL YOU, AS A MEMBER OF THE TASK FORCE, IT'S REALLY DELIGHTFUL TO SEE THIS KIND OF MEETING COME TOGETHER, IT'S EXACTLY WHAT WE HOPE HAPPENS WHEN WE ISSUE AN I STATEMENT. SO WHAT I'M GOING TO DO DURING THE COURSE OF THIS TALK IS TO PROVIDE AN OVERVIEW OF WHAT THE TASK FORCE IS AND HOW IT OPERATES, AND THEN DIVE INTO OUR PROCESS FOR CONSIDERING IRON SUPPLEMENTATION AND IRON SCREENING AND HOW WE ENDED UP WITH THE I STATEMENT THAT, YOU KNOW, HOPEFULLY LED TO THIS MEETING COMING TOGETHER. SO AGAIN I JUST TALKED ABOUT THE RECOMMENDATIONS CENTERS AND THE KEY THING IS HIGHLIGHTING THE RELEVANT RESEARCH GAPS AND IMPLICATIONS WHICH . [NO AUDIO] OR WHETHER OR NOT TO TAKE SUPPLEMENTS, AND THEN THE USE OF PREVENTIVE MEDICATIONS AND THIS WOULD BE, FOR EXAMPLE, SUPPLEMENTS AS WELL. AND AGAIN, EVERYTHING WE CONSIDER ARE SERVICES THAT ARE OFFERED IN THE PRIMARY CARE SETTING OR AT LEAST SERVICES FOR THE PRIMARY CARE PROVIDER TO REFER A PATIENT TO. NOW I'M GOING TO SORT OF GO OVER THE PROCESS OF HOW THEY COME OUT WITH A RECOMMENDATION. THE FIRST THING WE DO IS DEVELOP A RESEARCH PLAN. I'M GOING TO SHOW YOU AN ANALYTIC FRAMEWORK THAT WE USE WHEN WE COME UP WITH A RESEARCH PLAN. NOW, ONE OF THE THINGS THAT'S IMPORTANT TO US IN THIS PROCESS IS THE WORDS TRANSPARENT AS POSSIBLE. SO AFTER WE DEVELOP A RESEARCH PLAN, WE POST IT ON THE WEB FOR PUBLIC COMMENT AND REVISE THE RESEARCH PLAN BASED ON THE FEEDBACK THAT WE RECEIVE, AND THEN THE NEXT STEP IS DEVELOPING AN EVIDENCE REVIEW SO WE WORK WITH EVIDENCE BASED PRACTICE CENTERS THAT ARE FUNDED BY THE AGENCY FOR HEALTHCARE RESEARCH AND QUALITY, AND BASED ON THOSE EVIDENCE REVIEW, MOVE AHEAD TO A RECOMMENDATION STATEMENT. WE POST DRAFT RECOMMENDATION STATEMENTS FOR MEMBERS OF THE PUBLIC, THEY BEGIN TO PROVIDE COMMENTS. WE TAKE THESE COMMENTS VERY STEESERIOUSLY, THEN AFTER THE COMMENT PERIOD, WE REVISE AS APPROPRIATE AND THEN RELEASE THE RECOMMENDATION STATEMENTS, AND THE FINAL PROCESS IS RELATED TO THE DISSEMINATION AND THE RECOMMENDATION, AND TYPICALLY WHEN WE THINK OF DISSEMINATION, THAT'S WHEN WE PUT OUT THE RECOMMENDATION AND DIFFERENT GROUPS TAKE THEM UP, BUT I CONSIDER THIS A KEY PART OF OUR DISSEMINATION PROCESS AS WELL, SO I JUST WANT TO HIGHLIGHT HOW HAPPY WE ARE TO SEE THIS COME TOGETHER. ALTHOUGH I KNOW THERE'S NO Q & A PERIOD AT THE END OF THIS TALK, I'D BE HAPPY TO ANSWER ANY QUESTIONS ABOUT THE TASK FORCE, AND IF YOU HAVE ANY PARTICULAR CHALLENGING OR DIFFICULT QUESTIONS TO ASK, THEN I'LL DEFER THOSE TO DR. PHIPPS, OVER THERE. SO THIS IS A TYPICAL ANALYTIC FRAMEWORK THAT WE USE. AGAIN, WE BEGAN -- IF YOU LOOK ON THE LEFT SIDE WHERE IT SAYS PERSONS AT RISK, WE LOOK AT INDIVIDUALS WHO ARE NOT KNOWN TO HAVE A CONDITION THAT ARE AT AVERAGE RISK FOR WHATEVER CONDITION THAT'S UNDER CONSIDERATION, AND WE FIRST LOOK AT -- THIS IS A SCREENING ANALYTIC FRAMEWORK -- SCREENING, AND YOU SEE THAT ONE WITH THE OVERARCHING QUESTION OR THE OVERARCHING LINE THAT TAKES FROM SCREENING TO REDUCED MORBIDITY OR MORTALITY. WE ALWAYS LOOK FIRST AT WHETHER OR NOT WE CAN ANSWER THE QUESTION DIRECTLY THROUGH FOR EXAMPLE RANDOMIZED TRIALS OF SCREENING. INEVITABLY, ESPECIALLY FOR WILD HEALTH TOPICS, WE NEVER FIND THE LEVEL OF EVIDENCE THAT WOULD LEAD US DIRECTLY TO THE RANDOMIZED TRIAL SCREENING. SO INSTEAD WHAT WE HAVE TO DO IS GO THROUGH AN INDIRECT PATHWAY WHERE WE LOOK AT ALL THE LINKAGES THAT WOULD PROVIDE EVIDENCE AROUND WHETHER OR NOT SCREENING IS A GOOD IDEA OR A BAD IDEA, WHETHER OR NOT THE JUICE IS WORTH A SQUEEZE. SO WE LOOK AT WHETHER OR NOT SCREENING CAN IDENTIFY THE CONDITION EARLY, AND AGAIN, WE'RE INTERESTED IN IDENTIFYING ASYMPTOMATIC INDIVIDUALS, SO THAT'S WHERE EARLY DETECTION IS IMPORTANT, AND THEN WE LOOK AT TREATMENT AND WHETHER OR NOT TREATMENT WOULD MOVE AN INDIVIDUAL TOWARDS A CERTAIN INTERMEDIATE OUTCOME, SO FOR EXAMPLE, BIOMARKER IN THIS CASE MIGHT BE IF YOU IDENTIFY INDIVIDUALS WITH IRON DEFICIENCY, AND YOU TREAT TREET THEM, IT INCREASE THEIR HEMOGLOBIN CONCENTRATION, AND THE NEXT STEP IS LOOKING AT THE ASSOCIATION BETWEEN INTERMEDIATE OUT COME, THAT IS, FOR EXAMPLE, INCREASED HEMATOCRIT, TO SOMETHING THAT A PATIENT CAN FEEL, REDUCED MORBIDITY OR MORTALITY OR SOME OTHER MARKER, AND I'LL TALK ABOUT THE KINDS OF FINAL OUTCOMES THAT WE WERE INTERESTED IN, IRON DEFICIENCY ANEMIA. ANOTHER THING WE PAY VERY CLOSE ATTENTION TO THAT SOMETIMES I FEEL LIKE IT'S UNDERREPORTED WHEN THINKING ABOUT PREVENTION, ARE HARM, SO FOR EXAMPLE, LOOKING AT ADVERSE EFFECTS OF SCREENING, WHAT HAPPENS TO INDIVIDUALS PICKED UP THROUGH SCREENING THAT MIGHT NOT OTHERWISE HAPPEN WITHOUT THE SCREENING TEST THAT MIGHT BE A HARM, AND THEN WE ALSO LOOK AT ADVERSE EFFECTS OF TREATMENT. NOW, I'LL BE THE FIRST TO SAY THAT OFTENTIMES IT'S DIFFICULT FOR US TO PUT -- YOU KNOW, TO ESTIMATE ALL THESE DIFFERENT THINGS WITH TIGHT BOUNDS, TIGHT CONFIDENCE INTERVALS, SO WE OFTEN TIMES HAVE TO USE BOUNDING. SO YOU CAN THINK OF BOUNDING AS SORT OF THE INTELLECTUAL EXERCISE WHERE, FOR EXAMPLE, IF YOU KNOW WHAT THE OVERALL PROBLEMS OF IRON DEFICIENCY ANEMIA; WE'RE NEVER GOING TO DO ANY BETTER THAN THAT IN SCREENING FOR IT. YOU CAN SEE ALONG THE STEPS HOW YOU CAN USE THIS BOUNDING EVEN WHEN THE EVIDENCE IS IMPERFECT, IT KIND OF HELPS MOVE YOU ALONG THE ANALYTIC FRAMEWORK. WE HAVE SIMILAR THINGS THROUGH THE ANALYTIC FRAMEWORK FOR PREVENTIVE MEDICATION, IN THIS CASE, SUPPLEMENTATION AND ALSO FOR COUNSELING. SO AGAIN WE -- ONE THING YOU WILL NOT SEE IN THIS SLIDE IS COST, AND THIS IS REALLY IMPORTANT, BECAUSE THE TASK FORCE DOES NOT CONSIDER COST WHEN IT DOES ITS REVIEWS. WE ALSO DON'T CONSIDER ISSUES OF INSURANCE COVERAGE. INSURANCE COVERAGE IS FOR SOMEONE ELSE TO CONSIDER. WE'RE JUST LOOKING AT THE EVIDENCE AROUND DIRECT BENEFIT TO THE INDIVIDUALS THAT WE PROVIDE CARE FOR. ONE OF THE THINGS THAT I GET ASKED A LOT ABOUT IS ONCH UNDER THE ACA BECAUSE THOSE THINGS RECOMMENDED AS AN A OR A B END UP WITH COVERAGE. REALLY THAT'S NOT SOMETHING WE ADVOCATED FOR AND COVERING IS SOMETHING DIFFERENT, AND I'M GOING TO REALLY DRILL INTO THIS AGAIN WHEN I GET INTO WHAT AN I STATEMENT MEANS. SO AGAIN, WE HAVE THIS RIGOROUS PROCESS FOR REVIEWING EXISTING EVIDENCE, WE DID NOT SEE PRIMARY RESEARCH, HOW WE HAVE THESE EVIDENCE-BASED PRACTICE CENTERS THAT PROVIDE THE EVIDENCE FOR US, WE AS TASK FORCE MEMBERS EVALUATE THE BENEFITS AND HARMS, AND THAT LEADS TO THE STATEMENT. SO I ALLUDED TO THIS BEFORE AND I THINK THIS IS REALLY IMPORTANT, WE ARE MOST INTERESTED IN THE KIND OF HEALTH OUTCOMES THAT INDIVIDUALS CAN FEEL. FUNCTIONAL ISSUES, ANYTHING YOU CAN EXPERIENCE, EDUCATIONAL OUTCOMES, HEALTH OUTCOMES, THOSE SORTS OF THINGS. INTERMEDIATE END POINTS, SO CHANGES IN HEMOGLOBIN CONCENTRATION, WE DO LOOK AT BUT ONLY TO THE DEGREE THAT WE KNOW HOW WELL THAT'S LINKED TO THE HEALTH OUTCOMES THAT ARE IMPORTANT TO THE PATIENTS THAT WE TAKE CARE OF. SO AGAIN, WE'RE MOST INTERESTED IN HEALTH OUTCOMES AND YOU CAN SEE HOW THIS IS GOING TO PLAY INTO WHAT I'M GOING TO TALK ABOUT IN A SECOND. SO AGAIN I TALKED BEFORE ABOUT HOW WE LOOK ACROSS THE ANALYTIC FRAMEWORK, WE JUDGE BENEFITS AND HARMS, TAKING INTO ACCOUNT BOTH OUR SERPT AS WELL AS THE MAGNITUDE OF EXPECTED BENEFIT AND THAT'S WHAT LEADS TO OUR LETTER GRADE ASSESSMENT. SO HOOR ARE THE LETTER GRADES. As AND Bs ARE THINGS WE RECOMMEND. YOU CAN THINK OF C AS EVIDENCE OF BENEFIT AND HARM ARE CLOSE SO THERE SHOULD BE A CONVERSATION WITH THE PATIENT ABOUT WHAT'S THE BEST THING TO DO, AND A D IS A CASE THAT THE HARM OUTWEIGHS THE BENEFIT. AN I STATEMENT, I HOPE I DO THIS RIGHT BECAUSE IT'S REALLY CRITICAL TO SAY. AN I STATEMENT IS WHEN THERE'S INSUFFICIENT EVIDENCE ABOUT THE BENEFITS AND HARMS FOR THE TASK FORCE USING THE TASK FORCE METHODS TO SAY WHETHER OR NOT IT'S A DWOOD THIN A GOOD THING OR BAD THIN G. AN I STATEMENT DOESN'T MEAN DON'T DO IT, AN I STATEMENT DOESN'T MEAN IT'S WRONG, AN I STATEMENT DOESN'T MEANS THAT THE HARMS OUTWEIGHS THE BENEFITS OR THE BENEFITS OUTWEIGH THE HARMS. AN I STATEMENT SIMPLY MEANS USING THE TASK FOR METHODS, THERE'S TOO MUCH UNCERTAINTY FOR US TO MAKE A RECOMMENDATION, OKAY? INDIVIDUAL CLINICIANS KNOWING THEIR PATIENT POPULATIONS MAY CONSIDER AN I SOMETHING THAT WE GIVE AN I STATEMENT TO BE A REASONABLE THING TO DO. THE OTHER THING -- REMEMBER I TALKED ABOUT As AND Bs ARE COVERED BY INSURANCE UNDER THE ACA, FIRST DOLLAR, IF YOU HAVE THE RIGHT KIND OF PLAN. WE'RE NOT SAYING THAT INSURERS SHOULDN'T COVER THINGS THAT HAVE AN I STATEMENT, THE As AND Bs REPRESENT THE FLOOR OF WHAT SHOULD BE COVERED. WHEN WE ISSUE AN I STATEMENT, WE HOPE THAT CLINICIANS USE THEIR JUDGMENT AND LOOK TO OTHER SOURCES OF RECOMMENDATION, AND THEN THE THING THAT WE AS TASK FORCE MEMBERS DREAM ABOUT IS A MEETING LIKE THIS TO HELP US RESOLVE OUR ISSUES. SO I'M NOW GOING TO VERY BRIEFLY TALK ABOUT THE TASK FORCE REPORT, IT'S AVAILABLE ON THE WEB, AND IT'S GOING TO HAVE A LOT MORE DETAIL. SO FOR PREGNANT WOMEN, WE LOOKED AT ROUTINE IRON SUPPLEMENTATION AND SCREENING. THIS IS OUR ANALYTIC FRAMEWORK. I'M NOT GOING TO REVISIT THE QUESTIONS SPECIFICALLY OTHER THAN TO SAY YOU CAN SEE HOW THEY FIT IN GOING FROM ASYMPTOMATIC PREGNANT WOMEN THROUGH ROUTINE IRON SUPPLEMENTATION, CHANGES IN IRON STATUS, AND THEN SOME HEALTH OUT COME, EITHER RELATED TO MATERNAL OUTCOMES OR INFANT OUTCOMES. THIS THE SAME SORT OF THING FOR SCREENING, YOU CAN SEE THE DIFFERENCE, INSTEAD OF SUPPLEMENTATION, WE'VE SUBSTITUTED THE QUESTIONS WITH SCREENING AND LOOKING AT QUESTIONS AROUND, FOR EXAMPLE, THE ACCURACY OF SCREENING. SO I SAID THIS BEFORE, HERE ARE THE CONCLUSIONS AROUND PREGNANT WOMEN THAT ROUTINE IRON SUPPLEMENTATION RECEIVED AN "I" STATEMENT TO SAY THE CURRENT EVIDENCE IS INSUFFICIENT TO ASSESS THE BALANCE OF BENEFITS AND HARMS AND THE SAME FOR SCREENING AS WELL. THIS RAISES LOTS OF QUESTIONS, ESPECIALLY FOR THOSE OF YOU WHO ARE EXPERTS IN THE IRON WORLD, AGAIN, WE'RE LOOKING AT WHAT HAPPENS RELATED TO HEALTH OUTCOMES FOR PRIMARY CARE PATIENTS THAT SEEK CARE IN THE UNITED STATES. SO WE'VE FOUND INADEQUATE EVIDENCE RELATED TO ROUTINE SUPPLEMENTATION FOR THESE HEALTH OUTCOMES FOR MOMS AND THEIR CHILDREN, CHALLENGES ALSO RELATED TO THE INTERMEDIATE OUTCOMES WITH SIGNIFICANT EVIDENCE GAPS AROUND CHANGES IN IRON STATUS AND THESE MEANINGFUL HEALTH OUTCOMES THAT I ALLUDED TO BEFORE, AND SCREENING, SAME THING AS WELL. SO THE LACK OF EVIDENCE AROUND CHANGES IN IRON STATUS AND MEANINGFUL HEALTH OUTCOMES. SO AGAIN THIS IS WHAT LED TO THE "I" STATEMENT, I THINK I COVERED IT PREVIOUSLY, AND I WANT TO MAKE SURE I KEEP YOU ALL ON TIME. SO LET'S MOVE ON TO YOUNG CHILDREN AND YOU'LL NOT BE SURPRISED TO FIND OUT THAT THE SAME GAP THERE EXISTS. SO WE DID NOT LOOK AT SUPPLEMENTATION, WE LOOKED AT SCREENING ONLY, AND THE REASON THAT THE TASK FORCE DECIDED NOT TO LOOK AT SUPPLEMENTATION IS BECAUSE AS CHRIS MENTIONED EARLIER, THERE'S THE WIDESPREAD USE OF IRON FORTIFIED FOODS IN THE UNITED STATES AND AMPLE OPPORTUNITY TO GET EXPOSED TO IRON THROUGH DIET, AND THE SENSE TOO WAS THAT THE IMPACT OF MAKING A RECOMMENDATION ON PHYSICIAN PRESCRIBED ROUTINE SUPPLEMENTATION WOULD BE LOW. SO AGAIN WE FOCUSED ON THE INFANTICIDE ON SCREENING. SO AGAIN HERE IS THE SCREENING AB LYTIC FRAMEWORK, EXACTLY THE SAME AS YOU SAW BEFORE. THE KEY THING TO RECOGNIZE ON THIS SLIDE IS THAT WE'VE FOCUSED ON ASYMPTOMATIC OTHERWISE CHILDREN BETWEEN THE AGES OF 6 AND 24 MONTHS, LOOKING AT THE BENEFITS AND HARMS FOR SCREENING FOR IRON DEFICIENCY ANEMIA, WHETHER OR NOT THAT WOULD LEAD TO CHANGES IN IRON STORES OR IRON STATUS, AND HOW THAT EVENTUALLY IMPACTED MEANINGFUL HEALTH OUTCOMES FOR THE CHILD, AND AGAIN FOR HEALTH OUTCOMES, WE WERE PRETTY EXPANSIVE INCLUDING LOCKIN LOOKING AT ISSUES OF DEVELOPMENTAL DELAY. HERE WE ARE AGAIN, CURRENT EVIDENCE IS INSUFFICIENT TO ASSESS THE BALANCE OF BENEFITS AND HARMS OF SCREENING FOR IRON DEFICIENCY ANEMIA IN CHILDREN 6 TO 24 MONTHS, OLDER CHILDREN AND ADOLESCENTS IS A SEPARATE TOPIC. THE RATIONALE INCLUDES INADEQUATE EVIDENCE FOR THE EFFECT OF ROUTINE SCREENING OR TREATMENT ON THESE IMPORTANT CHILD HEALTH OUTCOMES, AND THE BARRIER RELATED TO CHANGES IN IRON STATUS AND ULTIMATELY HEALTH OUTCOMES. AGAIN INADEQUATE EVIDENCE RELATED TO HARMS OF ROUTINE SCREENING OR TREATMENT AND HARMS FROM THE ENTIRE PROCESS, AND AGAIN WE WERE FOCUSED ON TREATMENT IN THE UNITED STATES AND NOT OTHER COUNTRIES, DEVELOPING COUNTRIES, BECAUSE THE FEELING IS THAT THEY'RE REALLY NOT GENERALIZABLE TO WHAT HAPPENS IN THE U.S. OR SIMILAR COUNTRIES. I'D LIKE TO CONCLUDE BY THROWING OUT IDEAS THAT WE HAD FOR MOVING FORWARD. I THINK A FOCUS ON EXAMINING MATERNAL AND FEE TEL, INFANT AND CHILD HEALTH OUTCOMES ARE KEY AND GENERALIZABLE TO THE U.S. THIS IS A HARD CHALLENGE TO ASSESS CHANGE IN IRON STATUS WITH MEANINGFUL HEALTH OUTCOMES, BUT THAT'S REALLY THE BAR THAT WE HAVE. I HAVE HERE A LONG LIST OF RESEARCH OF INTEREST THAT WOULD HELP US, MOVE OFF THE I. BUT THE KEY THINGS IS JUST HAVING WELL DESIGNED, ADEQUATELY POWERED STUDIES IN THE U.S. OR SIMILAR COUNTRIES TO UNDERSTAND THE DEGREE TO WHICH SCREENING OR SUPPLEMENTATION IS EFFECTIVE NOT ONLY IN THE INTERMEDIATE OUT COME OF CHANGING IRON STATUS TO CHANGING HEALTH OUTCOMES. AGAIN, I KNOW I'M REPEATING MYSELF A LITTLE BIT, BUT THIS IS A REALLY KEY ISSUE AND IT UNDERLIES WHERE THE "I" STATEMENT CAME FROM. IT'S REALLY THE SAME EXACT THING FOR YOUNG CHILDREN, UNDERSTANDING HOW SCREENING FOR IRON TEE EFFICIENCY ANEMIA ULTIMATELY LEADS TO MEANINGFUL CHANGES IN HEALTH OUTCOMES FOR THE CHILD. I WILL BE AVAILABLE THE NEXT TWO DAYS FOR QUESTIONS AND I REALLY EAGERLY LOOK FORWARD TO LEARNING FROM YOU ALL, IT'S VERY HUMBLING TO BE IN A ROOM OF REALLY INTERNATIONAL EXPERTS IN IRON METABOLISM. THANK YOU. [APPLAUSE] >> SO THANK YOU VERY MUCH TO OUR THREE SPEAKER, DR. KEMPER, DR. TAYLOR, DR. COATES, I'D JUST LIKE TO EMPHASIZE WHAT WE'VE DONE HERE IS SET THE STAGE FOR WHAT WE'RE GOING TO BE TALKING ABOUT OVER THE NEXT TWO DAYS. WE LEARNED ABOUT THE "I" STATEMENT, AND WE LEARNED THAT THERE ARE MANY EVIDENCE GAPS. I ESPECIALLY WANT TO EMPHASIZE NOTES FROM DR. TAYLOR ABOUT THE SCOPE OF THIS WORKSHOP. ALSO THE RANGE OFEXPOSURES DR. ROSS TO THE STAGE TO OPEN UP THE FIRST SESSION. >> THANK YOU, PATRICK. SO IT'S A PLEASURE TO BEGIN THIS SESSION, WHICH IS A STAGE-SETTING SESSION AS WELL ON RELEVANT BIOLOGICAL UNDERPINNINGS. AND WE'LL HAVE THREE INITIAL SPEAKERS ON THE TOPIC OF IRON HOMEOSTASIS FROM DIFFERENT PERSPECTIVES, AND THEN I'LL FOLLOW WITH A PRESENTATION ON INFLAMMATION. SO WITH THAT, I'D LIKE TO INVITE GREG A ANDERSON TO COME AND BEGIN HIS PRESENTATION ON CURRENT UNDERSTANDING OF IRON HOMEOSTASIS. >> THANKS, CATHY. I'D PARTICULARLY LIKE TO THANK CHRIS AND PATSY FOR PUTTING TOGETHER THIS WORKSHOP. IT PROMISES TO BE A REALLY INTERESTING COUPLE OF DAYS AND I'M REALLY LOOKING FORWARD TO IT. I ALSO WANTED TO BE ABLE TO BE INVITED TO PRESENT THIS TALK BECAUSE THERE ARE MANY OTHER PEOPLE IN THIS ROOM THAT COULD BE A SIMILAR TALK BUT IT'S NICE TO BE AMONGST MANY FRIENDS, TO MEET SOME PEOPLE WHOSE WORK I RESPECTED FOR A LONG TIME BUT NEVER HAD THE OPPORTUNITY TO MEET, SO IT'S GOOD FROM THAT POINT OF VIEW. SO THIS IS A VERY IMPORTANT TOPIC, IT'S SOMETHING MY LAB HAS HAD A RESEARCH INTEREST FOR SOME TIME, AT LEAST IN ANIMAL MODELS, I'VE BEEN ASKED TO GIVE A GENERAL OVERVIEW OF IRON HOMEOSTASIS TO SET THE XENOIN MORSCENE ANDMORE DETAIL WILL COME FROM OTH ER PEOPLE. A LOT OF THE MOLECULAR BASIS OF OUR UNDERSTANDING OF IRON METABOLISM HAS REALLY COME IN MORE RECENT TIMES, PARTICULARLY IN THE LAST 10 OR 15 YEARS. THERE WAS A PARTICULARLY IMPORTANT PERIOD AROUND THE YEAR 2000, WHERE I THINK METHODOLOGIES, THE TIME WAS RIGHT, WHERE A RANGE OF IMPORTANT DISCOVERIES WERE NAID AND I JUST WANT TO HIGHLIGHT SEVERAL OF THEM, PARTICULARLY IDENTIFICATION OF THE TRANSPORTERS DMT1 AND -- AND THE IDENTIFICATION OF HEPCIDIN. WHAT WE'VE LEARNED HAS REALLY ADDED LAYERS OF COMPLEXITY ON TOP OF THAT. THE FIELD IS MUCH RICHER FOR THAT. THERE'S A LOT WE DON'T KNOW. FOR EXAMPLE, WHAT ARE THE EFFECTS OF SUBTLE VARIATIONS IN IRON HOMEOSTASIS WHEN WE DO EXPERIMENTAL STUDY, WE TEND TO WORK WITH EXTREME, WE TAKE A MOUSE OR RAT, WE MAKE IT HIGHLY IRON DEFICIENT OR IRON LOADED AND LOOK AT DIFFERENCE, BUT LOOK AT SUBTLE VARIATION EFFECTS IS MUCH MORE CHALLENGING. SO I'M GOING TO SAY A FEW WORDS ABOUT BASIC IRON PHYSIOLOGY, TALK ABOUT PATHOPHYSIOLOGY AND GIVE SOME THINGS WE SIMPLY DON'T KNOW. TO COVER IRON HOMEOSTASIS IN 20 MINUTES IS A CHALLENGING TASK BUT WE'LL DO WHAT WE CAN. FIRST SOME BASIC IRON PHYSIOLOGY. SO IRON COMES INTO THE BODY THROUGH TH THE DIET SMALL AMOUNTS EACH DAY, 1 TO 2 MILLIGRAMS, BALANCE BID IRON LOSS OF A SIMILAR AMOUNTS, IRON BINDS TO PLASMA TRANSFERRIN, DEBITS TRANSPORTED TO ALL TISSUES AND CELLS WHERE IT'S REQUIRED AND QUANTITATIVELY, ABOUT 80% OF THE IRON TRAFFIC ON ANY GIVEN DAY GOES TO THE BONE MARROW, WHERE THAT IRON IS USED FOR HEMOGLOBIN PRODUCTION IN RED CELLS, BUT ALL CELLS REQUIRE IRON, THIS IS A VERY DYNAMIC PROCESS OF IRON GOING INTO TISH EU INTO CELLS AND COMING OUT AGAIN. IN TERMS OF DIETARY INTAKE, WE THINK OF IT IN TERMS OF NON- -- IT'S NOT IN PARTICULARLY STABLE COMPLEX, WHICH IS WHY A RANGE OF DIETARY FACTORS CAN INFLUENCE ABSORPTION, SO LOW PH, GASTRIC ACID IS IMPORTANT, THEY ALL STIMULATE IRON ABSORPTION, WHERE PLANT -- IMPEDE ABSORPTION. THE IRON IS SEQUESTERED WITHIN THE RING. SO THAT MEANS -- MAYBE LESS STRONGLY REGULATED. I'LL PUT A QUESTION MARK THERE BECAUSE THE CURRENT THEORY ABOUT HOW HEME IRON IS ABSORBED HAS -- EPITHELIAL CELL BY THE SAME PATHWAY AS NON-HEME IRON SO YOU MIGHT EXPECT THEY'D BE REGULATED VERY SIMILARLY, SO THAT'S AN AREA THAT NEEDS FURTHER WORK. IRON ABSORPTION OCCURS THROUGH THE MATURE -- OF THE MID TO UPPER VILLUS AND IT'S PARTICULARLY PROMINENT IN THE PROXIMAL PART OF THE SMALL INTESTINE. DAVID FRASIER HAS LOOKED AT THE EXPRESSION OF VARIOUS GENES INVOLVED IN IRON HOMEOSTASIS IN DIFFERENT PARTS OF THE G.I. TRACT OF THE RAT IN THIS CASE AND WE'RE LOOKING HERE FROM THE STOMACH THROUGH THE COLON. ALL THESE GENES WERE EXPRESSED AT VERY HIGH LEVEL IN THE PROXIMAL PART OF THE SMALL INTESTINE AND THEY DROP OFF AFTER THAT. THAT'S A PART OF THE GUT PARTICULARLY WELL ADAPTED FOR ABSORBING IRON. IN TERMS OF THE ABSORPTION ITSELF, IRON NEEDS TO CROSS THE -- CROSS THE BUSH BORDER MEMBRANE AND THE BASAL -- MEMBRANES IN THE FORMER CASE IT USE THE TRANSPORTER DMT -- TRANSPORTER 1 AND AT THE BASAL -- EXPORTED -- EACH OF THOSE STEPS IS ASSOCIATED WITH A CHANGE IN THE OXIDATION STATE OF IRON, REDUCTION OF THE MEMBRANE MAY PLAY A ROLE, THEY'RE LIKELY -- INVOLVED AS WELL, AND THE EVIDENCE FOR THE INVOLVEMENT OF -- BASAL LATERAL MEMBRANE IS MUCH STRONGER, NOT ABSOLUTELY REQUIRED BUT IT CERTAINLY MAKES THAT PROCESS MORE EFFICIENT. AS I MENTIONED, HEME IRON AND POTENTIALLY OTHER FORMS OF IRON IS LESS WELL UNDERSTOOD. IN THE CASE OF HEME, IT'S THOUGHT TO ENTER THE CELLS INTACT AND THE -- BREAK DOWN THE HEME AND THAT IRON EXITS THE CELL VIA THE SAME BASAL PATHWAY AND SIMILAR FOR OTHER SORTS OF IRON, BUT MANY OF THOSE DETAILS ARE NOT KNOWN. SO THAT IERP WILL BAND TO TRANSFERRIN IN THE PLASMA AND WILL GET DISTRIBUTE TODAY VARIOUS SITES AROUND THE BODY THAT IRON IS REQUIRED. IRON ABSORPTION AND IRON SUPPLY IS VERY STRONGLY REGULATED SO FACTORS LIKE INCREASED IRON STORES OR INFLAMMATION WILL REDUCE ABSORPTION WHEREAS DECREASED IRON LEVELS, HYPOXIA WILL LEAD TO A STIMULATION OF ABSORPTION. -- DELIVERED ITS IRON TO CELLS BY BONDING TO TRANSFERRIN RECEPTOR 1 IN THE PLASMA MEMBRANE OF CELLS, THAT COMPLEX GETS INTERNALIZED, IRON VEE LEASED FROM THE TRANSFERRIN AND MOVES BY DMT1 INTO THE CYTOPLASM, AND THERE IT CAN BE USED FOR VARIOUS METABOLIC FUNCTIONS OR IF IT'S NOT NEEDED BY THE CELL AT THAT TIME, IT COULD BE STORED WITHIN FERRITIN OR COULD BE EXPORTED BY -- SEEMS TO PERFORM THAT FUNCTION FROM MOST BODY CELLS AND MAKES THAT PLPROCESS MORE EFFICIENT. I'VE JUST ADDED HERE INDICATIONS OF SOME OTHER WAYS IN WHICH IRON CAN BE ABSORBED. PARTICULARLY IMPORTANT IN THE CONTEXT OF TOXICITY IS THE UPTAKE OF NON-TRANSFER AND BOUND IRON, POTENTIALLY A VERY TOXIC FORM OF IRON, AND WE NOW KNOW THAT ZIP 14 -- FERRITIN CAN ALSO BE TAKEN UP BY SELLS AND IN THE CASE OF HEMOLYSIS, THEY CAN BIND TO -- THOSE COMPLEXES CAN ALSO BE TAKEN TO THE CELLS SO THERE ARE A RANGE OF OTHER METHODS BY WHICH IRON CAN GET INTO CELLS. WHAT HAPPENS WHEN IT'S IN THERE? WELL, IT'S AN AREA WE DON'T KNOW VERY MUCH ABOUT AT ALL. IRON NEEDS TO BE AVAILABLE FOR INSERTION INTO A WID WIDE RANGE OF PROTEINS IN MITOCHONDRIA, IN CYTOPLASM. THERE ARE A WHO DIFFERENT RAPING AND LIKELY TO BE A RAPING OF DIFFERENT WAYS IN WHICH IT'S DELIVERED AND WE DON'T KNOW TOO MUCH ABOUT THAT. WE KNEW VERY LITTLE ABOUT HOW IRON WAS HANDLED IN THE CYTOPLASM UNTIL CAROLINE -- WORKING ON THIS CAMPUS DISCOVERED THAT THE POLYRC BINDING PROTEINS ARE IMPORTANT IN IRON CHAPERONES BUT THERE ARE LIKELY TO BE OTHER CHAPERONES INVOLVED AS WELL. IRON IN EXCESS OF METABOLIC REQUIREMENTS CAN GET SEQUESTERED IN PRODUCTS LIKE FERRITIN, VERY EFFECTIVE STORAGE PROTEIN THAT CAN HOLD UP TO SEVERAL THOUSAND ATOMS OF IRON. IF FERRITIN BUILDS UP, YOU IT CAN AGGREGATE, HEMOSIDERIN. IMPORTANTLY IN THE CONTEXT OF THIS MEETING IS SMALL AMOUNTS OF FERRITIN ARE ALSO SECRETED INTO THE CIRCULATION. IT CAN BE A VERY USEFUL INDEX OF IRON STATUS, BUT OF COURSE IT CAN ALSO BE AFFECTED BY INFLAMMATION, ALTHOUGH MORE ABOUT THAT. REGULATORY SYSTEMS THAT DETERMINE -- SO JUST A LITTLE BIT ABOUT THE REGULATIONS. IRON HOMEOSTASIS INTAKE, AT THE CELLULAR LEVEL, IS VERY TIGHTLY REGULATED. THE BEST KNOWN REGULATORY SYSTEM IS THE IRE/IRP SYSTEM. IMPORTANT WORK WAS DONE CLOSE TO THIS BUILDING, ABOUT 100 METERS AWAY IN BUILDING 18 BY RICK, TRACY AND JOE A NUMBER OF YEARS AGO NOW. SO THIS IS A WELL-KNOWN SYSTEM FOR THE COORDINATE REGULATION OF FERRITIN AND TRANSFRIN RECEPTOR 1 WHERE THE CELL IS IRON-DEFICIENT, YOU GET -- MORE IRON INTAKE INTO THE CELL AND RELATIVELY LOWER EXPRESSION OF FERRITIN, BUT WHEN THE CELL IS IRON BOUNDARY MEET, YOU GET MORE IRON STORED IN FERRITIN UNLESS TAKEN INTO THE CELL. THERE ARE OTHER LEVELS OF REGULATION, TRANSCRIPTIONAL REGULATION IS LIKELY TO BE VERY IMPORTANT. WE REALLY DON'T KNOW TOO MUCH ABOUT THAT. WE KNOW THAT HYPOXIA IS IMPORTANT AS A TRANSCRIPTIONAL REGULATOR, CYTOKINES, VARIOUS HORMONES, AND IRON ITSELF CAN REGULATE PROTEINS AT THE TRANSCRIPTIONAL LEVEL, BUT APART FROM A FEW CASES, OUR DETAILS IN THAT AREA ARE STILL REGTIVELY LACKING. AT THE SYSTEMIC LEVEL, WE KNOW HEPCIDIN IS A VERY IMPORTANT REGULATOR OF HOMEOSTASIS AND A LOT OF WHAT WE KNOW ABOUT THIS COMES FROM TOM GANTS IN THE AUDIENCE, REAL EXPERTS IN THIS AREA, TO ASK ANY QUESTIONS ON THAT. HEPCIDIN IS A SMALL PEPTIDE PRODUCED BY THE LIVER THAT ACTS ON ITS TARGET CELLS TO DETERMINE HOW MUCH IRON ARE RELEASED INTO THE CIRCULATION. AND IN TURN, THE EASTERN REQUIREMENT OF THE TISSUES TO DETERMINDETERMINE HOW MUCH HEPCIDIN IS RELEASED SO IT'S A VERY TIGHTLY REGULATED PROCESS. BASICALLY MEANING THAT YOU TONIGHT GET IRON EXPORT FROM THE CELL AND IRON ACCUMULATES FROM WITHIN THE CELL. SO IN SITUATIONS WHERE YOU HAVE LARGE AMOUNTS OR HIGHER AMOUNTS OF HEPCIDIN, YOU HAVE LOWER IRON IN THE PLA MA AND WHEN YOU HAVE LOW LEVELS, MORE IRON CAN ENTER THE PLASMA. WE NOW KNOW A GREAT DEAL ABOUT THE REGULATION OF HEPCIDIN, WE KNOW THAT BMP SMED PATHWAY IS CENTRAL TO THE REGULATION -- BUT THERE ARE LOTS OF OTHER REGULATORY PATHWAYS AS WELL AND THIS IS STILL AN AREA OF VERY ACTIVE INVESTIGATION BY A RANGE OF LABORATORIES. I WANT TO SPEND A COUPLE MINUTES TALKING ABOUT ORGAN-SPECIFIC IRON METABOLISM. IRON SUPPLY IS PRIORITIZED TO DIFFERENT ORGANS, AND WITHIN ORGAN, HOM HOMOGENEOUS SINGLE CELL TISH EU THEY THERE ARE FACTORS THAT NEED TO BE TAKEN INTO ACCOUNT. I DON'T HAVE TIME TO GO THROUGH THIS IN DETAIL BUT SIMPLY TO POINT OUT THAT HERE ARE SOME OF THE MAJOR IMPORTANT TISSUES IN IRON HOMEOSTASIS, THE ERYTHROID MARROW IN THE BRAIN ARE RELATIVELY PROTECTED AGAINST IRON DEFICIENCY, WHERE THE LIVER, ALTHOUGH IT'S VERY IMPORTANT IN IRON HOMEOSTASIS, IS RELATIVELY LESS PROTECTED COMPARED TO THOSE OTHER ORGANS SO THIS IS AN IMPORTANT AREA WHERE MORE WORK IS NEEDED. MICHAEL ZIMMERMAN IS GOING TO SAY A LOT MORE ABOUT IRON IN THE MICROBIOME. WE ALL KNOW THAT THERE'S ABUNDANT EVIDENCE NOW THAT THE MICROBIOME PLAYS AN IMPORTANT ROLE IN A WHOLE RANGE OF HUMAN HEALTH ISSUES AND METABOLIC ISSUES, AND MOST BACTERIA REQUIRE, FOR SOME IT'S VERY IMPORTANT FOR THEIR SURVIVAL, INCLUDING, OF COURSE, PATHOGENIC MATERIAL WHICH CAN BE A PROBLEM. IT'S CERTAINLY LIKELY THAT THE MICROBIAL COMPLEMENT AS WELL MAY ALTER IRON HOMEOSTASIS, SO ANY CONSIDERATION OF IRON HOMEOSTASIS REALLY NEEDS TO CONSIDER THE EFFECTS ON THE MICROBIOME. WE'RE GOING TO HEAR A LOT MORE ABOUT MEASURING IRON STATUS AND THERE ARE A WHOLE RANGE OF PARAMETERS, THIS IS CERTAINLY NOT A COMPREHENSIVE LIST RELATED TO RED CELL INDICES AND VARIOUS BIOCHEMICAL PARAMETER, MANY OF WHICH HAVE BEEN AROUND FOR A LONG TIME THAT WE CAN USE TO MEASURE IRON STA TURKS MANY LIKE JIM COOK AND BARRY HAVE WORKED ON THIS FOR A LONG TIME AND THEY'VE NICELY SHOWED THAT SERUM FERRITIN CAN BE A GOOD MARKER OF INCREASED IRON STORES WHERE SOLUBLE TRANSFERRIN RECEPTOR CAN BE A USEFUL INDICATOR OF THE DEGREE OF IRON DEFICIENCY AND THAT THE COMBINATION OF THOSE TWO OR THE RATIO OF THE TWO CAN BE A USEFUL INDICATOR OF IRON STORES OVER A BROAD RANGE. THINGS LIKE LIVER BIOPSIES, BONE MARROW BIEP SEES, QUANTITATIVE PHLEBOTOMY ARE NOT USED AS OFTEN THESE DAYS. THEY STILL HAVE THEIR ROLE AND THERE'S A LOT MORE INTEREST IN MRI AND THE FERRISCAN PROCEDURE. PARTICULARLY IN IRON LOADING COMPANIES. ST. PIERRE IS A CHAMPION IN THAT AREA. SO THAT WAS A VERY BRIEF COVERAGE OF SOME OF THE BASIC ASPECTS OF IRON HOMEOSTASIS. WHAT ABOUT THE PATHOPHYSIOLOGY? WE KNOW THAT IRON IS AN IMPORTANT PRO OXIDANT, IT CAN CATALYZE THE FORMATION OF OXYGEN RADICALS THROUGH SOME WELL-KNOWN REACTIONS AND WE KNOW THAT REACTIVE OXYGEN SPECIES PRODUCED CAN ACT ON A WHOLE RANGE OF CELLULAR MACRO MOLECULES AND PROCESSES TO LEAD TO ADVERSE HEALTH OUTCOMES WITH -- ADVERSE CELLULAR OUTCOMES AND THIS UNDER LIES THE TISSUE DAMAGE YOU CAN SEE WITH IRON LOADING. WE ALSO KNOW YOU NEED TO KEEP IRON WITHIN A DEFINED BODY RANGE, IF YOU DEVIATE TO -- IRON DEFICIENT STAGE, DIRECTION WILL BE ON LOADING DIRECTION, YOU CAN HAVE SIGNIFICANT CLINICAL CONSEQUENCES. WE'RE NOT REALLY TALKING ABOUT IRON DEFICIENCY AT THIS WORKSHOP BUT JUST TO REITERATE THAT IRON DEFICIENCY REMAINS A MAJOR GLOBAL HEALTH PROBLEM NOT ONLY IN DEVELOPING COUNTRIES BUT IN DEVELOPED SOCIETIES AS WELL. WHAT WE'VE LEARNED IN IRON LOADING IS MORE RELEVANT SO I'LL SPEND A COUPLE MINUTES TALKING ABOUT THAT. THERE'S BEEN A LOT OF WORK ON IRON LOADING DISORDERS AND A LOT OF WHAT WE KNOW ABOUT THE BASIC MECHANISMS OF IRON HOMEOSTASIS HAVE COME FROM OUR UNDERSTANDING OF VARIOUS DISEASES. PERHAPS THE MAIN ONCE WE TALK ABOUT -- SERIES OF -- IRON LOADING ANEMIAS. THE PRIMARY DEFECT IS IN ONE OF THE PROCESS INVOLVED IN IRON PHYSIOLOGY. IN MANY CASES HERE THE REGULATION OF IRON METABOLISM INTAKE, IRON ABSORPTION. MOST OF THESE CONDITIONS TEND TO BE RARE TO UNCOMMON. WITH THE EXCEPTION OF HFE RELATED HAEMOCHROMATOSIS. THALASSEMIA -- THEY'RE OFTEN CALLED SECONDARY IRON LOADING DISORDERS BUT ALSO IN MANY OF THESE CASE, YOU ALSO HAVE INCREASED IRON ABSORPTION SO THIS IS A MIXED APOLOGY THERE. BUT A COMMON FEATURE IS DISRUPTIONS IN THE HEPCIDIN/FERROPORTIN AXIS IS A COMMON THEME. IRON GETS TRANSPORTED IN A NUMBER OF TISSUES, IN TERMS OF IRON DISLOADING -- MAJOR SITES OF IRON RELATED DAMAGE. THERE ARE ALSO OTHER IRON-RELATED DISORDERS, I'M NOT GOING TO GO THROUGH THESE, WE MIGHT HEAR MORE ABOUT AFRICAN IRON OVERLOAD FROM VICTOR LATER IN THE MEETING. IT CAN ALSO MAKE OTHER CONDITIONS WORK SO IT'S A COFACTOR IN A RANGE OF DISORDER AND YOU CAN'T REALLY TALK ABOUT THE PATHOPHYSIOLOGY OF IRON WITHOUT MENTIONING AT LEAST IRON IN DISORDERS OF THE CENTRAL NERVOUS SYSTEM, AND IRON HAS BEEN ASSOCIATED WITH THE PATHOLOGY OF A LARGE NUMBER OF THESE. ANEMIA OF CHRONIC DISEASE, WE'LL HEAR MORE FROM CATHY ROSS SORTLY WHERE INFLAMMATION REDUCES IRON ENTRY INTO THE PLASMA, INCREASES OF HEPCIDIN IS CERTAINLY RESPONSIBLE FOR SOME IRON DISTURBANCES BUT THERE ARE ALSO NON-HEPCIDIN RESULTS AS WELL, THIS COMES FROM THE PRO INFLAMMATORY CYTOKINES. THE EFFECT CONDITION CAN LEAD TO ANEMIA WHICH CAN HAVE SIGNIFICANT CLINICAL CONSEQUENCES, YOU SEE THIS IN INSTANCES OF INFECTION, ET CETERA. THIS SLIDE SHOWS SOME OF THE EFFECTS OF IRON ON MACROPHAGES. WE KNOW THAT IERP HAS -- EXCESS IRON HAS EFFECT ON A WHOLE RANGE OF CELLS BUT THIS JUST SHOWS YOU THE NUMBER AND COMPLEXITY OF SOME OF THE INTERACTIONS THAT OCCUR IN THIS CASE, AND IT WOULD TAKE MORE THAN MY ALLOTTED TIME TO GO THROUGH THAT IN DETAIL. TREATMENTS FOR IRON RELATED DISORDERS, SUPPLYING IRON IS PARTICULARLY RELEVANT IN THE SETTING OF IRON DEFICIENCY, SO I'M NOT GOING TO GO THROUGH THIS BUT OF COURSE IRON SUPPLEMENTS IS SOMETHING WE'LL BE SPENDING A LOT OF TIME TALKING ABOUT IN THIS MEETING BECAUSE THEY'RE WIDELY USED IN PREGNANCY AND INFANCY. IN TERMS OF TREATING IRON OVERLOAD DISEASES, THERE ARE REALLY TWO THINGS YOU NEED TO DO, REDUCE EXISTING IRON LOAD AMELIORATE THAT, AND THEY'RE BOTH TISSUES THAT ARE VERY IMPORTANT. IN TERMS OF REDUCTION IN IRON LOAD, VENESECTION AND IRON CHELATION USED, PREVENTING FURTHER IRON ACCUMULATION, BUT THERE'S A RANGE OF OTHER OPTIONS THAT CAN BE USED FOR THE EXISTING AMOUNT OF IRON IN THE DIET, REDUCING THE AMOUNT OF BIOAVAILABLE EASTERN. USING DRUGS TO BLOCK IRON ABSORPTION AND MORE RECENTLY, USING HEPCIDIN OR USING HEPCIDIN REMEDICS TO REDUCE IRON ABSORPTION, SOME OF THOSE AGENTS ARE EITHER IN CLINICAL TRIALS OR ARE WILL BE IN CLINICAL TRIALS SHORTLY. SO I JUST WANT TO FINISH BY TALKING ABOUT A FEW THINGS WE DON'T KNOW, THIS IS JUST A LIST THAT I'VE MADE UP AND THE LONGER I THINK ABOUT IT, THE MORE THINGS I CAN ADD TO THE LIST. IT'S NOT SPECIFICALLY RELATED TO PREGNANCY OR INFANCY, BUT THERE ARE CERTAINLY MANY OF THEM. THERE'S SEVERAL CATEGORIES, AT THE PLE MOLECULAR AND CELLULAR PROCESS LEVEL, THERE'S STILL LIKELY TO BE MOLECULES WE DON'T KNOW ABOUT, WE PROBABLY HAVE THE MAIN ONES BUT THERE ARE OTHERS INVOLVED. WE KNOW VERY LITTLE ABOUT THE STRUCTURE/FUNCTION RELATIONSHIPS OF MANY OF THESE PROTEINS. THERE'S STILL LOTS OF SCOPE FOR FURTHER WORK IN THAT AREA. WE KNOW VERY LITTLE ABOUT INTRACELLULAR IRON METABOLISM. SOMETHING I'VE NOT SPOKEN ABOUT IS THE RELATIONSHIP BETWEEN IRON AND OTHER METALS. THAT'S A VERY IMPORTANT AREA. A LOT OF NICE WORK BEING DONE IN BACTERIA THESE DAYS, LESS SO IN MAMMALIAN CELLS, SOMETHING WE NEED TO KNOW MORE ABOUT. I MENTIONED BEFORE THAT WE NEED TO KNOW MORE ABOUT THE SUBTLE CHANGES IN IRON STATUS AND CERTAINLY THE EFFECTS OF SUPRAPHYSIOLOGICAL INTAKE, UNDERSTANDING ABOUT ORGAN-SPECIFIC IRON HOMEOSTASIS AND PRIORITIZATION OF DIFFERENT ORGAN, AND LINKS BETWEEN IRON AND THE MICRO BOY ONLY OF COURSE IS AN IMPORTANT AREA. THE LAST COMMENT I'VE GOT ON THE SLIDE IS DON'T IGNORE ALL THE OLDER PHYSIOLOGICAL STUDIES, BECAUSE THERE WAS A LOT OF VERY NICE WORK DONE ON IRON DECADES AGO THAT TENDS TO GET IGNORED BECAUSE IT DIDN'T HAVE A MOLECULAR BASIS, BUT THERE'S A LOT OF INTERESTING AND USEFUL INFORMATION THERE. IN TERMS OF ASSESSING IRON STATUS, WE STILL NEED BETTER MARKERS, PARTICULARLY HOW WE CAN LOOK AT SUBTLE CHANGES, NEW MARKERS, COMBINATIONS OF MARKERS CAN BE USED. I'VE NOT TALKED ABOUT GENETIC PROFILING BUT THERE'S A LOT OF INTEREST IN GENETIC MODIFIERS OF -- THAT'S LIKELY TO BE A COMPONENT IN FUTURE ANALYSES. IN TERMS OF TREATMENT, THERE ARE SOME GOOD IRON SUPPLEMENTS AROUND BUT WE STILL NEED LOWER TOXICITY ORAL SUPPLEMENTS AND BETTER IRON CHELATORS AND MORE EFFICIENT DELIVERY METHODS, PERSONALIZED MEDICINE, INDIVIDUAL SPECIFIC AND LIFE STAGES, PARTICULAR GENETIC COMPOSITIONS, ESSMENTS SO THERE ET CETERA, SO THERE ARE SOME OF MANY POTENTIAL ISSUES THAT COULD BE CARRIED OUT. I THINK I'M OUT OF TIME NOW. SO I PROBABLY SHOULD STOP THERE. I WAS GOING TO TALK ABOUT ONE OTHER STUDY, BUT MAYBE WE CAN TALK ABOUT THAT IN DISCUSSION. SO THANK YOU VERY MUCH FOR YOUR ATTENTION. [APPLAUSE] >> THANK YOU. WE HAVE ABOUT FIVE MINUTES FOR QUESTIONS AND WE WOULD LIKE THE QUESTIONERS TO PLEASE GO TO THE MICROPHONE SO THAT WE CAN HEAR YOU AND RECORD THE QUESTIONS AS WELL AS THE ANSWERS. >> THANKS, GREG. THAT WAS WONDERFUL. SO DO YOU THINK IN A PERSON WITH NO KNOWN GENETIC ABNORMALITY, THAT EXPOSING THEM TO HIGH DOSE IRON SUPPLEMENTS OR FORTIFIED FOOD CAN CREATE IRON OVERLOAD OVER THE MEDIUM TO LONG TERM? >> THAT'S AN INTERESTING QUESTION. STUDIES DONE SOME TIME AGO SUGGESTING THAT THE BODY WILL REGULATE ITS IRON, LONG TERM THE BODY WILL REGULATE ITS IRON, HOMEOSTASIS, IT WILL ADJUST, SO THIS IS AN INTERESTING STUDY THAT WAS DONE WHERE THEY FED INDIVIDUALS A LITTLE BIT OF EXCESS IRON OVER LONG TERM BUT INDIVIDUALS DIDN'T GET IRON LOADED, THEY KEPT GOING BACK TO A SET POINT, WHICH WAS IN MEN ABOUT A GRAM OF STORED IRON, WHERE IF THEY GAVE A LITTLE LESS THAT BE THE NORMAL RECOMMENDED AMOUNT OF IRON, THAT ABSORPTION WOULD INCREASE TO BASICALLY GO TO THAT SET POINT. SO I THINK WITHIN REASON, AS LONG AS -- UNDER NORMAL CIRCUMSTANCES, NORMAL PHYSIOLOGY, THE BODY WILL ADAPT WELL TO KEEP IT'S LEVEL AT AN APPROPRIATE POINT. >> WHAT ABOUT A SUPPLEMENTAL DOSE? >> SO HIGHER LEVELS? >> YES. >> I THINK IT REALLY DEPENDS ON THE DOSE. IF YOU HAVE VERY HIGH AMOUNTS, YEAH, YOU CAN ACTUALLY CIRCUMVENT YOUR NORMAL REGULATORY PROCESSES IN THE GUT IF YOU HAD TOO MUCH IRON. SO IF IT'S VERY LARGE AMOUNTS, YES, YOU CAN OVERCOME THAT, BUT TO REASONABLE LEVELS, PROBABLY NOT. >> YOU DIDN'T MANAGE TO TALK ABOUT ANIMAL MODELS, BUT I THINK IT'S WORTH POINTING OUT WHAT ANIMAL MODELS GOOD FOR, WHAT ARE THE BENEFITS AND LIMITATIONS OF DIFFERENT ANIMAL MODELS IN OUR METABOLISM? >> SO THAT'S A GOOD QE. I DID HAVE A SECTION ON ANIMAL MODELS WHICH I DELETED IN THE INTEREST OF TIME. MOST OF THE ANIMAL MODEL STUDIES OF COURSE HAVE BEEN DONE IN RODENTS, PARTICULARLY IN MICE, AND BY AND LARGE, MOST OF THE PHYSIOLOGICAL PROCESSES, IRON INTAKE, REGULATING IRON INTAKE, ARE THE SAME, A LOT OF DISEASE PROCESSES, FOR EXAMPLE, ARE DIFFERENT WITH IRON LOADING, YOU DON'T GET EXACTLY THE SAME PHENOTYPE AS YOU DO IN HUMANS BUT A LOT OF THE SAME PROCESS OCCUR. I THINK THE GENERAL LESSON IS THAT ANIMAL MODEL MODEL STUDIES ARE USEFUL BECAUSE YOU CAN LOOK AT THINGS UNDER VERY DEFINED CONDITIONS BUT ULTIMATELY WE'RE LOOKING AT EFFECTS ON HUMAN HEALTH SO STUDIES HAVE TO BE VALIDATED IN HUMAN, AND THERE'S CERTAINLY A RECOGNIZABLE REALIZATION THESE DAYS THAT OFTEN MOUSE STUDY SES, FOR EXAMPLE, MAY BE TOO CONTROLLED IN TERMS OF MICROBIOME, IN TERMS OF GENETIC HOMOGENEITY AND THERE'S A LOT MORE INTEREST NOW IN USING -- BACKGROUNDS AND MIXED BACKGROUNDS FOR LOOKING AT STUDIES. >> IT MAY BE REALLY USEFUL TO KNOW THAT WE DON'T SEE THE DAMAGE TO THE TISSUE FROM HIGH OXIDATIVE STRESS IN MICE OR RODENTS AS WE DO IN HUMANS. >> THAT'S THE CASE, AND YOU CERTAINLY SEE THAT IN MOUSE MODELS IN IRON LOADING DISEASE, YOU SEE A LOT LESS OF THE TISSUE PATHOLOGY. >> JUST TO AMPLIFY ON THIS POINT, I DON'T THINK OUR METHODOLOGY IS PARTICULARLY SUITED FOR ANSWERING QUESTIONS ABOUT SUBTLE CHANGES. THE REASON FOR THAT IS THAT, THE NUMBER OF EXPERIMENTAL ANIMALS REQUIRED TO ANSWER QUESTIONS OF SUBTLE CHANGES AND THE NEED FOR POTENTIALLY INTERACTING GENES THAT MAY AMPLIFY THE EFFECTS FROM, FOR EXAMPLE, NUTRITIONAL SUPPLEMENTATION WITH IRON, ALL OF THAT DOESN'T EXIST IN THE EXPERIMENTAL ANIMAL SPACE. SO I THINK THAT WE SHOULD LOOK FOR ANSWER IN EPIDEMIOLOGY, BECAUSE WE WILL NOT GET THEM FROM SIMPLE ANIMAL MODELS. >> I THINK THAT'S VERY IMPORTANT POINTS, WELL TAKEN. >> JUST THE BASIC QUESTION, ARE WE USING THE RIGHT MARKER FOR IRON DEFICIENCY? WE HAVE IRON DEFICIENCY ANEMIA. MAYBE THAT'S A VERY -- MARKER, MAYBE THAT'S THE LAST STATION ON THE ROAD, SO MAYBE THERE ARE TISSUES MORE SENSITIVE TO IRON DEFICIENCY THAN THE BONE MARROW. SO THAT IS MY QUESTION. WE ARE LOOKING FOR NEW MARKERS WHICH MAY BE MORE SENSITIVE. MAYBE IRON DEFICIENCY ANEMIA IS A VERY ROUGH MARKER. >> SURE, POINT WELL TAKEN. I THINK IT'S A SCENARIO THAT'S REALLY NOT BEEN EXPLORED IN SUFFICIENT DETAIL, BUT YOU NEED SOMETHING THAT'S READILY ACCESSIBLE, OF COURSE, AS WELL IF YOU'RE GOING TO USE IT AS A ROUTINE MARKER, BUT AGAIN, I THINK IT'S A POINT WELL TAKEN AND IT'S A POTENTIAL FUTURE RESEARCH DIRECTION WE SHOULD LOOK AT. >> JUST AS A FOLLOW-UP TO THAT QUESTION, AND YOU MENTIONED THE DIFFERENT TISSUES DEAL WITH IRON DIFFERENTLY, THAT THEIR QUOTE-UNQUOTE REQUIREMENTS MIGHT BE DIFFERENT. IS IT TRUE THEN WE DON'T KNOW HOW WELL THE HEME THROJ CAL MEASURES, BLOOD MEASURE, RELATE TO TISSUE-SPECIFIC IRON NEEDS? >> I THINK BROADLY THEY PARALLEL EACH OTHER, BUT FOLLOWING ON FROM THE PREVIOUS QUESTION AS WELL, SO YOU EXPECT THERE ARE PARTICULAR DIFFERENCES AND THERE WOULD BE VALUE IN LOOKING AT OTHER TISSUES AND LOOKING AT POTENTIALLY TISSUE MARKERS, SO THAT'S A USEFUL AREA THAT COMES OUT OF THIS THAT MIGHT BE WORTH EXPLORING. >> THANK YOU VERY MUCH. SO OUR NEXT SPEAKER IS ELIZABETA NEMETH AND HER TOPIC IS HOW DOES HOMEOSTASIS CHANGE FOR PREGNANT WOMEN. >> THANK YOU VERY MUCH FOR INVITING ME TO THIS CONFERENCE AND VERY TIMELY. SO VERY BROADLY, IRON DURING PREGNANCY IS REQUIRED FOR NORMAL PLACENTAL DEVELOPMENT, NORMAL FETAL DEVELOPMENT AND MATERNAL HEALTH. MOUSE MODELS OR OTHER RODENT MODELS AND ANIMAL MODELS AS WELL AS HUMAN STUDY, WE KNOW WHAT THE CONSEQUENCE OF EXTREMES ARE. FOR EXAMPLE, SEVERE IRON DEFICIENCY IS DETRIMENTAL TO BOTH THE MOTHER AND THE FETUS. AND WE CAN DO CAREFUL MOUSE STUDIES TO SHOW THAT IF WE PREVENT IRON TRANSFER ACROSS PLACENTA, THAT IS INCOMPATIBLE WITH LIFE. SO FOR EXAMPLE, HERE IF WE MUTATE AN IRON UP TAKE -- TRANSFERS ON TO FEE TURKS BOTH OF THEM ARE EMBRYONIC LETHAL AND THERE ARE EXAMPLES OF MULTIPLE OTHER IRON TRANSPORTERS AND REGULATORS THAT HAVE THE SAME CONSEQUENCE. SO WE KNOW THAT VERY SEVERE IRON DEFICIENCY IS INCOMPATIBLE WITH LIFE, AND WE KNOW FROM HUMAN STUDIES THAT SEVERE IRON DEFICIENCY ANEMIA IS ASSOCIATED WITH A NUMBER OF NEGATIVE OUTCOMES, INCLUDING INCREASED RISK OF PRETERM LABOR, LONEY OWE NATAL WEIGHT, INCREASED -- IMPAIRED IMMUNE FUNCTION OR IMPAIRED NEUROLOGICAL DEVELOPMENT. WHAT WE KNOW MUCH LESS ABOUT AND IS THE TOPIC OF THIS CONFERENCE IS WHAT IS THE CONSEQUENCE OF HIGH MATERNAL IRON LEVEL DURING PREGNANCY. WE CAN CONSIDER THIS BOTH IN TERMS OF DIFFERENT PATHOLOGICAL CONDITIONS ASSOCIATED WITH HIGH IRON LEVELS SUCH AS THALASSEMIA OR FROM IRON SUPPLEMENTATION. SO WHAT ARE REALLY OUR REQUIREMENTS DURING PREGNANCY? FOR HEALTHY PREGNANCY, ABOUT 1-GRAM OF IRON IS NEEDED OVER THE DURATION OF PREGNANCY. AND THIS IRON IS USED FOR FETAL DEVELOPMENT AND PLACENTAL DEVELOPMENT, APPROXIMATELY 360 MILLIGRAMS. AN IMPORTANT USE OF IRON IS TO EXPAND MATERNAL RED BLOOD CELL MASS AND THEN WE ALSO NEED TO COMPENSATE FOR BASELINE MATERNAL BODY IRON LOSS DURING THESE NINE MONTHS. SO OVERALL, THAT COMES TO APPROXIMATELY 1-GRAM ON AVERAGE, BUT THE RANGE IS MUCH LARGER. THE NEXT MATERNAL LOSS AFTER PREGNANCY IS NOT QUITE AS HIGH BECAUSE SOME OF THIS MATERNAL RED BLOOD CELL MASS THAT WAS EXPANDED DURING PREGNANCY WILL BE CONTRACTED, THAT IRON WILL BE PUT BACK IN STORES ALTHOUGH WE DON'T EXACTLY PUT THAT ENTIRE AMOUNT BECAUSE SOME IRON IS LOST WITH BLEEDING AT DELIVERY. SO NET LOSS AFTER PREGNANCY IS A LITTLE LOWER THAN WHAT THE IRON NEEDS DURING PREGNANCY ARE. SO HOW DO WE REGULATE THIS INCREASED IRON NEED DURING PREGNANCY? ONE WAY IS TO INCREASE MOBILIZATION FROM STORES. AND THE STORES ARE, MACROPHAGES IN THE SPLEEN THAT RECYCLE RED BLOOD CELLS AND MACROPHAGES AND HEPATOCYTES IN THE LIVER, SO THESE ARE THE MAJOR SOURCES OF STORED IERP AND MOBILIZATION IRON FROM STORAGE IS REALLY MANIFESTED AS DECREASED SERUM FERRITIN BECAUSE SERUM FERRITIN IS DERIVED FROM THESE CELLS, PARTICULARLY MACROPHAGES TO A LESSER EXTENT HEPATOCYTES. SO AS IRON IS MOBILIZED, SERUM FERRITIN WILL DECREASE, AND YOU CAN SEE HERE DURING PREGNANCY, HERE'S GESTATION IN WEEKS, FERRITIN LEVELS GRADUALLY DECREASE ALL THE WAY DOWN TO DELIVER ROW AND START RECOVERING RIGHT AFTER PREGNANCY. IF WOMEN ARE UNSUMMIT MEANTED, THEIR STORES ARE GOING TO BE HIGHER, THE FERRITIN WILL NOT DROP AS LOW AND THEN IT CAN BOUNCE BACK FASTER. APART FROM MOBILIZING IRON FROM THE STORES, ANOTHER WAY IS TO INCREASE ABSORPTION OF DIETARY IRON, AND THAT DOESN'T HAPPEN RIGHT AWAY. ACTUALLY THE ABSORPTION DURING THE FIRST TRIMESTER IS EVEN SLIGHTLY LOWER BEFORE PREGNANCY BUT THAT IS BECAUSE MENSTRUATION CEASES, BUT THEN DURING SECOND AND THIRD TRIMESTER, THE ABSORPTION GREATLY INCREASES, PARTICULARLY DURING THE THIRD TRIMESTER, IT'S ALMOST 10 TIMES HIGHER THARN DURING THE FIRST TRIMESTER. AS WE HAVE THESE INCREASED FLOWS OF IRON FROM MULTIPLE SOURCES, MORE IESH IS AVAILABL IRON IS AVAILABLE FO R UTILIZATION, AND -- TO EXPAND MATERNAL RED BLOOD CELLS AND ALSO TO PROVIDER IRON TO THE FETUS AND PLACENTA. WE KNOW THAT ALL OF THE IRON THAT COMES INTO PLASMA IS PROVIDED THROUGH AN IRON TRANSPORTER CALLED FERRIPORTIN, WE KNOW THAT HEPCIDIN IS A NEGATIVE REGULATOR. SO IF YOU WANT TO INCREASE IRON SUPPLY DURING PREGNANCY, YOU REALLY WANT TO SUPPRESS HEPCIDIN, AND THAT WILL LEAD TO INCREASED FLOWS, INCREASING PLASMA LEVELS AND THEN ENABLE GREATER UTILIZATION OF IRON. SO THIS IS HOW ONE WOULD EXPECT FOR REGULATORY PHYSIOLOGY TO OCCUR DURING PREGNANCY. AND THAT IS INDEED WHAT WE'RE FINDING FROM MEASUREMENTS OF MATERNAL HEPCIDIN LEVELS. SO IN HEALTHY PREGNANCIES, IF YOU LOOK AT HEPCIDIN MEASUREMENTS IN THE FIRST, SECOND OR THIRD TRIMESTER, YOU CAN SEE THAT HEPCIDIN PRECIPITOUSLY DROPS AND IT'S PRACTICALLY UNDETECTABLE WITH ALL ASSAYS NOW IN THE THIRD TRIMESTER. INTERESTINGLY RIGHT AFTER DELIVERY, HEPCIDIN LEVELS BOUNCE BACK AND THAT'S PROBABLY RELATED TO LABOR EVENTS AND INFLAMMATION THAT OCCURS AND STRESS THAT OCCURS DURING LABOR. BUT PORPLY, THROUGHOUT SECOND AND THIRD TRIMESTER, HEPCIDIN IS VERY LOW. WE SEE THE SAME THING IN MOUSE MODELS, SO IF YOU LOOK AT THE DURATION OF MOUSE GESTATION, IT'S AROUND 19 DAYS, SO THESE TIME POINTS ARE EQUIVALENT TO END OF SECOND TRIMESTER AND KIND OF THIRD TRIMESTER, AND YOU CAN SEE THAT HEPCIDIN VERY SIMILARLY DROPS PRECIPITOUSLY AS PREGNANCY ADVANCES. AND WE THINK THAT THIS MATERNAL HEPCIDIN SUPPRESSION IS AN IMPORTANT REGULATORY EVENT, AND THAT IT OCCURS EARLY. IF WE LOOK AT WHAT HAPPENS TO IRON STORES IN THE MOTHER OR SERUM IRON, WE CAN SEE THAT HEPCIDIN ACTUALLY DROPPED LOOKED LIKE PRIOR TO MOBILIZATION OF IRON FROM STORES, SO YOU CAN SEE AS HEPCIDIN IS ALREADY VERY LOW AT THE END OF SECOND TRIMESTER, LIVER STORES START GETTING MOBILIZED AND ARE COMPLETELY EMPTY BY THE END OF THE PREGNANCY. BUT THESE TWO FACTORS TOGETHER, LOWERING HEPCIDIN AND MOBILIZATION OF IRON FROM STORES, EB ABLES SERUM IRON TO STAY RELATIVELY CONSTANT TO BE PROVIDED FOR ALL OF THE PROCESSES WE NEED THEM FOR. THIS IS IRON-REPLETE HEALTHY PREGNANCY. SO MATERNAL HEPCIDIN SUPPRESSION SEEMS TO BE AN IMPORTANT REGULATORY STEP. NOW WHY IS MATERNAL HEPCIDIN SUPPRESSED IS A BIG QUESTION. ONE POSSIBILITY IS THAT THERE IS PLASMA DILUTION DURING PREGNANCY, BUT WE DON'T THINK THAT'S THE REASON HEPCIDIN DROPS, BECAUSE WE CAN NOTICE EQUIVALENT HEPCIDIN DECREASES ON MRNA LEVEL WHICH IS NOT AFFECTED BY PLASMA DILUTION SO WE DON'T THINK THAT'S THE MECHANISM. ANOTHER REASON COULD BE IRON DEFICIENCY BECAUSE WE KNOW DURING IRON TEE EFFICIENCY, HEPCIDIN DECREASES BUT WE DON'T THINK THAT REALLY THE INITIAL MECHANISM BECAUSE HEPCIDIN SEEMS TO DECREASE BEFORE -- PARAMETERS LOWER BUT WE DON'T THINK THAT'S THE INITIAL REG LA TRILL STEP BUT IT COULD CONTRIBUTE TO FURTHER HEPCIDIN DEPRESSION DURING PREGNANCY IF IRON DEFICIENCY IS PRESENT. WE'RE SPECULATING THAT THERE'S PROBABLY A METABOLIC FACTOR, THAT ENSURES HEPCIDIN WILL BE SUPPRESSED BUT WE STILL DON'T KNOW THE IDENTITY OF THIS SUPPRESSOR. WE HAVE TESTED THE MOST RECENT CANDIDATE, ANOTHER HORMONE THAT WAS DISCOVERED BUT THAT HORMONE IS NOT AT ALL IP VOFL THE IN MATERNAL HEPCIDIN SUPPRESSION SO THE SEARCH IS ON. ANOTHER THING I WOULD LIKE TO POINT OUT IS THAT ALL OF THE REGULATORY CIRCUITRIES FOR HEPCIDIN SEEM TO BE PRESERVED DURING PREGNANCY SO HEPCIDIN IS STILL REGULATED BY IRON AND INFLAMMATION BUT IT SEEMS TO OCCUR ALL AT A LOWER SET POINT, LIKELY UNDER THE INFLUENCE OF THIS PREGNANCY SUPPRESS SORE. AND ANOTHER THING THAT WE REALLY DON'T KNOW ABOUT IS WHAT IS THE EFFECT OF IRON SUPPLEMENTATION ON MATERNAL HEPCIDIN DURING PREGNANCY. BECAUSE IT IS STRONGLY REGULATED BY IRON, EVERY TIME A DOSE IS TAKEN, IT MAY INCREASE HEPCIDIN WHICH WOULD IMPAIR ABSORPTION FTS SUBSEQUENT IRON DOSE AND THIS WOULD EXPLAIN WHY IT'S AS EFFECTIVE AS DAILY IRON SUPPLEMENTATION BUT I BELIEVE THIS WILL BE DISCUSSED LATER DURING THE CONFERENCE. SO WHAT I SHOWED YOU IN THE NORMAL PREGNANCY, IT SEEMS THE SUPPRESSION OF MATERNAL HEPCIDIN IS AN EARLY EVENT WHICH THEN PROVIDES -- ENSURES GREATER IRON FLOWS FOR TRANSFER ACROSS PLACENTA AND ALSO UTILIZATION FOR OTHER PROCESSES. HOWEVER, THE FETUS ITSELF MAY BE PRODUCING HEPCIDIN, AND IT MAY BE BLOCKING IRON TRANSFER ACROSS PLACENTA. MEASUREMENTS OF FETAL HEPCIDIN EXPRESSION SHOW THAT IT'S ACTUALLY QUITE LOW, AND IN THIS THIRD PAPER, REALLY UNDETECTABLE DURING HELP SIGH DIB 3, BUT REALLY EARLY ON, DURING PREGNANCY SEEMS TO BE VERY LOW. SO YOU MAY NOT REALLY -- IT MAY REALLY NOT AFFECT IRON TRANSFER ACROSS PLACENTA, BUT WE DI SIDED DECIDED TO FORMALLY TEST THIS AND DETERMINE IT'S THE MOTHER OR THE FETUS THAT DETERMINES HOW MUCH IRON IS TRANSFERRED ACROSS PLACENTA, OR THE MORE COMPLICATED SITUATION WOULD BE BOTH. SO WHAT WE DECIDE TODAY DO IS TO DO TRANSGENIC MOUSE CROSSES, SO WE CROSSED HETEROZYGOUS -- THE FATHERS HETEROZYGOUS FOR HEPCIDIN DEFICIENCY OR MUTATION, AND WE CROSSED THEM WITH EITHER MOTHERS THAT HAD NO HEPCIDIN OR MOTHERS THAT WERE HETEROZYGOUS SO THEY HAVE ACTUALLY NORMAL HEPCIDIN LEVELS. SO WE WOULD HAVE A MOTHER WITHOUT HEPCIDIN THAT WOULD HAVE BABIES THAT EITHER DON'T HAVE HEPCIDIN OR HAVE HEPCIDIN, AND HERE WE WOULD HAVE A MOTHER THAT DOES HAVE HEPCIDIN BUT THE BABY WOULD EITHER NOT HAVE HELP SIGH DIB OHEPCIDINOR WOULD HAVE HEPCIDIN. SO WHAT WE WERE HYPOTHESIZING IS THAT IF IT'S FETAL HEPCIDIN THAT'S IMPORTANT, THEN THESE POPS SHOULD BE IRON-LOADED. SO IF FETAL HELP SIDE IS CRITICAL, THESE PUPS SHOULD BE LOADED. IF MATERNAL HEPCIDIN IS CRITICAL THEN ONLY IRON DEFICIENT MOTHERS SHOULD BE LOADED. WHEN WE DID ANALYSIS, IT TURNED OUT ONLY MOTHERS LEVEL BUT NOT PUFFS LEVEPUP'SLEVEL INFLUENCED HOW MUCH W AS TRANSFERRED ACROSS PLA CENTER. HERE I'M SHOWING YOU LIVER SECTIONS STAINED FOR IRON. IF THE MOTHER HAD HEPCIDIN, MUCH LESS IRON WAS TRANSFERRED THAN FROM THE MOTHER THAT DIDN'T HAVE HEPCIDIN. SO LOWER HEPCIDIN CORRELATED WITH MORE IRON TRANSFER ACROSS PLACENTA, AND WE FORMERLY QUANTIFIED IT HERE, SO HERE'S A QUANTIFICATION OF LIVER IRON IN NEWBORN MICE. YOU CAN SEE PUP GENOTYPE HERE, THESE PUPS CAME FROM HELP HEPCIDIN-DEFICIENT MOTHER, THESE PUPS CAME FROM MOTHERS WITH NORMAL HEPCIDIN, AND YOU CAN SEE THAT HEPCIDIN DEFICIENT MOTHERS TRANSFERRED MORE IRON TO THE BABY THAN THE MOTHERS THAT HAD NORMAL HEPCIDIN LEVELS. SO IT APPEARS THAT DURING HEALTHY PREGNANCY, IT'S MATERNAL HEPCIDIN LEVEL THAT DETERMINES HOW MUCH IRON IS GOING TO BE AVAILABLE TO BE TRANSFERRED TO THE BABY. SIMILAR STUDIES IN HUMANS SUGGEST THE SAME THING, THIS WAS DONE BY DR. O'BRIEN'S LAB WHERE THEY DURING PREGNANCY GAVE IRON TRACES EITHER NON-HEME OR HEME IRON AND THEY MEASURED HOW MUCH OF THAT IRON TRACER WAS TRANSFERRED TO A HUMAN NEONATE. THE MATERNAL HEPCIDIN WAS MEASURED ONLY AT DELIVERY, BUT IT'S STILL CORRELATED, WHERE THE LOWER THE MATERNAL HEPCIDIN, THE HIGHER THE ACCUMULATION OF IRON TRACER IN THE NEONATE. SO AGAIN, LOWER MATERNAL HEPCIDIN LEVEL CORRELATED WITH GREATER TRAB TRANSFER OF IRON ACROSS PLACENTA. NOW WE WANTED TO CHECK, WHAT WOULD HAPPEN IF WE DIDN'T ALLOW HEPCIDIN TO GO DOWN? THE WAY WE MODELED IT IS TO INJECT MOTHERS WITH HEPCIDIN CONTINUOUSLY THROUGH EITHER THE EQUIVALENT OF THIRD OR SECOND AND THIRD TRIMESTER IN MICE. AND WHAT HAPPENED WAS THAT WE ACTUALLY GOT QUITE NEGATIVE CONSEQUENCES BOTH MOTHERS AND PUPS WERE VERY ANEMIC AND PLACENTA WAS SMALLER AND PALER. WE ALSO SAW THE PUP BIRTH WEIGHT WAS LOWER SO FROM THE MOTHERS THEY WERE TREATED WITH HEPCIDIN, THE PUPS WERE APPROXIMATELY 10% SMALLER, THE PUP HEME GLOW BEN WAS HALF OF WHAT THE NORMAL WAS AND THE MOTHER'S HEMOGLOBIN WAS ALSO LOWER. YOU CAN SEE HERE THESE PINKER PUPS ARE FROM MOTHERS WITH SOLVENTS AND THE OTHERS WERE MOTHERS WITH HEPCIDIN AND THERE WERE QUITE A FEW THAT WERE NOT VIABLE. SO IF WE MAINTAIN HIGH MATERNAL HEPCIDIN AND INDUCE SEVERE UNRESTRICTION, IT HAS VERY DETRIMENTAL CONSEQUENCES AND THIS WAS VERY SIMILAR TO VERY SEVERE IRON DEFICIENCY IN YOUTH BY DIET. SO IN NORMAL PREGNANCY AS I MENTIONED, LOWERING THE MATERNAL HEPCIDIN IS ESSENTIAL TO ALLOW IRON TO BE AVAILABLE FOR TRANSFER ACROSS PLA 16 TA AND NOW THE QUESTION IS, ARE THERE CONDITIONS IN HUMANS WHERE MATERNAL HELP SIG HEPCIDIN IS NOT APPROPRIATELY SUPPRESSED. WE DON'T KNOW YET, BUT ONE COULD SPECULATE THAT IN DIFFERENT INFLAMMATORY CONDITION, HEPCIDIN WOULD BE INAPPROPRIATELY ELEVATED, AND THAT MAY CAUSE IRON RESTRICTION AND INAPPROPRIATE AVAILABILITY FOR TRANSFER ACROSS PLACENTA. WE COULD ALSO -- IRON SUPPLEMENTATION WOULD NOT BE APPROPRIATE. DOES THIS HAPPEN? WE DON'T KNOW YET. THERE WERE VERY FEW STUDIES THAT LOOKED AT MILD I INFLAMMATORY CONDITIONS AND ONLY MILDLY ELEVATED SERUM HEPCIDIN LEVELS WERE NOTED, OBESE VERSUS LEAN PREGNANT WOMEN AND ALSO ON A STUDY OF PREECLAMPSIA VEST US VERSUS HEALTHY PREGNANCY. NO NEGATIVE IMPACT ON HEME THROJ CAL PARAMETERS IN THE MOTHER OR THE BABY, SUGGESTING THAT HEPCIDIN LEVELS WERE STILL SUFFICIENTLY LOW TO ALLOW EFFECTIVE IRON UTILIZATION DURING PREGNANCY. SO THE QUESTION IS, DURING MORE SEVERE INFLAMMATION, WILL INPLAM TRI EFFECTS BALANCED OUT TO PREVENT EXCESSIVE HEPCIDIN INCREASE. I TOLD YOU HEPCIDIN WOULD BE ACTING ON THE BAY SEW LATERAL SIDE OF ABSORBTIVE -- ALLOWING FAIR PORE TIN TO BE SUR PRESSED SO MORE IERP CAN B IRON CAN BE TRANSPORTED , BUT IT SEEMS THERE ARE ALSO ADAPTATIONS AT THE APICAL LEVEL AS WELL. WHAT DR. ANDERSON'S LAB FOUND IS THERE IS AN EGGS PRETION OF THESE APICAL TRANSPORTERS AS WELL, AS JE TAITIO GESTATION INCREASED -- DURING PREGNANCY, WE'RE NOT ONLY INCREASING ON THE -- WE DON'T KNOW YET HOW -- WE DON'T KNOW WHAT THE HEME TRANSPORTER IS OR HOW IT AFFECTS TRANSPORT ACROSS BASAL LATERAL SIDE. VERY BRIEFLY JUST TO HIGHLIGHT WHAT WE KNOW ABOUT PLACENTAL IRON TRANSFER, IN MATERNAL BLOOD IN NORMAL PREGNANCY, MOST OF THE IRON IS IN THE HOLO TRANSFAIRN FORM AND THAT NEEDS TO BE TRANSFERRED FROM MATERNAL BLOOD TO FETAL BLOOD. THIS IS TO THE BEST OF OUR KNOWLEDGE HOW THIS HAPPENS. BOUNCES TO RECEPTOR 1 AND THE CYTOSIS HAPPENS, ALLOWS RELEASE OF IRON. NOW THIS IRON HAS TO BE REDUCED BY SOME REDUCTASES, HAS TO BE TRANSPORTED OUT OF THE ENDOSOME, THERE ARE MULTIPLE TRANSPORTERS THAT COULD PLAY THAT ROLE. WE KNOW ON THE BASAL SIDE, AARON IS EXPORTED THROUGH FERROPORTIN AND THAT WAS SHOWN THAT IF WE KNOCK THAT OUT AND THERE'S NO IRON TRANSPORT ACROSS. NOW WHAT IS THE FATE ONCE IT'S EXPORTED SINCE IT'S YOUR TROA FOE BLAST, IT COULD BE OXIDIZED, WE STILL DON'T KNOW WHICH ARE CRITICAL OR IF THEY PLAY A REDUNDANT ROLE OR WHERE EXACTLY IN THE PLACENTA THIS HAPPENS, BUT THAT IRON CAN BE LOADED ON TRANSFAIRN AND SOMETIMES TRANSFERRED INTO FETAL BLOOD, IT'S ALSO POSSIBLE THAT IRON IS SOMEHOW TRANSFERRED AND CIRCULATED IN THE FETAL BLOOD -- WERE REPORTED IN FETAL BLOOD. SO THESE ARE THE HARDLY KNOWN OR PEUTTIVE TRANSPORTERS AND REGULATORS AND WE DON'T UNDERSTAND HOW THEY'RE REGULATING EITHER. WHAT IS BECOMING APATIENT IS THABECOMING APPARENT ISTHAT -- WE ARE NOW FINDING OUT THAT FERROPORTIN PROTEIN IS PARADOXICALLY DECREASED DURING MATERNAL IRON DEFICIENCY. WHAT THIS SUGGESTS IS THAT PLACENTA TAKES UP IRON FOR ITSELF, THE PLACENTA ACTUALLY HAS SOME IRON SENSING AND REGULATORY MECHANISMS TO KNOW THAT IT IS BY ITSELF -- IT WILL INCREASE ITS IRON IMPORT BUT WOULD DECREASE EXPORT, DETRIMENTAL IN TERMS OF SUPPLYING IRON TO THE KNEE TOE NATE, SO IT NEEDS TO BE WORKED OUT WHAT THESE MECHANISMS ARE AND ALSO HOW THEY ARE AFFECTED IN IRON SUPPLEMENTATION. VERY LAST SLIDE, I JUST WANTED TO SHOW WHAT THE HEME THROJ CAL CHANGES DURING PREGNANCY ARE BECAUSE THIS IS -- I TOLD YOU WE NEED AROUND 450 MILLIGRAMS OF IRON FOR THIS PROCESS, AND THIS IS DRIVEN BY INCREASING ANOTHER HORMONE, ERYTHRO.TIN. WE DON'T KNOW WHAT THE SIGNAL IS FOR PHYSIOLOGICAL INCREASE OF EPO DURING PREGNANCY, BUT CERTAINLY EPO CAN INCREASE IF THE MOTHER IS ANEMIC. HOWEVER, DESPITE THIS INCREASE IN WHITE CELL MASS, HEMOGLOBIN DECREASES DURING PREGNANCY AND THE NORMAL IS 2 GRAMS PER DECILITER, AND THE REASON IS THAT PLASMA VOLUME INCREASES MORE THAN RED BLOOD CELL MASS AND THAT IS CALLED DELUSIONAL ANEMIA. DILUTIONAL ANEMIA. THERE IS THE U-SHAPED CURVE AND WE THINK THAT THE LOW HEMOGLOBIN IS ASSOCIATED WITH IRON DEFICIENCY AND POSSIBLY IRON RESTRICTION, AND HIGH HEMOGLOBIN IS LIKELY RELATED TO IMPAIRED PLASMA VOLUME EXPANSION BUT IT STILL REMAINS TO BE DETERMINED TO WHICH EXTENT IRON SUPPLEMENTATION AND HEMOGLOBIN MAY CONTRIBUTE TO ANY INCREASED OUT COME FROM INCREASED HEMOGLOBIN. SO JUST TO SUMMARIZE, THERE IS APPROXIMATELY 1-GRAM OF IRON NEEDED FOR HEALTHY PREGNANCY, NEEDED FOR PLACENTA, FETUS AND MATERNAL HEALTH. INCREASED IERP SUPPLY IS PROVIDED BOTH BY INCREASING MOBILIZATION FROM STORES AND INCREASED ABSORPTION AND HORMONE HEPCIDIN IS UP WITH OF THE KEY -- SUPPRESSION IS A KEY REGULATORY STEP. WE ARE STARTING TO UNDERSTAND WHICH PLACENTAL IRON TRANSPORTERS ARE NECESSARY BUT WE DON'T UNDERSTAND HOW THEY'RE REGULATED WELL, AND WE KNOW THE TEAM THROJ CAL ADAPTATIONS ARE VERY IMPORTANT FOR OPTIMAL OUTCOMES BUT WE STILL DON'T UNDERSTAND WHAT IRON SUM MEP TAITION DOES TO ALL OF THESE PROCESSES. WE KNOW THAT IT IMPROVES MATERNAL IRON STORES AND HEMOGLOBIN AND IN NEWBORN BIRTH WEIGHT, ALL OF THESE STUDIES WERE RELATED TO GLOBAL POPULATIONS THAT INCLUDE IRON DEFICIENCY AND ANEMIC PATIENTS, BUT WE STILL DON'T UNDERSTAND HOW THEY AFFECT IRON-REPLETE WOMEN. THANK YOU VERY MUCH AND I WANT TO INVITE YOU NEXT YEAR TO OUR INTERNATIONAL BIOCONFERENCE IN LOS ANGELES. [APPLAUSE] >> SO THANK YOU VERY MUCH. AGAIN THE SPEAKER, PLEASE GO TO THE MICROPHONES. >> AS THEY SAID, IT WAS A BRAVE MAN WHO FIRST [INAUDIBLE]. I REALLY APPLAUD BOTH YOU AND KIM O'BRIEN TAKING ON THIS SUBJECT BECAUSE THIS IS A VERY, VERY COMPLEX SITUATION. I JUST WANTED TO ADD ONE MORE POSSIBILITY, YOU'RE ASKING WHO'S IN CHARGE, THE MOM OR THE FETUS OR BOTH. THERE ARE CONDITIONS THAT I DEAL WITH AS A NEONATOLOGIST WHERE THERE'S CLEARLY AN INCREASED FETAL IRON REQUIREMENT SO MUCH OF WHAT WE'RE GOING TO TALK ABOUT, I THINK, IN THIS CONFERENCE IS ABOUT SUPPLY SIDE, BECAUSE THAT'S ABOUT SUPPLEMENTATION, BUT ONE NEEDS TO TAKE INTO ACCOUNT DEMAND SIDE AS WELL, SO FOR EXAMPLE, DIABETIC PREGNANCIES WHERE THERE'S CHRONIC HYPOXEMIA, RAPIDLY GROWING FETUS, BIG BLOOD MASS, BOTH CONCENTRATION WISE AND SIZE WISE. WE SEE DEFICIENCY OR SIGNS OF DEFICIENCY, LOW FERRITINS, FOR EXAMPLE, IN THOSE BABIES WHEN THEY'RE BORN, AND YET MOTHER'S IRON STATUS IS COMPLETELY NORMAL. WHEN WE LOOK AT PLACENTA, THERE WE SEE INCREASED TRANSFER INTERCEPTOR EXPRESSION SO IT WOULD SUGGEST THAT EITHER THE PLACENTA OR THE FETUS BECOMES SOMEWHAT IRON-DEFICIENT IN THAT CONDITION, COMPLICATED PHYSIOLOGY BUT TAKE IT FOR GRANTED THAT THERE'S AUGMENTED ERYTHROPOIESIS IN UTERO, THERE MUST BE SOME WAY THE FETUS CAN ALSO CALL FOR SOME IRON. >> YES, IT WILL BE VERY INTERESTING TO FIND OUT -- SO FETUS COULD PRODUCE SOMETHING OR PLACENTA COULD PRODUCE SOMETHING OR MOTHER COULD PRODUCE SOMETHING IN RESPONSE TO OTHER METABOLIC CHANGES THAT RELATED TO PREGNANCY. WE DON'T KNOW WHETHER FETUS PRODUCES SOMETHING IN NORMAL FETUS, HEPCIDIN SEEMS TO BE LOW ENOUGH AS IF NOT TO BE PRESENT, SO FETUS IS ALWAYS SAYING BRING IT ON. >> RIGHT. >> UNLESS MAYBE IN THESE -- THERE COULD BE SOME CONDITIONS WHERE FETAL HEPCIDIN MAY BE INCREASED, I DON'T KNOW WHY THAT WOULD BE, AND I DON'T KNOW IF THAT WOULD BE IN SPECIFIC PATHOLOGIES, BUT IF FETAL -- IS INCREASED THAT WOULD PREVENT IRON TRANSFER. >> INFECTION DURING FREG SEE. >> FOR SEU WE COULD EXPECT THAT. SO IN THAT CASE, FETUS COULD ACTUALLY PATH LOMGICALLY PREVENT IRON TRANSPORT BUT USUALLY FETAL -- IS JUST ABSENT SO IT WOULD CONSTANTLY BE ASKING FOR IRON. WHETHER PLACENTA REGULATES EXPORT FROM THE PLACENTA IN ADDITION TO IMPORT, THAT'S A VERY IMPORTANT QUESTION. SO FAR MOSTLY MRNA LEVELS HAVE BEEN LOOKED AT, BUT PROTEIN LEVELS OF THESE TRANSPORTERS ARE VERY IMPORTANT BECAUSE SOME OF THESE TRANSPORTERS ARE MOSTLY REGULATED AT THAT ULTIMATE LEVEL, THE PROTEIN LEVEL, SO THAT IS WHAT WE'RE FINDING WITH FERROPORTIN, THAT ONLY THE PROTEIN IS PARADOXICALLY DECREASED WHEN THERE'S NOT ENOUGH IRON IN THE MOTHER. SO I THINK WE NEED TO EXAMINE THESE TRANSPORTERS IN PLACENTA TO REALLY UNDERSTAND, EVEN THOUGH PLACENTA IS ASKING FOR IRON, IS IT REALLY TRANSFERRING IT TO THE BABY. >> CORRECT. >> SO WE DON'T KNOW ABOUT FETAL FACTORS THAT FETAL MAY BE SEE CREATING, WE DON'T KNOW ABOUT PLACENTAL FACTORS AND HOW THEY'RE COORDINATED. >> DIABETES IN PREGNANCY, FO FOR EXAMPLE, PROBABLY GETTING MORE COMMON WHEN WE TALK ABOUT UNIVERSAL SUPPLEMENTATION, IT WOULD HAVE SOME RAMIFICATIONS THERE THERE. >> VERY NICE TALK. I JUST HAD A QUESTION FOLLOWING UP ON THE PREG SEAL SUPPRESSION OF HEPCIDIN. I KNOW THERE'S SOME REGULATION OF HEPCIDIN BY SEX HORMONES, ESTROGEN AND TESTOSTERONE, AND I'M WOULD BE DERING IF THERE'S ANY INFORMATION ABOUT HORMONAL CHANGES DURING PREGNANCY THAT MAY FEED INTO THAT SUPPRESSIVE EFFECT. >> WE HAVEN'T -- THAT WAS ONE OF OUR FIRST HYPOTHESIS OF WHO COULD BE SUPPRESSING MATERNAL HEPCIDIN, YOU HAVE INCREASING ESTROGEN AND PROGESTERONE SIMULTANEOUSLY DECREASING HEPCIDIN, SO WE WERE THINKING MAYBE THOSE COULD BE CANDIDATES. WE TESTED MICE THAT WERE CHRONICALLY SUPPLEMENTED WITH EITHER ESTROGEN, PROGESTERONE OR A COMBINATION, WE SAW NO EFFECT ON HELP SIGH DIP OR IRON STORES SO WE THINK THAT'S LESS LIKELY. >> U.C. DAVIS, THANK YOU VERY MUCH. I WAS VERY INTERESTED IN YOUR EXPERIMENTS WHERE YOU INJECTED HEPCIDIN TO SEE WHAT WAS HAPPEN TO OUTCOMES AND THEY WERE ADVERSELY AFFECTED, BUT IN THE SENSE THAT OVERRIDING THE SUPPRESSION OF HEPCIDIN THAT YOU PREVIOUSLY MENTIONED. SO I'M WONDERING IF YOU TRIED OR WILL TRY EXPERIMENTS IN WHICH YOU INDUCE THAT VIA INFLAMMATION RATHER THAN DIRECTLY INJECTING THE HEPCIDIN. >> WE'RE DOING THAT RIGHT NOW. SO THE EXPERIMENTS ARE ONGOING IN THE LAB AND WE REALLY DON'T HAVE ANYTHING RIGHT NOW BUT WE ARE DOING EXACTLY THAT THING. >> THANK YOU. >> THAT WAS A BEAUTIFUL TALK, AND I JUST WANTED TO COMMENT ON THE FETAL HEPCIDIN ISSUE. WE JUST COMPLETED A STUDY IN WOMEN CARRYING MULTIPLES AND OVER 150 OF THEIR BABIES AT BIRTH BORN FROM AROUND 20 WEEKS OF GESTATION UNTIL TERM. ALL OF THE BABIES HAD MEASURABLE HEPCIDIN AND IN THOSE NEONATE THERE WERE SIGNIFICANT CORRELATIONS TWEENL NEONATAL HEPCIDIN AND IRON STATUS. AGAIN, REITERATING WHAT MIKE HAS JUST SAID, THAT THERE'S LIKELY AN ABILITY OF THE FETUS TO REGULATE ITS IRON HOMEOSTASIS. >> SO WHEN YOU MEASURED THIS HEPCIDIN IN THOSE BABIES, WAS THAT AFTER DELIVERY OR WAS THIS -- >> CORD BLOOD. >> SO THERE IS A TRANSIENT SPIKE RIGHT AROUND BIRTH EVEN IN BABIES. IT WOULD BE NICE IF WE COULD SOMEHOW COLLECT HEPCIDIN PRIOR TO LABOR STARTING, TO SEE WHAT THE ACTUAL LEVELS ARE DURING PREGNANCY. >> HI, GARY BRITTING HAM. I WOULD ASK THE SIMPLER QUESTION WHICH IS, YOU EMPHASIZE A GRAM OF IRON IS NEEDED. WHAT IF TH ARE THE STORES AVAILABLE TO THE WOMAN DURING PREGNANCY AND HOW MUCH IRON CAN BE ABSORBED DURING THE COURSE OF THE PREGNANCY? >> ALL VER VARY REALLY WIDELY. FOR A MAN, WE SAY THERE'S AROUND 1-GRAM IN THE LIVER, WOMEN MAYBE HALF THAT IF THEY ARE REASONABLY IRON-REPLETE BUT MANY OF THEM HAVE EVEN LESS. THROUGH IRON ABSORPTION, CAN YOU PROBABLY OVER NINE MONTHS PROVIDE HALF A GRAM. SO UNLESS WOMAN HAS FULL IRON STORES AND TURNS ON IRON ABSORPTION FULLY, SHE WILL NOT MAKE UP THE 1-GRAM. AND ANYBODY ELSE IS WELCOME TO COMMENT ON THIS. THANK YOU. [APPLAUSE] >> ALL RIGHT. SO OUR NEXT TOPIC WILL BE HOW DOES IRON HOMEOSTASIS CHANGE IN INFANTS AND YOUNG CHILDREN. AND ON THAT TOPIC, BO LONNERDAL IS GOING TO PRESENT. >> THANK YOU VERY MUCH. I ALSO APPRECIATE BEING INVITED TO THIS VERY INTERESTING WORKSHOP. I WISH I COULD GIVE A PRESENTATION AS ELOQUENT AS THE PREVIOUS TWO SPEAKERS, BUT HONESTLY, IF YOU WILL WRITE A CHAPTER IN A BOOK ON IRON HOMEOSTASIS OF IP FANTS, IT INFANTS, IT WO ULD BE VERY, VERY BRIEF. SO INSTEAD, I WILL SHARE WITH YOU SOME DIFFERENT OBSERVATIONS THAT WE HAVE DONE IN CLINICAL STUDIES AND ALSO IN EXPERIMENTAL ANIMALS, MORE TO PERHAPS SET UP THE TOAP FOR WHAT WE'RE GOING TO TALK ABOUT TOMORROW AND THAT IS THE POSSIBILITY OF PROVIDING EXCESS IRON TO INFANTS. WHY DO INFANTS NEED IRON? WELL, WE CERTAINLY KNOW THEY DO NEED IRON. THIS IS TAKEN FROM LOOKING AT IRON IN THE BODY AT THREE DIFFERENT STAGES OF LIFE. YOU HAVE BIRTH ON THE LEFT SIDE HERE, AND YOU CAN SEE THAT THERE IS A SUBSTANTIAL AMOUNT OF IRON PROVIDED IN HEMO GLOBIN. PART OF THAT WILL BE BROKEN DOWN AND REUTILIZED, AND THEN SOMETIME BY 4 TO 6 MONTHS, YOU CAN SEE THAT NOW THE STORES ARE GETTING DOWN, WE HAVE A CERTAIN PROPORTION IN ESSENTIAL IRON IN MYOFLOW BIMYOGLOBIN AND ENZYMES AND THEN SOME IN HEMOGLOBIN, BUT THEN THERE'S NO DOUBT THAT A LOT OF IRON IS NEEDED FROM 4 TO 6 MONTHS UP TO ONE YEAR OF AGE. INFANTS ARE GROWING VERY QUICKLY AND THEY HAVE A HIGH DEMAND FOR IERP AND IT'S OUR TASK CERTAINLY TO PROVIDE THAT IRON TO THEM. I BORE OWED TWO SLIDES FROM KATE, ONE OF THE HIGHEST REGULATORS OF HOMEOSTASIS OF COURSE IS IRON STORES. THEREFORE, THE A IRON BEING AVAILABLAMOUNT OF IRONBEING AVAILABLE IS I MPORTANT. KAY HERE DISCUSSED HOW LONG SHOULD BODY IRON AT BIRTH LAST? THIS IS EXCLUSIVELY BREAST FED INFANTS, AND HOW LONG WILL IRON BE SUFFICIENT TO MAINTAIN DESIRABLE LEVELS OF TISSUE AND CIRCULATORY IRON, ASSUMING NO IRON IN STORAGE, AND WE KNOW THAT IT'S GENERALLY SAID LIKE I STARTED OFF WITH THAT INFANTS GENERALLY HAVE SUFFICIENT IRON STORES AT BIRTH TO LAST FOUR TO SIX MONTHS. THAT'S HEALTHY TERM INFANTS BORN TO IRON-SUFFICIENT WOMEN. THEN IF YOU MODEL SEVERAL SCENARIOS BASED ON BIRTH WEIGHT AND CORD CLAMPING TIME, WHICH IS ONE ESSENTIAL FACTOR AFFECTING IRON STORES, WE CAN SEE WHAT IS HAPPENING VERY NICELY IN KAY'S NEXT SLIDE HERE, AND SHE MODELED IT AFTER AN INFANT BORN AT 3.2 KILOGRAMS OR 3.5 KILOGRAMS BECAUSE THAT CERTAINLY HAS EFFECT ALSO. HERE YOU CAN SEE THE BODY IRON AVAILABLE TO MEET DESIRABLE TISSUE/CIRCULATING IRON, AND THE REFERENCE OF THE IRON NEEDED. THE SMALLER INFANT 3.2 KILOGRAMS CORD CLAMPING, AND THEN IF YOU HAVE DELAYED CLAMPING, THAT CHANGES UP TO ABOUT SIX MONTHS OF AGE. AND THEN IF YOU TAKE A LARGER INFAPT WITH EARLY CLAMPING, YOU CAN SEE THAT IT LASTS TO ABOUT 3.9 MONTHS OR 4 MONTHS, AND THEN IF YOU HAVE DELAYED CLAMPING, 8.2 MONTHS. SO THIS MOST LIKELY EXPLAINS WHY IN DIFFERENT POPULATIONS, IRON WILL KIND OF B BE SUFFICIENT FOR VARIOUS TIME FACTORS SUCH AS THE IRON ENDOWMENT AT BIRTH WHICH IS AFFECTED BY CORD CLAMPING. I JUST WANT TO USE ONE OF THE SLIDES THAT I OFTEN USE WHEN I TEACH, AND THIS IS TAKEN FROM HER BEAUTIFUL WORK ON THE LONG TERM CONSEQUENCES OF IRON DEFICIENCY IN EARLY LIFE THIS IS OF COURSE WHAT WE WANT TO AVOID. WE WANT TO PROVIDE ENOUGH IRON TO PREVENT THE EFFECT ON THE MENTAL DEVELOPMENT, PSYCHOMOTOR DEVELOPMENT, AND THIS IS SHOWING WHAT IS HAPPENING AT 12 MONTHS OF AGE, MANY OF THESE CONSEQUENCES HAVE LONG, LONG LASTING EFFECTS, BEAUTIFUL STUDIES, BUT YOU CAN SEE HOW YOU HAVE AN IMPAIRMENT IF THE HEMOGLOBIN LEVELS ARE GOING LOWER THAN NORMAL. IF HEMOGLOBIN IS INSUFFICIENT, THEN YOU WILL SEE CONSEQUENCES. SO WE WANT TO PREVENT THIS FOR SURE. WELL, ONE THING I WOULD LIKE TO HIGHLIGHT HERE BECAUSE IT KIND OF TIE TRAITS THE NEED FOR IRON AND THERE ARE ISOTOAP STUDYS THAT HAVE BEEN DONE AND BALANCED STUDIES WHERE THE EARLIEST AND OLDEST ONE, VERY DIFFICULT, OF COURSE, TO VIEW BECAUSE YOU HAVE TO -- TERMINATION AT SO MANY STAIMTION, THEN SIMILAR TO WHAT GREG SAID IN HIS VERY NICE PRESENTATION, ISOTOPE STUDYS WERE DONE SEVERAL DECADES AGO IN INFANTS AND THEY ARE ACCURATE. WE HAD AND THEY HAD VERY, VERY SENSITIVE WHOLE BODY COUNTERS, AND IF YOU'RE USING IRON -- YOU CAN REALLY STUDY WHAT IS BEING ABSORBED. TODAY, WHEN THEY GET INTO ETHICAL COMMITTEES, WE CERTAINLY WON'T GET -- STUDIES, SO INSTEAD WE USE STABLE ISOTOPE STUDY, WHICH I WILL SHOW YOU HERE, AND THAT OTHERS IN THE AUDIENCE CERTAINLY HAVE USED ALSO. THIS IS DATA ON ABSORPTION USE USE -- SIIMES, HERE YOU CAN SEAL ON THE LEFT SIDE HERE, YOU HAVE THE IRON CONTENT OF BREAST MILK, WHICH IS LOW, .3 MILLIGRAMS ON AVERAGE, AND THEN CAN YOU SEE FORMULA, WHICH AT THAT TIME WAS UNFORTIFIED WITH IRON, SO VERY LOW IRON FORMULA. THIS IS THE COMMON EUROPEAN LEVEL USED IN INFANT FORMULA, ABOUT 7 MILLIGRAMS PER LITER, AND THEN YOU HAVE THE U.S. IRON FORTIFICATION LEVEL OF 12, WHICH IS THE MOST COMMON ONE. AND YOU CAN SEE THAT IRON IS ABSORBED VERY, VERY WELL FROM BREAST MILK. AND WE CAN TALK ABOUT THE MAGNITUDE ABOUT THESE DIFFERENCE, BUT STABLE ISOTOPE STUDIES SHOW THE SAME THING. YOU CAN SEE THAT IF YOU HAVE THIS HIGH ABSORPTION AND NO CONCENTRATION, THIS IS THE AMOUNT OF IRON BEING ABSORBED. NO DOUBT IF YOU HAVE A LOW IRON FORMULA, YOU WOULD NOT ABSORB AS MUCH OR INFANTS WILL NOT ABSORB AS MUCH AS FROM BREAST MILK, WHILE IF YOU GO TO HIGHER LEVELS OF IRON FORTIFICATION, THERE IS MUCH MORE IRON ABSORBED THAT BE BREAST FETHAN BREAST-FED INFANTS. SO WE HAVE DONE A SERIES OF STUDIES IN SWEDEN ON BREAST FED AND FORMULA FED INFANTS, AND I WOULD SHARE JUST BRIEFLY WITH YOU SOME OF THE OBSERVATIONS THAT WE HAVE MADE. LIKE I SAID, NO DOUBT IRON SHOULD BE PROVIDED TO INFANTS IN SUFFICIENT QUANTITY TEES TO PREVENT IRON DEFICIENCY AND IRON DEFICIENCY ANEMIA. OARPD, IRON IS A PRO-OX DAPT ELEMENT AND MAY HAVE TOXIC EFFECTS WHEN PROVIDED IN EXCESS, BUT WE WANTED TO ADDRESS BOTH OF ISSUES IN OUR STUDY. THE POTENTIAL RISKS OF GIVING TOO MUCH IRON AT THE TIME WHEN WE DID THESE STUDIES, THEY HAVE BEEN GOING ON FOR ABOUT 15 YEARS, AND IN THE BEGINNING, AND I SHOW YOU SOME OF THE FIRST STUDIES TODAY AND SOME OF THE LATEST STUDIES TOMORROW, WE HAVE THE POSSIBILITY OF INCREASED FREE RADICALS, LIPID OXIDATION, ET CETERA, AND ALSO THE DECREASED ABSORPTION OF OTHER TRACE ELEMENTS THAT ARE ESSENTIAL IN EARLY LIFE. HERE QEN YOU SAHERE AGAIN YOU SAW THAT IN THE ABSORPTION STUDY. THIS IS A CALCULATION THAT WE MADE. IF WE NOW ASSUME BASE LEVELS IN THE DIET, WE USE THESE OBSERVATIONAL NUMBERS FOR IRON ABSORPTION, YOU CAN SEE THAT THE AMOUNT OF IRON ABSORBED FROM BREAST MILK PER DAY WOULD BE ABOUT .15 MILLIGRAMS. IF YOU HAVE AN IRON FORMULA -- IRON FORTIFIED FORMULA, LIKE YOU HAVE IN THE U.S., 1.2 MILLIGRAMS WILL BE ABSORBED. SO MUCH, MUCH MORE IRON FROM THAT. THE QUESTION IS, HOW MUCH SHOULD THEY HAVE, AND THEN WE HAVE DONE STUDIES AT THE EUROPEAN LEVEL OF 7, SWEDISH LEVEL THAT IS USED TODAY OF 4, AND THEN MORE INTERESTINGLY, PERHAPS, AT 2, WHICH WOULD BE ROUGHLY EQUIVALENT TO WHAT YOU GET FROM BREAST MILK. AND THE FIRST STUDY WE DID HERE, BASED ON OUR EXCLUSIVELY BREAST FED OR EXCLUSIVELY FORMULA FED INFANTS IN SWEDEN FROM 1 TO 6 MONTHS OF AGE, THE EUROPEAN LEVEL OF 7 MILLIGRAMS, WE HAD TWO GROUPS AT 4, 1 WITH FERROUS SULFATE -- [INAUDIBLE] NOP SIGNIFICANT DIFFERENCES IN WEIGHT OR LENGTH GAIN, ALSO NO SIGNIFICANT DIFFERENCES IN HEMOGLOBIN OR IRON STATUS IN THIS SWEDISH POPULATION OF HEALTHY TERM INFANTS. WHAT WE DID FIND IN THAT STUDY WAS THAT IT WOULD LOOK AT CERULOPLASMIN, YOU SEE IF YOU COMPARE THE BREAST FED AND THE INFANTS GETTING THE LOWER LEVEL OF IRON HERE, THEY WERE SIGNIFICANTLY HIGHER THAN IN THOSE THAT HAD 7 MILLIGRAMS LATER. I WILL SHOW YOU A STUDY LATER ON THAT SHOWED SIMILAR THINGS -- DOES THIS HAVE NEGATIVE CONSEQUENCES? WE DON'T KNOW. BUT IT'S AN OBSERVATION THAT'S CERTAINLY GIVING MORE IRON THAN PERHAPS IS NEEDED TO SEE AN EFFECT ON COPPER STATUS. WE'VE ALSO DONE A STUDY OF 2 MILLIGRAMS OF IRON PER LITER IN SATISFACTORY IRON STATUS UP TO SIX MONTHS OF AGE, AND THAT'S WHAT WE BELIEVE IS WHAT HEALTHY TERM INFANTS WITH ADEQUATE STORES REALLY NEED. AND IN THE U.S., WE ARE PROVIDING SIX TIMES AS MUCH FROM BIRTH ON, AND THAT'S THE TONE FOR WHAT WE NEED TO DISCUSS TOMORROW. WE HAVE BEEN INVOLVED IN A STUDY FUNDED BY USDA TO ADDRESS THE ISSUE WHEN EXCLUSIVELY BREAST FED INFANTS REALLY DO NEED ADDITIONAL IRON, AND IT WAS STARTED BY THE USDA TO BE DONE IN TWO DIFFERENT SETTINGS. IN HONDURAS, REPRESENTING PERHAPS THE LOWER SOCIOECONOMIC STATUS IN U.S., AND IN SWEDEN, REPRESENTING THE HIGHER. WITHOUT HAVING THE CONFOUNDERS THAT THEY WOULD HAVE IN THE U.S. WITH SOCIOECONOMIC GROUPS HAVING ADDITIONAL -- THE REASON WHO IN THEIR INFINITE WISDOM HAD SUGGESTED HERE THAT THE CURRENT RECOMMENDATION OF GIVING IRON DROPS AFTER SIX MONTHS OF AGE SHOULD BE CHANGED TO FOUR MONTHS OF AGE. KAY AND I WONDERED, WHAT IS THE RATIONALE FOR THAT, OR WHAT IS THE EVIDENCE OR SUPPORT FOR THAT? AND THERE WAS NONE. IT WAS MORE A GUT FEELING THAT IF YOU HAVE GOOD EFFECTS ON SIX MONTHS, YOU SHOULD HAVE EVEN BETTER EFFECTS IF YOU START AT FOUR MONTHS. SO WE DID THIS, WE LOOKED AT HEMOGLOBIN AND STATUS OF GROWTH AND MORBIDITY, AND WE GAVE THE SUPPLEMENT EERD FROM 4 TO 9 MONTHS OR 6 TO 9 MONTHS AND THEN WE HAD A PLACEBO GROUP. WE HAD A GROUP FOR -- WE PROVIDED FERROUS SULFATE, AND YOU CAN SEE THE INCLUSION CRITERIA. I DON'T WANT TO DWELL ON THE DETAILS HERE. THE STARTING IRON STATUS IN HONDURAS AND SWEDEN, US A CAN SEE, WAS TWICE DIFFERENT, THAT WAS LIKE WE HAD ATTEMPTED IRON STATUS IN HONDURAS AND SINCE AT THIS AGE IT'S NOT AS GOOD AS IT IS IN SWEDEN FOR MANY REASONS. IF WE SUMMARIZE IT BRIEFLY, SUPPLEMENTATION OF IRON TO BREAST-FED INFANTS INCREASED HB IN HONDURAS BUT NOT IN SWEDEN, INCREASED FERRITIN EQUALLY AT BOTH SITES, INTERESTINGLY, AND THEN NO ADVANTAGE OF EARLY IRON SUPPLEMENTATION FROM 4 MONTHS AS COMPARED TO 6 MONTHS OF AGE. SO THERE WAS NO ADVANTAGE OF THAT. AND I THINK THAT KIND OF EMPHASIS FROM WHO NOT TO CHANGE THE CURRENT RECOMMENDATION, WHICH WE STILL HAVE. WE DID FIND SOME INTERESTING OBSERVATIONS OR WE MADE SOME INTERESTING OBSERVATIONS IN THIS STUDY. IF YOU LOOK AT HEMOGLOBIN RESPONSE TO IRON FROM 4 TO 6 MONTHS BY SIGHT, YOU CAN SEE BACK IN HONDURAS THAT HAD POOR IRON STATUS, HEMOGLOBIN INCREASED, WHICH IS WHAT YOU WOULD EXPECT. IN SWEDEN -- NOT WHAT YOU WOULD EXPECT IF YOU HAD ADEQUATE IRON HOMEOSTASIS, RIGHT? THEN IF YOU LOOK AT 6 TO 9 MONTHS, LO AND BEHOLD IN HONDURAS, YOU'VE GOT THE SIGNIFICANT INCREASE IN HEMOGLOBIN, IN SWEDEN THERE WAS NO CHANGE. IRON HOMEOSTASIS NOW SEEMS TO BE WORKING, RIGHT? AND IF WE COLLAPSE THE TWO GROUPS AND LOOK AT HEMOGLOBIN HIGHER THAN 115 OR LOWER THAN 115, BETWEEN 4 AND 6, SO THIS IS COMBINED HONDURAS AND SWEDEN, YOU CAN SEE THAT IT DIDN'T MATTER IF YOU HAD HIGH HEMOGLOBIN OR IF YOU HAD LOW HEMOGLOBIN BETWEEN 4 AND 6, THEY JUST ABSORBED THE IRON AND HEMOGLOBIN WENT UP AND UP AND UP. THEN IF YOU LOOK AT 6 TO 9 MONTHS, THEN WHAT HAPPENS WITH THOSE THAT HAD SATISFACTORY HEMOGLOBIN OR THERE WAS NO CHANGE, IRON HOMEOSTASIS IS WORKING, AND IF IT WAS LOW, HEMOGLOBIN INCREASED, WHICH IS WHAT YOU WANT TO SEE, OF COURSE. WE FOLLOWED THIS UP WITH A STUDY IN SWEDEN WHERE WE LOOKED AT THE ABSORPTION OF IRON FROM BREAST MILK IN THOSE INFANTS WITH LOW IRON INTAKE. SO WE MEASURED IRON ABSORPTION USING STABLE ISOTOPES AVAILABLE WITH A -- AND WE LOOKED AT THE ABSORPTION OF BREAST MILK, WE USED THE REFERENCE DOSE APPROACH TO CORRECT FOR INDIVIDUAL STATUS AND WE LOOKED AT IT AT SIX MONTHS AND AT NINE MONTHS OF AGE. HERE YOU CAN SEE THAT AT SIX MONTHS OF AGE, IRON ABSORPTION WAS THE SAME. NO SIGNIFICANT DIFFERENCE. IF THEY HAD BEEN RECEIVING IRON SUPPLEMENTS DAILY, FOR TWO MONTHS, OR IF THEY HAD RECEIVED NO IRON, ORAL IRON AT THAT TIME, SO IN THIS CASE, YOU CERTAINLY HAD A MUCH BETTER IRON STATUS AND THERE WAS NO DIFFERENCE IN IRON ABSORPTION. IF WE LOOK AT THIS AT NINE MONTHS, WE SAW WHAT WE HAD EXPECTED, THOSE THAT HAD BEEN PROVIDED IRON DAILY, FOR QUITE SOME TIME THEY ABSORBED MUCH LESS THAN THOSE THAT HAD NOT. SO AGAIN, INDICATIONS OF IRON HOMEOSTASIS BEING MORE MATURE BY THIS TIME OF -- BY THIS AGE. THEN WE HAVE MODELED THIS IN A RAT PUP MODEL, AND AGAIN, I AGREE WITH WHAT HAS BEEN SAID, RODENTS HAVE THEM IN THE PATIENTS BUT WE COULD ACTUALLY SHOW SIMILAR EFFECTS ON WHAT WE SAW ON IRON HOMEOSTASIS AT DAY 10 AND 20, BUT WE COULD MIMIC WHAT WE SAW AT 6 AND 9 MONTHS IN HUMAN INFANTS IN THE RAT PUPS, AND, THEREFORE, WE THOUGHT THAT WE SHOULD TRY TO LOOK AT WHAT IS HAPPENING AT THE MOLECULAR LEVEL. WE ARE NOT TAKING OUT THE SMALL INTESTINES OF OUR HUMAN INFANTS, BUT IN THIS CASE, WE CAN DO THAT, SO WE CAN LOOK AT THE MECHANISM BEHIND IRON HOMEOSTASIS. WHAT WE DO IS THAT WE TAKE -- SUCK LING RAT PUPS AND BY ORAL LAVAGE, WE PROVIDE ORAL SUPPLEMENTS IN A WAY SIMILAR TO WHAT YOU WOULD GIVE TO HUMAN INFANTS. THIS IS CALCULATED ON A PER-BODY-WEIGHT BASIS, AND IT'S SIMILAR TO WHAT YOU WOULD GET FROM A FORMULA WITH A MODERATE LEVEL OF IRON SUPPLEMENTATION OR MORE SIMILAR TO WHAT YOU HAVE IN THE U.S., SO THESE ARE DIETARY IRON LEVELS PROVIDED DAILY TO SUCKLING OR BREAST FEEDING RAT PUPS. WE WERE ALSO INTERESTED IN THE POSSIBILITY OF THE RAT PUPS BEING COMPROMISED AND IN ORDER TO GET THEM IRON-DEFICIENT, YOU HAVE TO INFUSE IRON DEFICIENCY DURING PREGNANCY, AND THERE WE HAVE A CONTROLLED IRON DEFICIENT PUPS AND WE HAVE THOSE PROVIDED EXTRA IRON DAILY SIMILAR TO THOSE THAT WERE IRON-SUFFICIENT DID. THEN WE LOOKED AT A LOT OF THINGS BUT WE PARTICULARLY LOOKED AT THE IRON TRANSPORTER BOTH AT THE GENE AND THE PROTEIN LEVEL. HERE YOU CAN SEE A COMPOSITE OF THE IRON SUFFICIENT AND IRON DEFICIENT PUPS, AND CAN YOU SEE THE EXPRESSION OF THE DMT1 GENE AT DAY 10, NO SIGNIFICANT DIFFERENCE, DOESN'T MATTER IF THEY HAD LOW OR HIGH IRON STATUS, NO SIGNIFICANT DIFFERENCE, BUT AT DAY 20, VERY NICELY SHOW THAT THE DAILY IRON DROPS SIGNIFICANTLY REDUCED THE MP1, AND IF THEY WERE LOW IN IRON, YOU HAD A SIGNIFICANT UPREGULATION. SO AGAIN SHOWING IRON HOMEOSTASIS AT THE TIME OF WEANING IN THAT PUPS, WHICH MAY BE TRANSLATED BOTH TO 6 TO 9 MONTHS IN HUMAN INFANTS, THEN THE HOMEOSTASIS IS REGULATED BY THESE TWO TRAPTERS. TRANSPORTERS. YOU CAN SEE HERE THE SAME FOR THEIR PORE TIN IN THE FACT THAT EARLY LIFE HERE, WE SAW SOME DIFFERENCES THE OPPOSITE DIRECTION OF WHAT YOU WOULD LIKE TO SEE, BUT AT DAY 20, WE SAW THE SIMILAR THINGS THAT WOULD SOLVE FOR DMT1, NO LEVELS OF -- WHEN HIGH IRON IS GIVEN AND A HIGH LEVEL WHEN YOU HAVE NO IERP GIVEN. SO THE MESSAGE AND THE PROTEIN OF DMT1 AND -- IS KIND OF LACKING CONTROLS AT EARLY AGE. WE HAVE ACTUALLY LOOKED, WE WORKED ON THE -- RECEPTOR WHICH I THINK IS AN IMPORTANT COMPONENT OF IRON ABSORPTION, HUMAN INFANTS AND PIGLET'S, AND THERE WE SAW THAT NOT ONLY DO WE SEE THIS LACK OF REGULATION BUT ALSO IT'S MISLOCALLIZED, WHICH WE HAVEN'T PURSUED THAT BUT IT MAY BE A COMBINATION OF BOTH, MISPLACEMENT OF THE IMPORTANT TRANSPORTERS. SO WITH THAT, I WOULD LIKE TO CONCLUDE THAT MECHANIC REGULATED IRON HOMEOSTASIS ARE IMMATURE AT YOUNG AGE AND WE DON'T KNOW WHEN THEY MATURE, AND THIS OPENS UP THE POSSIBILITY OF HIGH ACCRETION OF IRON IF EXCESS IRON IS GIVEN AND THAT'S WHAT WE'RE GOING TO DISCUSS MORE TOMORROW. THANK YOU. [APPLAUSE] >> I FEEL MUCH MORE COMFORTABLE ON THIS SIDE OF THE PLA 16 TA THAN ON THPLACENTA.SO THIS WHOLE CONVERSAT ION IS BECOMING WHEN AND CAN YOU TRUST HEPCIDIN OR THE REGULATORY MECHANISM, RIGHT? SO THEY ALSO DID SOME STUDIES ON THE LATE PRETERM BABY OR THE 2,000 TO 2500-GRAM BABY, THESE WERE SEMINAL STUDIES, NOT TOTALLY ACCRETED IRON IN UTERO, PRETTY RAPID RATES OF POSTNATAL GROWTH, AND SHOWED THOSE BREAST-FED SWEDISH BABIES, HE RANDOMIZED AND SHOWED THEM THAT IF YOU DIDN'T GIVE THEM ANY IRON, THERE WAS A GOOD DECREE OF DEFICIENCY AND THAT THERE WAS SOME DEVELOPMENTAL CONSEQUENCES, 1 AND 2 MILLIGRAMS PER KILO SEEMED TO NOT HAVE THAT HAPPEN. BUT I REMEMBER WHEN STEFFAN, WHO WAS THE PRIMARY -- WHEN HE DEFENDED HIS PH.D. WHICH I WAS AT, THERE WAS SOME IMPLICATION THAT BY 6 WEEKS OF AGE, THEY THOUGHT THE SYSTEM WAS STARTING TO BECOME REGULATED. SO I KNOW THIS IS ALL ABOUT THE STANDARD TERM BABY WE'RE TRYING TO DO HERE, BUT SOMETIMES IT'S THESE SLIGHT OUTLIERS THAT HELP US. IN THE PRETERM BAIBL, STABLE ISOTOPE STUDIES USUALLY COME UP WITH A NUMBER OF ABOUT 40%, BUT GOING WAY BACK TO 1963, THERE WAS -- WE COULDN'T DO IT ANYMORE, THE IRON 59 WAS GIVEN IN CHILDREN, VERY WIDE RANGE OF IRON ABSORPTION. SO WHAT'S YOUR OPINION ABOUT WHEN THAT SYSTEM DOES START TO SHOW REGULATION IN HUMANS? NOT IN THE RATS, BUT HUMANS? BECAUSE ULTIMATELY THAT'S WHAT WE'RE TRYING TO DECIDE WHAT TO TRUST HERE. >> IT'S HARD TO TELL. I WISH I COULD ANSWER IT, BUT YOU'RE RIGHT IN THESE THINGS. FIRST I THINK ONE OF THE -- THEY DIDN'T USE THE REFERENCE NOTES, THAT'S WHY THEY GOT THE VERY HIGH -- IN THE RAT STUDY, I DIDN'T PLAN TO GO INTO IT, BUT IT'S FROM EVERYTHING WE SAW, IT SEEMED LIKE HEPCIDIN REGULATION WAS NORMAL, WE HAVEN'T PUBLISHED THAT BUT WE DID THAT ANALYSIS. THERE DOESN'T SEEM TO BE DISREGULATION OF HEPCIDIN EARLY ON, IT SEEMS TO AT LEAST WHAT WE HAVE FOUND RELATED TO THE -- AND THEIR PORE TIN. WE NEED DATA FROM HUMANS TO SEE THIS. OF COURSE YOU CANNOT TAKE BIOPSIES FROM HEALTHY INFANTS, BUT DECISIONS ARE ALLOWED OF COURSE TO TAKE IS EXPLORATORY -- WHEN YOU SUSPECT -- WHEN YOU HAVE A HEALTH PROBLEM WHERE THE MUCOSA IS ACTUALLY HEALTHY AND YOU COULD ANALYZE THAT. HASN'T BEEN DONE, I KNOW A RESEARCHER IN BOSTON IS TRYING TO DO THIS, I THINK WE NEED SOME MORE MOLECULAR EVIDENCE AT VARIOUS AGES AND DEGREES, BOTH IN THE PRETERM AND THE TERM INFANT. >> SO IN THE INFANTS WHERE IT LOOKED LIKE THERE WAS SOME REGULATORY CAPACITY A LITTLE EARLIER THAN YOU FOUND IN YOUR STUDY, I WONDER IF YOU THOUGHT ABOUT HOW THE RATIO OF HOW IRON, ZINC AND COPPER CHANGE OVER EARLY INFANCY AND WHAT THAT MIGHT BE DOING TO TRANSPORT MECHANISMS AND PROTEINS IN AN IMMATURE NEONATAL? >> I THINK THEY ARE INTERRELATED AND I AGREE WITH YOU, THEY SHOULD BE LOOKED AT TOGETHER. VERY FEW STUDIES UNFORTUNATELY ARE DOING THAT. IT SEEMS LIKE YOU'RE CORRECT THAT THERE CERTAINLY APPEAR TO BE HAPPENING EARLIER. WE DON'T KNOW WHY, WHAT IS TRIGGERING THIS MATURATION? WE DON'T KNOW THE MECHANISM FOR THAT. ONE OF THE THINGS -- WE SEE MUCH -- INTRODUCTION OF SOLID FOODS THAN WE DO IN SWEDEN AND THAT CAN HAVE AN EFFECT, PERHAPS. >> COULD YOU COMMENT ON THE DIFFERENCES BETWEEN YOUR FINDINGS OF THE SWEDISH GROUP AND ZIGLER'S FINDING WITH THE IOWA BREAST-FED MOMS WHERE HE DID SEE AN EFFECT OF IRON SUPPLEMENTATION AT SIX MONTHS, YOU KNOW, STARTED EARLIER THEN MEASURED AT SIX MONTHS? >> IN IRON STATUS, YOU MEAN? >> YEAH. >> I THINK IT MAY BE THE BACKGROUND ON THE WOMEN WHICH MAY BE DIFFERENT IN THAT STUDY. >> I JUST MENTIONED IT BECAUSE U.S. DATA -- >> -- [INAUDIBLE] THINKING ABOUT WHAT'S GOING ON RIGHT AT THE TIME OF -- AND THE MICROBIOME CHANGES AT THAT JUNCTION IN LIFE MUST NECESSARILY BE TREMENDOUS, AND THAT MAY BE GETTING INTO THE DEVELOPMENT OF THIS IRON REGULATORY SYSTEM. SO I WONDER IF YOU ARE AWARE OF ANY STUDIES IN -- ANIMAL STUDIES WHERE BASED OP SIMILAR TRACER ANALYSIS TO LOOK AT BIOAVAILABILITY IN THE PREPS AND ABSENCE OF BIOME? >> CERTAINLY A GOOD POINT. I'M NOT AWARE OF ANY RESEARCH ON THIS AND -- BIOTIC ANIMALS, THAT MAY BE MY LACK OF KNOWLEDGE BUT I HAVEN'T SEEN T WE WILL COME BACK AND TALK ABOUT THIS TOMORROW, MICHAEL ZIMMERMAN WILL TALK ABOUT IT, AND WE HAVE ACTUALLY DONE SOME FOLLOW-UP STUDIES ON THE RAT STUDIES HERE WHERE WE LOOKED AT THE MICROBIOTA ALSO TOGETHER WITH THE -- OF THOSE ANIMALS AND I THINK IT'S A VERY INTERESTING FACTOR AND I AGREE WITH GREG THAT ALL STUDIES IN THE FUTURE REALLY SHOULD LOOK AT THIS, BECAUSE IT CERTAINLY HAS EFFECTS EFFECTS. >> SO THANK YOU TO DR. TAYLOR AND OTHERS FOR ASKING TO ATTEND, AN MY TOPIC FOR THIS SESSION IS CURRENT UNDERSTANDINGS ABOUT CHRONIC AND ACUTE INFLAMMATORY RESPONSE. SO I'D LIKE TO TALK ABOUT TWO MAIN POINTS, DESCRIBE THE CHRONIC AND ACUTE INFLAMMATORY RESPONSES IN ADULTS, AND HERE I'LL TALK ABOUT PROPERTIES AND MECHANISMS OF THE ACUTE PHASE RESPONSE, AND THE ACUTE PHASE RESPONSE AS A MEANS TO DEPRIVE MICROBES OF NUTRIENTS. SO THERE'S BEEN QUITE A BIT OF RESEARCH IN THIS AREA, SOME QUITE DETAILED AND THE LIKE, AND MOST OF THE TALK IS GOING TO FOCUS THERE. I WAS ALSO ASKED TO DISCUSS ANY CHANGES IN THESE RESPONSES IN PREGNANCY AND INFANCY, AND THERE WE WENT INTO A REAL -- OF DATA SO I'LL BE BRIEF, BUT THERE ARE SOME INTERESTING POINTS. AND THEN TO IDENTIFY KNOWLEDGE GAPS AND THEIR IMPORTANCE TO UNDERSTANDING IRON HOMEOSTASIS IN PREGNANCY AND INFANCY. SO HERE ARE SOME KEY REFERENCES THAT I USED IN PREPARING BY SOARES AND WEISS ABOUT HOST-MICROBE INTERACTIONS, AND ONE HERE THAT I'LL REFER TO ON CYTOKINE SIGNALING. AND THEN I ALSO WOULD JUST LIKE TO MENTION SOME RESOURCES. YOU HEARD MENTIONED EARLIER THE BOND PROJECT WHICH IS THE BIOMARKERS AND NUTRIENTS FOR DEVELOPMENT, AND THAT HAS BEEN IMPORTANT FOR LOOKING AT MICRO NUTRIENT STATUS IN THE LIKE, AND THEN A SPINOFF FROM THAT IS INSPIRE THE INFLAMMATION IN NUTRITIONAL SCIENCES IPT PRE TAITION OF RESEARCH EVIDENCE, SO AGAIN LOOKING AT INFLAMMATION AND ITS IMPACT ON MICRO NUTRIENT STATUS AND STATUS MEASUREMENTS. AND THEN FINALLY, NICHD IRON AND MALARIA PROJECT WEBSITE LISTED THERE. OKAY. SO CHRONIC AND ACUTE INFLAMMATORY RESPONSES IN ADULTS, REALLY TALKING ABOUT THE ACUTE PHASE RESPONSE. IT'S A SET OF BASIC MECHANISMS, AND NOT LIMITED TO ADULTS. IT'S AN INNATE RESPONSE TO TISSUE DAMAGE, THAT COULD BE WOUNDS, BURNS, ET CETERA, AND TO INFECTION. SO INNATE RESPONSE TO DAMAGE BUT TO DAMAGE OF DIFFERENT TYPES. SO IN A SENSE A HETEROGENEOUS RESPONSE. IT'S IMMEDIATE, BEGINS LOCALLY AT THE SITE OF DAMAGE, EVOLUTION NAIRLY CONSERVED, ALL MAMMALS AND MOST VERTEBRATES, AND IT'S PART OF AND RELATED TO THE INNATE IMMUNE SYSTEM. I DESCRIBE IT HERE AS HARD WIRED IN THE SENSE IT'S MAYBE MODIFIABLE BY ANTI-INFLAMMATORY AGENTS, ET CETERA, BUT REALLY NOT PREVENTABLE, AND IN FACT, I THINK WE NEED TO KEEP IN MIND THAT INFLAMMATION IS REALLY AN ADAPTIVE RESPONSE THAT IS NECESSARY FOR THE APPROPRIATE RESPONSE TO WOUNDING OR INFECTION. ACUTE, IMMEDIATE, BUT IT CAN ALSO BE CHRONIC AND PERSISTENT. AND SO THE TEM PARTICLIT TEMPORALITY CAN B E DESCRIBED AS ACUTE OR CHRONIC BUT THERE'S ALSO ISSUES OF SEVERITY, SO IT CAN BE MILD, IN OTHER WORDS IT RESOLVES OVER TIME OR PERSISTENT, AND ALSO SEVERE, EVEN LIFE-THREATENING OR FATAL. SO WE HAVE REALLY A RANGE OF CROW NICHRONICITY TO ACUTE TO PERHAPS -- AND ALSO A RAPING OF SEVERITY. WHEN THE LOCAL RESPONSE ESCALATES INTO THE CIRCULATION, AND THAT WOULD BE THROUGH THE CIRCULATING CELLS, MONOCYTES AND THE LIKE IN THE RELEASE OF CYTOKINES SUCH AS THE IL-6 CYTOKINES, IL1 CYTOKINES -- THE LIVER BECOMES ENGAGED AND THAT'S WHEN YOU GET THE ACUTE PHASE RESPONSE, SO IT'S REALLY A RESPONSE OF HEPATOCYTES TO INFLAMMATORY SIGNALS, AND IT INVOLVES MORE THAN PROTEINS AS METABOLISM, PER SE, IS RE-REGULATED. WE TALK MOSTLY ABOUT PROTEINS. SO ON THIS SLIDE IS REALLY JUST A SCHEMATIC OF WHAT I'VE JUST SAID, SO THE LIVER IS A CENTRAL ORGAN IN RESPONSE TO THIS INJURY OR INFECTION, AND THE LIVER REALLY BEING POSITIONED ANATOMICALLY TO RECEIVE A DUAL BLOOD SUPPLY, SO THAT THE PORTAL VEIN DRAINING THE INTESTINE PROVIDES SIGNALS DIRECTLY FROM THE INTESTINE AND THESE CAN BE INFLAMMATORY MOLECULES OR BACTERIA, BACTERIAL PRODUCTS LIKE POLYSACCHARIDE, AND THEN PERFUSION ALSO THROUGH THE INFERIOR VENA CAVA OR HEPATIC VEIN PROVIDING SIGNALS FROM THE PERIPHERY. THE BLOOD SUPPLIES AND DRAIN INTO THE SINUSOID OF THE LIVER, AND SINUSOIDS ARE SEPARATED FROM THE HEPATOONLY BY THE ENDOTHELIAL LAYER ENDOTHELIUM SO THE HEPATOCYTES ARE REALLY ABLE TO SENSE QUITE IMMEDIATELY AND DIRECTLY THESE SIGNALS THAT ARE PRESENT IN THE CIRCULATION TO THE LIVER. SO THIS SLIDE JUST ILLUSTRATES FURTHER THE LIVER'S INTERACTION WITH OTHER TISH E TISSUES, DR. ANDERSON'S PRESENTATION EMPHASIZED THIS AS WELL, AND I CIRCLED PROTEIN SYNTHESIS AS ONE OF THE STEPS THAT IS IMPORTANTLY REGULATED IN THIS RESPONSE, SO THIS IS THE ACUTE PHASE RESPONSE, ACUTE PHASE REACT ANTIS, AND ALSO ACUTE ALTERATIONS IN ENERGY AND METABOLITES INCLUDING CENTRAL FACTORS THAT COULD LEAD TO THINGS LIKE FEVER AND THE LIKE. SO THE CARDINAL SIGNS OF INFLAMMATION THAT WE LEARN IN PATHOLOGY COURSES ARE REALLY METABOLIC RESPONSES TO THE PAIB, THE HEAT, THE REDNESS, THE -- OF TISSUES AND THE LIKE AND LOSS OF FUNCTION. SO HERE'S A LIST OF HUMAN ACUTE PHASE PRO TEEBS O PROTEINS OR A PARTIAL LIST, SOME REVIEWS SAY THERE ARE 200, OTHERS OVER 180. THEY'VE BEEN GROUPED INTO VARIOUS SYSTEMS OR CATEGORIES, SO COMPLEMENT SYSTEM WOULD INCLUDE THINGS LIKE COMPLEMENT INHIBITOR, COMPLEMENT BINDING PROTEIN INVOLVED IN ANTIBACTERIAL FUNCTIONS, COMPLEMENT FUNCTIONINGS, COAGULATION FACTORS, ANTIPROTEASE, AND THEN WE GET TO A CATEGORY OF TRANSPORT PROTEINS, INFLAMMATORY RESPONDER, WHAT IS LISTED HERE AS "OTHERS" AND DECREASED PROTEINS. SO MOST OF THESE PROTEINS INCREASE IN ACUTE PHASE RESPONSE AND DECREASE. WHAT WE SEE IMMEDIATELY IS THAT IRON TRANSPORT AND IRON HOMEOSTATIC PROTEINS ARE IMPORTANT PLAYERS IN THIS ACUTE PHASE RESPONSE. THEY ARE, IN FACT, ACUTE PHASE REACTOR. INCREASED IN THE ACUTE PHASE RESPONSE, OTHERS, FERRITIN IS DECREASED, BUT TRANSFERRIN, TRANSFERRING IRON, IS ONE OF THE PROTEINS THAT IS DECREASED, AND OTHERS, OTHER MICRO NUTRIENT TRANSPORTERS, FOR EXAMPLE, MICRO -- IN THIS LIST OF DECREASED PROTEINS. SO THIS IS AN OLD SLIDE BUT IT'S KIND OF GRAPHICALLY SHOWS THE TIMES -- THAT TIME COURSE THEORY IN TERMS OF THE RESPONSE OF ACUTE PHASE PROTEIN, IT VARIES IN THE TIME TO THE PEAK RESPONSE, IT VARIES IN THE PEAK LEVEL REEF SPONS AN OF RESPONSE AND THEN DURATION OF RESPONSE. SO WE SEE HERE, FOR EXAMPLE, FOR C-REACTIVE PROTEIN COMMONLY USED AS A MAR MARKER OF INFLAMMATION BUT THE RESPONSE IS REALLY VERY DRAMATIC AND THIS IS A PROTEIN, IT'S THE REACTIVE PROTEIN TO THE POLYSACCHARIDE, SO WE SEE IT REALLY SHOOT UP AFTER -- TO HIGH LEVELS AND THEN COME DOWN RELATIVELY QUICKLY. HERE'S SERUM AMYLOID A, AGAIN, RAPID RESPONSE AND FOLLOW-UP, WHEREAS SOME OF THESE OTHER ACUTE PHASE REACTANTS INCREASE MORE GRADUALLY AND PERHAPS TO LOWER RELATIVE LEVELS AND THEN TAPER OFF, AND HERE WE HAVE TRANSFAIRN, WHICH IS DECREASED AS IS ALBUMIN. UP WITH THING I'D LIKE TO SAY ABOUT THIS, SO THE RESPONSE IS HEAD ROW GENIUS IN TERMS OF THE TIME COURSE, I THINK IT'S IMPORTANT TO REALIZE THAT ALTHOUGH THESE RESPONSES HAVE BEEN MAPPED OUT, REALLY BEEN MAPPED OUT UNDER A WIDE VARIETY OF INDUCING CONDITIONS. SO INFECTION, INJURY, BURNS, ET CETERA, DIFFERENT SE VAIRTS OF INSULTS. INDICATOR,S, EVEN AS WAYS OF CONNECTING DATA, WE NEED TO BE COGNITIVE OF THE FACT THAT THEY'RE CHANGING OVER TIME AND CHANGING THEM OUT, WE NEED TO BE VERY, VERY CAREFUL HOW WE USE THEM AS INDICATORS. I'M SURE THAT TOPIC WILL COME UP MORE TOMORROW. HERE'S A DIAGRAM REVIEWED IN WHICH IT TALKS ABOUT THE CYTOKINE MEDIATORS OF THE ACUTE PHASE RESPONSE. SO HERE WE SEE A VARIETY OF INSULTS, INFECTION, INJURY, INFLAMMATION ITSELF, TUMORS, LEADING INTO RESPONSES OF MACROPHAGES AND MONOCYTES AND OTHER INFLAMMATORY CELLS, PRODUCING INFLAMMATORY MEDIATOR, PROTEINS, BUT ALSO SHOWING HERE THE LIVER, HERE'S THE ENDOTHELIUM, AND HERE ARE COOPER CELL, MACROPHAGES OF THE LIVER ARE REALLY INTIMATELY CLOSE TO THE HEPATOSITES AND THEY'RE ALSO PRODUCERS OF CYTOKINES, SO THAT 80% OF THE BODY'S MACROPHAGES ARE LOCATED IN THE LIVER AND IN PROXIMITY TO THESE HEPATOCYTES, SO THIS LEADS TO THEN A -- PRODUCTION OF THE ACUTE PHASE PROTEIN. SO ALSO IN THIS REVIEW, THEY PROVIDED TWO EXAMPLES OF DATA, AND THE FIRST ONE IS SHOWN HERE, GAMMA FIBRINOGEN, AND THE POINT THAT THEY WANTED TO MAKE HERE IS THAT SOME OF THE ACUTE PHASE REAK TIB ARE MORE RESPONSIVE TO INTERLEUKIN SIX AND IN OTHERS, THE INTERLEUKIN 6 EFFECT IS MODERATED BY INTERLEUKIN 1 BUT IN DIFFERENT WAYS. SO HERE FOR FIBRINOGEN, WE SEE THAT IL6 INDUCED IN THESE IN VITRO EXPERIMENTS THE HIGHEST LEVEL OF EXPRESS OF THE GAMMA FIBRINOGEN MRNA, WHEREAS THE ADDITION OF IL1 TO THE IL6 ACTUALLY ATTENUATED THAT RESPONSE. ON THE OTHER HAND, THE IL6 RESPONSE IS ACTUALLY SYNERGIZED WITH OR INCREASED AS THE CYTOKINES CHANGE, SO MAY THE RESPONSE IN ACUTE PHASE RESPONSE TO THE VARIOUS PROTEINS. SO AGAIN, I THINK THIS IS AN AREA FOR THE FUTURE. ADDITIONAL RESEARCH. JUST IN TERMS OF POSSIBLE MECHANISMS IN TERMS OF THE INTERACTION OR CROSSTALK BETWEEN IL1 DATA AND IL6, THEY'VE PROPOSED A NUMBER OF DIFFERENT MECHANISMS AND IT JUST MENTIONED VERY BRIEFLY HERE THAT IL1 COULD INHIBIT EARLY SIGNALING THROUGH THE IL6 PATHWAY, THERE COULD BE SEQUESTRATION OF TRANSCRIPTION FACTOR, STABILIZATION OF ANTAGONIST SUCH AS SOCS3, ASSOCIATION WITH ATYPICAL RESPONSE ELEMENTS IN THE DNA, KIND OF REDIRECTION, OR COMPETITION AND REPRESSION OF THE ELEMENTS THAT ARE USUALLY USED. SO GETTING ON TO IRON THEN, THE SYSTEMIC REDUCTION IN CIRCULATING IRON OR HYPOFERREMIA IS DRIVEN BY SOME IS MECHANISMS AND CAN BE COMPENSATED IN PART OR REDISTRIBUTE -- THERE'S A REDISTRIBUTION OF IRON TO PARTICULAR ENDOTHELIAL SYSTEM WHICH MAY LEAD TO HYPERFERRITINEMIA. SO LIMITING IRON TO CIRCULATING OR EXTRACELLULAR MICROBES, THIS MAY -- A CONSEQUENCE OF THIS MAY BE TO LIMIT THE IRON TO CIRCULATING OR EXTRACELLULAR MICROBES, BUT IF IT'S SUSTAINED, THEN THE REDUCED IRON AVAILABILITY MAY COMPROMISE ERYTHROPOIESIS SO WE WOULD HAVE ANEMIA OF INFLAMMATION. THIS HAS ALREADY BEEN SAID EARLIER, THIS IS THE FOUND IN CERTAIN CANCER, AUTOIMMUNE DISEASES AND THE LIKE, AND IT'S ACTUALLY SAID TO BE THE SECOND MOST FREQUENT ANEMIA WORLDWIDE. SO I WANT TO TALK A LITTLE ABOUT THE ACUTE PHASE RESPONSE AS A MEANS TO DEPRIVE MICROBES OF NUTRIENTS, SO SOARES AND WEISS SAY IN THE EVENT OF AN INFECTION, WHEN THE MICROBES BECOME SYSTEMIC, THEN IMMUNE-DRIVEN RESISTANCE MECHANISMS EXERT A NEGATIVE IMPACT. IN MOST CASES THE EXPRESSION OF MOLECULES THAT TARGET THE PATHOGENS. THEY GO ON TO SAY HOWEVER, THERE ARE RESISTANCE MECHANISMS THAT PREVENT PATHOGENS FROM ACCESSING METABOLITES AND/OR NUTRIENTS THAT ARE ESSENTIAL FOR THEIR SURVIVAL AND/OR PROLIFERATION, AND DEFENSE STRATEGY THIS REFER TO AS NUTRITIONAL IMMUNITY. SO IN THE CASE OF THESE MECHANISMS, THEY ENCOMPASS MECHANISMS THAT RESTRICT MICROBES FROM ACCESSING IRON, BECAUSE IRON IS NEEDED FOR THE GROWTH OF THE MICROBES, BUT AS WELL, OTHER TRACE MINERALS. ZINC, MANNIN, MANGANESE, COPPER. SEVERAL INFECTION RESISTANCE GENES ACT VIA CONTROL OF THE HOST'S IRON METABOLISM. THE ADAPTIVE RESPONSES SUPPLYING IRON TO MICROBES INCREASE, IN MOST CASES, THEIR PATHOGENICITY, WHILE THOSE WITHHOLDING IRON FROM MICROBES LIMIT THEIR VIRULENCE. SO EXAMPLES THEN COME FROM CLINICAL OBSERVATIONS THAT HOST IRON OVERLOAD IS ASSOCIATED WITH POORER OUTCOMES IN AIDS, MALARIA, AND TUBERCULOSIS, WHEREAS AS WE KNOW, DIETARY IRON SUPPLEMENTATION, THEY EXACERBATE OVERALL MORTALITY RATES IN AREAS OF ENDEMIC INFECTIOUS DISEASE. UNBOUND IRON OR HEME IN THE BODY IS A DANGER SIGNAL. IT'S A SOURCE OF IRON TO PATHOGENS, IT CAN GENERATE TOXIC FREE RADICALS, AND HAS POTENTIAL FOR TISSUE DAMAGE. THEREFORE, IRON IS CAREFULLY CHAPERONED, IRON ITSELF BY TRANSFERRIN, LACTOFERRIN, FERRITIN, CHAPERONES ARE AP PROTEINS MODULATED BY INFECTION. COMING TO HEPCIDIN, IT'S AN ANTIMICROBIAL-LIKE PEPTIDE HORMONE, MASTER REGULATOR OF IRON METABOLISM AND PART OF THE INNATE IMMUNE RESPONSE TO INFECTION. IT MEDIATES THE HYPOFERREMIA OF INFECTION AND IS SYNTHESIZED MAINLY BY HEPATOCYTES. IT ACTS IN CONJUNCTION WITH FERROPORTIN TO LIMIT IRONY FLUX FROIRON EFFLUXFROM CELLS, ACT PERIPHERALLY ON DUE DEENL ENTAROT SITES, SPLE NICK AND LIVER MACROPHAGES, PLA 16 -- THE IMMUNE RESPONSES TO EXTRACELLULAR PATHOGENS ACCOMPANIED THE PRODUCTION OF PRO INFLAMMATORY CYTOKINES WHICH INDUCE THE TRANSCRIPTION OF THE HAMP GENE, INDUCING EXPRESSION. OTHER FACTORS, HOWEVER, REPRESS, SO HA HAM HAM HAM P EXPRESSION, ANEMIA, TISSUE HYPOXIA, VARIOUS HORMONES WHICH WE'VE BRIEFLY DISCUSSED AS SHOAP HERESHOWN HERE AND THEN ALSO BY THE LEVEL OF IRON FROM HI TO LOW. THESE ARE JUST SOME CARTOONS TO ILLUSTRATE SOME OF THE MECHANISMS THAT ARE USED BY THE HOST TO LIMIT THE PRESENCE OF IRON IN VARIOUS COMPARTMENTS. SO IN THE CASE OF EXTRACELLULAR PATHOGENS, THE STRATEGIES WOULD BE TO REDUCE IRON IN THE EXTRACELLULAR ENVIRONMENT, AND THAT COULD BE THROUGH THE INFLUENCE OF HEPCIDIN ON -- RECEPTOR AND DIFFERENT CHANGES IN THE END SOMOL -- FOR NON-HEME IRON, WE HAVE CHANGES IN THE UPTAKE OF TRANSFERRIN, ALL ATTEMPTING IN A SENSE SO MAINTAIN THE IERP INTRACELLULARLY AND PREVENT ITS ACCUMULATION IN THE EXTRACELLULAR SPACE. WHEN WE COME TO PATHOGENS THAT RESIDE INTRACELLULARLY, THEN THERE ARE ALSO MECHANISMS TO LIMIT THE ACCUMULATION OF IRON IN THOSE CELLS, CHANGES IN FERROPORTIN AND THE LIKE -- INTERFERON GAMMA RECEPTOR AND -- DOWNSTREAM OF THE INFLAMMATORY CYTOKINES. IF, HOWEVER, YOU HAVE A SITUATION WITH HIGH IRON AND HIGH HEPCIDIN, THAT WOULD FAVOR LIMIT BEING THE EXPORT AND THAT MIGHT ACTUALLY BE A BAD THING FOR THE INTRACELLULAR PATHOGEN. SO I THINK IT REALLY PRESENTS HOW COMPLEX THE INFLAMMATORY RESPONSE IS AND HOW THE RESPONSE TO DIFFERENT KINDS OF INFECTIOUS AGENTS IS GOING TO BE FAVORED BY OR PERHAPS NOT FAVORED BY THE IRON SUPPLEMENTATION OR THE PRESENCE OF IRON IN THESE DIFFERENT COMPARTMENTS. SO JUST TO SUMMARIZE THE PATHOGENS CLASS-SPECIFIC MECHANISMS THAT SEEM TO BE ADAPTIVE RESPONSES TO LIMIT THE GROWTH OF THE PATHOGENIC AGENTS. FREE HEME IS ALSO A DANGER SIGNAL, AND SO AS WE SEE HERE THAT WHEN DAMAGED RED BLOOD CELLS RELEASE THEIR HEME, THAT THAT HEME ITSELF CAN SERVE AS A PRO INFLAMMATORY SIGNAL AND REACTIVE OXYGEN PRODUCTION, DAMAGED HEME CAN ALSO SERVE AS A LIGAND FOR TOTAL -- RECEPTORS AND RESPONSES SUCH AS REDUCED NITROUS OXIDE PRODUCTION. I'M GOING TO GO QUICKLY HERE. SO CHANGES IN THE RESPONSE IN PREGNANCY AND INFANCY. PREGNANCY WAS CLASSIFIED IN THE CATEGORY OF NORMAL OR INSIGNIFICANT CHANGES FOR C-REACTIVE PROTEINS. SO AS COMPARED TO MALIGNANCIES, TRAUMA, ET CETERA, PREGNANCY ITSELF DIDN'T SEEM TO BE IMPACTFUL ON THE C-REACTIVE PROTEIN RESPONSE. HERE IS DATA ON HEPCIDIN, WE'VE ALREADY TALKED ABOUT THE DIFFERENCES BETWEEN PREGNANT AND NON-PREGNANT, AND I WOULD JUST ADHERE THAT PREGNANT WITH INFLAMMATION, THOUGH, HAS A HIGHER LEVEL OF SERUM HELP SO I DIN THAN PREGNANCY WITHOUT INFLAMMATION. WHAT WE DON'T REALLY KNOW IS WHAT THE MAGNITUDE IS AND WHAT THE BIOLOGICAL SIGNIFICANCE OF THE MAGNITUDE IS. I THINK IT WAS ALSO MENTIONED PERHAPS EARLIER THAT THERE IS A SMALL DIFFERENCE IN SERUM HEPCIDIN LEVELS THAT OCCURS AROUND -- WHERE POSE NATAL DAY 1, THE LEVELS ARE SLIGHTLY HIGHER AS COMPARED TO LATER IN THE INFANT. THE PLACENTAL SYNCYTIOTROPHOBLAST UP TAKE, WHEN IRON EXPORT IS LIMITED THAT, COULD HAVE AN IMPACT ON THE IRON AVAILABLE TO THIS CIRCULATION. AND ALSO TO ADD THAT THE PLACENTA ALSO EXPRESSES HEMOXEGENASE, SO THERE'S SOME RELATIONSHIP BETWEEN ECLAMPSIA AND EXPRESS OF HO HAD BEEN 1. HO-1. THEY SEEM TO BE PROTECTIVE. FINALLY HERE'S A SLIDE FOR INFANTS LOOKING AT THE ACUTE PHASE RESPONSE IN NORMAL NEWBORNS SOON AFTER BIRTH, AND THIS IS A STUDY OF PRESUME PLI IRON -- AS WE SEE THAT RIGHT AFTER BIRTH, THERE IS A SPIKE IN IL-6, THEN RIGHT AFTER THAT, SOME OF THE OTHER ACUTE PHASE -- BUT THEN THEY GO BACK DOWN SO THIS MAY BE RELATED TO DELIVERY AND, OF COURSE, CHANGES IN OXYGEN UTILIZATION AT BIRTH. SO IN TERMS OF RESEARCH GAPS/QUESTIONS, I THINK WE NEED TO BETTER UNDERSTAND THE BASICS OF ACUTE PHASE RESPONSE IN THE GROUPS OF INTEREST. WHEN I SHOWED YOU DATA EARLIER, THERE WERE ACTUALLY DATA FROM HELP G2 CELLS, WHICH IS A HEPATOCARCINOMA CELL LINE, IT'S CERTAINLY NOT NORMAL HEPATOCYTES, NOT CERTAINLY FOR PREGNANT WOMEN OR INFANTS SO I THINK WE NEED SOME BASIC CONFIRMATION THAT WHAT HAS BEEN SHOWN IN MODEL SYSTEMS ALSO APPLIES IN THE GROUPS OF INTEREST. TO UNDERSTAND THE QUANTITATIVE RELATIONSHIPS BETWEEN TWEEN HEPCIDIN AND IRON UP TAKE AND STORAGE, AND TO UNDERSTAND LOCAL CONTROL OF HEPCIDIN EXPRESSION. SO OTHER THAN LIVER, WHAT IS IF DOING THERE AND IS IT IMPORTANT FOR IES IRON HOMEOSTASIS LOCALLY. SO UNDERSTANDING IRON, ANGIOGENESIS AND PLACENTAL PERFUSION IS ALSO AN IMPORTANT QUESTION THAT RELATES TO INFLAMMATION, AND THEN FINALLY TO UNDER STANT HOW INTAKE FORMS, AND AMOUNTS, AFFECT SER UM MARKERS, AND PREGNANCY AT DIFFERENT STAGES, BECAUSE WE KNOW FOR EXAMPLE AT IMPLANTATION, THERE HAS TO BE SOME LOCAL INFLAMMATORY RESPONSE FOR THE IMPLANTATION RESPONSE, SO WHAT HAPPENS WITH IRON SUPPLEMENTATION EVEN AT THE TIME OF IMPLANTATION. AND THEN CORRELATION OF THESE MARKERS OF INFLAMMATION AND ALSO VARIOUS GENETIC FACTORS. THANK YOU. [APPLAUSE] >> MAYBE I CAN JUST REPEAT YOUR QUESTION. SO DR. AN DER SOP IS ASKING IF THERE'S A BEST MARKER OF INFLAMMATION. I'M RELUCK AT THAT PARTICULAR TIME TO SAY THAT THERE IS. THERE'S CERTAINLY COMMONLY USED MARKERS, SO C-REACTIVE PROTEIN PROBABLY BEING THE MOST COMMONLY USED, BUT WE SEE THAT THE MAGNITUDE OF RESPONSE IS GREAT, TEMPORALITY IS GENERALLY RATHER SHORT, SO WHEN WE'RE TALKING ABOUT MORE CHRONIC INFLAMMATION OVER TIME IS THAT STILL A GOOD MARKER, ARE WE LOOKING AT THE TAIL END OF WHAT WOULD BE A HIGHER RESPONSE OR ARE WE LOCKING AT A MORE PERSISTENT LOW LEVEL RESPONSE THAT PERHAPS WASN'T WELL ILLUSTRATED IN THAT DIAGRAM. MAYBE WE NEED A COMBINATION, A KIND OF COMBINATORIAL MARKER THAN WOULD BE BETTER IN A SINGLE ONE. I THINK IT'S A REALLY IMPORTANT QUESTION, ESPECIALLY WHEN THERE'S A TEMPTATION, I THINK, TO USE THESE FOR IP PRE TAITION, AND SOMETIMES EVEN FOR CORRECTION OF NUTRITIONAL VALUE. >> VERY NICE TALK. I JUST WANTED TO COMMENT ON SOME EVOLUTION OF OUR INTERPRETATION OF THE HYPO -- RESPONSE. ONE THING THAT WAS PUZZLING ABOUT THE HYPOFAIRY MIC RESPONSE IS IT DIDN'T SEEM LIKE REDUCING THE CONCENTRATION OF IRON TRANSFAIRN BY 50% SHOULD MAKE SUCH A BIG DIFFERENCE IN THE LIVES OF BACTERIA WHO HAVE -- UP TAKE TRANSPORTERS. SO WE ARE NOW THINKING THAT WHAT IT IS REALLY ABOUT IS TO PREVENT THE GENERATION OF NON-TRANSFER OF -- WHICH SOME BACTERIA CAN VERY RAPIDLY AND AVIDLY TAKE UP AND USE AS A SIGNAL FOR INCREASING THEIR PATHOGENICITY. SO YOU CAN IMAGINE THAT DURING INFEK SHUP, THERE'S A LOT OF TISSUE DESTRUCTION, A LOT OF RECYCLING -- BY MACROPHAGES, AND THAT THERE WILL BE A STRESS WHERE A LOT OF IRON IS POTENTIALLY DELIVERED INTO THE EXTRA CELL FLUID SYSTEM, SO HEPCIDIN RISES PERHAPS IN PART TO PREVENT THE RELEASE OF A NON-TRANSFERRING -- IRON AND THAT MIGHT BE A BETTER EXPLANATION THAN WHAT WE USED TO GIVE, WHICH IS THAT THE -- RESPONSE IS SMALL IS WHAT IT'S ALL ABOUT. >> GREAT, THANK YOU. OKAY. SO WE'RE A COUPLE MINUTES LATE AND I APOLOGIZE FOR THAT, BUT WE'RE ABOUT TO TAKE A BREAK, AND RATHER THAN SAY 15 MINUTES, CAN WE SAY 10, BE BACK HERE IN 10 MINUTES, AND WE'LL RESUME WITH OUR SHORT PRESENTATIONS. >> FOR THE NEXT PART OF OUR MORNING'S PRESENTATION, WE'RE GOING TO HAVE FOUR BRIEF PERSPECTIVE TALKS, AND THEY'RE GOING TO BE PRETTED IN ORDER BY MICHAEL GEORGIEFF, VICTOR GORDEUK, WHICH IS GOING TO BE A PRERECORDED VIDEO PRESENTATION, UNFORTUNATELY HE WAS NOT ABLE TO BE HERE, AND FOLLOWED BY KAY DEWEY AND MARIANNE WESSLING RESNICK. THE MORNING SPEAKERS WILL COME TO THE TABLE AND WE'LL HAVE OUR OPEN DISCUSSION SESSION. >> WE SHOULD PROBABLY COMMENT AS WE ORGANIZE, THIS IS KIND OF MORPHED IN A BUNCH OF DIFFERENT WAYS. I THINK EACH OF THE FOUR OF US IS GOING TO TALK ABOUT SLIGHTLY DIFFERENT TOPICS THAT ARE RELATED TO THE MAIN ONES THAT YOU JUST HEARD OF AND WE HAVE A FEW SLIDES TO GO THROUGH BUT THE MORE GENERAL QUESTION SESSION WILL HAPPEN AT THE PABL. PANEL JOB. SO MY JOB IS TO EXPAND ON THE PHYSIOLOGY THAT YOU HEARD BOTH WHAT DR. -- AND DR. LONNERDAL TALKED ABOUT, A LITTLE OF WHAT KIM O'BRIEN WOULD SAY IF SHE WAS GIVEN THAT TASK BUT SHE'S GOT A DIFFERENT TASK IN SESSION 3, AND I WANT TO SAY THESE COMMENTS THAT I'M GOING TO GIVE YOU APPLY TO THE FETUS AND THE NEWBORN, SUPPLEMENTATION DURING PREGNANCY AND OF YOUNG INFANTS. WHILE THIS CONFERENCE IS ABOUT SUPPLEMENTATION, UNDERSTANDING THE PHYSIOLOGY AND UNDERSTANDING WHAT IT IS WE ARE MEASURING AND WHAT WE CAN AND CAN'T SAY ABOUT THE MARKERS THAT WE MEASURE HINGES ON KNOWLEDGE OF THE PHYSIOLOGY. SO WHAT MANY OF US ARE GOING TO TALK ABOUT IN THE NEXT FOUR TALKS DOVETAILS INTO WHAT PANEL 2 WILL BE DISCUSSING. SO I'M HERE TO ACTUALLY TALK ABOUT PRIORITIZATION OF AARON, OF IRON, AND BETWEEN THE TWO COMPARTMENTS, THAT IS BETWEEN THE FETUS AND THE MOTHER, AND THEN INTRAORGAN PRIORITIZATION IN THE FETUS AND THE NEWBORN. SO WE'VE GONE OVER THIS QUITE A BIT BUT WE KNOW THAT FETUSES OF IRON-DEFICIENT MOTHERS ARE VERY OFTEN IRON-SUFFICIENT, IN FACT, IT PUT THE FIELD OF NEWBORN IRON DEFICIENCY, WHAT IS WHAT I STUDY, ON HOLD FOR MANY, MANY YEARS. IT WAS JUST ASSUMED THAT A FETUS WOULD TAKE WHAT IT NEEDS. THERE HAVE BEEN ATTEMPTS TO FIND CUTOFFS OF WHERE IN THE MATERNAL FETAL DIAD DO YOU FINALLY GET TO A POINT WHERE THE ENTIRE DIAD IS COMPROMISED AND THE FETUS ACTUALLY SUFFERS. SOME HAVE ESTIMATED THAT TO BE A FAIRLY LOW MATERNAL HEMO GLOBIN -- JUSTIN IFISHE FINISHED A HUGE STUDY -- FOUND AN INFLECTION POINT AT A MATERNAL FERRATIN AROUND 14, WHERE THE FETUS ACTUALLY STARTS TO SHOW SOME COMPROMISE IN TERMS OF ITS STORES. SO WE KNOW THAT PROGRESSIVE -- FROM KIM'S WORK, WE KNOW THAT PROGRESSIVE DECREES OF MATERNAL IRON KE DEFICIENCY RESULT IN GREATER IRON TRANSPORT PERCENTAGE WISE TO THE FETUS THROUGH UPREGULATION OF PRA PLACENTAL GFR. THE FLIP SIDE, A FETUS THAT MAINTAINS IRON STATUS OR ATTEMPTS TO MAINTAIN IRON STATUS, WE HAVE THE REVERSE SITUATION WHERE WE HAVE MOTHERS THAT ARE COMPLETELY IRON-SUFFICIENT WHERE FETUS HAVE CONDITIONS WHERE THERE IS INCREASED FETAL DEMAND AND THE QUESTION IS HOW MUCH CAN THE PLACENTA COMPENSATE. MORE IMPORTANTLY WHEN YOU TALK ABOUT SCREENING, THERE IS QUITE A BIT OF EVIDENCE NOW THAT HAS ACCUMULATED OVER A 25-YEAR PERIOD ON THE PRIORITIZATION OF IRON TO RED CELLS OVER IN THIS CASE THE BRAIN BUT PROBABLY OTHER TISH EU BUT WHEN WE TALK ABOUT RELEVANT HEALTH OUTCOMES OF IRON STATUS, WE TEND TO THINK ABOUT THE BRAIN DEVELOPMENT AND IMMUNE STATUS AND OTHER ORGAN FUNCTION. WE FIRST DI COVERED THIS, THAT POLY -- NEWBORN INFAPTS OF DIABETIC MOTHERS, BORN OF TOTALLY U.S SUFFICIENT MOTHERS, HAVE A 40% REDUCTION OF THE -- SUGGESTING THAT THEY DID NOT HAVE ENOUGH IRON TRANSPORT AND THAT THE DRIVING OF A CHRONIC HYPOXIA THAT YOU SEE IN DIABETIC PREGNANCIES IN THE FETUS INCREASES THE RED CELL MASS AT THE EXPENSE OF THE BRAIN AND THE HEPATOCYTE, AND THE LIVER IRON. ONE THING -- IN THE NEXT PANEL THAT WE FEEL IS IMPORTANT HERE IS THAT 40% LOSS ANCHORS US QUITE FIRMLY IN THE ANIMAL MODELS. MOST OF THE DIETARY ANIMAL MODELS THAT SHOW US ALL THE EFFECTS FROM THE GENOMICS OR THE STRUCTURAL AND BEHAVIORAL LEVELS ARE ABOUT 40% IRON DEFICIENT MODELS. WE KNOW THAT IF YOU MODEL THAT IN SHEEP, THROUGH EITHER HYPERTHREEM YA OR GIVING ERYTHRO.TIN TO THE SHEEP, YOU WILL SEE PREFERENTIAL SEQUESTRATION IN THE RED CELLS, IF YOU GO THE OTHER WAY, YOU FLE BOTH MIEZ SHEEP, PUT THEM ON A LOW IRON DIET, YOU WILL SEE AN ATTEMPT TO CONTINUE ERYTHROPOIESIS EVEN IN THE FACE OF LOSING BRAIN IRON. AND POTENTIAL NEUROLOGICAL CONSEQUENCES OF NON-ANEMIC IRON DEFICIENCY, SEVERAL STUDIES, JUST HAVE ONE OF THEM UP HERE, SHOW THAT NON-ANEMIC IRON DEFICIENCY OR PREANEMIC IRON DEFICIENCY IN TODDLERS REDUCES MOTOR AND AFFECTIVE DOMAIN FUNCTION, WE SPENT A LOT OF NIH MONEY, IRON UP TAKE BY HIPPOCAMPAL NEURONS IN MICE AND SHOWED NON-ANEMIC MICE SHOWING SIGNIFICANTLY COMPROMISED LEARNING AND MEMORY, AND MORE RECENT STUDIES, WE'VE LOOKED AT BRAIN METABOLISM IN MONKEYS THAT ARE BECOMING IRON DEFICIENT OVER TIME AND WE ALREADY SEE CHANGES IN METABOLISM IN THE BRAIN PRIOR TO THE ONSET OF ANEMIA OR EVEN MICRO CYTOCYST. HERE'S SOME OF THE DATA FROM THOSE STUDIES. THIS IS IN HUMANS ONE OF THE FEW AUTOPSY STUDIES THAT ARE OUT THERE. OBVIOUSLY BABIES DON'T DIE OF IRON DEFIRN SEE SO WE REALLY DON'T HAVE A GOOD SENSE OF WHERE IRON CONCENTRATIONS ARE, BUT THESE ARE INFANTS OF DIABETIC MOTHERS WHO DIED ON DAY ONE, POLY -- YET COMPARED TO CONTROL INFANTS WHO DIED ON DAY 1-RBGS THEY HAD A MASSIVE REDUCTION IN -- A FAIRLY LARGE REDUCTION IN HEART IRON AND BRAIN IRON. SO YOU SEE THIS HIERARCHICAL DISTRIBUTION OR EFFECT OF IRON DEFICIENCY MUST LIKE DESCRIBED IN POSTNATAL IRON DEFICIENCY. SO NOT A NEW FINDING, AND THIS WAS PUBLISHED BACK IN '92. ABOUT THE SAME TIME WE WERE DOG THE SAME MODELING IN SHEEP, AND YOU CAN SEE SKELETAL MUSCLE WAS COMPROMISED MORE THAN HEART, HEART MORE THAN BRAIN. BUT THIS WAS IN A POLYCNFEMIC -- MODEL. IF YOU TRY AND LOOK THE WHAT THE DRIVER IS AND YOU PUT THE BRAIN CELLS AND -- IN COMPETITION WITH EACH OTHER, THESE ARE FLE BOTH MIEZED LAMBS FED A LOW IRON DIET. IF YOU LOOK AT THE PERCENTAGE OF IRON THAT IS INCORPORATED INTO RED CELLS AND PERCENT THAT'S INCORPORATED INTO BRAIN AS A FUNCTION OF THAT, YOU SEE THAT BRAIN IRON CONCENTRATION AS A FUPTION OF IRON INCORPORATED INTO RED CELLS, AND I SEE THAT THE RED CELLS WIN AND, IN FACT, THESE ANIMALS WHO ANEMIC DOWN TO HEMO GLOBINS OF ABOUT 6 STILL HAVE A STRONG RE TICK LOW SITE RESPONSE AT THE EXPENSE OF THEIR BRAINS. SO OUR CONCEPTUAL MODEL IS THAT ANEMIA, WHICH IS WHAT WE CURRENTLY SCREEN FOR IN YOUNG CHILDREN, IS THE LATE FINDING. AND BEFORE THAT HAPPENS, THERE IS AN ENORMOUS AMOUNT OF OTHER EVENTS, INCLUDING ABNORMAL IRON PANEL INDICES, THIS WOULD BE LOW FERRATIN, CHANGE OF -- ALL OF THEM KIND OF COMMON ONES. BUT BEFORE THAT EVEN HAPPENS, THERE ARE CHANGES IN METABOLISM TO VARIOUS ORGAN SYSTEMS, PARTICULARLY THOSE THAT HAVE HIGH OXYGEN CONSUMPTION, CHANGES IN -- MOSTLY IN THE KREBS CYCLE AND IN MITOCHONDRIAL FUNCTION. THERE ARE READOUTS OF THOSE THAT YOU CAN SEE IN PROTEOME AND METABOLOMICS ARRAYS, AND YOU CAN SEE THEM IN THE CSF AS WELL. SO QUICK SUMMARY, IRON APPEARS IN THE FETUS AND THE NEONATE TO BE PRIORITIZED TO THE FETUS OVER THE MOTHERS AND TO THE RED CELLS OVER THE BRAIN AND THAT NON-ANEMIC IRON DEFICIENCY HAS NEURODEVELOPMENTAL CONSEQUENCES BOTH IN MODELS AND IN HUMANS. THE RESEARCH OPPORTUNITY IS IT'S UNCLEAR WHETHER AND HOW LONG THIS PRIORITIZATION OF IRON TO RED CELLS CONTINUES POSTNATALLY, SO THAT'S WHY I PREFACE MY COMMENTS SAYING THE STUDIES HAVE BEEN DONE PRETTY DISTINCTLY IN MULTIPLE SPECIES IN THE FETUS AND NEWBORN BUT WE DON'T KNOW POST NATELY HOW LONG THAT TPS AND WHETHER EVENTUALLY RED CELLS CAN CONTRIBUTE IRON BACK TO THE SYSTEM. AND THAT'S BECAUSE THE MECHANISMS OF BOTH INTERCOMPARTMENT, MOTHER FETUS, AND INTERORGAN BRAIN VERSUS RED CELLS VERSUS HEART ARE NOT FULLY UNDERSTOOD IF, AND THERE MAY BE IMPORTANT -- WHERE ALTERING MAY BE ADVANTAGEOUS, FOR EXAMPLE, TO -- IN MALARIA, WHERE WE WANT TO KEEP THE BRAIN GROWING BUT NOT WANT TO FEED THE RED CELLS. SO THAT WOULD BE THE TAKE-HOME POINT. [APPLAUSE] >> SO NOW WE'RE GOING TO HAVE THE PRERECORDED PRESENTATION FROM DR. GORDEUK. >> GOOD MORNING, EVERYONE. IT'S NICE TO TALK TO YOU BY WAY OF A VIDEO CAM. AND MY TOPIC IS ETHNIC AND GENETIC FACTORS AFFECTING IRON STATUS. I'M SPECIFICALLY LOOKING AT THIS IN WOMEN OF CHILD BEARING AGE AND IN PREGNANT WOMEN. SO THE PURPOSE OF MY ANALYSIS, I HAVE USED THE -- OVERLOAD SCREENING STUDY OR THE HEIR STUDY. WE STUDIED OVER 100,000 PRIMARY CARE PATIENTS GREATER THAN OR EQUAL TO THE AGE OF 25 YEARS, AND SPECIFICALLY LOOKED AT GENETIC AND ETHNIC FACTORS THAT AFFECTED IRON STATUS IN THE GENERAL POPULATION. SO THIS STUDY I ASKED THE QUESTION WHAT DOES HEIRS REVEAL REGARDING IRON STATUS OF WOMEN OF CHILD BEARING AGE. FOR THIS PURPOSE I LOOKED AT WOMEN BETWEEN THE AGES OF 25 AND 44 YEARS AS ONE PART OF THE ANALYSIS, AND WOMEN PREGNANT AT THE TIME OF SCREENING AS THE SECOND PART OF THE ANALYSIS. I FOCUSED ON SPECIFIC ETHNICITIES THAT WERE THE MOST COMMONLY STUDIED, ASIANS, BLACKS, HISPANICS AND WHITES, LOOKED AT THE EFFECT OF HFE C282Y AND H63D GENOTYPES, DEFINED LOW IRON STORES AS A SEER OWSERUM FERRITIN LESS THAN OR EQUAL TO 15 -- AND ELEVATED IRON STORES, ONE A SERUM FERRITIN GREATER THAN 300 MICRO GRAMS PER LITER AND THE SECOND IS A SERUM FERRITIN GREATER THAN 200 IN COMBINATION WITH A TRANSFAIRNT SATURATION OF GREATER THAN 45%. FIRST LOOKING AT LOW IRON STORES, FOUND AN OVERALL PRE PREVALENCE OF 13% IN ALMOST 24,000 WOMEN ANALYZED IN THIS STUDY, AND AMONG A LITTLE OVER 2,000 PREGNANT WOMEN, THE OVERALL PREVALENCE OF IRON DEFICIENCY WAS 19%. YOU CAN SEE THAT THIS VARIES A LITTLE ACCORDING TO ETHNICITY THAT'S SHOWN TO THE LEFT OF THE SLIDE. LOOKING AT LOW IRON STORES ACCORDING TO THE HFE C282Y GENO TIME, WE FOUND -- IN WOMEN OF CHILD BEARING AGE WITH YOU THIS DID NOT OLD UP IN THE PREGNANT WOMEN PROBABLY BECAUSE OF THE SMALL NUMBER OF HOMO ZYGOTES. LOOKING AT LOW IRON STORES BY THE HFE H63D GENOTYPE, WE FOUND NO EVIDENCE OF PROTECTION FROM IRON DEFICIENCY IN THIS ANALYSIS ANALYSIS. NOW TURNING TO INCREASED IRON STORES, DEFINITION OF SERUM FERRITIN GREATER THAN 300 AND LOOKED AT IT BY ETHNICITY, WE FOUND AN OVERALL PREVALENCE OF 1.7% OF ELEVATED IRON STORES BY THIS DEFINITION, WITH THE GREATEST PREVALENCE AMONG THE AFRICAN-AMERICANS, AND THE PREVALENCE AMONG THE PREGNANT WOMEN WAS 0.9%, WITH THE GREATEST PREVALENCE AMONG AFRICAN-AMERICANS. TURNING TO THE DEFINITION OF THE COMBINATION OF -- .7%, WOMEN 25 TO 44 YEARS AND .5% IN PREGNANT WOMEN. IN THIS CASE, THE GREATEST PREVALENCE WAS 1.2% AMONG ASIAN WOMEN, AND THE WOMEN OF CHILD BEARING AGE IN GENERAL. AMONG PREGNANT WOMEN, THE GREATEST PREVALENCE WAS IN HISPANICS. THAT LOOKED AT THE INCREASED IRON STORES ACCORDING TO HFE C282Y AND FOUND EVIDENCE THAT HOMOZYGOCITY WAS A MARKED RISK FACTOR IN BOTH WOMEN OF CHILD BEARING WOMEN OVERALL AND PREGNANT WOMEN, SHOWN HERE. THIS ALSO HELD UP BY THE SECOND DEFINITION OF FERRITIN GREATER THAN 200 IN COMBINATION WITH TRANSFAIRNT -- GREATER THAN 45%, HOWEVER, HFE H63D DID NOT PROVE TO BE A SIGNIFICANT RISK FACTOR BY EITHER DEFINITION AS SHOWN HERE. AND IN WOMEN OF CHILD BEARING AGE OVER ALL IN PREGNANT WOMEN. I THEN LOOKED AT THE RISK FACTORS FOR IRON OVERLOAD AND LOGISTIC REGRESSION MODEL AMONG WOMEN OF CHILD BEARING AGE LOOKING AT IRON OVERLOAD WITH THE DEFINITION OF SERUM FERRITIN GREATER THAN 300, AND LOOKING AT WHAT WERE THE INDEPENDENT RISK FACTORS FOR INCREASED IRON STORES BY DEFINITION. HERE WE FOUND THAT C282Y HOME OWE SIGH DEPOSIT WAS OVERWHELMINGLY THE GREATEST RISK FACTOR, THE RISK RATIO WAS 53, BUT I ALSO FOUND THERE WERE SIGNIFICANT RISK FACTORS WITH AGE AND ETHNICITY, WITH AFRICAN-AMERICAN ETHNICITY, AND WITH INCREASING WAGE, AND WITH THIS DEFINITION, C282Y HAD -- REFINED, INDEPENDENT RISK FOR -- IRON STORES AS WELL. THESE SOASTHESE ASSOCIATIONS HELD UP IN A SIMILAR MODEL LOOKING AT PREGNANT WOMEN. AGAIN, C282 WAS THE OVERWHELMINGLY GREATEST RISK FACTOR, BUT AGAIN, INCREASE IN AGE WERE SIGNIFICANT RISK FACTORS AS THE C282Y HETEROSIGH GOSS IT, IN THIS CASE -- WAS ALSO A SIGNIFICANT RISK FACTOR FOR ELEVATED COMBINATION AS SHOWN HERE. THIS ALSO HELD UP IN THE PREGNANT WOMEN SUBGROUP. ZOO IN SUMMARY, IRON DEFICIENCY WAS FOUND IN 13% OF WOMEN OF CHILD BEARING AGE AND 19% OF PREGNANT WOMEN, HSC282Y -- IN THESE ANALYSIS. INCREASED IRON STORES WERE FOUND IN UP TO 1.7% OF WOMEN OVERALL AND .9% OF PREGNANT WOMEN AND HFE C282Y HOME POE ZYGOSITY WAS THE STRONGEST RISK FACTOR. INCREASED IRON STORES, ADDITIONAL RISK FACTORS WERE ASIAN ETHNICITY, BLACK ETHNICITY, AGE, C282Y HETEROSIGH GOSS IT AND H63D. TURNING TO THE POTENTIAL CAUSES OF A NON-HFE INCREASE IN IRON STORAGE, I'VE LISTED FOUR POTENTIAL CAUSES HERE, HEPATITIS C, INCREASED DIETARY IRON, AND ADDITIONAL IRON LOADING MUTATIONS. I DID A STUDY -- I'VE BEEN INVOLVED IN STUDYING IRON OVERLOAD IN AFRICAN -- IN SUB-SAHARAN AFRICA BACK IN THE 1990s, AND WE FOUND A STROK ASSOCIATION OF HIGH DIETARY IRON WITH IRON OVERLOAD IN THAT CULTURE. HOWEVER, IN UP WITH ANALYSIS, WE TOOK AFRICANS THAT DID NOT DRINK THE BEVERIDGE THAT HAD THE HIGH IRON CON AT THE PRESENT TIME, BECAUSE THEIR FLOWER I THEIR FLOUR IS NOT FORTIFIED WITH IRON, WE COMPARED THEM TO AMERICANS WHO DID NOT DRINK ALCOHOL BULL -- HAVE A RELATIVELY HIGHER MEAT CONSUMPTION, WE FOUND THAT SERUM KERATIN CONCENTRATIONS WERE DOUBLE IN THE AFRICAN-AMERICANS COMPARED TO ZIMBABWEANS SIMILAR TO EFFECT OF DIETARY -- IN ANOTHER STUDY, WE LOOKED AT THE FERROPORTIN Q248H IN THE SUBIMREUP OF PERSONS INCLUDED IN THE HEIRS STUDY. THIS IS AN AFRICAN-SPECIFIC MUTATION THAT HAS MILD HEPCIDIN RESISTANCE. WE FOUND THERE WAS AN ASSOCIATION WITH INCREASED FERRITIN IN MALES BUT NOT AN ASSOCIATION WITH INCREASED FERRITIN IN FEMALES IN THIS SUBGROUP OF THE HEIRS STUDY. WHAT ABOUT POTENTIAL CONSEQUENCES OF THE MODERATE INCREASE IN IRON STORES WE OBSERVED IN THE PATIENTS WE STUDIES IN THESE ANALYSES? THIS MILD INCREASE IN IRON STORES HAS BEEN ASSOCIATED WITH SYMPTOMATIC PORPHYRIA CUTANEA, ALSO CONTRIBUTED TO HEPATIC DYSFUNCTION, GENERAL INCREASED RISK OF CANCER, SOME STUDIES HAVE SUGGESTED A GENERALIZED INCREASE IN THE RISK OF CANCER, AND THERE ARE A NUMBER OF STUDIES THAT WOULD INDICATE AN INCREASED RISK OF DIABETES MELLITUS. THAT WAS THE PRESENTATION I HAD THIS MORNING AND I HOPE WILL BE PEP HELPFUL IHELPFUL IN THE DELIBERATIONS OF THE PROCEEDINGS. THANK YOU VERY MUCH. [APPLAUSE] >> HE'S A VERY GOOD VIDEO SPEAKER. NICE ART TOO. SO I'D LIKE TO INVITE KAY DEWEY WHO'S GOING TO TALK ON PERSPECTIVE OF REQUIREMENTS. >> THANK YOU VERY MUCH. I'VE BEEN VERY ENERGIZED BY THE TALKS THIS MORNING AND I WANT TO HAVE JUST A FEW COMMENTS ON IRON REQUIREMENTS DURING PREGNANCY AND INFANCY. I'LL BRIEFLY TOUCH ON THE DIETARY REFERENCE AND THE ASSUMPTIONS THAT UNDERLIE THEM BECAUSE I THINK THIS MIGHT BE USEFUL FOR OUR DISCUSSIONS LATER TODAY AND TOMORROW. AND THEN SWITCH MOSTLY TO INFANCY, TALK ABOUT WHO'S AT RISK REGARDING IRON DURING PREGNANCY AND EVOLUTIONARY PERSPECTIVE ON MEE METEOROLOGISTING IRON NEEDS DURING INFANCY. SO WITH RESPECT TO DIETARY REFERENCE INTAKES, WE'VE ALREADY TALKED ABOUT THE COMPONENTS THAT GO INTO THE INCREASED REQUIREMENTS FOR ABSORBED IERP SO I WON'T DISCUSS THAT, BUT HERE YOU HAVE OVER HERE THE ABSORBED IRON REQUIREMENT BY TRIMESTER. THIS IS THE ABSORPTION ASSUMPTION, 18% IS THE SAME AS IT IS FOR OTHER AGE AND GENDER GROUPS REGARDLESS OF PREGNANCY, BUT YOU CAN SEE THAT IT GOES UP TO 25% IN THE CALCULATIONS FOR THE SECOND AND THIRD TRIMESTER. DISCUSSION ABOUT WHETHER THAT IS A GOOD ESTIMATE, WOMEN WHO HAVE MUCH LOWER ABSORPTION IF THEY HAVE VEGETARIAN DIETS OR LOTS OF COMPONENTS THAT BLOCK ABSORPTION. BUT IN ANY CASE, THAT TRANSLATES INTO THE REQUIREMENTS THAT YOU SEE OVER HERE, WHICH ARE ACTUALLY FAIRLY LOW IN THE FIRST TRIMESTER, NOT THAT HIGH IN THE SECOND TRIMESTER AND THEN A LITTLE HIGHER IN THE THIRD TRIMESTER. BUT IN FACT, THE EAR AND THE RDA FOR AWFUL PREGNANCY WAS BASED ON THE ESTIMATES FOR THE THIRD TRIMESTER. AND THE RATIONALE FOR THAT WAS TO BUILD IRON STORES, SO IF YOU CONSUME 22 OR MORE MILLIGRAMS PER DAY STARTING AS SOON AS YOU KNOW YOU'RE PREGNANT, THAT'S MORE THAN YOU NEED EARLY ON, BUT THEORETICALLY YOU'RE BUILDING YOUR IRON STORES, AND THEN YOU END UP AT THE RIGHT LEVEL IN THE THIRD TR TRIMESTER, SO THAT'S WHAT LED TO THE EAR OF 22 ACROSS THE BOARD FOR ALL WOMEN 19 TO 30 WHICH TRANSLATES INTO AN RDA OF 27. AND SO IN LIGHT OF CONCERNS ABOUT IRON EXCESS, WE MIGHT WANT TO REVISIT THIS ISSUE OF WHETHER WE SHOULD BE USING THIS VALUE FOR ALL OF PREGNANCY. SO SWITCHING TO INFANCY, BO HAS ALREADY TALKED ABOUT THE BABIES WHO MIGHT BE RUNNING OUT OF THEIR BIRTH IRON STORES WITHIN THE FIRST SIX MONTHS AND THOSE ARE PRIMARILY GOING TO BE THE BREAST FED INFANTS, NOT RECEIVING IRON-FORTIFIED MILKS. IN PARTICULAR, THEY WOULD BE BABIES WHO ARE PRETERM OR LOWER BIRTH WEIGHT WHO HAVE MUCH LESS IRON IN THEIR TOTAL BODY BECAUSE THEY'RE LOWER WEIGHT, AND AS HE MENTIONED, WHEN WE DID THE MODELING, WE ALSO TOOK INTO ACCOUNT EARLY UMBILICAL CORD CLAMPING, WHICH GREATLY REDUCES THE TOTAL A IRON IN THE BODY SHORTLY AFTER BIRTH. THEN THE MOTHER'S PRENATAL IRON STATUS IS A FACTOR IN MANY CASES, AND ONE FACTOR THAT'S NOT OFTEN RECOGNIZED IS THAT MALE INFANTS ARE AT MUCH HIGHER RISK OF IRON TEE EFFICIENCY AND ANEMIA IN THE FIRST YEAR OF LIFE THAN FEMALES. WE DON'T UNDERSTAND EXACTLY WHY BUT IT'S BEEN SHOWN IN A NUMBER OF STUDIES. SO THOSE ARE THE BABIES WHO MIGHT BE AT RISK OF IESH DEFICIENCY BEFORE SIX MONTHS BUT ON THE OTHER SIDE OF THE EQUATION, MAY BE AT RISK OF EXCESS IRON EARLY ON, AND WITHOUT A LOT OF PHYSIOLOGICAL MECHANISMS TO TAMP DOWN ABSORPTION DURING THAT AGE, THAT'S SOMETHING THAT WE MIGHT BE CONCERNED ABOUT. NOW WHEN WE GO PAST SIX MONTHS, THESE ARE THE VALUES FOR THE EAR AND THE RDA, AS MOST OF YOU PROBABLY KNOW, THE RDA IS VERY HIGH, FROM 6 TO 12 MONTHS, AND A LITTLE BIT LOWER IN THE WHO REQUIREMENT VALUES, BUT STILL HIGH. YOU TILELY GE ACTUALLY GET VERY LITTLE FROM BREAST MILK, AND BO ILLUSTRATED, SO THE AMOUNT NEEDED FROM OTHER FOODS IS A VERY HIGH TOTAL PROPORTION SO FOR THAT REASON THEY KNEELED -- THERE WERE SOME DATA PRESENTED FOR INTAKES IN THE UNITED STATES SHOWING THEY DIDN'T LOOK ALL THAT LOW ON THE AVERAGE, BUT KEEP IN MIND THAT THAT INCLUDES A LOT OF FORMULA-FED INFANTS AND A LOT OF INFANTS FED A FAIRLY LARGE AMOUNT OF IRON FORTIFIED INFANT CEREALS. WHEN WE LOOK AT BREAST FED INFANTS IN PARTICULAR, WE DON'T SEE SUCH HIGH INTAKE, EVEN IN THE UNITED STATES, WE'RE MUCH MORE LIKELY TO SEE DEFICIENT INTAKES IN THAT CATEGORY. SO THAT HAS LED ME TO ALWAYS WONDER WHETHER OUR ESTIMATES DURING INFANCY ARE RIGHT BECAUSE WE NEVER SEEM TO MAKE IT THERE WITH BREAST FED INFANTS. SO I WENT AND SORT OF LOOKED AT WHAT THE DIETS MIGHT HAVE BEEN IN PREAGRICULTURAL SOCIETY, WHICH WOULD HAVE BEEN BREAST MILK AND THEN PREMASS TI KATEED OR PRECHEWED FOODS THAT THE ADULTS WOULD HAVE BEEN EATING AND THEN GIVING TO THE BABY. AND THOSE FOODS PROBABLY REFLECTED THE DIETS OF THE ADULTS AND IN FACT PREAGRICULTURAL SOCIETIES GENERALLY HAD A VERY HIGH PROPORTION OF ANIMAL SOURCE FOODS IN THEIR DIETS SO THE NUTRIENT DENSITY OF THOSE FOODS IS PROBABLY VERY HIGH. SO TO LOOK AT THAT, I ESTIMATED WHAT THE IRON INTAKE WOULD HAVE BEEN AT 9 TO 11 MONTHS HERE IN THIS GRAPH, AND THE BAR SHOWN HERE IS 100% OF THE RECOMMENDED NUTRIENT INTAKE BY WHO. SO WITH BREAST MILK ONLY, YOU'RE ONLY GOING TO GET 2% OF THAT. VERY, VERY LITTLE. IF YOU ADD IN THE TYPICAL COMPLEMENTARY FOODS THAT ARE FED IN A LOT OF SOCIETIES, WE'RE ONLY AT ABOUT 34%. IF YOU THEN ADD IN A HIGHER QUALITY DIET THAT INCLUDES ANIMAL SOURCE FOODS IN ADDITION TO A TYPICAL RICE OR WHEAT OR MAIZE PORRIDGE, YOU'RE STILL ONLY AT 53%, BUT WHEN WE MODELED WHAT IT WOULD LOOK LIKE WITH THE PREMASS TI KATEED FOODS, TO MY ASTONISHMENT, WE REACHED 98%. SO THAT ANSWERED THE QUESTION FOR ME OF HOW COULD IT BE THAT BABIES TODAY AROUND THE WORLD DON'T MEET THEIR IRON NEEDS AND WE HAVE TO GIVE THEM FORTIFIED PRODUCTS FROM AN EVOLUTIONARY ASPECT, THAT DEPARTMENT MAKE SENSE TO ME, BUT LOOKING AT THIS, IT DOES. SO I JUST WANTED TO THROW THOSE OUT THERE AS IDEAS FOR US TO DISCUSS WHEN IT COMES TO IRON NEEDS LATER ON. THANK YOU. [APPLAUSE] >> SO NOW MARIANNE WESSLING RESNICK WILL TALK ABOUT TARGETS OF IRON TOXICITY DURING PREGNANCY AND EARLY LIFE. >> THANK YOU. I LOOK FORWARD TO MORE DISCUSSIONS. I'M GOING TO LOOK AT THE QUESTION OF IRON IN PREGNANCY AND EARLY LIFE FROM THE ANGLE OF TOXICITY. AND MOSTLY APPROACH IT AT A MOLECULAR LEVEL. SO WE'VE ALREADY SEEN WHAT -- CHEMISTRY IS. I JUST WANT TO REMIND YOU THAT IERP AND OXYGEN HAVE A VERY INTIMATE RELATIONSHIP. OBVIOUSLY WE REQUIRE IRON TO CARRY OXYGEN, WE REQUIRE IRON IN THE RESPIRATORY CHAIN, AND PART OF THAT RESPIRATORY EFFECT IS TO PRODUCE SUPER OXIDES. SOME IRON CONTAINING PROTEINS ACTUALLY HELP REDUCE POTENTIAL DAMAGE CAUSED BY FREE RADICALS, BUT OF COURSE WHEN IRON IS PRESENT IN EXCESS, YOU HAVE SO CALLED FENTOT CHEMISTRY THAT CAN PRODUCE THE HIGH DROX AL RADICAL WHICH IS VERY DAMAGING AND CAN PROMOTE DAMAGE TO PROTEINS, LIPIDS AND DNA. SO WE LIVE WITH FENTON CHEMISTRY AND WE KNOW -- I'M GLAD THAT VICTOR TALKED ABOUT HEME CHROMATOSIS BECAUSE WE KNOW THAT THERE ARE EFFECTS OF EXCESS IRON AND WE KNOW THAT THE TARGET TISSUES ARE LIVER, HEART AND PANCREAS FOR THE MOST PART WHERE WE SEE INCREASED INCIDENCE OF -- IS MENTIONED, WE SEE CARDIOMYOPATHIES AND WE SEE A LOT OF ENDOCRINOPATHYS AS WELL, BUT I WANTED TO PUT ON THE TABLE AMONGST THESE TARGET TISSUES THE DEVELOPING BRAIN. THIS MOSTLY COMES FROM ANIMAL STUDIES WHERE WE CAN MEASURE THE A IRON ACQUIRED BY BRAIN, SO WHEN YOU EXPOSE MICE AND RATS TO IRON DURING DEVELOPMENT, WE SEE THAT THERE'S AN INCREASED FLUX IN THE DEVELOPING BRAIN. THESE ARE VERY HIGH IRON LEVELS BUT THAT RESULTS IN COGNITIVE EFFECTS, BEHAVIORAL AND EMOTIONAL EFFECTS. AND WE DON'T REALLY KNOW WHAT HAPPENS IN THE HUMAN BRAIN DURING DEVELOPMENT, OF COURSE WE CAN'T DO THESE STUDIES, BUT THERE ARE SEVERAL STUDIES THAT SUGGEST AT THE HIGH END OF IRON INTAKE, YOU DO SEE CONSEQUENCES IN BEHAVIORAL AND MENTAL HEALTH. SO I JUST WANTED TO PUT THAT ON THE TABLE, AND I ALSO WANT TO PUT ON THE TABLE THE IDEA OF DEVELOPMENTAL ORIGINS OF ADULT CROPPING DISEASE. SO THE HIGH IRON EXPOSURE, FOR EXAMPLE, THAT MIGHT AFFECT DEVELOPMENT IN THE BRAIN MAY NOT HAVE CONSEQUENCES UNTIL WELL AFTER THE FIRST YEAR, SECOND YEAR, THIRD YEAR OF LIFE. JUST AS WE SEE END KRI NOP THEES EVOLVE OVER TIME, WE NEED TO PAY ATTENTION TO THIS FACT. AND SO A LOT OF WHAT PEOPLE HAVE DONE LOOKING AT THE EPIGENETIC CHANGES THAT GO INTO DEVELOPMENTAL ORIGINS OF DISEASE ARE REALLY LOOKING AT STRESSORS AND A GENERAL FACTOR IS OXIDATIVE STRESS AND IT'S NOT USUALLY HIGH IRON, SO IT'S DIFFICULT BUT I AM GOING TO EXTRAPOLATE SOME IDEAS FROM STUDIES THAT HAVE LOOKED AT OXIDANT EFFECTS. AND I WAS ASKED TO FOCUS ON STEM CELL BIOLOGY, SO HE THOUGHT THAT THAT WOULD BE A GOOD PLACE TO START. ALL I'VE DONE HERE IS PUT UP A CARTOON OF HEMATOPOIESIS OF PRODUCTION OF RED CELLS, GIVE RISE TO OTHER LINEAGES, MYELOID, LYMPHOID, BUT FOR OUR PURPOSES I THOUGHT IT WAS BE USEFUL TODAY TO FOCUS ON THE RED CELL BECAUSE THAT OFTEN -- THE HEMOGLOBIN IS USED AS A MARKER. NOW, WHAT'S INTERESTING ABOUT THE DEVELOP MENTAL PROCESS IN THE MARROW IS THAT THE HEMATOPOIETIC STEM CELLS ARE IN A NICHE WITH A MEE SAN KIE MALL PROGENITOR CELLS, AND THIS STROMAL NICHE IS HYPOXIC AND THAT'S IMPORTANT TO NOTE. BECAUSE THAT LOW REACTIVE OXYGEN, THE ENVIRONMENT HELPS TO PREVENT DAMAGE TO DNA THAT WOULD BE PROPAGATED ON THE PROGENITOR CELLS TO THE -- INTO THE FINAL PRODUCT. SO THERE'S A LOT OF INFORMATION FROM IN VITRO STUDIES USING HUMAN STEM CELLS THAT -- IT'S ULTIMATELY IMPORTANT FOR THERE TO BE A LOW OXYGEN ENVIRONMENT FOR DIFFERENTIATION AND COMMITMENT TO THE APPROPRIATE LIN YANK. LINEAGE. IRON CAN HAVE AFFECTS ON THIS PROCESEFFECTS ON THISPROCESS TOO. WE KNOW IN INDIVIDUALS LOADED WITH IRON, THEY OFTEN BECOME ANEMIC, AND NEITHER COULD BE DUE TO EFFECTS ON EE RETHROW POIESIS, SO FOR EXAMPLE, THERE'S A KNOCKOUT MODEL THAT LOOKS AT THE LEUKEMIA C VIRUS RECEPTOR, IN EARLY STAGES, THERE'S A CRITICAL ACCUMULATION OF HEME AND FAILURE FOR PROPER RED CELL DEVELOPMENT. WE ALSO KNOW IN HEMA CHROMO PTOSIS PATIENTS TREATED WITH CHELATION, FOR EXAMPLE, TO LOWER THE NICHE, THEY PERFORM BETTER IN PRODUCTION SO THIS IS AN IMPORTANT FACTOR TO KEEP IN MIND WHEN WE THINK ABOUT IRON AS AN EXPOSURE. THESE STEM AND PROGENITOR CELLS ALSO GIVE RISE TO ADD POE SITES AND OSTEOBLASTS, SO THINKING ABOUT OTHER PATHWAYS FOR DIFFICULT REB SHAITION, WHAT ARE THE EFFECT OF ROS HERE, AND OFTEN WE'RE LOOKING AT CHEMICALS THAT PRODUCE REACTIVE OXYGEN SPECIES AND NOT IRON BUT WE KNOW THAT IF YOU HAVE AN OXIDATIVE ENVIRONMENT IN VITRO, THE -- WILL PREFERENTIALLY UNDERGO ADIPOGENESIS AND IF YOU TAKE AWAY IRON IN THE SAME SYSTEM, YOU SEE IMPAIRED OSTEOBLAST FORMATION, AND IF YOU ADD IRON, WE KNOW THAT THIS IS IMPORTANT FOR RENEWAL, SELF-RENEWAL AND PROLIFERATION, SO THERE SEEMS TO BE ALMOST A SWITCH IN TERMS OF LINEAGE DIFFERENTIATION AND COMMITMENT. AND OF COURSE WE HAVE EVEN LESS INFORMATION ABOUT OTHER TISSUES. SO LOCKING A I WANTED TO REMIND EVERYBODY THAT IT'S THE ERYTHRO BLASTS THAT PRODUCE ERYTHROFERRONE. THIS HAS A POSITIVE EFFECT ON IRON ABSORPTION. WE KNOW THAT EPO LEVELS ARE HIGH IN PREGNANT WOMEN AND WE KNOW THAT THAT PROMOTES ERYTHROBLAST FORMATION. BUT I DID WANT TO BRING INTO THE EQUATION SOME RECENT EVIDENCE THAT HAS SUGGESTED THAT THE TRANSPARENT RECEPTOR 2 WHICH IS -- ACTUALLY CAN ASSOCIATE WITH THE ECORECEPTOR AND MODIFIED A RESPONSE TO ECO, AND OF COURSE IRON -- THE PRESENCE OF IRON WILL MODIFY THE FUNCTIONS OF TFR TO ALTER AN EPO RESPONSE. SO HERE'S ANOTHER SITUATION WHERE THE PRESENCE OF EXCESS IRON CAN IMPACT THE FORMATION OF RED CELLS WHEN WE THINK ABOUT MARKERS. SO OVERALL, WE HAVE A PATHWAY THAT CAN ULTIMATELY AFFECT ADULT CROPPING DISEASE, SO IT'S NICE TADULTCHRONIC DISEASE, BUT THE CONSEQUENCES OF IRON LOADING MAY ULTIMATELY BE OBSERVED MUCH LATER IN LIFE, AND IT'S TRUE THAT HEME CROW MATOSIS PATIENTS HAVE DEFECTS IN BONE MINERAL -- ARE AT RISK OF OSTEOPOROSIS, AND WE SEE A LOT OF DIABETES AND METABOLIC DISEASE IN THESE PATIENTS AS WELL. SO I JUST WANT TO PUT ONE MORE IDEA ON THE TABLE THINKING SPECIFICALLY ABOUT ERYTHROPOIESIS. WE HAVE TO BEGIN TO RECOGNIZE IT'S NOT JUST IRON, THERE ARE OTHER MICRO NUTRIENTS REQUIRED TO SUPPORT IRON FUNCTION, SO SUPPLEMENTING OR FORTIFYING WITH IRON IS IMPRACTICAL IF YOU'RE ZINC-DEFICIENT, MANY OF THE TRANSCRIPTION FACTORS ARE INVOLVED IN THESE EARLY PHASES OF STEM CELL BIOLOGY. WE HAVEN'T REALLY MENTIONED VITAMIN A DEFICIENCY ANEMIA, BUT OBVIOUSLY THIS HAS GOT TO IMPACT SOME OF THESE PROCESSES AS WELL. MANG KNEEMANGANESE -- AND OF COURSE COPPER DEFICIENCY IS DESCRIBED AS WELL. SO IT'S NOT JUST IRON. WE HAVE TO PAY ATEPTION T ATTENTION TO ALL OF THE MICRO NUTRIENTS AND DEVELOP PRACTICAL POLICIES FROM THERE. SO JUST BRIEFLY, IDENTIFIED RESEARCH GAPS, ANIMAL STUDIES SUGGEST POSTNATAL EXPOSURE TO HIGH IRON AT A TIME OF GREATER INFLUX TO THE BRAIN PROMOTES NEURONAL DAMAGE, SO THIS SUGGESTS POSSIBLE LINKS BETWEEN IRON EXPOSURE AND BRAIN DEVELOPMENT IN CHILDREN SHOULD BE EXPLORED. EARLY DAMAGE TO TISSUES WITH KNOWN SENSITIVITY TO IRON-INDUCED OXIDATIVE STRESS COULD BE REFLECTED IN CHRONIC DISEASE LATER IN LIFE. EFFECTS OF IRON ON STEM CELL PROLIFERATION AND DIFFERENTIATION REALLY DO DESERVE SOME ATTENTION WITH A FOCUS ON UNDERSTANDING DISEASE IMPLICATIONS LATER IN LIFE, SUCH AS OSTEOPOROSIS AND METABOLIC SYNDROME. SO IN VITRO STUDY, WE CAN CERTAINLY CARRY OUT IN HEMATOPOIETIC STEM CELL REGULATION. IN PARTICULAR, STRESS ERYTHROPOIESIS IS NOT CLEAR. THE INFLUENCE OF IRON SENSOR TFR2 ON EPO SENSITIVITY MAY BE RELEVANT IN IRON LOADING ANEMIA. AND FINALLY KEY MICRO NUTRIENTS SUPPORT IRON'S FUNCTION IN ERYTHROPOIESIS SHOULD BE CONSIDERED IN THE COMPLETE PICTURE TO FORMULATE APPROPRIATE RECOMMENDATIONS. THANK YOU. [APPLAUSE] >> ALL RIGHT, THANK YOU. SO IT'S TIME FOR OUR DISCUSSION, AND WOULD ALL OF THE MORNING PRESENTERS PLEASE COME UP TO THE TABLE AND WE'LL START AGAIN THERE. >> SO I'D LIKE TO START OUT BY ASKING FOR COMMENTS OR QUESTIONS FROM THE SPEAKERS BACK AND FORTH TO EACH OTHER, AND THEN WE'LL GO TO COMMENTS OR QUESTIONS FROM THE AUDIENCE HERE AT THE MICROPHONES, BUT THERE ARE PERSONS WHO ARE WATCHING THIS ON VIDEOCAST AND THEY'VE BEEN GIVEN THE OPPORTUNITY TO SEND IN SOME QUESTIONS. SO YOU MAY SEE PEOPLE COMING UP HERE DELIVERING QUESTIONS TO US THAT WE'LL THEN DECIDE TO READ IN AND ANSWER. SO FIRST OF ALL, THOSE OF YOU WHO SPOKE THIS MORNING, DO YOU HAVE QUESTIONS OR COMMENTS THAT YOU'D LIKE TO ADDRESS TO EACH OTHER? HAVE YOU HAD A CHANCE ALREADY? GO. >> MAYBE I COULD ASK MICHAEL A QUESTION. YOU TALKED ABOUT HAVING MODULATING THE PRIORITIZATION OF IRON TO DIFFERENT TISSUES. HOW MIGHT YOU GO ABOUT THAT? >> I WISH I KNEW. NO, HE THINK THAT'S A TERRIFIC RESEARCH AGENDA TO FIGURE OUT WHAT THE BASIC MECHANISMS ARE BEHIND THAT, WHETHER IT'S TRANSFER IPT ACCEPTOR CYCLING, WHETHER IT'S COUPLING AND UNCOUPLING, WHAT IT IS THAT PREFERENTIALLY DISTRIBUTES, AND I JUST BRIEFLY MENTIONED IT BUT YOU COULD IMAGINE A SITUATION WHERE FOR THE PURPOSES OF MORTALITY, YOU KNOW, IF YOU DON'T WANT TO FEEDBACK TIER YA, YOU DON'T WANT TO FEED MALARIA, AND SO ON, SO THERE'S GOOD EVIDENCE THAT IRON SUFFICIENT RED CELLS WILL GENERATE LOTS OF MALARIA. SO MAYBE YOU WANT A SITUATION WHERE YOU COULD KEEP THAT DOWN WHILE YOU CONTINUE TO SUPPLY VITAL ORGANS THAT ARE DEVELOPING EARLY IN LIFE, LIKE THE BRAIN AND THE HEART, BUT I HAVE NO GOOD IDEAS YET AS H HOW ONE WOULD ACTUALLY DO THAT BECAUSE I DON'T KNOW THE BASIC BIOLOGY BEHIND IT. >> SO MARIANNE YOU BROUGHT UP THE CONCEPT OF THE POSSIBLE LAYER EFFECTS AND GENETIC REGULATION. IS THERE ANYTHING THAT WE HAVEN'T COVERED IN TERMS OF THE BASIC BIOLOGY, THE FOUNDATION THIS MORNING THAT IS AT THE EPIGENETIC LEVEL? WE HEARD A LITTLE ABOUT SNFs, GREG, IS THERE ANYTHING YOU WANT TO ADD THERE? EESPECIALLY IN RESPONSE TO IRON. >> I THINK IT'S AN INTERESTING AREA THAT HASN'T BEEN TERRIBLY WELL INVESTIGATED BUT IRON CERTAINLY PLAYS A ROLE IN A NUMBER OF THE ENZYMES THAT ARE INVOLVED NR EPIGENETIC REGULATION, AND IT'S SOMETHING THAT'S ANOTHER ONE OF THOSE THINGS LIKE MICROBIOME THAT WE NEED TO BEAR IN MIND, IT'S ANOTHER LEVEL OF REGULATION THAT PERHAPS ATTENTION HAS NOT BEEN GIVEN TO. IT'S AN IMPORTANT AREA, NO MAJOR SUGGESTIONS. >> SO ACTUALLY WHAT WERE YOU TALKING ABOUT TOO, AN IRON DEFICIENCY TO THE OTHER SIDE OF THE COIN ALSO SEEMS TO AFFECT THE EPIGENETICS, THE -- CONTAIN IRON, THEIR ACTIVITY IS DEPENDENT ON THE IRON MOIETY, AND ONE OF THE THINGS THAT JARDS REGULATE IS BRAIN DERIVED NEUROTROPHIC FACTOR, SO I THINK THERE'S A CONNECTION BETWEEN EARLY DEFICIENCY AND THE LONG TERM SUPPRESSION OF BDNF WE'VE SEEN IN OUR MOUSE MODELS, SO AGAIN, THERE SEEMS TO BE THIS SWEET SPOT. >> YES, I WOULD AGREE AND I RAISED THE QUESTIONS ASSOCIATED WITH IRON TOXICITY BECAUSE I THINK IT'S -- THE PHRASE IS FIRST "DO NO HARM," SO WE FOCUS A LOT ON EFFECTS OF IRON DEFICIENCY, EFFECTS OF IRON LOADING, VERY SIMILAR CO SIMILAR CONSEQUENCES, AND I THINK THERE'S A BROADENING UNDERSTANDING THAT THESE EARLY STAGE ALTERATIONS IN IRON STATUS CAN LEAD TO VERY DRAMATIC CHANGES IN ADULT HEALTH. SO WE'RE LOOKING AT ONE NARROW WINDOW OF EXPOSURE OR DEFICIENCY AND I DON'T THINK THERE'S VERY GOOD INFORMATION ABOUT FURTHER ON DOWN THE ROAD WHAT ARE THE ULTIMATE HEALTH CONSEQUENCES, BUT THEY COULD BE QUITE PROFOUND. SO IN TERMS OF EPIGENETIC MARKS, I THINK THAT IT WOULD BE NECESSARY TO DO A COMPREHENSIVE STUDY TO LOOK AT IRON STATUS TO MEASURE THE MARKS TO SEE WHAT THEY LOOK LIKE, AND THEN PERHAPS LOOK AT TARGET TISSUES OTHE OVER THE LIFESPAN. WE ALL HAVE THIS DIFFICULTY WITH HUMAN STUDIES, AND WHAT CAN WE DO WITH CHILDREN, VERSUS WHAT WE CAN DO WITH -- MODELS WHICH ARE EASIER AND ECONOMICALLY VIABLE, BUT I THINK THE POINT IS RAISED EARLIER BY TOM GANTS THAT THEY DON'T DEVELOP THE SAME TYPES OF PROBLEMS WITH IRON OVERLOAD, SO I WAS INTERESTED IN YOUR STUDIES ON LANDS AND ARE THERE OTHER ANIMAL MODELS LIKE PIGS AND SHEEP THAT WE SHOULD BE STRIVING TO DEVELOP OR ESTABLISH IN TERMS OF LOOKING AT CHANGES IN IRON METABOLISM IN AN ANIMAL MODEL THAT COULD BE MORE RELEVANT TO THE HUMAN CONDITION? >> THAT'S A TERRIFIC QUESTION. SO YES, ABSOLUTELY, THAT'S ACTUALLY WHY I KIND OF LISTED OUT MICE, RATS, SHEEP, MONKEYS, HUMANS. SO I THINK WHAT SHE'S GETTING AT, IRON IS SO FUNDAMENTAL TOLL METABOLISM, TO MITOCHONDRIAL HEALTH, WHICH WE NOW KNOW IS IMPORTANT IN TERMS OF SETTING LIFE COURSE, WE'RE ABLE TO TRACK FOR EXAMPLE ON OUR LAB MITOCHONDRIAL MOVEMENT ALONG NEURONS TO THE POINT OF DEN DENDIDRITOGENESIS, IS CLEARLY IMPORTANT. IF YOU LOOK AS WE'RE SITTING HERE, IF YOU GUYS ARE AWAKE OUT THERE, YOU HAVE A TOTAL BODY OXYGEN CON SUMS. OF THAT, ABOUT 20% IS GOING TO YOUR BRAIN. ANYBODY KNOW HOW MUCH IS GOING TO THE NEONATE'S BRAIN? 60%. 60%. NOW, KEN KASALA DID A VERY INTERESTING STUDY WHERE HE COMPARED AMONG MAMMALS THE RELATIVE AMOUNT OF OXYGEN CON SUMS AND, THEREFORE, METABOLIC LOAD AMONG MAMMALS. THE RAT, THE MOUSE, THAT WE LOOK AT, 2%. SO IT'S NOT A VERY HIGH DEMAND SYSTEM. AS I WAS SHOWING THE RED CELLS VERSUS THE BRAIN, WHAT'S THE COMPETITION THERE? WELL, THE COMPETITION IS GROWTH AND EXPANSION OF THE RED CELL MASS AND KEEPING A NORMAL HEMOGLOBIN FOR THAT, VERSUS THE METABOLIC BRAIN. IF YOU'RE GOING TO SET THE TWO IN COMPETITION IN A LIMITED IRON ENVIRONMENT. SO IN A HUMAN, WHERE YOU'VE GOT 60% GOING TO THE BRAIN AT A VERY SLOW RATE OF DOUBLING OF BLOOD VOLUME, YOU KNOW, YOU'RE GOING TO HAVE A DIFFERENT DYNAMIC THAN IN A MOUSE WHERE YOU HAVE 2% GOING TO THE BRAIN AND YOU HAVE AN ANIMAL THAT IS RAPIDLY DOUBLING ITS WEIGHT AND, THEREFORE, ITS BLOOD VOLUME. SO YOU HAVE TO BE VERY CAREFUL WITH OUR MODELS. I THINK THE NON-HUMAN PRIMATE IS A VERY GOOD WAY TO GO IN THE STUDIES THAT WE ARE DOING, WE'RE NOT SACRIFICING ANY MONKEY, WE ARE DOING SPINAL TAP, LOOKING AT MET BLO BOW LOW MICS D AT LEAST YOU'VE GOT MOST OF YOUR BOXES COVERED AND YOU HAVE AN ANIMAL THAT HAS A METABOLIC RATE AND A GROWTH RATE THAT ARE MUCH MORE SIMILAR TO HUMANS. >> GREG, WOULD YOU LIKE TO COMMENT ON YOUR MODEL ORGANISM? I THINK YOU ADMITTED -- WHILE HE'S DOING THAT, I THINK WE HAVE A COMMENT AS WELL. WE'D ALSO LIKE TO INVITE PEOPLE FROM THE AUDIENCE TO GO TO THE MICROPHONES AND PARTICIPATE IN THIS DISCUSSION, SO PLEASE DON'T BE HESITANT TO DO THAT. >> I'D JUST MAKE ONE POINT WITH THE ANIMAL MOTTLES AN MODELS AND CURRENT GENOME EDITING CAPABILITY, WE'RE NOT RESTRICTED TO TRANSGENIC MICE SO IT'S POSSIBLE TO MANIPULATE WHAT PEOPLE ARE DOING. ONE OF THE LIMITATIONS OF THAT IS COST. LARGER ANIMAL STUDIES COST A LOT MORE MONEY AND THAT'S A LIMITATION AS WELL. SO I THINK THERE ARE -- THE MOUSE AND RAT HAVE TAKEN US A LONG WAY, BUT THERE ARE -- THERE MAY BE OTHER ORGANISMS THAT CAN DO A BETTER JOB THAT NEED TO BE LOOKED AT, AND SOME OF THESE STUDIES MAY COST A LOT BUT ULTIMATELY GOING TO LARGER ANIMALS, WORKING ON HUMAN PRIMATES MAY IN THE LONG TERM BE THE MOST COST-EFFECTIVE WAY TO GO. >> SO ONE OF THE -- [INAUDIBLE] >> UNFORTUNATELY ONE OF YOU HAD A SLIDE UP THERE -- IT'S FORTUNATE YOU HAD THE SLIDE UP THERE ABOUT M RI. MRI IS GOOD FOR -- MRI IS GOOD FOR IRON OVERLOAD. I'M NOT AWARE THAT WE CAN STILL DETECT IRON UNDERLOAD BY MRI. SPINAL TAPS, UNLESS YOU HAD SOME SORT OF A CONVENIENCE POPULATION I GUESS THAT YOU'RE TAPPING FOR OTHER REASONS, MAYBE NEWBORNS WHO ARE BEING RULED OUT FOR SEPSIS WHERE YOU MAY ALSO HAVE CORD BLOOD, YOU LOOK AT METABALOME AND PROTEOME AND THOSE, IF WE GET THESE READOUT, FOR EXAMPLE, FROM A NON-HUMAN PRIMATE WHERE WE KNOW THAT THERE ARE MARKERS THAT WE CAN DETECT ABNORMAL BLAINE BRAIN METABOLISM IN THE SETTING OF BRAIN DEFICIENCY, PERHAPS WE CAN LOOK AT IT THAT WAY. SO YEAH, IT'S A LITTLE TRICKY. I THINK DAN -- RUNS ASKED ME AND PROBABLY SEVERAL OTHER PEOPLE, IS THERE A SIGNATURE BEHAVIOR OR A SIGNATURE READOUT OF AN IRON-DEFICIENT BRAIN, BUT SO MUCH OF KNEW TREEP NUTRIENT EFFECTS ON BRAIN IS DUE TO TIMING AND SO MANY OF THEM WORK THROUGH DISRUPTING FUNDAMENTAL METABOLISM THAT MAYBE OTHER THAN -- I DON'T THINK EVEN THE DOPAMINERGIC1 IS SINGULAR TO IRON, I DON'T KNOW THAT ANYTHING IS THAT SPECIFIC. SO I DON'T THINK IT LIES IN THE BEHAVIORAL REALM. >> [INAUDIBLE] >> NOT HUMAN. PETER -- DID A LOT OF WORK ON THAT AND ALSO CARDIAC MUSCLE BUT THAT WAS IN GROWTH OF MODELS. I'M NOT AWARE OF ANY IN HUMANS. >> I'M JUST GOING BY THESE RECENT STUDIES WHERE -- RECEPTOR 1 -- KNOCKOUT IN MUSCLE CELLS BECAUSE -- [INAUDIBLE] >> WE CERTAINLY SEE MOTOR EFFECTS WITH IRON DEFICIENCY IN INFANCY. WHETHER THOSE ARE STRICTLY BRAIN EFFECTS OR THEY ARE ALSO LOCAL MUSCLE EFFECTS, I WOULD SUSPECT THAT THEY ARE BOTH, BUT I DON'T THINK ANYBODY HAS PARSED THAT OUT WITH DR. LOWE'S HELP OUT THERE. [INAUDIBLE QUESTION] >> I WOULD MAKE ONE COMMENT, THERE IS HOPE FOR MRI, THERE ARE NEW TECHNIQUES, THERE'S QUANTITATIVE SUSCEPTIBILITY MAPPING THAT MAY TAKE SENSITIVITY TO LOWER LEVELS OF IERP. THE CONVENTIONAL MEASURES THAT HAVE BEEN USED ARE ONLY SENSITIVE TO REALLY IRON OVERLOAD, BUT WHAT I REALLY WANT TO DO IS ASK MARIANNE ABOUT RIX OF IRON TOX IS NIT PREGNANCY, AND TO COMMENT ON VICTOR GORDEUK'S PRESENTATION, WHAT HE WAS USING AS THE MEASURE OF IRON EXCESS WAS THE FERRITIN, AND THE FERRITIN IS VERY GOOD AT LOW LEVELS, THERE ARE VERY FEW THAINGS CAUSE -- ALMOST NOTHING THAT CAUSES A LOW FERRITIN OTHER THAN IRON DEFICIENCY. BUT THAT'S NOT THE CASE AT HIGHER LEVELS, AND ESPECIALLY WHIP CREASING OBESITY, WHICH CAN INCREASE FERRITIN AS WELL, IT'S DIFFICULT TO KNOW REALLY WHETHER THERE ARE TOXIC AMOUNTS OF IRON THAT ARE ACCUMULATED. IF YOU LOOK AT GREG'S WHERE HE SHOWED THE OPTIMAL LEVEL OF IRON DEFICIENCY AND IRON LOAFER ODOR, IT'S A VERY WIDE RANGE THAT'S CONSIDERED OPTIMAL. IT'S SOMETHING LIKE 1 TO 4 OR 5 GRAMS OF IERP, AND THE RISK THAT THERE COULD BE ACCUMULATION OF THAT AMOUNT DURING THE COURSE OF PREGNANCY SEEMS VERY -- >> I WOULD AGREE, WHEN I WAS ASKED TO PARTICIPATE, I DID A PRETTY LARGE LITERATURE SEARCH GOING BACK AND LOOKING AT WHAT ARE THE RISKS OF HIGH IRON AND YOU CAN SEE THAT THERE'S MORE INFORMATION FOR THE DEVELOPING FETUS AND THE SMALL INFAPT THAN FOR THE PREGNANT WOMAN. AND EXPOSURE DURING PREGNANCY ITSELF. BUT I HAVE TO SAY THAT IF WE LOOK AT -- IF WE TAKE THE APPROACH THAT THERE'S A LIFE COURSE, I DON'T KNOW THAT WE HAVE GOOD INFORMATION ON PREGNANCY, MULTIPLE PREGNANCIES AND CONDITIONS THAT MIGHT COME UP LATER IN LIFE DUE TO THAT HIGH WINDOW OF EXPOSURE DURING PREGNANCY, BUT REALLY I DIDN'T FIND INFORMATION THAT WOULD GIVE ME CONFIDENCE THAT THERE IS A LARGE IMMEDIATE RISK FOR HIGH IRON DURING THE NINE MONTHS OF PREGNANCY. LATER ON, I DON'T THINK THE EFFECTS HAVE BEEN STUDIED. >> I WOULD LIKE TO ASK, WHICH ORGAN DO YOU THINK IS MOST SENSITIVE, SENSITIVE TO IRON DEFICIENCY DURING PREGNANCY? WHICH ORGAN IS IRON MOST IMPORTANT FOR THE DEVELOPMENT? >> BRAIN. >> WE HAVE A PICTURE ABOUT -- THE BRAIN? >> YEAH, THAT'S MY OPINION. >> THAT'S MY OPINION TOO ACTUALLY. WHEN I STARTED DOING IRON STUDIES IN PREGNANT WOMEN, I FOCUSED ON PREGNANT -- THE WOMAN, BUT WHEN -- THE MOST IMPORTANT THING TO THE FE FETUS -- SO THE MOST PORP ORGAN IS THE BRAIN, WE ARE LIVING FROM THE BRAIN. SO THERE'S A WINDOW IN BRAIN DEVELOPMENT WHERE YOU HAVE IRREVERSIBLE DAMAGE BY IRON DEFICIENCY. LIKE IN FOLATE DEFICIENCY, YOU HAVE THIS WINDOW WHERE YOU DEVELOP SPINAL CORD PROBLEMS IF YOU DON'T GET ENOUGH FOLATE, AND THERE ARE SOME ANIMAL STUDIES ACTUALLY SHOWING THERE IS A WINDOW ALSO FOR IRON DEFICIENCY AND BRAIN DEVELOPMENT. >> I THINK WE HAVE THE EXPERT AT THE OTHER MICROPHONE. >> MICHAEL AND I WERE PART OF THIS AMAZING PROGRAM PROJECT GRANT WHERE WE TRIED TO ADDRESS THAT IN RODENTS, MONKEYS AND HUMAN INFANTS. NOW WE DIDN'T GET TO THE NARROW WINDOWS YOU'RE TALKING ABOUT, YOU KNOW, FIRST GESTATION, WE WERE SO FAR BEHIND THAT WE WERE TRYING TO GET AT -- WHETHER IT WAS DURING GESTATION OR DURING INFANCY, THAT WAS OUR FIRST STEP. THOSE PAPERS ARE JUST STARTING TO COME OUT, BUT IN THE HUMAN -- PART OF THE CHALLENGE WE HAD IN THE HUMAN INFANT, IT WAS THE LONG TERM TEACHING THAT THE FETUS WAS PROTECTED FROM MATERNAL IRON DEFICIENCY, SO THAT ALL OF THE STUDIES OF DEVELOPMENT WERE WITH IRON DEFICIENCIES DETECTED IN INFANCY. SO THESE STUDYS WERE SORT OF AMONG THE VERY FIRST TO SYSTEMATICALLY LOOK AT WHAT DOES NEURODEVELOPMENT LOOK LIKE IF YOU HAVE IRON DEFICIENCY DURING GESTATION FOR THE FETUS OR DURING INFANCY? AND AS WE'RE SUMMARIZING THE EFFECT, IT LOOKS LIKE MANY OF THE THINGS OVER THE YEARS I HAVE ATTRIBUTE TODAY IRON DEFICIENCY AND INFANCY ARE ALREADY THERE WITH IRON DEFICIENCY IN CORD BLOOD. SO THAT'S THE QUICK PREVIEW OF WHAT THE CONSENSUS WILL BE. MICHAEL, DO YOU -- >> I WOULD ECHO THAT, AND I THINK IF YOU ASK US THIS EVERY YEAR, IT GOES FURTHER AND FURTHER BACK. SO PART OF IT HAS TO DO WITH THE IRON DEFICIENCY LITERATURE WHICH IS VERY MUCH OF A LAMP POSE LITERATURE, YOU KNOW, WHERE ARE YOU LOOKING FOUR YE FOR YOUR KEYS, UNDER THE LAMP POS POST BECAUSE THE LIGHT IS GOOD THERE, BUT THEY MIGHT BE SOMEWHERE ELSE. THE THREE AREAS DO DEMONSTRATE IRRESPECTIVE OF IRON, THEY DO DEMONSTRATE A RAMP-UP, ALL THREE OF THEM, MID GESTATION TO EARLY THIRD TRIMESTER, WITH A PEAK, AND THEN IT'S KIND OF SETTLING DOWN AT ABOUT 18 MONTHS TO THREE YEARS OF AGE. THAT'S WHEN THOSE SYSTEMS ARE BEING SHAPED. SO IF YOU ASK THE QUESTION WHEN WOULD ALTERATIONINGS IN THE BIOLOGY HAVE -- ESPECIALLY IF THEY'RE EP JE NE TECH, HAVE THEIR GREATEST CHANCE OF AFFECTING, I WOULD SAY, IN THAT TIME PERIOD. AND THAT MAY START TO EXPLAIN SOME OF THE FINDINGS NOW, SOME OF THESE LATER FINDINGS. BUT THERE'S A PAPER OUT THERE FROM U.C. DAVIS GOES FROM PERINATAL IRON STATUS AND MATERNAL IRON HAS AN IMPACT ON RATES OF AUTISM. SO YOU REALLY START TO ASK THE QUESTION, WHERE DO YOU BREAK THE CYCLE? DO YOU BREAK IT PREPREGNANCY? I'M NOT SURE YOU CAN ANSWER THAT QUESTION. >> I DON'T HAVE THE ANSWER. IF WE CONSIDER IRON SUPPLEMENTATION, SHOULDN'T WE START VERY EARLY IN PREGNANCY. >> OR HEALTHY EATING BY TEENAGERS BEFORE THEY BECOME PREGNANT. >> THESE HAVE CONSEQUENCES, YOU KNOW. >> I THINK SHE'S RIGHT ABOUT ONE THING ABOUT HISTORY AND THAT IS THAT WHOLE IDEA THAT THE FETUS WAS PROTECTED, I THINK REALLY SET THE FIELD BACK FOR A LONG TIME, AN WHEN YOU AND I -- ABOUT 20 YEARS AGO, THEY SAID YOU STUDY NEONATAL IRON DEFICIENCY BECAUSE I DISCOVERED THESE POPULATIONS AT RISK AND ONE DAY OUR WORLDS WILL MEET AND IN FACT THAT IS WHAT HAPPENED. THERE IS A CONTINUUM AND IT'S MORE A QUESTION OF WHAT EFFECTS ARE WE TALKING ABOUT BASED ON THE TIMING OF THE DEFICIENCY RATHER THAN A YES/NO KIND OF QUESTION. >> GREAT CONSEQUENCE FOR DEVELOPING COUNTRIES. >> SHIFTING GEARS, FIRST I WANT TO THANK KAY FOR GETTING U US TO TALK ABOUT THE BREAST FED INFANT, FRONT AND CENTER, AND I WANTED TO ADD A FEW FURTHER THOUGHTS ON THE EVOLUTION BECAUSE I CAN'T RESIST. THE OTHER THING YOU COULD CONSIDER IS THAT THE AVERAGE BIRTH WEIGHT WAS NOT 3.2-KILOS OR 3.4-KILOS LIKE OUR BABIES. THEY WERE NOT LOW BIRTH WEIGHT BUT THEY WERE LOWER BIRTH WEIGHT. BIRTH WEIGHT DOUBLING WASN'T AS FAST WITH THOSE SMALLER BABIES AND WITHOUT OUR HUGE EABS. THE INTERBIRTH INTERVAL WAS LONGER. THE AGE OF FIRST PREGNANCY WAS LATER. SO THERE ARE A TON OF REASONS THAT THE MOTHERS AND THE BABIES MIGHT HAVE ENTERED INTO THE INFANCY PERIOD IN THE MORE ADVANTAGED IRON STATUS AND PUTTING LESS DEMANDS ON BREAST MILK. I LIKE THE PREMASS TI KATEED FOOD TOO, BUT THE REASON I WANTED TO CONGRATULATE YOU AND BRING IT TO ALL OF OUR ATTENTION IS THAT THERE'S SUCH AN ISSUE OF WHAT TO DO WITH IRON SUPPLEMENTATION OF THE BREAST FED BABY, THERE ARE STRONGLY HELD OPINIONS AND IT'S OFTEN AN EVOLUTIONARY ARGUMENT SO I HOPE IT'S SOMETHING WE CIRCLE BACK TO IN THE COURSE OF THESE COUPLE OF DAYS. >> SO I HAVE A COMMENT WHICH IS THAT A LOT OF THE EPIDEMIOLOGY OF IRON DEFICIENCY IS TAINTED BY THE COMBINATION OF IRON DEFICIENCY WITH OTHER -- TEE EFFICIENCY. BUT WE HAVE SOME MODELS THAT CUT THROUGH THAT, AND ONE OF THEM IS REFRK TREE IRON DEFICIENCY ANEMIA, WHICH IS A GENETIC CONDITION IN WHICH THE IRON DEFICIENCY IS PURE. IT IS A DEFECT IN THE UPTAKE OF IRON IN THE GUT DUE TO HIGH HEPCIDIN, AND REMARKABLY, THOSE CHILDREN ARE NOT -- DESPITE A VERY SEVERE IRON DEFICIENCY, THEY'RE NOT OBVIOUSLY IMPAIRED. THEY SHOULD BE PROBABLY STUDIED IN MORE DETAIL BUT THEY'RE NOT OBVIOUSLY IMPAIRED. SO I THINK WHEN YOU LOOK AT THE EPIDEMIOLOGIC DAY TA YOU HAVE TO WORRY ABOUT THE CONTAMINATION BY OTHER COEXISTING NUTRIENT DEFICIENCIES. >> LET ME JUST COMMENT ON THAT. THAT'S A VERY GOOD POINT, IT WOULD BE REALLY NICE IF WE KNEW HOW IRON GOT INTO THE BRAIN. THAT IS NOT KNOWN. WE KNOW THERE IS CERTAINLY A TRANSFERRIN RECEPTOR TRANSMEMO BRAIN APPROACH, BUT WHEN WE KNOCKED OUT DMT IN THE MOUSE HIPPOCAMPUS IN NORMAL CELLS, THOSE CELLS DIDN'T DIE. IN FACT, THEY LOOK ABNORMAL BUT THEY DON'T LOOK TERRIFICALLY ABNORMAL. BEHAVIORALLY WHEN WE TEST THEM, THEY ARE WORSE THAN IRON-SUFFICIENT BUT THEY ARE NOT WANDERING AROUND NOT KNOWING WHAT THEY'RE DOING EITHER, SO I THINK THAT THAIS THAT'S A VERY BASIC QUESTION THAT NEEDS TO BE ANSWERED. I THINK THE OTHER THING IT POINTS OUT IS THAT IN ANY OF THESE STUDY, THERE ARE SOME RULES OF ENGAGEMENT IN YOUR DEVELOPMENTAL RESEARCH WHERE YOU MATCH THE OUTCOME OR THE METRIC THAT YOU'RE USING TO THE RESPECTIVE BIOLOGY. THAT'S BASED OPPED ONTHE DURATION -- SO AS WE TALK ABOUT THE EPIDEMIOLOGY, IT IS IMPORTANT TO USE THE RIGHT TEST AT THE RIGHT TIME AS WELL TO ASSESS. BUT IF IT TURNS OUT THAT IRON DEFICIENCY HAS NO EFFECT ON HUMAN DEVELOPMENT, IT WILL BE AN ENORMOUS DISCONNECT FROM WHAT WE SEE, BASIC BIOLOGY IN ALL OTHER MAMMALS. >> I THINK I WANT TO ALSO COMMENT ON TOM'S POINT AND THANK YOU, BECAUSE I THINK THAT NOW WE OFTEN FORGET WE HAVE GENETIC TOOLS TO IDENTIFY A CONDITION JUST LIKE THAT, SO WE CAN ACTUALLY LOOK AT RAW DATA IF WE HAVE A LARGE ENOUGH POPULATION TO DO POPULATION STUDY EPIDEMIOLOGY STUDY TO SEE WHAT CAPTIONS ISSUE, RESUMES SHORTLY >> IF YOU CAN TAKE YOUR SEATS WE'RE GOING TO TRY TO GET STARTED ON TIME SO WE DON'T KEEP YOU FOLKS HERE TOO LONG. TALKING POLITICS (INAUDIBLE). HOPING THAT ALL THE FOLLOWING (INAUDIBLE). >> AGAIN IN THE INTEREST OF TIME WE'LL GET STARTED. I'M CHRISTINE TAYLOR, I'LL BE MODERATING THE SESSION TWO WHICH IS ON MEASUREMENTS AND SCREENING CHALLENGES. JUST A LITTLE BIT OF BACKGROUND, WE ARE GOING TO BEGIN WITH A CLASSIC BLOOD MEASURES OF IRON, THAT'S HISTORICALLY FOCUSED ON DETERMINING ANEMIA. BUT THAT PERHAPS A MORE CHALLENGING TIME DIFFERENTIATING BETWEEN THINGS SUCH AS SUFFICIENCY, ADEQUACY AND EXCESS. SO THOSE KINDS OF ISSUES WE HOPE WILL BE RAISED TODAY. I DO THINK THAT OVER THE SPAN OF THE WORKSHOP, THIS QUESTION OF MARKERS WILL EXPAND. THE TASK FORCE, THE U.S. PREVENTIVE SERVICES TASK FORCE HAS SIGNALS THAT THE HEMOTO LOGICAL MEASURES THAT WE ARE ALL COMMONLY AWARE OF ARE NOT WELL ASSOCIATED WITH HEALTH OUTCOMES, THAT'S NOT A SURPRISE TO US BUT I NEED TO UNDERSCORE IT THAT THESE HEMOTO LOGICAL CHANGES AND WHAT THE TASK FORCE WAS LOOKING FOR IN TERMS OF HEALTH OUTCOMES ARE NOT WELL MATCHED. THEN THERE'S THE LARGER OVERARCHING QUESTION, ASSUME YOU GET TO THAT POINT, WHAT ARE THE MARKERS THERE THAT ARE IMPORTANT. THOSE ARE THE LARGER QUESTIONS THE CONTEXT THAT WERE SENT. WE'LL BEGIN WITH CHRISTINE PFEIFER FROM CDC WHO WILL DO CONVERSATIONS ABOUT STRENGTH, LIMITATIONS AND AN LAT LITCAL CHALLENGES. -- ANALYTICAL CHALLENGES. >> >> THANK YOU, CHRISTINE. HIGH, EVERYBODY. BY WAY OF INTRODUCTION I'M NOT AN EXPERT ON IRON ME METABOLISM, I AM LEADING NUTRITIONAL BIOMARKERS MEASUREMENTS AND CDC, SO I HAVE THE MUCH MORE MUNDANE TASK TODAY TO TALK TO YOU ABOUT PRETTY STANDARD THING LABORATORY MEASUREMENTS SO I WILL TRY TO DO MY BEST TO KEEP YOU AWAKE AFTER LUNCH. BY WAY OF DISCLOSURE, NO CONFLICT OF INTEREST TO DISCLOSE, I'M A MEMBER OF THE BOND IRON GROUP AND WORKEDD ON COMPILING LAB RELATED ISSUES FOR INDICATORS AND SOME OF THAT I WILL SHOW YOU TODAY. AND MY CHARGE FOR THIS PRESENTATION WAS TO TALK ABOUT STRENGTHS, LIMITATION CHALLENGES AND STANDARDIZATION OF COMMONLY USED METHODS DISCUSS NHANES MEASURES, DEFINE STATUS, EVOLUTION AND RATIONALE AND IDENTIFY SOME RESEARCH NEEDS. SO I WOULD LIKE TO START WITH ALIGNING THE DIFFERENT IRON STATUS INDICATORS TO THE DIFFERENT BODY COMPARTMENTS. FOR THE IRON STORES WE HAVE TWO USE IRON INDICATORS SUSTAINABLE BONE MARROW IRON WHICH IS NOT USED IN CLINICAL PRACTICE BUT CONSIDERED THE GOLD STANDARD AND THEN WE HAVE THE COMMONLY USED -- WHICH PRESENTS A SMALL PORTION OF THE ACTUAL PARAFFIN IN THE HEPATOCYTES AND MACROPHAGES THAT CONSTITUTE BODY IRON STORES. WHEN WE DEPLETE THESE STORES WE TALK ABOUT IRON DEPLETION. THE NEXT COMPARTMENT IS THE TRANSPORT IRON TO MET CELLULAR REQUIREMENTS. THE MOST COMMON ARE SERUM TRANSFERENCE SATURATION WHICH IS A CALCULATED ENTITY AND I WILL TALK MORE ABOUT THAT IN A COUPLE OF SLIDES. ERYTHROCYTE AND GERM SOLUBLE TRANSFERENCE RECEPTOR F FIRST QUARTERR. ONCE THESE -- TFR. ONCE THE IRON SUPPLY NO LONGER MEETS THE REQUIREMENT WE'LL CALLING THIS IRON DEFICIENT ELECTROPOIESIS BUT WE DON'T NECESSARILY HAVE LOWER HEMOGLOBIN VALUES. THE THIRD COMPARTMENT IS FUNCTIONAL IRON AND HEMOGLOBIN IS MOST TYPICALLY USED AS THE INDICATOR TO INDICATE A IMPAIRED FUNCTIONAL IRON STORE. THE BOND GROUP ARRIVED AT SEVERAL BIOMARKERS AS CURRENTLY EXPERIMENTAL BIOMARKERS AND THOSE ARE HEPS DIDN'T AND NON-TRANSFEIGN IRON SO I'M NOT GOING TO TALK ABOUT THOSE BIOMARKERS AT THIS POINT. THERE ARE SEVERAL IMPORTANT BIOLOGICAL CONFOUNDERS FOR EACH BUOY MARKER AND WE HEARD A LOT OF GOOD INFORMATION THIS MORNING ABOUT INFLAMMATION AND ANEMIA OF CHRONIC DISEASE, AND SEVERAL PROTEINS ARE AFFECTED BY THAT THERE ARE OTHER CONFOUNDING PARAMETERS SUCH AS INCREASED ERYTHROPOIETIC SICKLE CELL ANEMIA AND DIFFERENT HEMOGLOBIN ON THINKS SO IN THOSE CASES TPR IS ELEVATED OPATHIES. LEAD POISONING IS A CONFOUNDING FACTOR FOR PERFORIN. FOR HEMOGLOBIN CONFOUNDING FACTORS ARE DEHYDRATION, ALTITUDE, SMOKING, PREGNANCY, SO THOSE THINGS HAVE TO BE TAKEN INTO CONSIDERATION WHEN INTERPRETING THE LABORATORY RESULTS. AS FAR AS PREANALYTICAL CONDITIONS GO TO OBTAIN A VALID SAMPLE FOR LAB ANALYSIS, THE IRON INDICATORS ARE PRESENTING A PRETTY SIMPLE STRAIGHT FORWARD SITUATION COMPARED TO MANY OTHER NUTRITIONAL BIOMARKERS THAT ARE MUCH MORE SENSITIVE TO OXIDATION TO HEAT, LIGHT, ET CETERA. SO IT REALLY CAN BE SUMMED UP IN THREE SIMPLE CONDITIONS, BLOOD NEEDS TO BE REFRIGERATED AND PROCESSED WITHIN A FEW DAYS OF SERUM COLLECTION. SERUM IS STABLE FOR FEW DAYS, RIDGE RATED AND -- REFRIGERATED AND FROZEN AT NIGH NEWS 20 AND BELOW AND SUBJECTED TO UP TO THREE CELL CYCLES WITHOUT NEGATIVELY AFFECTING THE CONCENTRATION. SO WHEN WE LOOK AT ANALYTICAL METHODS THINGS ARE STRAIGHT FORWARD FOR THE HEMOLOGIC INDICATORS, IT CAN BE MEASURED IN ANY LAB, ANY HOSPITAL, ON FULLY AUTOMATED INSTRUMENTS WITH GOOD PRECISION AND FAST THROUGH PUT AND THERE'S A FEW HAND HELD POINT OF CARE INSTRUMENTS OUT THERE THAT DO A VERY GOOD JOB AND CAN BE USED IN LOW RESOURCE SETTINGS AS WELL. THE ONLY POINT THAT I WOULD REALLY MAKE IS CAPILLARY BLOOD IS USED TO DETERMINE HEMOGLOBIN, IF SAMPLING TECHNIQUE TRAINING STANDARDIZATION HOW TO COLLECT THE SAMPLE IS SEE IN OBTAINING A RELIABLE SPECIMEN AND THEREFORE ACCURATE LAB RESULT. WHEN WE COME TO SERUM BASED BIOINDICATORS, THEY ARE MAINLY PREDOMINANTLY MEASURED AND FULLY AUTOMATED CLINICAL ANALYZERS SO IT'S A VERY HIGH USER CONVENIENCE, SIMPLE TO CONDUCT, THE PROTEINS FAIR TIN TRANSFEIGN AND SPFR ARE MEASURED BY UNIBASE ASSAYS WHEREAS THE IRON BINDING CAPACITY OR UNBOUND IRON BINDING CAPACITY ARE MEASURED CHEMISTRY ANALYZERS AND UNDERLYING PRINCIPLE IS CALORIE METRIC METHODS. THE TRANSFERENCE SATURATION IS A CALCULATED ENTITY AND PRESENTS THE PERCENTAGE OF BINDING SITES AND TRAINS PARENT MOLECULES OCCUPIED BY IRON MOLECULES. SO FOR IT YOU NEED THE MEASURED IRON AND SERUM BOUND TO TRANSFAIR RENE AND ASSESSMENT IS AMOUNT OF AVAILABLE BINDING SITES WHICH YOU CAN GET THREE WAYS BY MEASURING THE FREE BINDING SITES WHICH WOULD BE THE UIBC, THE TOTAL NUMBER OF BINDING SITES WHICH IS THE PIBC OR THE DIRECTLY MEASURED TRANSFAIR PRINT IMMUNOLOGIC ASSAY. DEPENDING WHICH ENTITY YOU MEASURE, THE TRANSFERENCE CALCULATION IS TRANSLATED APPROPRIATELY. OBVIOUSLY THERE ARE MANY ADVANTAGES TO USING THESE CLINICAL ANALYZERS FOR MEASURING THE SERUM BASED BIOMARKERS SUCH AS HIGH SAMPLE THROUGH PUT, MINIMUM OPERATOR INVOLVED GENERALLY GOOD PRECISION AND DIFFERENT COMMERCIAL KITS AVAILABLE FOR THE INSTRUMENT PLATFORM. THE COST IS RELATIVELY LOW EXCEPT TRANSFAREN RECEPTOR, PROBABLY THE BIGGEST DISADVANTAGE I WOULD POINT OUT IS THAT THE USER HAS NO CONTROL OVER LOT TO LOT VARIABILITY OR ANY ASSAY RECALIBRATION OR REFORMULATION. WHENEVER YOU'RE IN A SITUATION THAT YOU DO LONGITUDINAL MEASUREMENTS ON A SURVEY OR ON A STUDY, YOU MAY RUN INTO PROBLEMS THAT THE ASSAY CHANGED EVER SO SLIGHTLY AND IF YOU DON'T HAVE IN HOUSE CONTROL TO POINT OUT TO KNOW THE ASSAY CHANGED YOU'RE GOING TO BE IN TROUBLE WHEN YOU INTERPRET THE DATA AND OVERINTERPRET THE DATA. THE SAMPLE VOLUME COULD BE AN ISSUE THOUGH THE INSTRUMENT NEEDS ONLY 15, 20, 30-MICROLITERS TO ACTUALLY MEASURE THE SAMPLE IN BUT IT NEEDS AT LEAST 150-MICROLITERS TO SAMPLE FROM. SO WHEN YOU'RE DEALING WITH PEDIATRIC SAMPLES OR OTHER CAPILLARY COLLECTED SAMPLES REALLY DOING THEM ON CLINICAL ANALYZERS IS OFTENTIMES NOT A GOOD CHOICE. THE INSTRUMENTATION ITSELF IS MODERATELY EXPENSIVE AND REQUIRES REGULAR MAINTENANCE AND PERIODIC TECHNICAL SERVICE. SO WHEN IT COMES TO ASSAY STANDARDIZATION ISSUES WE MAINLY HAVE PROBLEMS WITH PROTEINS, THE IRON INDICATORS THAT ARE PROTEINS BECAUSE OF THE HETEROGENEITY OF THE ANOLYTE, CERTAIN, THE DIFFERENT AGE AND FORMS. THE HETEROGENEITY OF ANTIBODIES USED SOMETIMES POLYCLONAL, MONOCLONAL SOMETIMES A COMBINATION AN THOSE ARE DRIVING THE DIFFERENT EPITOPE SPECIFICITIES. THERE ARE SPECK TALL DIFFICULTIES AND NOT OVERCOME IN PRODUCING REFERENCE MATERIAL THAT IS IDENTICAL TO THE CIRCULATING SERUM FORM. SO WE'RE USING SURROGATES AND THESE SURROGATES MAYBE RESPONDING DIFFERENTLY THAN THE ACTUAL NATIVE SERUM SAMPLE. THERE IS FOR THE PROTEIN ASSAYS, THERE IS NO PHYSICAL CHEMICAL REFERENCE METHOD AVAILABLE AT PRESENT THAT ESTABLISHES WHAT WE CALL TRUE LEVELS. AND THAT'S NOT TRIVIAL BECAUSE MEASURING IS VERY DIFFICULT BY MASS SPECTROMETRY, IF YOU TRY TO DO IT BY ISOTOPE DELUSION MASS SPECTROMETRY YOU HAVE TO HAVE A STABLE LABELED PROTEIN BECAUSE OF DIFFERENT IRON SUPPRESSIONS AND OTHER THINGS GOING ON. WE DON'T HAVE THOSE COMPOUNDS AVAILABLE TO DO ISOTOPE DELUSION MASS SPECTROMETRY. THERE ARE INTERNATIONAL REFERENCE MATERIALS AVAILABLE FOR IRON STATUS INDICATORS BUT I WOULD MAKE THE POINT, DIFFERENT REFERENCE MATERIALS CAN PROVIDE DIFFERENT VALUES. FOR EXAMPLE, THE NIST REFERENCE MATERIALS GENERALLY TRY TO ASSIGN CERTIFIED VALUES, BY USING HIGH ORDER REFERENCE METHODS. IF THERE IS A -- THEY OBVIOUSLY CANNOT DO THAT. WHO INTERNATIONAL STANDARDS GENERALLY PRODUCE MATERIALS THAT ASSIGN VALUES BY CONSENSUS, BY USING COMMON CLINICAL ASSAYS. SO THAT MAY BE THE BEST THAT CAN BE DONE IN THE SITUATION IF THERE IS NO HIGH ORDER REFERENCE METHOD. BUT IT MAY NOT BE GOOD ENOUGH TO KNOW WHAT THE TRUTH IS. AS FAR AS RAISING THE COMPARABILITY OF VARIOUS ASSAYS I WOULD SAY HEMOGLOBIN AND SERUM IRON I WOULD RATE VERY GOOD TO GOOD. FERRITIN I RATE MODERATE AND SERUM TRANSFERIN RECEPTOR AS POOR COMPARABILITY. I WANT TO SHOW YOU ON THIS SLIDE HOW POOR LOOKS. THIS IS WITH THE WHO REFERENCE REAGENT, 07202 MATERIAL. AND SEVEN DIFFERENT METHODS, LABORATORY TESTS MEASURE IT, GREEN SHADED AREA BASICALLY SHOWS YOU THE FIVE METHODS USE THE SAME UNIT OF MEASURE. SO YOU CAN SEE VALUES WERE OBTAINED FROM 18 TO 100-MILLIGRAMS PER LITTER. AND -- LITER AND IF YOU CALCULATE BETWEEN THAT WE'RE TALKING 100% OR 70% DIFFERENCES. IT'S HUGE. HOWEVER, NOT ALL IS LOST. TO THE RIGHT OF THE RED SHADED AREA YOU SEE S 1, 2, 3, THESE ARE NATIVE SERUM SAMPLES. AND HERE YOU SEE THE SAME PATTERN IN THE NATIVE SERUM SAMPLE AS WITH THE REFERENCE MATERIAL SO BIG DIFFERENCES ACROSS LABS. BUT WHEN YOU USE THE INFORMATION THAT YOU GOT ON THE REFERENCE MATERIAL TO HARMONIZE OR RECALCULATE THE CONCENTRATIONS ON THE NATIVE SERUM SAMPLE YOU CAN SEE YOU CAN ACHIEVE QUITE GOOD CORRESPONDENCE. IT REDUCES THE BETWEEN LAB CB TO ABOUT 10 TO 20% WHICH ISN'T TERRIBLE CONSIDERING WHAT WE HAVE SEEN BEFORE. SO THIS IS A SMALL TEST OF COULD THIS ASSAY BE HARMONIZED, THE CDC OUR PARTNER LAB IS CURRENTLY EVALUATING IN MUCH LARGER COMMUTABILITY STUDY WHERE THEY'RE USING 20 HIGH QUALITY SERUM MATERIALS, WHETHER THE DIFFERENT TFR ASSAYS THAT ARE CURRENTLY OUT THERE, ARE COMMUTABLE FOR THE REFERENCE STANDARD AND SO COULD THEY BE HARMONIZED, COULD IMPROVEMENTS IN COMPARABILITY BE ACHIEVED. I WANT TO DEDICATE TIME TO RATIO OF TFR TO FERITEN BECAUSE THIS INDICATOR IS LESS WELL KNOWN, THERE'S SEVERAL WAYS TO EXPRESS THE RATIO AND EXISTS CONFUSION AS TO HOW TO CALCULATE, WHAT IT MEANS AND LA LABORATORY DATA CAN BE USED TO CALCULATE AND INTERPRET THE RATIO. I THINK THIS MORNING IT WAS SHOWN NICELY HOW FERITIN SENSITIVE UNTIL THE BODY IRON STORES ARE DEPLETED, WHY TFR IS SENSITIVE AFTER THE IRON STORES ARE DEPLETED. THESE TWO INDICATORS COVER THE FULL RANGE OF IRON STATUS. THIS WAS VALIDATED IN THE PHLEBOTOMY STUDY FROM THE COOK GROUP AND THEY HAVE SHOWN THE RATIO OF TFR TO FERITIN IS LINEARLY RELATED TO BODY GRAM BODY WEIGHT. SO I MENTION THERE ARE SEVERAL WAYS TO CALCULATE, THE SIMPLE RATIO IS AS THE NAME SAYS, DIVIDING TFR BY FERITIN. BODY IRON IS LOG OF TFR TO FERITIN BUT YOU HAVE A FEW CO-EFFICIENTS TO HAVE THE RELATIONSHIP AND THE TFR INDEX IS TFR DIVIDED BY THE LOG OF FERITIN. LET ME GIVE YOU MORE BACKGROUND ON EACH OF THESE. THE SIMPLE RATIO WOULD DERIVE FROM THE PHLEBOTOMY STUDY. THEY USED IN HOUSE ELISA ASSAY PUBLISHED BY FLOWERS ET ALL AT THE TIME WHICH WAS -- ET AL AT THE TIME WHICH IS EQUIVALENT TO THE RAM ASSAY. THIS IS USED BY OTHER INVESTIGATORS. IT'S A SIMPLE CALCULATION AND YOU USE THE LESS THAN 500 OR GREATER THAN 500 TO INDICATE AMPLE IRON STORES OR DEPLETED IRE STORES. THE DISADVANTAGE IS FERRITIN YOU ARE ASSAY DEPENDENT, YOU HAVE TO HAVE EITHER AN ASSAY THAT YOU KNOW THE RELATIONSHIP OF TO THE ASSAY USED WHEN THE CUT OFF WAS DERIVED OR THAT PERFORMS EQUIVALENTLY. AND THE INTERPRETATION IS ALSO CATEGORICAL. THE BODY IRON IS JUST A PROGRESSION FROM THE SIMPLE IRON MODEL WHEN YOU TAKE THE LOGARITHM AND HAVE AN EQUATION TO CALCULATE BODY IRON AS MILLIGRAMS PER KILOGRAM BODY WEIGH. THE INTERPRETATION IS SIMPLE IN THIS ONE BECAUSE YOU HAVE THE POSITIVE VERSUS THE NEGATIVE BALANCE AND THE INTERPRETATION IS CONTINUOUS. PLUS THE IRON SURPLUS OR DEFICIT CAN BE EXPRESSED PER INDIVIDUAL BODY SIZE IF YOU MULTIPLY WITH THE WEIGHT OF THE PARTICIPANTS. AGAIN, THE DISADVANTAGES, THE APPLICATION IS ASSAY DEPENDENT. WE HAVE SEVERAL YEARS AGO INDIRECTLY VERIFIED THE COMPARABILITY OF THE ORIGINALLY USED FLOWERS TFR ASSAY AND RAM TFR ASSAY AND THEY ARE COMPARABLE SO PEOPLE USING THE RAMCO ASSAY CAN USE SIMPLE RATIO OR THE BODY IRON. THEN WE ESTABLISH RELATIONSHIP BETWEEN THE FLOWERS ASSAY AND THE ROCHE ASSAY BECAUSE THE ROCHE ASSAY IS USED IN NHANES SO THEY CAN USE BODY IRON IN NHANES SO PEOPLE USING ROCHE CAN CALCULATE ESTIMATES AND INTERPRET DATA ACCORDINGLY. THE LAST INDEX THE TFR INDEX, WAS INTRODUCED BY (INDISCERNIBLE) AND CUT POINTS WERE PUBLISHED FOR THE DISTINCTION BETWEEN ANEMIA OF CHRONIC DISEASE AND IRON DEFICIENCY ANEMIA OR COMBINATION OF THE TWO CONDITIONS. THIS INDEX HAS BEEN ADOPTED ON THE ACCESS BECKWIN CUOLTER INSTRUMENT. THE DISADVANTAGE AS IN THE PREVIOUS TWO CASES IS THAT WERE ASSAY DEPENDENTS SO WITH THAT PARTICULAR ASSAY YOU CAN USE THESE CUT OFFS BUT OTHER ASSAYS YOU HAVE TO ADJUST THE DATA FOR NO RELATIONSHIP. SO I'M MOVING THEN TO LAST PART OF MY TALK. IS THE IRON STATUS SPECIMEN NHANES. SO HEMATOLOGIC INDICATORS HAVE BEEN ASSESSED THROUGHOUT TIME IN NHANES, HEMOGLOBIN AND HEMATOPOIESIS HAS ALWAYS BESURED AND ALWAYS WILL BE. OTHER PARAMETERS FROM THE CDC WERE STARTED WITH NHANES 2. THEN IN NHANES 1 A FEW BIOCHEMICAL INDICATORS WERE INTRODUCED, NAMELY SERUM IRON AND TOTAL BINDING CAPACITY AND THE TRANSFER TIN SATURATION AND N HAZE TESTIMONY ERYTHROCYTE FOR FOREIGN WAS ADDED. SO THE EARLY STAGE OF IRON DEFICIENCY WERE NOT CAPTURED BY THESE INDICATORS, BUT THEN BY THE TIME NHANES 3 CAME ABOUT IN 1988, THE FERRITIN MODEL WAS INTRODUCED. SO THAT MODEL MEASURED FERRITIN, TRANSFARIN SATURATION AND ERYTHROCYTE PERFORIN SO THE MODEL HAD TO OVERCOME THE MISS CLASSIFICATION WE HAVE WITH SINGLE INDICATOR MODEL AND IT WAS USED IN HAVING TWO ABNORMAL VALUES FOR TWO OF THREE INDICATORS AND CLASSIFYING A PERSON AS IRON DEFICIENT. FINALLY IN 2003, THE BODY IRON MODEL WAS INCLUDED IN NHANES AND FOR A FEW YEARS THERE WAS OVERLAP BETWEEN FERRITIN AND BODY IRON MODEL TO COMPARE THE TWO. CURRENTLY THE BODY IRON MODEL IS STILL CONTINUED IN NHANES. THE DRIVE TO SWITCH FROM THE FERRITIN MODEL TO THE BODY IRON MODEL WAS MANY FOLD. ONE REASON WAS THAT IT WAS BELIEVED WITH THE BODY IRON MODEL WE CAN GET A BETTER ASSESSMENT OF THE FULL RANGE OF IRON STATUS. ANOTHER ONE WAS A LOGISTIC CONSIDERATION THAT SOME OF THE ASSAYS USED IN THE FERRITIN MODEL SPECIFICALLY THE ERYTHROCYTE PERFORIN WAS NO LONGER BEING WIDELY USED. AND ANOTHER CONSIDERATION WAS ALSO THE WHO RECOMMENDATION THAT RECOMMENDED TO HAVE FERRITIN AND TFR DATA ON DIFFERENT POPULATION STUDIES SO THAT INTERPRETATION CAN BE COMPARED FROM ONE COUNTRY TO ANOTHER. HERE I HOME THE DIFFERENCES IN THE MODEL INTERPRETATION. THE FERRITIN MODEL DOES NOT INDICATE THAT THE DEGREE OR SEVERITY OF THE IRON DEFICIENCY, IT MAY ASSESS SLIGHTLY LATER STAGE DEFICIENCY THAN PRESENCE OR ABSENCE OF BONE MARROW IRON STORES. SO RESULT IN A LOWER PREVALENCE THAN SERUM FERRITIN ALONE. THE MODEL MAY DETECT IRON DEFICIENT ERYTHROPOIESIS IN ADDITION TO IRON STORE DEPLETION AND PRODUCES CATEGORICAL YES, NO, ESTIMATES. THE BODY IRON MODEL ASSESSES THE RANGE OF THE IRON STATUS, DERIVED FROM A DIRECT CALCULATION FROM SERUM PHLEBOTOMY A GOLD STANDARD METHOD TO ASSESS BODY IRE AND BETTER PREDICTS ABOUT OF BONE MARE -- IRON THAN SERUM ALONE AND PROVIDE A BETTER ESTIMATE OF THE IMPACT OF IRON INTERVENTION AS FAR AS AMOUNT OF IRON ABSORBED. THEN LASTLY, IT CAN BE ANALYZED ADS A CONTINUOUS VARIABLE. ON THIS SLIDE I SHOW YOU THE DIFFERENT OUTPUTS FROM NHANES AND WHAT THE DATA WERE USED FOR. SO THE DATA IN NHANES 2 WERE VERY EXTENSIVELY ANALYZED TO ASSESS DIFFERENT MODELS AND IN THE END TO DECIDE ON USING THE FERRITIN MODEL GOING FORWARD AND VALIDATING THE MODEL. AND A CONVENIENT SAMPLE FROM NHANES 3 WAS USED TO VALIDATE THE BODY IRON MODEL GOING FORWARD. I MENTION THAT THERE WAS A TIME OF OVERLAP BETWEEN 2003 AND 2006 WHEN BOTH MODELS WERE USED AND COMPARED, THAT WAS DONE IN THE COXWELL PAPER IN CHILDREN AND NON-PREGNANT WOMEN. AND IN THE (INAUDIBLE) PAPER THE IRON STATUS USING THE BODY IRON MODEL WAS ESTABLISHED FOR PREGNANT WOMEN. FOR THAT WE WENT BACK AND ANALYSESSED IN SHUSH PLUS SAMPLES FROM PREGNANT WOMEN TFR SO THAT WE COULD HAVE MANY MORE YEARS OF DATA. TO INCREASE THE SAMPLE SIZE. FINALLY WE HAVE AN ANALYSIS FOR THE TFR REFERENCE RANGES IN CHILDREN AND IN PREGNANT WOMEN BASED ON I BELIEVE EIGHT YEARS OF NHANES DATA. WITH THAT I'M SUMMARIZING THE THREE MAIN CHALLENGES IN DETERMINING IRON STATUS, ONE, LABORATORY ASSESSMENT RELIES ON SEVERAL BIOCHEMICAL INDICATORS, THE DIAGNOSIS OF IRON DEFICIENCY THROUGH SERUM FERRITIN IS COMPLICATED BY CONCOMITANT INFLAMMATION AND THE LACK OF STANDARDIZATION FOR TFR, A NEWER INDICATOR FUNCTIONAL IRON DEFICIENCY THAT IS LESS AFFECTED BY INFLAMMATION RESULTS IN REFERENCE RANGES AND CUT POINTS. SO IN TERMS OF RESEARCH NEEDS FOR IRON STATUS INDICATORS, I WOULD DEFINITELY SAY THAT HARMONIZATION OF TFR ASSAYS TO INCLUDE COMPARABILITY IS A TOP PRIORITY. THE IMPROVEMENT IN COMPARABILITY FOR FERRITIN ASSAYS IS DEFINITELY RELIABLE -- DESIRABLE, SORRY, COMING FROM THE FOLATE FIELD I CAN TELL YOU THAT FOLATE IS IN MUCH WORSHIP THAN FERRITIN, WHEN I LOOK AT FERRITIN ASSAYS THEY LOOK PRETTY GOOD TO ME. BUT THEN I'M VERY DAMAGED COMING FROM FOLATE. ULTIMATELY IT -- WE REALLY HAVE TO STRIVE TO DEVELOP HIGHER ORDER REFERENCE METHODS AND CERTIFIED REFERENCE MATERIALS BUT IT'S NOT AN EASY TASK AND IT WILL TAKE YEARS. THEN TO PUT THE THOUGHT IN YOUR HEAD ABOUT THE NEED TO HAVE SOME RELIABLE ASSAYS THAT CAN MULTIPLEX AND MEASURE MULTIPLE IRON STATUS INDICATORS USING A MINIMUM SPECIMEN VOLUMES MORE LIKE 10, 15 MICROLITERS AND THE EMPHASIZE IS ON RELIABLE -- UNRELIABLE. SOME THINGS ARE OUT THERE, THEY'RE OKAY BY CAN BE IMPROVED, I BELIEVE. SO WITH THAT, I WANT TO THANK THE PEOPLE THAT CONTRIBUTED TO THIS SUMMARY AND FOR YOUR ATTENTION. >> WE HAVE A COUPLE OF MINUTES FOR QUESTIONS, WHILE PEOPLE ARE COMING TO THE TABLE. I KNOW YOU TOP HEAP SIDEN OFF THE TABLE. HOW DO YOU THINK ABOUT THE ANALYTICAL ISSUES SURROUNDING HEPSIDEN. QUICKLY. THINK FAST. SO BASICALLY, FOR HEAPSIDEN WE HAVE LESS IN TERMS OF REFERENCE MATERIALS OR METHODS THAN FOR THE OTHER ASSAYS SO THERE IS EVEN MORE NEED FOR THAT. AS FAR AS I UNDERSTAND, YOU HAVE TO MEASURE IT BY MASS SPECTROMETRY, SO THERE'S A HIGHER LEVEL HIGHER DEGREE NEEDED FOR IT. >> COMMENT ON THAT. SO TWO KINDS OF ASSAYS, ONE IS MASS SPECTROMETRY, THE OTHER IS ELISA. THEY CAN DEHARMONNIZE, SO THERE WILL BE AN ASSAY. BUT REGARDING OUR STANDARD ASSAYS ONE PROBLEM WITH THE FERRITIN ASSAY, IT'S AN ENTIRELY EMPIRIC ASSAY, WE HAVE NO IDEA WHY IT WORKS OR WHAT THE PHYSIOLOGIC CONNECTION IS TO IRON STORES. WE HAVE NO IDEA WHAT THIS STUFF IS EVEN BEING SECRETED. FROM POINT OF VIEW OF FUNCTIONAL BIOLOGY THIS IS AN EMPIRIC ASSAY, A WEAK CONNECTION FOR FUNDAMENTAL BIOLOGY, UNLIKE TRANSFER RENNES SATURATION AND OTHERS. THAT'S WEAKNESS ESPECIALLY TRYING THE ANALYZE IN ANIMAL MODELS. >> FOLLOWING THAT POINTS, DO YOU THINK THERE'S A NEED OR APPROPRIATENESS TO DEVELOP A FERRITIN SATURATION ASSAY? AND HOW DO YOU -- HOW DO WE GO ABOUT IT CONSIDERING SUCH CAPACITY FOR IRON STORAGE BUT WHEN WE'RE MEASURING FERRITIN WE'RE USING AS AN INDIRECT ME MEASURE OF IRON. HOW DO WE GO ABOUT DOING THAT? >> I WOULDN'T KNOW, I HAVE NEVER CONSIDERED THE QUESTION SO I'M NOT SURE WHAT HAS BEEN SHOWN FROM MY UNDERSTANDING THE CIRCULATING SERUM FERRITIN CORRELATES WELL WITH THE IRON STORES. SO I'M NOT SURE WHY YOU WOULD NEED THE FERRITIN SATURATION ASSAY. >> JUST AN IDEA WHETHER FERRITIN OR CIRCULATING FERRITIN HOW LATENT IT IS WITH IRON, WITHIN CERTAIN COMPARTMENTS OF THE CELL THE SATURATION OF FERRITIN VARIES SIGNIFICANTLY. WONDERING IF IT WOULD IMPROVE THE ACCURACY OF THE ASSAYS GIVEN CIRCULATING FERRITIN IF WE HAD AN IDEA HOW MUCH IRON WAS DIRECTLY ASSOCIATED WITH THE PROTEIN. >> THAT WILL BE THE LAST QUESTION. >> KY COMMENTS ON THIS? SECRETED FERRITIN IS POOR IN IRON. SO LOOKING AT IF YOU CAN MEASURE IT RELIABLY, IT WOULDN'T BE A GREAT INDICATOR, SO IT TEASE PROTEIN THAT'S IMPORTANT RATHER THAN THE IRE IN SERUM FERRITIN. >> THANK YOU, CHRISTINE, VERY MUCH. [APPLAUSE] OUR NEXT PRESENTER IS ANDY HOOFNAGLE. CLINICAL PERSPECTIVES. >> THANK YOU TESTIMONY AS CHRIS MENTIONED I'M A CLINICAL PATHOLOGIST, I HELP RUN THE CLINICAL LAB AT THE UNIVERSITY OF WASHINGTON MEDICAL CENTERS. AND SHE ASKED ME TO COME AND GIVE A PERSPECTIVE OF IRON DEFICIENCY TESTING FROM THE CLINICAL LAB. I WILL TRY TO EXPAND INTO HOW I HOPE WE AS CLINICAL PATHOLOGISTS CAN HEMIFIELD OF RESEARCH. I PUT THE APPLE WITH A BUNCH OF NAILS IN IT. THERE'S FOLKLORE ABOUT HOW TO TREAT ANEMIA AND THE OLD DAYS THEY USED TO STICK NAILS IN THE APPLES AND LEECH OUT THE IRON FROM THE NAIL INTO THE APPLE AND YOU WOULD EAT THE APPLE AND YOU WOULD TREAT THE WEAKNESS WHICH I THOUGHT WAS INTERESTING. ANYBODY HEARD OF THE FOX FIRE BOOK? IT'S THE APPROXIMATE LAY SHAH VERSION OF GOOD HOUSEKEEPING. THEY SUGGEST USING A KERNAL OF CORN DIPPED IN CHICKEN BLOOD AS A CURE YOUR PALLOR REIN WEAKNESS AND CURE FOR AN EAR ACHE. SO I WILL START WITH DEFINITION, AS CHRISTINE SAID WE HAVE BASE. OFFICE AND CUBICLE WITH NO WINDOWS, NICE TO GET OUT ONCE IN WHILE BUT WE LIKE TO RELY ON DEFINITION SO WANT TO DEFINE THE WORDS CHRISTINE USED AND EXPAND UPON THEM. SHE PROVIDE AD GREAT FOUNDATION. FIRST IS ACCURACY. I KNOW THAT WE USE THAT WORD ALL THE TIME. WHEN THINKING TRYING TO DO EPIDEMIOLOGICAL STUDIES AND COMPARE BETWEEN ONE ANOTHER IT'S NICE KNOW WHAT THE TRUTH IS, WHEN WE THINK DEFINITION OF ACCURACY, CLOSENESS AND AGREEMENT BETWEEN TEST RESULT AND TRUE RESULT WE CAN THINK WHAT WOULD MAKE TEST RESULT INACCURATE. THEY'RE BASICALLY TWO THINGS. ONE IMPRECISION. AND WHEN WE THINK ABOUT IMPRECISION WE CAN THINK ABOUT THE IMPRECISION WITHIN THE BATCH BETWEEN BATCHES, IN OTHER WORDS FROM DAY TO DAY, OR BETWEEN LABORATORY, OUR LABORATORY VERSUS THE CDC AS AN EXAMPLE. WE CAN EVEN EXPAND UPON THAT. DIFFERENT PLATFORMS, WE TALKED ABOUT ROCHE VERSUS BECKMAN, HOW DIFFERENT ARE THE ASSAYS RUNNING ONE SAMPLE BETWEEN THOSE DIFFERENT LABS AND PLATFORMS. THE OTHER IS BIAS. WE HAVE TO CALIBRATE OUR ASSAY. WILL GO INTO MORE DETAIL LATER BUT TURN SIGNAL FROM ASSAY INTO A CONCENTRATION AND WHAT WE USE WITHCAL BRAYTORS IS IMPORTANT FOR NUMBER AND CONCENTRATION ACTUALLY SEE. AND OF COURSE THERE'S SAMPLE SPECIFIC MATRIX EFFECTS. WE JUST TALKED ABOUT HARMONIZING ELISA TO A MASS SPEC ASSAY, BUT THERE ARE SAMPLE SPECIFIC MATRIX THAT WILL NOT AFFECT THE MASS SPEC ASSAY AND VICE VERSA. THERE ARE BIASES FROM THE TRUE RESULTS THAT HAPPEN JUST BASED ON SOMETHING THINGS THAT INTERFERE IN EACH MATRICES. WHAT WE'RE TRYING TO PROVE, WHAT WE MEAN BY ACCURATE HOW CLOSE WILL RESULT BE IN SEATTLE ON THURSDAY VERSUS LONDON ON MONDAY? WHEN I HAVE BEEN THINKING ABOUT THE WORD ACCURACY, THIS IMAGE POPPED INTO MY HEAD. I DON'T KNOW WHY BUT ONCE I THOUGHT ABOUT THIS IMAGE SUDDENLY ANOTHER, IMAGE POPPED INTO MY HEAD. AND THAT IS ALL I'LL SAY ABOUT THAT. WE ALSO USE HARMONIZATION. WHAT I TRIED THE DO USING THE BULLS EYE HERE IN THE BOTTOM RIGHT HAND CORNER IS TO TELL YOU WHAT I THINK ABOUT HARMONIZATION, WHAT WE'RE TRYING TO DO IS MAKE RESULTS AS CLOSE AS POSSIBLE. AS AN EXAMPLE, WE HAVE DIFFERENT PLATFORMS IN THE SAME LABORATORY AND GIVE THE SAME RESULT. THE SAME PLATFORM IN DIFFERENT LABORATORY IT IS OR DIFFERENT PLATFORMS IN DIFFERENT LABORATORIES, WE WANT THEM TO SAY THE SAME THING BECAUSE WE WANTS COCOMPARE POPULATIONS BETWEEN THEM, HOW DO WE HARMONIZE THING? WE CAN USE A NON-CERTIFIED REFERENCE MATERIAL, WE CAN AGREE WITHIN CONSORTIUM, SOMETIMES DIFFICULT TO DO BUT AGREE TO AGREE, WE CAN RECALIBRATE TO SINGLE CENTRAL LABORATORY THIS IS ONGOING IN DIFFERENT U STUDIES. BUT WE HAVE TO AGREE AS A CONSORTIUM THAT THIS IS HOW WE'RE GOING TO MOVE FORWARD. THE GOAL SO TO IMPROVE BETWEEN PLATFORM CONCORDANCE. WE MAY NOT BE RIGHT, MAY NOT BE THE TRUE ANSWER. AN EXAMPLE OF WHAT WE'RE TRYING TO FIX, THIS IS EXACTLY THE SAME FDA APPROVED IMMUNOASSAY RUN IN TWO LABORATORIES ONE IN LA AND ONE IN LONDON. AS YOU CAN SEE BY THE LINEAR REGRESSION, THEY'RE ON AVERAGE 40% DIFFERENTED AND R SQUARED IS .66 HARD TO IMAGINE THIS IS THE SAME ASSAY. IT'S EXACTLY THE SAME. THIS IS A DIFFERENT STORY SO DOES THIS AFFECT PATIENT CARE, IS IT A PROBLEM TO HARMONIZE RESULT? WE HYPOTHYROIDISM WITH TSH, IF YOU LOOK AT THE THREE HOSPITALS THAT ARE WITHIN A HALF MILE APART, IN THE CITY OF SEATTLE THEY HAVE THREE PLATFORMS THEY'RE RUNNING SO IF YOU HAD YOUR TSH RUN AT HARBOR VIEW, IF THE CUT OFF IS AGREED TO BE FIVE WHICH THERE'S DEBATE A AROUND THAT BUT IF YOU MEASURE AT HARBOR VIEW VERSUS VIRGINIA MASON, YOU CAN SEE TWO YOU WALK AWAY BEING PERFECTLY NORMAL THYROID FUNCTION. YOU MIGHT WACKER AWAY WITH -- TREATED FOR HYPOTHYROIDISM SO IT AFFECTS PATIENT CARE, SOMETHING WE NEED TO KEEP IN MIND. ONE STEP BEYOND HARMONIZATION IS STANDARDIZATION. HERE WHAT WE ARE TRYING TO DO IS WE WANT EVERYBODY TO HIT THE BULL'S EYE, WE WANT EVERYBODY TO BE RIGHT. THE WAY WE DO THIS IS DEVELOPING REFERENCE PROCEDURES. THINGS WE CAN HANG OUR HAT ON. WE KNOW THIS METHOD WILL GIVE US AS CLOSE TO AN ACT CHAT RESULT AS IS -- ACCURATE RESULT AS IS POSSIBLE AT THIS MOMENT. WE USE CERTIFIED REFERENCE MATERIALS WHICH I WILL GO INTO MORE DETAIL LATE AND FINALLY WHEN WE DO OUR CALIBRATION IN THE FIELD, WHEN YOU'RE RUNNING IN TO THE CLINICAL LABORATORY WE USECAL BRAYTORS THAT ARE TRACEABLE TO THE CERTIFIED REFERENCE MATERIAL. WE TRY TO HAVE A CENTRALIZED PLACE THAT TELLS PEOPLE HOW THEY'RE DOING, THIS CALLED CERTIFICATION PROGRAMS SO THERE'S A VITAMIN D STANDARDIZATION PROGRAM, HORMONE STANDARDIZATION PROGRAM RUNOUT OF CDC AND HEMOGLOBIN A 1C PROGRAM THE MGSP THAT HELPS US DIAGNOSE DIABETES. SO WE HAVE TO USE AT THE OUTSET, WHAT WE THINK IS GOING TO BE AN ACCEPTABLE METHOD AND FINALLY, GENERATE COMMUTE IT WILL MATERIALS, I WILL DEFINE THAT IN A SECOND TOO. SO I'M PART OF AMERICAN COLLEGE OF PATHOLOGISTS ACCURACY BASED WORKING GROUP AND WE HAVE BEEN WORKING A LONG TIME ON PROFICIENCY TESTING USING COMMUTABLE SAMPLES, TRYING TO MAKE SURE EVERYBODY HITS THE BULLS EYE DAY AFTER DAY AFTER DAY AFTER DAY. SO AFTER A STANDARDIZATION OR CERTIFICATION PROGRAM HOW DO WE MACK SURE CLINICAL LABS ARE DOING WELL. THE IDEA IS ON REGULAR WE SEND OUT DIFFERENT SAMPLES, MIGHT BE SOME MATRIX THAT HAVE BEEN SPIKED, MIGHT BE STALIZED HUMAN SAMPLES WHICH INCLUDES ADDING PROPYLENE GLYCOL OR SOMETHING LIKE THAT. IDEALLY, WE'RE USING MINIMALLY PROCESSED NATIVE HUMAN SAMPLES. EXAMPLES OF PROFICIENCY TESTING SCHEMES COLLEGE OF PATHOLOGISTS OR OTHERS THAT ALLOW CLINICAL LABORATORIES TO MAKE SURE THEY HAVEN'T DRIFTED OVER TIME. AT THE HEART OF MEDICINE IS PRECISION. THAT IMPRECISE ASSAY VERSUS A PRECISE ASSAY, WE WANT OUR ASSAY TO BE PRECISE AND LINEAR BECAUSE WE WANT TO KNOW IF INCREASE THE BIOMARKER I INCREASE THE RISK FOR SOMETHING ELSE. PART OF THE REASON THAT CHRISTINE MENTIONED HOW FRUSTRATING IT CAN BE TO WORK WITH FDA APPROVED IMMUNOASSAYS IS BECAUSE WE HAVE NO CONTROL OVER REAGENTS. WE GET WHAT WE GET. AS YOU CAN SEE HERE FROM DATA FROM THE CDC IT NHANES MEASURING VITAMIN D YOU CAN SEE THAT THERE'S LOTS OF VARIABILITY SO THAT INTRODUCES IMPRECISION IN THE EPIDEMIOLOGICAL STUDIES THAT WE'RE TRYING TO DO TO UNCOVER THE TIE BETWEEN BIOMARKER AND OUTCOMES. WHAT DOES IMPRECISION DO TO TRUST IN MEASUREMENTS FROM CHRIS SAMPOS AND JOYCE, SAY WE SET CUT OFF OF 30 NANOGRAMS PER ML AND GIVEN VARIABILITY IN OUR MEASUREMENTS, SAY WE ACCEPT A VARIABILITY OF 10%, YOU CAN -- EVERYTHING IS QUITE BLURRY, DID THAT MESS ANYBODY UP? SOMEBODY CLEANING THEIR GLASSES AFTER THAT. THE POINT BEING IMPRECISION LEADS TO BLURRING OF WHAT WE HOPE TO BE GOOD CUT OFF. IF I SAY THE MEASUREMENT IS 30, MY 95% CONFIDENCE INTERVAL AT 10% CV IS SOMEWHERE BETWEEN 24 AND 36 SO WHAT DOES IT HAVE TO DO THE PATIENTS. I'M GOING THE TALK REFERENCE RANGES NOW. BECAUSE INTERPRETATION OF CLINICAL BIOMARKER OR LABORATORY RESULTS BEGINS WITH A REFERENCE RANGE. IN FACT YOU CANNOT REPORT A RESULT WITHOUT A REFERENCE RANGE ACCORDING TO COLLEGE OF AMERICAN PATHOLOGISTS. SO HOW DO WE SET A REFERENCE RANGE? TURNS OUT I GET TO DO WHAT I WANT, I THE CLINICAL LAB DIRECTOR DECIDES WHAT THE REFERENCE RANGE IS GOING TO BE, I CAN READ A TEXTBOOK, 100 PAPERS MEASURE THE BIOMARKER IN 120 PEOPLE AND PICK AND EXCLUDE OUTLIER AND CALL THAT NORMAL. BUT REMEMBER WHEN I SAY SOMETHING IS NORMAL, EVERYTHING ELSE IS ABNORMAL. THERE ARE EXCEPTIONS. FROM INTELLIGENT PEOPLE WHO DO LOTS OF AWESOME STUDIES AND TELL US WHAT THE CUT OFF SHOULD BE. I GET TO USE THE CUT OFF AS AN EXAMPLE, ABOVE 10 NANOGRAMS PER ML, YOU ARE AT INCREASE RISK OF DISEASE, SET IT AT 10 AND POINT TO THE GUIDELINE. OR BELOW 8 PICO GRAMS PER ML INDICATE SEVERE DEFICIENCY I CAN POINT TO THE GUIDELINE AND USE IT AS MY CUT OFF. SO LET ME TALK FOR A MOMENT ABOUT USING DISTRIBUTION. IF I USE THE CENTRAL 95% OF NORMAL REFERENCE POPULATION, THAT MEANS TWO AND A HALF PERCENT ARE GOING TO BE ABNORMALLY LOW AND TWO AND A HALF ARE ABNORMALLY HIGH BY DEFINITION 5% OF EVERYBODY ABNORMAL. 20 THINGS IN YOU, ONE OF THEM IS GOING TO BE ABNORMAL AND BY CHANCE. THIS IS WHAT WE'RE STUCK WITH IN THE LABORATORY,CAN BE FRUSTRATING. WHAT IS THE CUT OFF BELOW WHICH THERE'S BAD OUTCOME, THE HIGH -- UPPER CUT OFF ABOVE WHICH THERE'S RISK OF TOXICITY, LET'S USE THOSE CUT OFFS. I LIKE THAT APPROACH, I THINK IT'S FANTASTIC. THEN I DON'T HAVE TO RELY ON DOING THE REFERENCE RANGE STUDY MYSELF. I GET TO RELY ON SOMETHING THAT INTELLIGENT PEOPLE TELL ME. BUT I WANT YOU TO REMEMBER THAT NOW THERE'S THE TOP AND THERE'S A BOTTOM. LET'S GO NOW FOLLOW THAT FOR JUST A MOMENT. IF WE THINK ABOUT A SINGLE LABORATORY AND WE HAVE A DISTRIBUTION OF RESULTS WE EXPECT, WE INTRODUCE BIASES THAT WE SEE BETWEEN LABORATORIES AND THEN WE ADD IMPRECISION INTO EACH OF THOSE. ANY ABOUT THE RESULTS IN MY CLINICAL POPULATION. THIS IS THE POPULATION IN THE EXPERIMENT I DID TO ESTABLISH CUT OFF. BUT THIS BLUE LINE DOWN HERE IS THE ACTUAL DISTRIBUTION WE OBSERVE ACROSS OUR PATIENT POPULATION. SO EVEN THOUGH WE ESTABLISH CUT OFFS WE HAVE TO REMEMBER THAT IT'S A LITTLE BLURRY. WE'RE TRYING TO TREAT JUST LIKE ALEX WAS SAYING TRYING THE TREAT TO POPULATION. WE CAN'T FORGET WE HAVE INDIVIDUALS IN OUR OFFICE THAT WE'RE TREATING WE HAVE TO SET A CUT OFF FOR THE POPULATION RECOGNIZING THAT THERE'S SOME BLUR. SO ANOTHER EXAMPLE, WHAT DOES IT MEAN TO HAVE A CUT OFF AND GO INTO PRODUCTION? GREAT EXAMPLE IS TROPONIN. SO WE HAVE A CLINICAL CUT OFF WHICH ALMOST COMPLETELY DISCRIMINATES BETWEEN THOSE THAT HAD MYOCARDIAL INFARCTION TO THOSE THAT HAVEN'T IN CERTAIN STUDIES. ONCE DEPLOYEDED IN THE FIELD IT BECOMES OVERLAP, PATIENTS WHO HAD A MYOCARDIAL INFARCTION MIGHT BE NEGATIVE, THOSE WHO HAVEN'T POSITIVE. WHAT DOES IT MEAN? THE PATIENTS GO TO THE CATH LAB AND GET TREATED THOUGH THEY DIDN'T IN MYOCARDIAL INFARCTION. SO WE HAVE REFERENCE RANGES LIKE I SAID, I WANTED TO PUT THIS UP BECAUSE FOR MANY OF THE HEMOTO LOGICAL MEASUREMENTS WE'RE TALKING ABOUT, WE HAVE MALE VERSUS FEMALE REFERENCE RANGES WHICH IS GREAT. FOR SOME WE DON'T. IRON YOU WOULD EXPECT BUT IT'S HARD THE GET A BIG ENOUGH POPULATION TO BEGIN TO SEPARATE ANOTHER THE GENDERS AND SOME OF THESE WERE SET MANY YEARS AGO. SO WE HAVE THESE, TA THAT'S GREAT BUT WHAT I FIND FASCINATING, TRUE FOR EVERYTHING NOT JUST IRON BUT IRON IS EXAMPLE, IF YOU START TO COMPARE REFERENCE RANGES FROM INSTITUTION TO INSTITUTION, MAYO REQUESTS AN REP OF LARGE REFERENCE LABORATORIES IN THE UNITED STATES, AND AS YOU CAN SEE WE'RE ALL KIND OF AGREEING ON THE LOWER LIMIT FOR MALES AND ALL AGREEING ON UPPER LIMIT FOR FEMALES, UNTIL YOU GET TO AREA P. THIS IS SALT LAKE CITY, THEY LOWER LIMIT FOR MEALS IS HIGHER AND THE UPPER LIMIT FOR FEMALES IS HIGHER THAN YOU EXPECT AS WELL. SCRATCH YOUR HEAD, GOLLY, IS BIOLOGY DIFFERENT THERE? IF YOU EXPAND YOUR SEARCH TO COLORADO AND YOU GO FROM 4200 FEET ABOVE ELEVATION TO ONE MILE, YOU CAN SEE AGAIN, AT ELEVATION THE NORMAL POPULATION HOW REFERENCE RANGE ARE DEVELOPED HAVE HIGHER HEMOGLOBIN LEVELS BECAUSE THEY'RE BREATHING FASTER BECAUSE THERE'S LESS OXYGEN SO IF WE USE HEMOGLOBIN TO DEFINE ANEMIA AND I VISIT COLORADO AND SKI LIKE I DOND A TAKE MY BLOOD, I WILL BE ANEMIC WHICH IS UNFORTUNATE BECAUSE I DON'T THINK I AM. BUT THAT'S ME LIVING AT SEA LEVEL 26 FEET ABOVE SEA LEVEL IN SEATTLE. IMPORTANT TO REMEMBER KIDS AREN'T LITTLE ADULT SO BIOMARKERS IN 1 TO 3 YEARS OF AGE ARE DIFFERENT THAN WE SEE IN ADULTS SO HERE, JUST LOOK AT THE DIFFERENCE BETWEEN UDUB AND MAYO FOR UP PER LIMIT OF FERRITIN IN FEMALES AND AREA P FOR CHILDREN, HOW DID THIS HUNDRED, SEEM AS ROUND NUMBER, HOW DID THEY PICK THAT? SO CHRISTINE TALKED PERCENT TRANSFER RENNES SATURATION. THESE ARE ROUND NUMBERS, VERY ROUND NUMBERS, THERE'S NO DIFFERENCE IN BETWEEN MALES AND FEMALES IN MALE AREA P, QUEST IN KIDS VERY DIFFERENT. LET'S THINK ABOUT ADULTS. SHOULDN'T THE PERCENTAGES BE THE SAME? THE ANSWER IS YOU'RE DIVIDING TWO LAB RESULTS. SO THE TRANSFARIN, IRON VARIABILITY BETWEEN LABORATORIES , THERE WILL BE DIFFERENCES IN CALIBRATION, SO EVEN A PERCENT WOULD YOU EXPECT TO BE THE SAME BECAUSE YOU'RE NORMALIZING IN SOME WAY. SO I WANT TO TALK CURRENT STATE OF BIOMARKERS IN CLINICAL CARE AND TO DO THAT I WILL LOOK AT THE RESULTS OF THE PROFICIENCY TESTING THAT WE DO AT THE COLLEGE OF AMERICAN PATHOLOGISTS. AND SO JUST AS AN EXAMPLE I WILL START WITH SODIUM BECAUSE IT'S AS GOOD AS IT GETS, THIS IS NOW DATA FROM 6,028 LABS. THEY HAVE ALL SENT BACK RESULTS OF SAMPLES WE HAVE SENT TO THEM AND TELLING US WHAT THEY GOT. FOR INSTANCE THERE'S 511 AVID ARCHITECTS AND THE CV BETWEEN THEIR ASSAYS IS .7 SO THAT'S THE STANDARD DEVIATION DIVIDED BY THE MEAN. .7% WHICH EVEN ACROSS ALL OF THESE METHODS IS 1.7%, THAT'S AMAZING. SO THAT'S AS GOOD AS IT GETS IN CLINICAL CHEMISTRY. THOSE NUMBERS WERE SMALL, MEANT TO BLOW IT UP. YOU CAN SEE VERY GOOD CV. HEMOGLOBIN, FANTASTIC AS WELL. ACROSS 584 LABS WE SEE A VERY LOW CV, BETWEEN THE METHODS IS 1.8 FANTASTIC ASSAY. IRON MEASUREMENTS NOT AS GOOD, LOOK AT THE ALL METHOD MEAN FOR IRON WE'RE UP TO 7.7%. 10% IS 95% CONFIDENCE INTERVAL IS WIDE SO 7.3 WE'RE GETTING THERE. SO IT'S NOT AS GOOD. IT REALLY DEPENDS ON WHAT METHOD YOU USE, YOU WILL SEE HERE THESECLERY METRIC MEASUREMENTS HERE, INTRA, THE SAME PLATFORM DEPLOYED IN LABORATORIES HAS A CV OF ALMOST 15%. SO IRON ISN'T THE SAME EVERYWHERE. THE FERRITIN, THIS IS OUR -- HANGING OUR HAT ON THE FERRITIN. I DON'T KNOW IF YOU GUYS SATURDAY NIGHT LIVE WHEN YOU WERE A KID BUT MR. BILL WAS MY FAVORITE, I DON'T KNOW IF YOU SAW HIM GET GROUND UP BY A BLENDER, FANTASTIC, STILL TO THIS DAY, THIS IS AN AVID ARCHITECT. THE MEAN THAT WE'RE GETTING IN FERRITIN DIFFERS 103 VERSUS 77. BOTH FDA APPROVED ASSAYS, THEY'RE BOTH MADE BY THE SAME MANUFACTURER. AND THEY'RE NOT CALIBRATED THE SAME. SO THIS LEADS YOU TO A PERCENT CV IN REAL LIFE, 2016 DATA, A PERCENT CV OF 17%. THINK ABOUT THE 95% CONFIDENCE INTERVAL OF MEASUREMENT WITH A CV OF 17%, IT'S 2-POINT -- SORRY, TWICE THAT. SO THE RANGE IS GIGANTIC. I MENTION CALIBRATION. ONE SOURCE OF BIAS BETWEEN THE PLATFORMS AND BETWEEN LABORATORIES IS HOW WE CAB OPERATE OUR ASSAY, THE JOB IS TO MEASURE DIFFERENT SAMPLES OF KNOWN CONCENTRATION, DEVELOP A CALIBRATION CURVE, TAKE A SIGNAL FROM UNKNOWN, AND TRACE THAT BACK TO A SPECIFIC CONCENTRATION. THIS IS WHAT WE LIKE CALIBRATION CURVES TO LOOK LIKE. TWO TIMES CONCENTRATION OF ANOLYTE, THICKS ARE GOING TO BE MUCH LESS PRESIZE. IDEALLY WE MAKE A REFERENCE METHOD PROCEDURE. THE GOAL OF THIS IS TO ASSIGN ACCURATELY WHAT THE ANOLYTE CONCENTRATION IS, THEY'RE LABORIOUS, TAKE DAYS. THEY USE A TON OF SAMPLE VOLUME THAWS THEY DOING IT IN REPLICATE AND NOT REALLY AVAILABLE FOR MANY PROTEINS. SO HEMOGLOBIN BECAUSE OF ITS -- THE HEME IN THE HEMOGLOBIN WE CAN USE SPECTRA TO TOMTRY, IRON, THERE'S COOL CHEMISTRIES WE CAN USE SPECTRA FOE TOMTRY, THERE'S NOS FOR TRANSFER REIN RECEPTOR. FOR STANDARD REFERENCE MATERIALS THIS IS DIFFERENT, WE TALKED ABOUT WHETHER OR NOT IT WOULD BE A CONSENSUS VALUE VERSUS CERTIFIED. CERTIFIED YOU HAVE TO HAVE A REFERENCE METHOD PROCEDURE BUT YOU CAN GET CONSENSUS VALUES ON THIS FOR INSTANCE THIS WHO OR WHO REFERENCE MATERIAL. WE WILL USE THIS TO CALIBRATE THE ASSAY IN THE FACTORY AND THEN USE OTHERCAL BRAYTORS TRACEABLE TO THE REFERENCE MATERIAL IN OUR PRODUCTION CLINICAL LABORATORIES. WE NEED TO MAKE SURE THE REFERENCE MATERIALS BEHAVE LIKE PATIENT SAMPLES. THIS IS THE COMMUTABILITY. IF THIS IS THE RELATIONSHIP BETWEEN A REFERENCE METHOD AND COMPARISON METHOD AND ALL THE PATIENTS LIE HERE BUT THEN YOUR REFERENCE MATERIAL LIE HERE, THEY'RE USEFUL. THAT'S WHY WE'RE TRUE TRYING TO MOVE TO MINIMALLY TREATED SERUM SAMPLES IS OUR PROFICIENCY TESTING MATERIALS COLLEGE OF AMERICAN PATHOLOGISTS SO WHAT CAN WE DO FOR IRON STATUS? WE CAN HARMONIZE THING, FOR INSTANCE HARMONIZE PROTEINS LIKE SOLUBLE TRANSFER REIN RECEPTOR, WHATEVER YOU DECIDE IS THE PROTEIN OF INTEREST. I RECOMMEND THAT NOW BEFORE EPIDEMIOLOGICAL STUDIES. WE CAN DECLARE ONE LAB METHOD, THE GOLD STANDARD, WHATEVER IS BEING RUN AT THE CDC, GREAT EXAMPLE HOW WE CAN DO THAT. AND THEN RECALIBRATE OTHER ASSAYS OR RESULTS FROM OTHER DATA BACK TO THAT ORIGINAL. WE COULD THINK ABOUT STANDARDIZATION FOR HEMOGLOBIN AND IRON IT'S POSSIBLE TO MAKE A STANDARDIZATION PROGRAM BUT I DON'T THINK IT'S NEEDED. WE DON'T USE SERUM IRON THAT MUCH. HEMOGLOBIN IS FANTASTIC. WE COULD TRAY TO STANDARDIZE PROTEINS BUT IT'S HARD TO STANDARDIZE PROTEIN ASSAYS TODAY. WE'RE WORKING ON IT, I PROMISE BUT NOT EASY TO DO. INSTEAD WE WANT TO HARMONIZE, ONE BIG THING TO DO FOR THE FIELD TODAY IS DEVELOP SAMPLE BANKS, WELL ANNOTATED SAMPLES FROM A RANGE OF BIOLOGY SO THAT YOU CAN BEGIN TO HARMONIZE THINGS BACK TOO ONE ANOTHER. THE EXAMPLE OF TRANSFER REIN RECEPTORS IS THERE ANY DANGER TO SCREEN? SOMETIMES WE TELL THEM NOT TO SCREEN, DON'T USE SOLUBLE TRANSFER INVENTOR,'S NOTS OFFERED IN HOSPITAL LABS OR MAJOR ACADEMIC, THERE'S A COUPLE OF REFERENCE LABORATORIES WHO SAY THE FOLLOWING, DO IN THE USE THIS FOR ROUTINE CLINICAL EVALUATION OF PATIENTS FOR IRON STATUS. SO EVEN THOUGH WE HAVE GOT GREAT DATA THAT SUGGESTS THIS MIGHT BE A USEFUL BIOMARKER WE'RE TELLING PEOPLE NOT TO USE IT FOR REASONS ALEX TALKED ABOUT THIS MORNING. SO IN CONCLUSION WE HAVE TO AS A CLINICAL LAB HAVE TO HAVE REFERENCE RANGES OR CUT OFF DEPENDING WHAT ASSAY WE USE, THEY MAY NOT TRANSLATE, ASSOCIATION OF OUTCOMES WITH BIOMARKERS IS ASSAY DEPENDENT. PROFICIENCY TESTING CAN HELP IN EPIDEMIOLOGICAL STUDIES AN CLINICAL CARE, I THINK SAMPLE SETS SHOULD BE DEVELOPED AS SOON AS POSSIBLE, SORRY IF I WENT OVER A COUPLE OF MINUTES. [APPLAUSE] >> WE HAVE FILE FOR ONE OR TWO QUESTIONS OTHERWISE WE WILL HAVE A PANEL DISCUSSION AND UX TALK TO ANDY THEN. GREAT. THANK YOU. AS I MENTIONED AT THE INTRODUCTION WE HAD WONDERED ABOUT PLASMA VOLUME EXPANSION AND HERE TO TALK ABOUT THAT IS LAURA VRICELLA. WELCOME, LAURA. >> THANK YOU, CHRISTINE FOR INVITING ME TODAY. I'M A CLINICAL PROFESSOR, NOT A PROFESSOR YET, DON'T TELL THEM I SAID THAT. I'M ASSISTANT PROFESSOR AT ST. LOUIS UNIVERSITY AND MY SPECIALTY IS MATERNAL FETAL MEDICINE SO WHAT I DEAL WITH ON A DAY-TO-DAY BASIS AS A CLINICIAN IS ADVERSE PREGNANCY OUTCOMES THAT BEFALL SOME OF OUR OWN OCCUPATIONS THE GOAL OF MY TALK TODAY IS TO LOOK INTO THE ROLE OF BLOOD VOLUME EXPANSION AND PREGNANCY AND FIND OUT WHAT ITS ROLE MAYBE IN ADVERSE OUTCOMES. I'LL BEGIN BY DESCRIBING PLASMA IN NORMAL AND PATHOLOGIC STATES, ALSO GOING TO DISCUSS A NEW APPROACH TO ASSESSMENT OF BLOOD VOLUME ABOUT CITY TRICK POPULATION WHICH WE ADAPTED FROM THE ICU POPULATION. I WILL THEN DESCRIBE CURRENT UNDERSTANDING VERY BRIEFLY OF THE IMPACT OF INFLAMMATION, OBESITY AND IRON METABOLISM ON OBSTETRIC OUTCOMES. THAT'S TOUCHED ON BY SOME OTHER INDIVIDUAL TODAY AS WELL. I WON'T TAKE TOO MUCH TIME ON THAT. SO PLASMA VOLUME EXPANSION IS ESSENTIAL TO SUPPORTING GOOD HEALTHY OBSTETRIC OUTCOMES. MEDIATED BY RENAL AND CARDIO PULMONARY ADAPTATION, PLASMA VOLUME INCREASES BY O&A 50% OF PRE-PREGNANCY VALUES APPROACHING TERM AND RED BLOOD CELL EXPANSION MEDIATE BIDDER ITSELF THROW POIETIN INCREASES BUT ONLY BY 25%. THIS RESULTS IN A NET DELUSION OF RED BLOOD CELLS AND THE PHYSIOLOGIC ANEMIA OF PREGNANCY WHICH IS PREVIOUSLY BEEN DESCRIBED. THIS RESULTS IN NORMAL HEMOGLOBIN LEVELS IN PREGNANCY RANGING FROM 10.5 TO 11 WHICH IS LOWER THAN ANDY'S REPORT ON NATIONAL REFERENCE RANGES. THIS IS LOWEST AT ABOUT THE MID TRIMESTER FROM 28 TO 32 WEEKS. CORRESPONDING TO THE TIME OF MAXIMUM VOLUME EXPANSION. YOU CAN SEE GESTATIONAL AGE AS VANCES PLASMA AND RED BLOOD CELL VOLUME INCREASES BY THE HEMATOCRIT DECREASES WITH PEAK AFFECT AROUND 32 WEEKS BEFORE PLATEAU OCCURS. NORMAL FETAL GROWTH WEIGHT AND BIT WEIGHT IS CORRELATEDDED WITH MATERNAL VOLUME STATUS IN ANIMAL AND HUMAN STUDIES. CONVERSELY WE FOUND INSUFFICIENT VOLUME EXPANSION AN PREGNANCY IS ASSOCIATED WITH POOR OUTCOMES, FETAL GROWTH RESTRICTION,SMALL FOR FETAL AGE AND DEMISE. THIS IS A STUDY THAT COMPARED THE PLASMA VOLUME EXPANSION AMONG HEALTHY PREGNANCIES THAN IDIOPATHIC FETAL GROWTH -- SIGNIFICANT REDUCTIONS IN PLASMA VOLUME AND VOLUME EXPANSION AMONG MOTHERS OF GROWTH RESTRICTED FETUSES WERE SERVED. DISEASES OF CHRONIC RENAL IMPAIRMENT SUCH AS ADVANCED DIABETES OR LUPUS NIGH FREETIS AND SPECIFIC CONDITION SUCH AS PLEA PREECLAMPSIA POSE HIGH RISK OF BY INHIBITING VOLUME EXPANSION. AND THIS RESULTS IN VERY HIGH RATES OF GROWTH RESTRICTION, FETAL DEMICE, INDICATED PRE-TERM BIRTH WITH SIGNIFICANT NOT ONLY FETAL BUT NEONATAL MORBIDITY AS WELL. SO UPDATED BLOOD VOLUME ARE NEEDED FOR U.S. OBSTETRIC POPULATION, THE MAJORITY OF STUDIES WE BASE ASSESSMENTS OF EXPANSION ON TODAY ARE DONE FROM 1930s TO THE 1980s WHEN THE DEMOGRAPHICS OF THE OBSTETRIC POPULATION WAS DIFFERENT FROM THAT TODAY. THE ACCELERATING OBESITY TRENDS IN THE UNITED STATES ARE COLLIDING WITH THE TRENDS OF WOMEN DELAYING PREGNANCY AND THEIR 30s AND 40s. SO WOMEN OVER AGE 35 NOW COMPRISE GREATER THAN 10% OF FIRST TIME MOTHERS. AND THOSE OVER 40 COMPRISE OVER ABOUT 3% OF FIRST TIME MOTHERS. THE RESULT IS AN OBSTETRIC POPULATION THAT IS OLDER HEAVIER AND PLAGUED WITH MORE ASSOCIATED MEDICAL COMORBIDITIES THAT ACCOMPANY THESE CONDITIONS. THIS IS GREAT JOB SECURITY FOR MYSELF MATERNAL FETAL MEDICINE AND HAS GREAT IMPLICATIONS FOR A LOT OF LONG TERM HEALTH OUTCOMES FOR THE MOTHERS AND THE FETUS IN NEONATES THAT YOU HAVE DESCRIBED TODAY. UPDATED BLOOD VOLUME ESTIMATES ARE SORELY NEEDED FOR THIS CHANGE IN OBSTETRIC POPULATION. THERE ARE SEVERAL ESTABLISHED APPROACHES TO BLOOD VOLUME ESTIMATION. NOT GOING INTO THIS TOO MUCH TODAY BUT I WILL BRIEFLY DESCRIBE THE WAY MOST BLOOD VOLUME PERFORMS. THE BLOOD IS COMPOSED OF LA PLASMA AND CELLULAR COMPONENT WHICH IS LARGELY THE VAST MAJORITY OF RED BLOOD CELLS, THE ESTIMATION CAN BE PERFORMED EITHER BY DIRECTLY MEASURING ONE COMPONENT IN CALCULATING THE OTHER OR BY SIMULTANEOUS DIRECT MEASUREMENT OF THE RED BLOOD CELL AND THE PLASMA COMPONENTS. WHICH IS THE MORE ROBUST MANNER AND TECHNICALLY MORE DIFFICULT SO THE MAJORITY OF STUDIES PERFORMED HAVE DIRECTLY CALCULATED EITHER PLASMA OR THE RED BLOOD CELL COMPONENT AND THEN EXTRAPOLATED THE OTHER. SO ALL THE AVAILABLE TECHNIQUES WHICH I LISTED HERE, HAVE BEEN USED IN PREGNANT WOMEN IN THE PAST, HOWEVER THEY HAVE LIMITATIONS WHICH TRIGGERED US TO START TO LOOK FOR ADDITIONAL METHODS WHICH MAYBE NOT ONLY EASIER TO APPLY TO THE OBSTETRIC POPULATION BUT MORE ACCEPTABLE IN TODAY'S ENVIRONMENT. PREECLAMPSIA APPEARS A VOLUME CONTRACTED STATE. THIS STUDY WAS PERFORMED MEASURING BOTH PLASMA AND RED BLOOD CELL VOLUMES AMONG HEALTHY PREECLAMPTIC AND GESTATIONAL HYPERTENSIVE WOMEN. THIS STUDY FOUND THAT PREECLAMPTIC WOMEN HAVE LOWER TOTAL END UNIT PLASMA VOLUME AS WELL AS TOTAL BLOOD VOLUME COMPARED TO HEALTHY WOMEN AND THOSE WITH GESTATIONAL HYPERTENSION. THERE WAS SOMETHING UNIQUE ABOUT PREECLAMPSIA THAT WORKS IN VOLUME CONTRACTION AS OPPOSED TO CONTROL HEALTHY PATIENTS BUT ALL WITH GESTATIONAL HYPERTENSION AS WELL WHICH IS INTERESTING TO ME BECAUSE WE ARE COMING TO VIEW GESTATIONAL HYPERTENSION ON THE SPECTRUM OF PREECLAMPSIA BUT THERE WAS A DIFFERENCE IN TERMS OF THE OBSERVED AFFECT ON VOLUME STATUS. HOWEVER SIMILAR STUDIES HAVE NOT YET BEEN PERFORMED ON TO IDENTIFY POTENTIAL DIFFERENCES IN OBESE WOMEN IN PREGNANCY. STUDIES OF NON-PREGNANT WOMEN HAVE SHOWN UNIT BLOOD VOLUME DECREASES IN OBESE WOMEN WHEN COMPARED TO LEAN WOMEN AND THIS IS BECAUSE ADIPOSE TISSUE IS RELATIVELY LESS WELL PROFUSED COMPARED TO LEAN TISSUE. THEREFORE OBESE WOMEN HAVE GREATER TOTAL BLOOD VOLUME BUT LOWER BLOOD VOLUME PER KILOGRAM COMPARED TO LEAN WOMEN. THIS PROMPTED US TO LOOK FOR ANOTHER METHOD WE COULD USE TO ESTIMATE BLOOD VOLUME EXPANSION AMONG OBESE WOMEN IN CONTEMPORARY OBSTETRIC POPULATION. WE APPLIED A DELUSIONAL METHOD OF BLOOD VOLUME DETERMINATION THIS USES HYDROXY ETHEL STARCH, A UM VIEW EXPANDER AVAILABLE AND ACCEPTABLE FOR USE IN PREGNANT WOMEN. HYDROXY ETHEL STARCH IS STABLE, HAS A LARGE MOLECULAR WEIGH, A LONG HEALTH HALF LIFE, RELATIVE TO OTHER DELUSIONAL MARKERS AND IT MAINTAINS AN INTRAVASCULAR STEADY STATE FOR 15 MINUTES. IT IS HYDROLYZED TO ACCOUNT FOR GLUCOSE AND HYDROXY ETHEL GLUCOSE BY BOILING. USING IT AS MARKER WE CALCULATE IT BY HYDROLYZING PLASMA SPECIMENS AND MEASURING IN GLUCOSE CONCENTRATIONS BEFORE AND AFTER THE INJECTION OF HEAD OF STARCH AND 30 NORMAL WEIGHT AND 30 OBESE WOMEN. WE USED THE VOLUME AHEAD OF STARCH INJECTED THE HEMATOCRIT AND THE CHANGE IN PLASMA GLUCOSE CALLLATION THE BLOOD VOLUME OF LEN AND OBESE WOMEN. AS THEY APPROACHED TERM PREGNANCY. AS YOU CAN SEE WE FOUND ALTHOUGH TOTAL BLOOD VOLUME WAS GREATER IN OBESE VERSUS LEAN WOMEN, APPROXIMATELY 8,000 CCs VERSUS APPROXIMATELY 6,000 CCS THE UNIT BLOOD VOLUME DECREASE AS MATERNAL BODY MASS INDEX INCREASE. THE LEAN WOMEN LABELED WITH ONE HAVE A GREATER UNIT BLOOD VOLUME EXPRESSED IN CC PER QO THAN OBESE WOMEN LABELED. IN SUMMARY, THE OBESE WOMEN HAD A LOWER UNIT BLOOD VOLUME THAN THE LEAN CONTROL WHICH IS A SIMILAR PATTERN TO THAT SEEN IN PRIOR STUDIES DONE OF NON-PREGNANT WOMEN. YOU CAN SEE COMPARING TO TWO VALUES FOR THE LEAN AND OBESE NON-PREGNANT WOMEN, THERE'S SIGNIFICANT INCREASE WHEN YOU LOOK AT THOSE TWO GROUPS OF PREGNANCY, LARGELY DUE TO PHYSIOLOGIC VOLUME EXPANSION WE HAVE BEEN DISCUSSING. NOW I'M GOING TO DISCUSS THE ROLE OF PLASMA VOLUME EXPANSION ON IRON HOMEOSTASIS AND OBSTETRIC OUTCOMES. YOU DISCUSSED THE YOU SHAPE RELATIONSHIP BETWEEN HEMOGLOBIN LEVELS AND ADVERSE PREGNANCY OUTCOMES. WITH INCREASED RISK OBSERVED AT LOW AND HIGH END OF THE SPECTRUM. THE ANEMIA IN EARLY PREGNANCY HAS BEEN ASSOCIATED WITH PRE-TERM DELIVERY AND LOW BIRTH WEIGHT INFANT THIS IS POSTULATED THE HYPOXEMIA AND RESULTED OXIDATIVE STRESS. CONVERSELY HIGH HEMOGLOBIN CONCENTRATION HAVE BEEN FOUND IN STATES OF VOLUME CONTRACTION SUCH AS PREECLAMPSIA, DIABETIC NEUROPATHY WELL KNOWN TO BESISK RISK FACTORS DEMISE AND INDICATED PRE-TERM BIRTH. SOME STUDIES HAVE SUGGESTED THAT IRON SUPPLEMENTATION IN IRON REPLETE WOMEN INCREASES HEMOCONCENTRATION AND ASSOCIATED POOR OUTCOMES SUCH AS PREECLAMPSIA, WE HAVE DISCUSSED SOME OF THESE STUDIES TODAY AND SOMETHING THAT HAS ME CURIOUS IS IS IT ACTUALLY THE VOLUME CONTRACTION THAT IS THE PROBLEM OR IS IT A STATE OF VOLUME OVERLOAD. ONE STUDY SUGGESTED THAT ACTUALLY SUPPLEMENTING WHICH SUGGESTED IT MAYBE MORE THAN JUST THE VOLUME CONTRACTION. THIS REQUIRES SYSTEMIC INFLAMMATION IS IMPLICATED IN OUTCOMES SUCH AS PREMATURE RUPTURED MEN BRAINS, FEE L A MALFORMATION -- FETAL MALFORMATIONS AN RECURRENT PREGNANCY LOSS, THOUGH PREGNANCY ITSELF IS INFLAMMATORY STATE IT APPEARS THAT DEANGLES IN THE MEDIATORS OF THE NORMAL INFLAMMATORY PROCESSES OF PREGNANCY ARE THE MECHANISM THAT PRETTIES POSES TOWARDS ADVERSE PREGNANCY OUTCOMES. WE HAVE SEEN HE WILL VAILINGS IN AMNIOTIC FLUID AND HAS A HIGH PREDICTIVE VALUE FOR CHOUGH OWE (INAUDIBLE) IT'S WELL DESCRIBED IN THE LITERATURE. THERE IS -- WHICH IS PHYSIOLOGICALLY ELEVATED IN PREGNANCY HAS BEEN ASSOCIATED WITH AN INCREASE RISK OF PRE-TERM BIRTH, BUT THIS FINDING IS THOUGHT TO BE MOSTLY MEDIATED BY INFLAMMATION WHICH THE FERRITIN IS INDICATOR AS ACUTE STAGE REACTANT. HEAPSIDIN DECREASES IN PREGNANCY TO IF FACILITATE IRON BUOY AVAILABILITY TO MOTHER AND FETUS, HAS BEEN SHOWN TO INCREASE IN VARIOUS INFLAMMATORY STATES OF PREGNANCY. (INAUDIBLE) HAVE NOT BEEN WELL DESCRIBED HOWEVER. OBESE WOMEN HAVE ELEVATED HEPSIDEN LEVEL COMES PAIRED TO LEAN CONTROL, THIS IS POSITIVELY CORRELATED WITH CRP LEVELS. THIS SUGGESTS -- THIS IS FURTHER EVIDENCE OBESITY IS AN INFLAMMATORY STATE. AND PREECLAMPTIC WOMEN HAVE BEEN FOUND TO HAVE ELEVATED H,PSIDIN IL-6 AND FERRITIN WITH DECREASED MEAN CORE HEMOGLOBIN COMPARED TO HEALTHY CONTROL. I DISCUSSED THIS PREVIOUSLY, OBOESTY IN ITSELF IS A STATE OF INCREASE INFLAMMATION, IT IS THOUGHT OBESITY PRE-DISPOSES TOWARDS THE -- TO THE ADVERSE OUTCOMES SEEN IN INFLAMMATION AS WELL, THE ONLY OTHER THING I WANTED TO ADD ABOUT OBESE WOMEN IN PREGNANCY IS THAT INFLAMMATION SEEN IN THESE WOMEN IS ALSO IMPLICATED IN THE INCROSS RISK OF FETAL MALFORMATIONS. IN SUMMARY, BLOOD VOLUME EXPANSION IN PREGNANCY HAS BEEN FOUND TO SUPPORT HEALTHY OUTCOMES AND THAT FAILURE TO VOLUME EXPAND CORRELATES TO DISEASE STATES. OBESE WOMEN IN PREGNANCY HAS REDUCED PLASMA VOLUME EXPANSION, IMPAIRED IRON HOMEOSTASIS AND INCREASED INFLAMMATION. AREAS THAT I WOULD LIKE TO SEE FOCUS FOR FUTURE STUDY, WOULD BE FIRST OF ALL UPDATED ESTIMATES OF PLASMA VOLUME EXPANSION FOR OBSTETRIC POPULATION, FURTHER STUDY ON THE ROLE OF OBESITY AND IMPAIRED IRON HOMEOSTASIS AND ADVERSE OUTCOMES AND THE APPROPRIATENESS OF IRON SUPPLEMENTATION IN IRON REPLETE WOMEN. THANK YOU. [APPLAUSE] >> UNLESS THERE'S AN URGENT QUESTION WE'LL HOLD QUESTIONS AGAIN FOR THE PANEL. THAT MEANS THAT PARMINDER SUCHDEV WILL TALK ABOUT ASSESSMENT AND INFLAMMATION. >> THANKS FOR THE INVITATION TO BE HERE. I WOULD LIKE TO ACKNOWLEDGE CONTRIBUTORS TO THIS WORK, CO-AUTHORS FOR THIS PROJECT AS WELL AS OVERALL IN THE PROJECT. MANY FOLKS ARE IN THE ROOM SO GRAB ONE OF US IF YOU HAVE QUESTIONS BECAUSE THERE'S A LOT TO PURSUE IN THAT SHORT PERIOD OF TIME. SO WHAT I WOULD LIKE TO DO IS SUMMARIZE EFFECTS OF INFLAMMATION ON NUTRIENT BIOMARKERS WE ALLUDED TO THIS MORNING AND THE WAYS WE CAN STATISTICALLY ACCOUNT FOR THESE ASSESSES OF INFORMATION ON BIOMARKERS AND TALK ABOUT KEY FINDINGS FROM THE BRENDA PROJECT THAT WILL BE COMING OUT SOON. SO NO NEED TO GO OVER THIS AGAIN, INNATE PHYSIOLOGICAL WHICH PRODUCES CYTOKINES AN PRODUCES ACCUSE PHASE PROTEINS SO POSITIVE OR NEGATIVE. SKI TWO COMMON ONES ARE C ONE ALPHA PROTEIN. THEN SOME NUTRIENT BIOMARKERS OF CELLS WE TALKED ABOUT ARE CELLS ACUTE PHASE PROTEINS WHICH IS WHAT CREATES THE ISSUES. SO SIMILAR TO BACKGROUND BEFORE IS ANOTHER STUDY SHOWING THE EVOLUTION PROTEINS OVER TIME SO C REACTIVE PROTEIN WHICH WE USE IN CLINICAL SETTINGS IS GREAT BECAUSE IT GOES UP RAPIDLY AND RESOLVES TO NORMAL WITHIN COUPLE OF DAYS SO GOOD MEASURE OF ACUTE INFECTION VERSUS ATP CAN TAKE UP TO 24 TO 48 HOURS TO BECOME ELEVATED AND STAYS ELEVATED LONGER SO A BETTER MEASURE OF CHRONIC INFLAMMATION BUT THE CHALLENGE MUCH OF WHAT WE KNOW ABOUT WHAT HAPPENS ACUTE OVER TIME ADULTS WHO UNDERWENT TRAUMA. WE KNOW VERY LITTLE ABOUT KIDS WHO HAVE GOTTEN THE FLU VACCINE OR COLD. ACUTE PHASE WHAT IT LOOK LIKE, WE TALKED ABOUT THIS ALREADY BUT THE EFFECTS OF INFLAMMATION ON NUTRIENT BIOMARKERS MAY DEPEND ON WHAT THE TYPE OF INFLAMMATION S SO WHETHER ACUTE OR CHRONIC AND JUST FROM A TOP -- IN TERMS OF OBESITY EPIDEMIC HOW IT CHANGES THESE THIS THINGS AND WHETHER IT'S CLINICAL INFLAMMATION IN TERMS OF HAVING PHYSICAL SIGNS OR SUBCLINICAL, IT'S THE FOCUS OF MY TALK IS MORE SUBCLINICAL INFLAMMATION SO OTHERWISE HEALTHY PEOPLE WHO HAVE A TEMPORARY INFORMATION OCCURRENCE AND WILL RETURN BACK TO NORMAL, SO ONE WAY TO DO THAT IS JUST -- DIVIDING POPULATION FOUR GROUPS WHICH IS SOMETHING PROPOSED BY DAVID THURMAN, NORMAL CRP AND AGP YOU CONSIDER NORMAL AND BE THE REFERENCE VERSUS ELEVATED CRP INCUBATION HAVING ELEVATED IS CONVALESCENT ELEVATED ATP SO THE FOCUS OF THIS TALK IS ON POPULATION NOT INDIVIDUALS COULD BE MAYBE INTERPRET FORD INDIVIDUALS, BUT THAT'S A RESEARCH QUESTION. WE DO KNOW SOME ABOUT THE EFFECT OF INFLAMMATION ON NUTRIENT BIOMARKERS IS A SUMMARY TABLE FROM PUBLISHED INSPIRE REPORT AND WE TALK ABOUT FERRITIN BUT OTHER IRON BIOMARKERS THEMSELVES ARE ALSO AFFECTED BY INFLAMMATION, AND IT'S NOT JUST IRON BIOMARKERS BUT ALSO VITAMIN A BIOMARKERS THAT ARE ALSO AFFECTED BY INFLAMMATION. WHY DO WE CARE ABOUT THAT'S EFFECTS ON MICRONUTRIENT BIOMARKERS. WHAT IT'S GOING TO DO IS LEAD TO VARIOUS CONCLUSIONS IN DIAGNOSIS OF INDIVIDUAL AND MORE IMPORTANTLY IN TERMS OF PUBLIC HEALTH UNDERESTIMATING THE MICRODEFICIENCY IN A POPULATION AND WHICH THEN INTERFERE WITH OUR ABILITY TO ASSESS THE IMPACT OF MICRONUTRIENT INTERVENTION SO THIS IS A GRAPHICAL REPRESENTATION OF A CHILD WITH FERRITIN CUT OFF OF 12 AND THREE CHILDREN OVER TIME. SO IN CHILD A THEY HAVE THE INFLAMMATORY EVENT AND IF YOU MEASURE BLOOD TIME A IT'S IRON DEFICIENT, WHEN THEY HAVE INFLAMMATION THERE'S A TEMPORARY RISE OF FERRITIN THERE'S TEMPORARY IRON DEFISH AND RETURNING TO NORMAL WILL BE OKAY. INDIVIDUAL B YOU MAKE THE WRONG DIAGNOSIS, YOU HAVE TO MEASURE BLOOD WHEN INFLAMED YOU CALL THEM IRON DEFICIENT WHEN THEY'RE NOT INFLAMED IRON DEFICIENT SO THIS IS THE PROBLEM WITH IGNORING THE EFFECT OF INFLAMMATION. SO WHAT DID THE WORLD HEALTH ORGANIZATION CURRENTLY RECOMMEND IN TERMS OF USING FERRITIN TO ASSESS IRON STATUS OF POPULATIONS IN SETTINGS OF INFLAMMATION? SOME GUIDELINES BUT NOT NECESSARILY VERY HELPFUL, TRY TO DO SURVEY IN A SEASON OF LOW INFLAMMATION, THAT'S HARD TO KNOW WHEN THAT IS, MEASURED ACUTE PHASE PROSEN AND EXCLUDE INDIVIDUALS SO SOME SETTINGS WHERE MANY OF US WORK THAT CAN BE 60, 80% POPULATION SO YOU'RE LEFT WITH A SAMPLE SIZE THAT'S LIMITED THE OTHER THOUGHT IS MORE SIMPLE APPROACHES JUST USE A CHANGE CUT OFFICER TIN SO RATHER 12 OR 15 FOR ADULTS MAKE IT 30 FOR EVERYONE. BUT THERE MIGHT BE OTHER WAYS SO IN ADDITION TO THESE ALREADY MENTIONED, THE OTHER THOUGHT IS APPLYING CONSTRUCT FACTOR, THIS IS THE APPROACH THAT DAVID THURMAN CAME UP WITH AND REGRESSION QUESTION BUT THE PROBLEM WITH NO CONSENSUS ON PREFERRED METHOD. WHICH APPROACH IS BEST? WE TALKED ABOUT THIS DOING WELL IN TERMS OF YOU WANT A PROTEIN -- THIS WAS AN INDIVIDUAL INDICATOR BUT ALSO APPROACH TO BE VALID, PRECISE, FEASIBLE IS BIG PART OF THIS, IN ORDER DO SOMETHING THAT'S UNIQUELY COMPLICATED THAT END USERS CAN DO IT AND VARY SEVERITY OF INFORMATION IS VERY IMPORTANT. WE DO THIS, IT'S AN EXAMPLE OF HEMOGLOBIN, WE TALK ABOUT HEMOGLOBIN, INCREASES WITH ELEVATION AND ADAPTIVE RESPONSE BASED ON SEVERAL STUDIES IN HIGH ALTITUDE LEVELS NUMBER OF REGRESSION LEVELS WAS MADE AND EQUATED TABLES OF HEMOGLOBIN CUT OFF OR THE HEMOGLOBIN VALUES BASED ON ALTITUDE, SO THOUGHT IS COULD THIS BE THE END PICTURE OF WHAT WE COULD DO FOR CRP AND ATP SO THAT'S WHERE WHERE E WE ARE'DING TOWARDS. SO IN THE PROJECT BIOMARKERS REFLECTING INFORMATION IN TERMS OF ANNEAL Y WE HAD TWO OBJECTIVES, ONE TO DEAL WITH TODAY LOOKING AT THE RELATIONSHIP BETWEEN NUTRIENT BUY MARKERS, THIS IS COLLABORATION BETWEEN NICHD, CDC AND OTHER PARTNERS. SO BRENDA BASICALLY TOOK A BUNCH OF DATA SETS THAT WERE ON PEOPLE'S HARD DRIVES AND FORGOTTEN AND TRY TO REVIVE THEM, THESE WITH THE 17 DATA SETS USED IN THE PROJECT THEY HAD HAD TO BE NATIONAL OR SUBNATIONAL SURVEYS AND DONE IN THE LAST TEN YEARS AND THEY HAVE TO HAVE MEASURE OF MARKER OF INFLAMMATION, HEMOGLOBIN, AND MARKERS OF IRON AND VITAMIN A STATUS. SO YOU CAN SEE GEOGRAPHICCAL DATA, THIS WAS BASED ON THE DATA AVAILABLE AT THIS TIME THIS IS THE LABORATORY METHODOLOGY USED IN THE BRENDA COUNTRIES TO GIVE YOU SENSE OF VARIABILITY, THE GOOD PART IS FOR HEMOGLOBIN COUNTRIES EXCEPT THE U.S. USE THE (INAUDIBLE) DEVICE AND FOR FERRITIN AN INFLAMMATORY BIOMARKERS MAJORITY USE A SIMPLE ASSAY A SANDWICH ELISA WHICH COSTS A WHOPPING $5 OR FIVE INDICATORS, OFTEN USED IN RESOURCE LIMITED SETTINGS TO MEASURE SEVERAL MICRONUTRIENTS. THESE ARE THE KEY QUESTIONS AND FINDINGS TO COVER. DO WE NEED BUY MARKERS OF INFLAMMATION WHEN ASSESSING IRON STATUS, IF THE ANSWER TO THAT IS YES, WHICH MEASURE? CRP ATP OR BOTH. SINCE THIS WAS A TALK OR SESSION WORKSHOP ABOUT THE U.S. HOW DEFINE THE POPULATION. FIRST I WANT TO GIVE A SENSE OF THE INFLAMMATION IN THESE 17 DATA SETS FROM THE BRENDA PROJECT. RANKING FROM THE U.S. TO COUNTRIES OF HIGH INFLAMMATION, PAKISTAN, PREVALENCE OF ELEVATED CRP IN CHILDREN, IN THE U.S. IT'S 6% OF KIDS IN THE U.S. HAVE ELEVATED CRP, 40% IN AFRICAN COUNTRIES. LOOK AT ATP YOU CAN SEE IN EVERY COUNTRY PROBLEM OF ELEVATED AGP IS HIGHER THAN CRP BECAUSE IT'S A MEASURE OF CHRONIC INFLAMMATION. WHEN YOU LOOK AT WOMEN -- SORRY AND KIDS ON ANY INFLAMMATION MEANING EITHER CRP OR ATP WAS 50%. THERE'S A LOT OF INFLAMMATION IN THE WORLD. AND A LOT OF US AREN'T LOOKING AT IT, THAT'S ONE ISSUE. WITH WOMEN THE OVERALL PREVALENCE WAS LESS THAN 20%, WITH COUNTRIES SUCH AS U.S. AND MEXICO, CHRONIC DISEASE OBESITY, IT WAS HIGHER THAN THAT OF KIDS OTHERS WE ONLY HAVE CRP IN A LOT OF THESE COUNTRIES OF CHRONIC DISEASE, WE DON'T HAVE ATP IN THE U.S. AND MEXICO. WE WANT TO SUSPECT THAT TO BE HIGHER. WHAT THE RELATIONSHIP BETWEEN CRP AND FERRITIN? SCATTER PLOT ASSOCIATION BETWEEN CRP AND FERRITIN IN ONE COUNTRY, THIS IS SHOWS YOU WHAT THE SCATTER PLOT SHOWS SO THERE'S A LINEAR RELATIONSHIP A THIRD OF THE VARIATION AND FERRITIN EXPLAINED BY CRP ALONE. THAT'S A HIGH NUMBER, WHAT'S MOST IMPORTANT IS ARBITRARY CUT OFF FOR CRP OF 5, THAT RELATIONSHIP DOESN'T CHANGE IT STAYS TO CRP LEVEL LOWER THAN THAT OF 5, ANOTHER WAY TO DO THIS IS META ANALYSIS OF ALL THOSE COUNTRIES 12,000 KIDS, WE RANK PREVALENCE OF LOW FERRITIN OR ESTIMATED BY CRP AND ATP BECAUSE ATP -- YOU CAN SEE IT'S A PRETTY LINEAR RELATIONSHIP, EVEN AT CUT OFF OF LESS THAN 1, THERE'S VARIATION SO IF YOU USE LIKE THE ATP 5TH, IRON DEFICIENCY WAS 17%, VERSUS 30% WE ARGUE THE PREVALENCE OF THAT POPULATION IS CLOSER TO 30% WHERE THERE'S NO INFLAMMATION. WHAT ABOUT U.S.? THESE -- THE PROBLEM WITH THE U.S. IS WE ONLY HAVE CRP, THE CRP IS LEFT SKEWED SO CUT OFF OF 5 -- SO THERE'S NOT A LOT OF ELEVATION. FOR WOMEN IT'S BETTER, SOME VARIATION BUT THERE'S LESS INFLAMMATION AND WE DON'T HAVE ATP. SO HERE IS THE SUMMARY OF WHAT I SHOWED YOU LOOKING AT THE ASSOCIATION BETWEEN ESTIMATED IRON DEFICIENCY, BY CRP COMPARING TO FERRITIN AND OTHER BIOMARKERS. SO THE FERRITIN YOU JUST SAW BASICALLY THE LOWER CRP, LESS INFLAMMATION YOU HAVE THE HIGHER ESTIMATE OF IRON DEFICIENCY YOU'RE GOING TO HAVE. IF YOU LOOK AT TRANSFER RECEPTOR IT GOES THE OTHER DIRECTION SO WHEN YOU ADJUST FOR INFLAMMATION, REMOVE THE EFFECT OF INFLAMMATION YOUR PREVALENCE OF ESTIMATED IRON DEFICIENCY IN TFR GOES DOWN, TOTAL BODY IRON WHICH TALKED EARLIER DERIVED RATIO OF OF THE TWO, A LOT ADVOCATE IRON BECAUSE OF OPPOSITE DIRECTIONS FOR PFR MAYBE WILL WASH EACH OTHER OUT. THIS IS NOT THE CASE, IT SEEMS TO BE DRIVEN BY FERRITIN SO IT'S NOT AS STRAIGHT OF A LINE BUT THERE'S AN EFFECT BY CRP. WHEN YOU LOOK AT ATP IT'S SIMILAR. IN THE SAME DIRECTION. MAYBE A STRONGER MAGNITUDE. CHILDREN AND WOMEN YOU STILL SEE THESE LINEAR EFFECTS BUT THE SLOPES ARE A LITTLE -- NOT AS SHARP. GIVEN THERE IS -- APPEARS TO BE LINEAR RELATIONSHIP BETWEEN CRP AND ATP AND SOMEBODY'S IRON BIOMARKERS, WHAT WE EXPLORED WAS A REGRESSION APPROACH, ESSENTIALLY WHAT YOU'RE DOING AN INDIVIDUAL HERE WITH ELEVATED ATP AND FERRITIN IS OVER HERE AND YOU'RE BASICALLY TRYING TO ESTIMATE SERUM FERRITIN CONCENTRATION WOULD BE IF THEY DIDN'T HAVE ELEVATED ATP. AND THEN WHAT YOU WANT TO DO, RATHER THAN PROGRESSING DOWN TO ZERO, REDEGREES TO WHAT YOU THINK IS THE REFERENCE VALUE FOR A NORMAL ATP SO YOU DON'T OVERCORRECT. SO YOU CAN DO A FANCY REGRESSION EVASIONCATION AND THAT CAN BE INTIMIDATING BUT WE HAVE MACROS OF STATISTICAL SOFTWARE YOU DO A SIMPLE REGRESSION WITH FERRITIN AS THE OUTCOME, CRP AND USE THAT SLOPE AND YOU BASICALLY SUBTRACT THAT EFFECT AND THEN YOU CREATE AN ADJUSTED FERRITIN LEVEL AND THEN OWE USE YOUR SAME CUT OFF THAT YOU USED BEFORE. SO THAT'S -- YOU CAN DO THE FOR CRP ONLY, ATP ONLY OR IF YOU HAVE BOTH DO IT FOR BOTH. SO THEN WHEN WE APPLY THIS REGRESSION METHOD HOW DOES THIS AFFECT -- THE PREVALENCE OF IRON DEFICIENCY OR USING FERRITIN IN THESE BRENDA COUNTRIES. SO THIS IS UNADJUSTED SO THIS IS JUST PREVALENCE OF LOW FERRITIN IN CHILDREN, LESS TAN 12 AND YOU CAN SEE THIS THE REPUBLIC OF GEORGIA, NOT STATE OF GEORGIA, THERE'S NO LOW FERRITIN IN GEORGIA, VERSUS PAKISTAN, LOW FERRITIN AND APPELLEING THE REGRESSION APPROACH EVERY CASE WHICH MAKES SENSE, THOSE LINEAR CURVES I SHOWED YOU BEFORE, ESTIMATED PREVALENCE OF LOW FERRITIN INCREASES, THIS RANGES LESS THAN 1% IN GEORGIA TO AS MUCH AS 25 PERCENTAGE POINTS IN SOME AFRICAN COUNTRIES. IF YOU LOOK AT JUST THESE COUNTRIES IN RED WHICH ARE COUNTRIES WHICH MEASURE CRP AND ATP, WE'RE ADJUSTING NOT JUST CRP THE AVERAGE DIFFERENCES CLOSE TO 25%. THAT COULD DEFINITELY MAKE A DIFFERENCE IN IMPACT OF -- THERE ARE SUMMARY TABLES WHAT WERE SEEN BY DIFFERENT APPROACH BY DIFFERENT BIOMARKERS SO THE METHODS HERE EXCLUSION WHICH MEANS YOU EXCLUDE BASED ON ELEVATED CRP OR CRUSH FACTOR AND BOTH OF THESE USE KNOWN CUT OFFS WITH CRP OF 5 AND ATP OF 1, SO THE AFFECTS ARE SIMILAR IN TERMS OF MAGNITUDE. YOU SEE ABOUT 8 PERCENTAGE POINT INCREASE IN IRON DEFICIENCY USING FERRITIN, ABOUT 7% LOW TFR AND A SIMILAR EFFECT WITH TOTAL BODY IRON BUT THE REGRESSION QUESTION REALLY LARGE DIFFERENCES SO ALMOST 23% WITH FERRITIN RECEPTOR AND INCREASE TOTAL BODY IRON. WOMEN, AFFECT AREN'T AS BIG BUT A SIMILAR EFFECT WITH EXCLUSION REGRESSION FACTOR APPROACH BUT PRETTY MODEST AFFECT WITH -- IN THE SAME DIRECTION. WHAT ABOUT THE U.S. THEN? SO IN THE U.S. WE LOOKED AT NHANES AND AGAIN WE ONLY HAVE CRP BUT IF YOU LOOK AT EXCLUSION IN CHILDREN YOUR ESTIMATED IRON DEFICIENCY IS HALF A PERCENTAGE POINT DIFFERENT AND ABOUT THE SAME FOR TOTAL BODY IRON. BUT THERE ARE -- WITH THE REGRESSION QUESTION YOU'RE CLOSE TO THREE PERCENTAGE POINTS FOR FERRITIN AS WELL AS TOTAL BODY IRON. THEN WITH THE WOMEN, IT IS HIGHER BECAUSE AGAIN THERE'S MORE INFLAMMATION IN WOMEN THAN THERE IS IN CHILDREN SO YOU SEE A 7 PERCENTAGE POINT DIFFERENCE USING FERRITIN. WHAT ARE KEY QUESTIONS AND FINDINGS BACK TO THAT? DO WE NEED TO MEASURE BIOMARKER INFLAMMATION? WE WOULD ARGUE YES. LIKELY EVEN IN LOW INFLAMMATION SETTINGS, OF LOW INFLAMMATION SETTINGS SUCH AS U.S., THERE MIGHT NOT BE AS MUCH INFECTION BUT OTHER TYPES OF INFLAMMATION SUCH AS CHRONIC DISEASE AND DO WE NEED TO MEASURE MORE MORE THAN ONE INFLAMMATION BIOMARKER? YES W SAY YES BECAUSE THEY'RE MEASURING DIFFERENT PHASES OF ACUTE PHASE RESPONSE AND ACCOUNTING FOR ACUTE AND CHRONIC INFLAMMATION AND THAT I THINK IS A BIG GAP IN THE U.S. IS THAT WE DON'T HAVE ATP TO LOOK AT THE AFFECT OF CHRONIC INFLAMMATION. WHAT APPROACH SHOULD WE USE? WE ARGUE REGRESSION QUESTION BECAUSE IT ACCOUNTS FOR SEVERITY BUT IT ACCOUNTS FOR THAT LINEAR RELATIONSHIP WE SEE BETWEEN BIOMARKERS OF NUTRITION AND INFLAMMATION. WHAT ABOUT THE U.S.? WE SAW A LARGE INCREASE IN ESTIMATED IRON DEFICIENCY USING LOW FERRITIN ESPECIALLY IN WOMEN AND UNABLE TO EVALUATE OTHER BIOMARKERS WITHOUT ATP SO SOME COMMENTS ON THIS REGRESSION QUESTION SINCE I KNOW I PRESENTED VERY FAST AND IT'S SOMETHING THAT HAZEN BEEN DONE A LOT IN THE LITERATURE AND SOME STRENGTH AND WEAKNESSES, STRENGTH IS THAT IT REFLECTS A STATISTICAL ASSOCIATION BASED ON SCATTER PLOTS WE SHOW. AND ALLOWS YOU TO ACCOUNT FOR THE FULL RANGE AND SEVERITY OF INFLAMMATION. NOT JUST CRP 5 YES OR NO, CRP IS LIKE 50, YOU'RE GOING TO ADJUST MORE THAN CRP BEING OF TEN. AND REALLY RETAIN SAMPLE SIZE WHICH IS A HUGE ADVANTAGE IN TERMS OF NOT HAVING TO THROW DATA BY EXCLUDING. SOME LIMITATIONS ARE THE BIGGEST ONE IS VALIDITY, WE HAVE NO IDEA IF THE ESTIMATE OF CORRECTED LOW FERRITIN IS BETTER MEASURE OF IRON DEFICIENCY. THIS IS THE WRONG TYPE OF STUDY TO ASSESS THAT. THAT'S THE BIG QUESTION. WHAT IS TRUE IN WHAT WE'RE TRYING TO MEASURE. DOING REGRESSION EQUATIONS, IT'S HARD TO GET SURVEYS TO MEASURE BIOMARKERS OF IRON STATUS AN INFLAMMATION BUT HAVE TO DO STATISTICAL MANIPULATION IS A CHALLENGE BUT WAYS TO ACCOUNT FOR THAT, THE WHO SOFTWARE TO GET GROWTH FOR EXAMPLE SO YOU CAN COME UP WITH AN APP TO TAKE THE DEATH AND PRODUCE CORRECTED VALUES. OHIO TAKE THE DATA AND PRODUCE CORRECTED VALUES. SUCH AS THE U.S., WE TALKED ABOUT STANDARDIZATION HARMONIZATION, HARRISONIZATION NOW THEY KNOW THE DIFFERENCE BETWEENS BETWEEN THE TWO BUT HARMONIZE BY MARKERS FERRITIN TO IRON BIOMARKERS BUT IF WE'RE RECOMMENDING TO MEASURE INFLAMMATORY BIOMARKERS WHEN MEASURING IRON STATUS, THOSE NEED TO BE STANDARDIZED AS WELL. WE DIDN'T GET INTO THAT AT ALL DUE THE TIME. EXPLORE DIFFERENCES IN AFFECTS BY ETIOLOGY OF INFLAMMATION, MALARIA IS A BIG QUESTION AND DEVELOPING WORLD BUT HERE IN THE U.S. OBESITY IS A BIG ONE. WHAT IS THE APPLICABILITY OF THESE IN CLINICAL SETTINGS? WE DON'T KNOW THAT. TO DO THAT WE NEED LONGITUDINAL STUDIES OF INFLAMMATORY AND NUTRIENT BIOMARKERS WITH AND WITHOUT ACCOMPANYING NUTRIENT INTERVENTION TO SEE HOW THIS HOLDS TRUE. THAT'S IT. [APPLAUSE] >> QUESTIONS FOR DR. SUCHDEV. >> QUESTION ABOUT CRP. YOU USE CUT OFF AND TURN INTO CATEGORICAL VARIABLE. WHAT HAPPENS IF YOU USE A CONTINUOUS VARIABLE IN YOUR MODEL, DOES IT PERFORM BETTER? OR DOES IT -- >> SORRY TO MAKE THAT CLEAR, WHEN YOU USE CUT OFF THAT'S THE EXCLUSION APPROACH, AND THE THURMAN APPROACH IS USING THE CUT OFF APPROACH SO IN PREMISE OF REGRESSION QUESTION WILL USE CONTINUOUS VARIABLE GIVEN THAT WHAT YOU SEE WHEN YOU LOOK AT ASSOCIATION BETWEEN CRP AND FERRITIN, CRP OF 2 VERSUS CRP OF 1 YOU WILL SEE A DIFFERENCE IN FERRITIN AT LOW CONCENTRATIONS. A PIECE I DIDN'T EXPLAIN, ANOTHER ADVANTAGE IS PUTTING THESE 17 DATA SETSING TO, WE LOOK AT THE FIRST -- THE LOWEST DECIBEL AND CAME UP WITH NORMAL CRP, THAT WAS ABOUT .5 IN CHILDREN AND WOMEN. SO THAT'S WHAT WE WERE REGRESSING TO. ANOTHER THING TO LOOK AT IN OTHER SETTINGS HOW GOOD THAT HOLDS UP WHEN YOU HAVE MORE DATA INTO THAT DATA SET. >> THANK YOU VERY MUCH FOR THAT PRESENTATION. OUR NEXT SPEAKER IS DR. SAN RAIN PASRICHA. HIS TALK IS GOING TO BE THE CHALLENGING QUESTION OF CUT OFF SANT-RAYN PASRICHA. >> THANK YOU VERY MUCH. THANK YOU VERY MUCH FOR INVITING ME, THIS MEETING HAS BEEN SO FUN SO FAR BUT I WILL TRY TO LOWER THE MOOD. SO I'M A HEMATOLOGIST, I WORK IN THE LAB AND ALSO SPENT TIME THINKING ABOUT THINGS LIKE THIS. I HAVE WORKED ON SIMILAR PROJECTS TO THIS CONSULTANCY FOR WHO AND AUSTRALIAN RED CROSS BLOOD -- BOTH ARRANGED HOW WE DEFINE IRON DEFICIENCY BUT NOT WHAT I'M PRESENTING HERE IS NOT THAT WORK. SPECIFICALLY THOUGH IT'S OBVIOUSLY YOU CAN READ ABOUT WHAT THE WHO IS UP TO IN THIS PAPER A COUPLE OF YEARS AGO AND PROBABLY ALLOWED TO SAY THERE IS A GUIDELINE SOMEWHERE ALONG THE WAY. THERE WAS A BRILLIANT COUPLE OF TALK ON LAB REFERENCE RANGES SO FORTH SO COVER A BIT OF THAT TERRITORY AND HOW WE COME ABOUT HAS BEENING THRESHOLDS. ONE WAY YOU CAN DO THIS IS DIAGNOSTIC ACCURACY STUDIES. YOU ARE TRYING TO DEVELOP SENSITIVITY AND SPECIFICITY OF A PARTICULAR BIOMARKER AGAINST THE GOLD STANDARD. THERE ARE WAYS TO DO IT WHICH IS COCOME UP WITH REFERENCE RANGES IN A PARTICULAR POPULATION. THAT MIGHT BE THE OVERALL POPULATION OR IT MIGHT BE A POPULATION THAT YOU SOMEHOW DEFINE AS HEALTHY. IT'S IMPORTANT TO UNDERSTAND THAT DIFFERENT RANGES AND GROUPS AND I'M THINKING HERE OF MEN AND WOMEN FOR EXAMPLE, AND CHILDREN AND PREGNANCY, THAT THE DIFFERENT REFERENCE RANGES REPRESENT DIFFERENT PREVALENCE OF DISEASE IN THOSE GROUPS IF YOU DIDN'T CLARIFY EXCLUDE. SOMETHING WEAR NOT REALLY THOUGHT TOO MUCH ABOUT IN IRON BUT I THINK DUE TO WORK IN THE LAST DECADE WE'RE ALLOWED TO THINK ABOUT NOW IS TRYING TO FIND THINGS HOMEOSTATIC REGULATION. SO IN VITAMIN D BIOLOGY ONE WAY REFERENCE RANGES ARE DEVELOPED IS PHYSIOLOGIC EFFECTS OF PARATHYROID HORMONE AND WE KNOW THE HOMEOSTATIC REGULATION OF IRON AND START THINGS FROM THAT PERSPECTIVE AS WELL. BUT I'M GOING TO TALK FIRST DIAGNOSTIC ACCURACY STUDY. THIS IS THE TABLE THAT MAKES EVERYONE GET CHEST PAIN, IMOLE SURE YOU HAVE BEEN EXAMINED ON THIS AT SOME POINT IN YOUR LIFE. I PRESENT THIS TO A LARGE GROUP AND GET IT WRONG IN FRONT OF EVERYBODY. WHAT WE TRIERING TO E THERE -- POSITIVE AND NEGATIVE PREDICTIVE VALUES BUT IN TERMS OF ONE THING THE PEOPLE ARE AFTER IS THE SENSE TESTIFITY AND SPECIFITY, THAT'S WHAT I'LL TALK ABOUT FIRST. HERE WHAT YOU'RE TRYING TO WORK OUT THAT WAY TO HAVE A DISEASE BUT THAT DIVIDED BY THAT. AND SPECIFICITY IS OPPOSITE. IF YOU DON'T HAVE IT, WHAT IS THE CHANCE YOUR TEST WILL BE NEGATIVE. IT'S THAT DIVIDED BY THAT. THE PROBLEM IS THESE TWO PARAMETERS BOTH IMPORTANT BUT THEY'RE A TRADE OFF SO THERE IS NO OPTIMAL SOLUTION HERE NECESSARILY UNLESS YOUR TEST IS OPTIMAL. SO ILLUSTRATE RECEIVE PRAYING CHARACTERISTIC CURVE SPECIFICITY -- SPECIFICALLY OR TRUE POSITIVE VERSUS FALSE POSITIVE RATES AND ESSENTIALLY WE HAVE A GREAT TEST, BASICALLY PERFECT ALL THE WAY ALONG SENSITIVITY AND SPECIFICITY, THAT AREA BEING ONE BUT IF LOUSY,'S .5 WHICH IS GOOD ADS TOSSING A COIN. THIS IS BIOLOGY AND ASSAY CHARACTERISTICS TO MOVE THIS UP TOWARDS HERE. THEN WHAT WE DO NEXT IS PICK A CUT OFF WE LIKE THAT FITS THE CHARACTERISTICS AND THE USE OF THE TEST FOR US. YOU CAN DO THAT IN A FEW WAYSK YOU CAN SAY I'LL TRY TRADE OFF SENSITIVITY AND SPECIFICITY, TRY TO GET THEM BOTH SIGH I WILL MULL TRAINIOUSLY OPTIMAL AND THAT'S A -- SIMULTANEOUSLY OPTIMAL. THAT MUCH IS GIVING YOU THE WORST OF BOTH WORLDSES. I DON'T KNOW WHAT YOU'RE AFTER THAT,'S GOOD PLACE TO START BUT MIGHT NOT BE THE END OF THE STORY, DO YOU BELIEVE FOR EXAMPLE THAT IRON DEFICIENCY IS THE WORST DISEASE IN THE WORLD AND YOU NEVER WANT TO MISS IT YOU MIGHT PICK A MORE SENSITIVE ONE AND CONVERSELY YOU THINK IRON SUPPLEMENTATION IS THE MOST DANGEROUS TREATMENT IN THE WORLD IT SHOULD ONLY BE RESERVED FOR PEOPLE WHO NEED IT, MAKE A MORE SPECIFIC CUT OFF. SO REALLY WHAT WE'RE TRYING TO GET AT, WHAT WE WANT TO KNOW, WE'RE LOOKING FOR A WINDOW TO THE GOLD STANDARD. THE GOLD STANDARD MIGHT BE BONE MARROW IRON STORES, IRON ABSORPTION, MIGHT BE HEMOGLOBIN RESPONSE THE IRON. I GIVE THIS PERSON IRON THEY WILL GET BETTER OR MIGHT BE SOMETHING MORE SUBTLE WHICH WOULD BE FUNCTIONAL OUTCOME, THING LIKE SYMPTOMATIC FATIGUE OR IN THE LONGER TERM CHILD DEVELOPMENT OR FETAL OUTCOMES AND PREGNANCY OR MIGHT BE SOMETHING REALLY EITHER ONE REMOVED FROM THAT, IMMUNE FUNCTION OR TRYING TO MAKE THE WORLD A BETTER PLACE AND IMPROVE CHILD MORTALITY. THE PROBLEM BE THESE OUTCOMES IN DIAGNOSTIC TEST ACCURACY SETTINGS IS MORE THAN ONE THING THAT CAN CAUSE THESE PARTICULAR OUTCOMES. SO YOU CAN DO THIS TO PEOPLE AND IT'S FUN TO -- NOT FUN TO BE ON THE OTHER END OF THE NEEDLE, THIS END OF THE NEEDLE. BUT YOU CAN'T DO THIS EVERY TIME YOU MEET A PATIENT. NOT ANY MORE. SO WHAT WE WANT TO DO IS TRY TO GET BIOMARKERS THAT REFLECT NECESSARY GOLD STANDARDS. FROMS THERE'S LOTS DISCUSSED AT LENGTH TODAY, I WILL TALK ABOUT TWO OF THESE. IN PARTICULAR. I'M GOING TO TALK ABOUT FERRITIN WHICH IS PROBABLY -- HEMOGLOBIN. THESE ARE PROBABLY THE ONES MOST COMMONLY DEPLOYEDED IN FIELD OR IN THE CLINIC. AS YOU MENTION GOLD STANDARD ABSENT BONE MARROW IRON STORES, THAT'S -- WE COULD SPEND ANOTHER DAY IRON STORES AS BEING A SATISFACTORY GOLD STANDARD BUT I WILL TRY TO GET THAT ACCEPTED FOR NOW. OF COURSE THE QUESTION IS WHERE THE CLINICAL CONSEQUENCES OCCUR BEFORE THAT. BUT THIS IS A BONE MARROW STAIN, THIS IS A PEARL STAIN OF PARTICLE OF THE BONE MARROW AND WHEN YOU HAVE BONE MARROW IRON STORES IT GOES AWAY. AFTER A WHILE, HEMOTOLL GISTS CAN TELL A DIFFERENCE BETWEEN THE TWO DEPENDING HOW THEY'RE GOING THAT DAY, AND HOW MUCH IT'S IN THE MICROSCOPE SO I WANT TO TALK QUICKLY TO TALK CURRENT THRESHOLDS WITH FERRITIN, SEEING THIS ALREADY. SO CURRENTLY WHO RECOMMENDS FERRITIN IN 12 YOUNG KIDS ADJUSTED IF THEY HAVE INFLAMMATION OR UNDER 15 IF ADULTS. THAT'S NOT THE CUT OFF, IN THE N -- THEY SUGGEST IN PREGNANCY WOMEN UNDER -- FIR TIN UNDER 30 COUNTS AS IRON DEFICIENCY SO THERE'S ALL SORTS OF THINGS USED. I WILL COME BACK TO THAT BUT I WANT TO SHOW YOU WHERE THE CUT OFF COMES FROM. ONE IS COMPARING FERRITIN TO BONE MARROW IRON STORES, ANYTIME THE ONLY SOURCE BUT IT IS ONE THERE AT LEAST A HUNDRED STUDIES TO COMPARE FERRITIN TO IRON STORES BUT NEARLY ALL ARE ON CONVENIENT SAMPLES FROM HOSPITALS WE HAVE BEEN ALL BEEN THERE BORE MARROW IRON STORES IN PATIENTS FROM HOSPITALS MOST PEOPLE IN HOSPITALS WITH BONE MARROW ARE NOT WELL, USUALLY ON THEIR WAY OUT. VERY SICK, CANCER LIEU CHEMOY INFLAMMATION, ANEMIA, RHEUMATOID ARTHRITIS AND FERRITIN IS DISTORT T BY THIS INFORMATION. SO ONLY A SMALL NUMBER OF STUDIES LOOK AT COMMUNITY NOT INFLAMED POPULATION, AND SOME OF THE AUTHORS ARE HERE. I WILL TAKE YOU THROUGH THESE ONE AT A TIME. THIS IS HALLBERG IN 1993. THIS WAS THE MAGICAL PERFECT STUDY DESIGN WITH A FLAW. SO THIS STUDY COLLECTED BONE MARE ROPE SAMPLES, THIS IS IN SWEDEN AND THEY PUT THE -- BONE MARROW WORKED OUT THE IRON PARTICLES GREAT, COLLECT SERUM AT THE SAME TIME AND THEN THE STUDIES IN 1968, IN 1992, THEY MEASURED THE SERUM FOR FERRITIN. NOW, THE STUDIES THEMSELVES ADMIT THAT AT LEAST A 20% DECAY IN THE FERRITIN VALUES. LAST 1 YEARS, THERE'S A COMPLEX REASON, AT LEAST 20 PEST DETERIORATION, THIS IS MINUS 20. THAT SAID, -- THERE'S SOMETHING MISSING HERE. THAT'S NOT RIGHT. THEY CAME UP WITH THE CUT OFF OF 15, 16 NANOGRAMS PER ML BASED ON STUDY HAVING OPTIMAL SENSE TESTIFITY AND SPECIFICITY. THE NEXT STUDY, THERE'S ONLY A LITTLE MOVEMENT ON THIS BUT THE NEXT STUDY WAS DONE IN PATIENTS WITH GASTRIC AND PEPTIC ULCER DISEASE, I THINK PROBABLY THEY HAVE NOT THAT INFLAMED. PEOPLE -- IT'S NOT TERRIBLE, IT'S NOT SEPSIS BUT IN THESE PATIENTS THEY TOOK ADULT OUTPARENTS WITH GASTRIC ULCER DISEASE, PEPTIC ULCER DISEASE, LOOK AT BENEFIT MARROWS AN CAME UP WITH CUT OFFS ESSENTIALLY AT 15 TO SENSITIVITY AND SPECIFICITY OF 70 AND 96% BUT IMPROVED TO 92% AND CUT OFF OF 30. NEXT, THIS WAS DR. MILMAN WHO IS HERE, I'LL TRY NOT TO SAY ANYTHING WRONG THE NEXT FEW MOMENTS BUT THIS STUDY WITH CONTROL GROUP IN THE STUDY THAT TOOK HEALTHY VOLUNTEERS LIKELY MEDICAL STUDENTS, THEY ALWAYS GET IT AND THE -- THEY HAD BONE MARROW DONE AT FERRITIN OF 15, HAD A SENSITIVITY OF 60% AND SPECIFICITY OF 100%, THEY WENT UP TO 30, THEY HAD 100% SENSITIVITY AND 89% SPECIFICITY. THIS IS STRANGE. THE NEXT STUDY IS SORBY. THIS IS THE HEALTHY CONTROL GROUP AS PART OF THE STUDY. THEY SHOWED THAT A SENSITIVITY OF 100%, SPECIFICITY 90% IN PATIENTS WITH FERRITIN UNDER 40. COUNTING THE DOTS WHICH IS FUN, THEY HAD SENSE TVTY OF 15 AND 57% SPECIFICITY OF 100%. AND THE OTHER THING THEY LOOKED AT ABSORPTION, THERE WAS QUITE A CORRELATION BETWEEN FERRITIN LEVELS AND IRON ABSORPTION. THIS IS A STUDY THAT I LOVE BECAUSE OF ITS CREATIVITY AND FORCE OF PURITY. THIS IS SOMETHING THE LOOK FROM, THIS WAS A MODERN STUDY A COUPLE OF YEARS AGO TAKING PATIENT'S THIS IS THE ONLY STUDY IN YOUNG KIDS, 6 TO 66 MONTH OLD CHILDREN. THEY TOOK THEM FROM ABOUT TO HAVE ELECTIVE SURGERY, OLD FRACTURES BEING FIXED IN VARIOUS OPERATIONS THAT KIDS HAVE, BUT THEY WERE WELL SO THEY WEREN'T SICK AND WHILE UNDER ANESTHESIA, THEY TOOK BONE MARROW. HOW CLEVER WAS THAT. WE SHOULD HAVE DONE THAT. THESE KIDS WHAT THEY FOUND IS WITH A CUT OFF OF 12 WHICH WAS THE CUT OFF IN THIS POPULATION, SENSITIVITY IS 44%, WITH A SPECIFICITY OF 90%, YOU HAVE TO INCREASE THE CUTS OFF TO IMPROVE VALUES. THIS IS THE ONLY STUDY OF BONE MARROW IN PREGNANCY. THIS STUDY WAS DONE IN MALAWI. THE MAIN CRP WAS 40-MILLIGRAMS PER LITER THEY FOUND OPTIMAL CUT OFF OF 30 AND THAT'S THE SOURCE OF NHF UK GUIDELINES HOW THEY USE FERRITIN. TO SUMMARIZE STUDIES COMPARING FERRITIN WITH BONE MARROW, NOT NECESSARILY UP TO DATE. NOT NECESSARILY BY METHODS AND ANALYZERS AND REFERENCE MATERIALS, WHO REFERENCE MATERIALS THAT WHAT WE'RE USING TODAY AND THE EPIDEMIOLOGIC STUDY ARE NOT NECESSARILY USED IN MODERN ERA. THEY HAVE SAMPLE SIZES, THEY WEREN'T REPRESENTATIVE OR HAVE BE ETHNICALLY DIVERSE AND THERE'S NOT MUCH DATA IN KEY GROUPS WE WANT TO KNOW ABOUT SO PREGNANCY IN YOUNG CHILDREN. BUT WHAT I WILL SAY IS EVIDENCE FAVORING THE INCUMBENT CUT OFF IS LIMITED. AND ACTUALLY FERRITIN CUT OFF OF 15 IS LIKELY SPECIFIC SO IF YOU HAVE FERRITIN UNDER 15 YOU PROBABLY ARE DEFICIENT. ADMITTING HALF THE CASES IN ALL LIKELIHOOD. OTHERWISE YOU CAN THINK ABOUT THIS. YOU CAN LOOK AT STUDY COMPARING FERRITIN LEVELS TO THEN SUBSEQUENT HEMOGLOBIN RESPONSE SO WE LOOK AT THIS IN VIETNAMESE WOMEN, WE GAVE THEM IRON. AMONG ANEMIC WOMEN, WE HAVE CURE OF ANEMIA OR INCREASE BY ONE GRAM PER DECALITER, THE SENSITIVITY AND SPECIFICITY WAS 26-MILLIGRAMS PER ML. OF COURSE NOW YOU CAN ALSO -- YOU CAN DO IRON ABSORPTION SO LOTS OF LITERATURE COMPARING FERRITIN TO B A SOURCE. KEY QUESTION, SECOND PROBLEM YOU COUNTED ELEVATED ABSORPTION. IF WE KNEW THAT WE COULD WORK OUT FERRITIN CUT OFF BASED ON THESE STUDIES. SHOUGH CONSIDERATION FOR FERRITIN THRESHOLDS THE EVIDENCE FOR FERRITIN UNDER 15 IS WEAK. POSSIBLY THE PREVAILING EVIDENCE TO SUPPORT HIGH THRESHOLD. BUT IF YOU CHANGE THE THRESHOLD YOU WILL CAUSE CATASTROPHIC DAMAGE TO THE HEALTHCARE SYSTEM. BECAUSE YOU'RE GOING THE DIAGNOSE HALF YOUR -- SOME HALF POPULATION BEING IRON DEFICIENT. AND ONE THING FREQUENT BLOOD DONORS HAVE A FERRITIN UNDER 13 SO YOU WOULDN'T BE ABLE TO FIND FEMALE BLOOD DONOR TWO OR THREE TIMES FERRITIN SO SURE THEY WOULD HAVE SOMETHING TO SAY ABOUT THAT. SHOULD WE USE THE CUT OFF IN PUBLIC HEALTH, TRYING TO -- I WILL TALK ABOUT THAT IN A MOMENT. IF THE DIAGNOSIS IS CLINICALLY, SOMEONE COMES TO SEE YOU THEY'RE FATIGUED, THEY'RE SAYING BASICALLY I'M MIND DEFICIENCY, IS THAT A DIFFERENT SCENARIO TO A SCREEN POPULATION, SO YOU HAVE PEOPLE THAT INDISCRIMINANTLY PERFORM FERRITIN FOR THEM. ONE FIRST THING TO CONSIDER ABOUT THE CLINICAL SYNDROME OF ANY DEFICIENCY BUT IT IS IMPORTANT TO THINK ABOUT THE PROBABILITY OF THE INDIVIDUAL IN FRONT OF YOU SO THERE IS THIS WHOLE BABY (INAUDIBLE) GRAM SO PUTTING VALUES HERE FROM THE -- SENSITIVITY IS 60%, SPECIFICITY IS 95% FOR FERRITIN 15. YOU CAN CALCULATE THE POSITIVE LIKELIHOOD RATIO FROM THAT. THE PERSON IN FRONTS OF YOU IT'S THE MUST PREVALENCE OF FERRITIN DEFICIENCY, NOW UP TO KNOW WHETHER TEASE GOING ON SO YOU CAN PLOT, THE RATIO GOING THROUGH THE LINE, YOU HAVE DONE FERRITIN AT 60% SO THAT'S SOMETHING. BUT NOW YOU MADE SOMEONE WHO IS FATIGUED AND TIRED. NOW, SAY YOU GOT 70% CHANCE IRON DEFICIENT. NOW THEY ARE IRON DEFICIENT, YOU MADE THE DIAGNOSES SO THE ONGOING INTERPRETATION OF THE CUT OFF. LUCKILY NO ONE KNOWS WHAT TO DO. SO WHATEVER YOU DO IS RIGHT. SO WE SURVEYED 2 HUP LABS IN THE UK IN EUROPE AND SAW PEOPLE USING WHATEVER CUT OFF THEY FEEL. SO LIKE WHAT ANDY SHOWED BEFORE, IT'S FREE FOR ALL AND YOU CAN SEE FERRITIN COUNT FROM 5 TO 30 FOR WOMEN AND FROM CHILDREN LOOK LIKE UNDER 5 UP TO 50. SO RANDOM NUMBER GENERATED FOR DIAGNOSING DEFICIENCY -- THE UK IS A SOCIALIST BERNIE SANDERS TYPE COUNTRY WITH A CENTRALIZED HEALTH SYSTEM. WE'RE SUPPOSED TO BE GETTING TOLD WHAT TO DO. LASTLY, HEMOGLOBIN TO DEFINE ANEMIA AND PREGNANCY, THE OTHER BIG ONE, THE WHO IS NHB OF 110 RIGHT ACROSS PREGNANCY AND IT GOES UP TO 120 THE DAY YOU DELIVER. THE MAIN TEXTBOOKS DON'T SAY THAT, THEY DOCUMENT UP WITH ALL SORTS OF CUT OFFS SO (INAUDIBLE) THE BIBLE FOR HEMATOLOGIST, HARRISON USES 100, MEMORIZE THESE TEXTBOOKS YOU CAN SEE CDC DROPS TO 105 HALFWAY THROUGH PREGNANCY AND COMES BACK UP, THERE'S RANGE OF PEOPLE OUT THERE. IS THE CUT OFF FOR HEMOGLOBIN WHO COME FROM CONSULTATIONS OVER THE YEARS BUT IT WAS THE 1968 CONSULTATION THAT ESTABLISHED THESE CUT OFFS AND WHO JUST BUILT ON THESE. BASICALLY REFERENCE THE PREVIOUS ONE EVERY TIME. SO FOLLOWING THE REFERENCE TRAIL, THIS ONE THIS ONE AND THIS ONE, IT'S ALL THE SAME BUT THERE'S NOT BEEN A LOT OF EVOLUTION. THESE ARE STUDIES LAY THE 1968 CUT OFF, SO YOU CAN SEE THESE ARE ALL EPIDEMIOLOGIC STUDIES AND STEAL STEELWORKERS THEY WERE SWEATING THEY DIDN'T MEASURE FERRITIN, THEY ALLOWED PEOPLE TO SELF-ALLOCATE CONTROL, THERE'S NO STUDY DESIGN I CAN LEARN FROM THE STUDIES. I HOPE NONE OF YOU ARE HERE, SORRY. BUT YAPPY IT'S SAFE. THESE STUDIES ARE NOT WHAT WE NECESSARILY EXPECT TODAY TO EPIDEMIOLOGIC DESIGN, THE WAY MEASURING NOW IS COMPLETELY DIFFERENT TO BACK THEN, WE CAN DO A LONG WAY EXCLUDING IRON DEFICIENCY BY CLINICALLY -- WE HAVE STAFF METHODS WE CAN USE NOW AND POPULATIONS CONSIDERED ITSELF IN THISTY JOEOGRAPHY, AGE -- PREGNANCY, GEOGRAPHY, AGE RANGE. YOU CAN SEE THAT AFRICAN AMERICANS AND WHITE POPULATIONS APPEAR TO HAVE DIFFERENT HB THRESHOLDS BETWEEN UP TO HALF A GRAPH DECALITER IN DIFFERENT STUDIES. AND BUT AGAIN FORTUNATELY IT DOESN'T MATTER EVERYONE IS DOING WHAT THEY WANT. YOU CAN SEE IN WOMEN FERRITIN -- HB THRESHOLD IS 90 OR 125 SO FALL ANYWHERE IN THE RANGE AND BE DIAGNOSED ANEMIA DEPENDING ON LUCK OF THE DAY. IN CHILDREN IT'S AGAIN, A LOT OF DISCREPANCY. THE SOURCE OF REFERENCES THAT PEOPLE ARE MAINLY FROM TEXTBOOK SO I'M INVOLVED WITH WHO EFFORTS BUT DOESN'T MATTER BECAUSE PEOPLE USE TEXTBOOKS SO MAINLY -- (INAUDIBLE) IT MATTERS BECAUSE THE CUT OFF DETERMINES PREVALENCE OF ANEMIA. SO IF IN THIS MODEL IF YOU TOOK HB CUT OFF OF 120 OR 50% ANEMIC YOU CAN TAKE WHO 17 PEST AND TAKE SOME OF THE OTHER CUT OFF SAY 105 IS 8% SO TOTALLY CHANGES YOUR ESTIMATE OF THE PREVALENCE OF ANEMIA. NOW THIS HAS BEEN UPDATED SO AT THE MOMENT THERE WAS ONLINE CONSULTATION. TRY THE MAKE SURE EVERYONE IN THIS ROOM RECEIVES AN EMAIL WHEN THE SECOND LOT IS SUBPOENAED OUT THE NEXT HOPEFULLY FEW DAYS, WHO PEOPLE RIGHT NOW THIS WILL BE SENT BACK AND WE WILL ASK PEOPLE TO VOTE ON THE PRIORITY QUESTION HOW THIS SHOULD BE UPDATED AND HOPEFULLY HAVE A PLAN HOW TO UPDATE THIS. SO I THINK THE WAY FORWARD, I FEEL MOTIVATED BY THE DEBATE ON MONDAY, HOW CAN WE MAKE FERRITIN GREAT AGAIN. I THINK WHAT WE NEED TO DO IS NO MORE SYSTEMATIC ARE VIEWS, NOT ALLOWED. THEY'RE NOT GOING TO CUT IT. WE NEED PRIMARY HIGH QUALITIES DATA. I THINK WE NEED LARGE SCALE MODEL EPIDEMIOLOGIC STUDY, A BIT OF AMBITION, WE CAN GET BONE MARROW BECAUSE THAT'S THE WAY TO GO, YOU HAVE TO THINK ABOUT HOW TO GOAL GET THEM. GET FROM BONE MARROW DONORS FOR STEM CELL TRANSPLANT. LOOK AT OTHER GOLD STANDARDS SUCH AS ERYTHROCYTE INCORPORATION AN HOMEOSTATIC AND WE NEED TO LOOK AT CORROBORATION WITH FERRITIN FROM COHORT STUDIES SO LOOK AT FUNCTIONAL OUTCOMES OR TRIALS. THESE ARE DONE IN LOW INCOME COUNTRIES BUT WE NEED TRIALS IN DEVELOPED SETTINGS TOO AND WHO PROJECT CONCEPTION, THAT'S ALL. THANK YOU VERY MUCH. [APPLAUSE] >> FEW MINUTES FOR QUESTIONS IF ANYONE DOES HAVE A QUESTION. FROM >> VERY NICE SUMMARY, I HAVE A LITTLE PROBLEM, WHICH IS WE ARE DEFINING DISEASES THE REVERSAL OF WHICH MAYBE NOT NOTICEABLE BY THE PATIENT. SO WHAT IS THE THRESHOLD FOR CONDITION IN WHICH IF WE TREAT THE CONDITION THE PATIENT CAN TELL THE DIFFERENCE? >> THAT'S WHAT I WAS TALKING ABOUT WITH THAT (INAUDIBLE). ACTUALLY STUDIES SHOWN IF YOU GIVE IRON TO FA TEALED INDIVIDUALS, THEY RESPOND AND FEEL BETTER. IF YOU GIVE PEOPLE WHO DON'T FEEL FATIGUED AND FEEL WELL, THE DATA IS THINNER ABOUT WHETHER THEY FEEL BETTER. SOME STUDIES CHAUFFER TIN AS HIGH AS -- THERE'S AN RCT IN SWITZERLAND THAT SHOW CUT OFF OF 50 IN WOMEN WHO PRESENTED FATIGUE WITH IMPROVEMENT IN SYMPTOMS. SO IF WE FOCUS ON THE INTERVENTION WHICH IS SO -- WHEN YOU TALK ABOUT INTERVENTION YOU WERE SAYING GIVE IRON TO SOMEONE AND HEMOGLOBIN IMPROVES OR SOME OTHER MEASURE IMPROVES THEY HAD IRON DEFICIENCY BUT IF WE GIVE IRON THE SOMEONE AND THEY FEEL BETTER, ISN'T IT A BETTER DEFINITION? IT'S AN EXCELLENT DEFINITION SO THE QUESTION IS WHETHER I THINK YOU CAN START BY DIVIDING OUTCOMES INTO IMMEDIATE BIOMARKER OUTCOMES, THE STANDARD QUALITY OF LIFE TYPE FATIGUE TYPE OUTCOME AND OUTCOMES ESPECIALLY IN PREGNANCY AND IN CHILDREN, THEY'RE THE TWO GROUPS, MAYBE THERE'S NOTHING TO MEASURE, YOU'RE NEVER GOING TO KNOW THIS CHILD WAS AFFECTED BY PRENATAL IRON DEFICIENCY OR IRON DEFICIENCY IN INFANT BECAUSE IT'S ALL ABOUT IMPROVING A MEAN POPULATION IN THE FUTURE. DEFINING -- THINK ABOUT IN THOSE THREE WAYS YOU WON'T GET A ONE TO ONE RELATIONSHIP WITH THE LATTER. WITH THE FORMER THAT'S A CLINICAL DEFINITION AND I THINK ACTUALLY THAT'S REALLY -- IF I MET A PATIENT WHO WAS HAD FATIGUE AND HAD A FERRITIN ANYWHERE UNDER PROBABLY 50 I WILL TREAT THEM TO SEE WHAT HAPPENS. THEN THE BIOMARKERS ARE USED TO HELP INFORM THE LATTER ONES. >> I THINK THAT IF WE REDO THIS WHICH APPARENTLY YOU WOULD AGGREGATE, SHOULDN'T WE ALSO FOCUS ON OUTCOMES THAT ARE MEANINGFUL TO PATIENTS OR TO THE MOTHERS? >> THAT'S WHAT I TALKED ABOUT IN THE -- IN THAT SLIDE, THE WAY THAT I WOULD HAVE TO THINK IT BEST TO DO THAT BY CORROBORATING YOUR FERRITIN WITH OUTCOMES FROM INTERVENTIONAL STUDIES WHERE YOU HAVE BEEN ABLE TO INTERVENE TO TRY TO IMPROVE THOSE OUTCOMES AND SEE WHAT BASELINE FERRITIN WAS ASSOCIATED WITH THE DIFFERENTIAL. >> HEMOGLOBIN HOW SHOULD WE DEFINE THEM? IN THE OVERALL HEALTHY POPULATION OR SHOULD WE DEFINE IN THE POPULATION INCLUDED FOLATE DEFICIENCY, VITAMIN A DEFICIENCY, SO ON? >> SO I THINK THE LATTER IS THE WAY I WOULD APPROACH IT. >> SO DO I. >> >> I THINK THE PROBLEM IS EVERY ONE OF THOSE BIOMARKERS IS OUR OWN THRESHOLD BUT YOU HAVE TO EVENTUALLY ACCEPT LIFE AND JUST MOVE ON BUT I WOULD DO IT IN A SO CALLED -- I WILL GIVE YOU AN EXAMPLE, THERE'S INTERGROWTH STUDY WHICH SOME OF YOU MIGHT HAVE COME ACROSS, IT'S MASSIVE STUDY DONE, AND GROWTH STUDY, WHO HAVE DONE THESE TWO WIG STUDIES, THEY NOT NECESSARILY (INAUDIBLE) A NON-SMOKER IN THE GROWTH YOU HAVE TO -- WHOLE PARAMETERS WITH THESE -- CENTERS ALL OVER THE WORLD THEY WORK OUT A DISTRIBUTION OF GROWTH BOTH TO GIVE YOU THE NORM GRAM FOR PROCESSING HOW WE ASSESS GREET. WITH HB IT'S SIMILAR. >> THAT IS WHAT WE HAVE DONE IN PREGNANT WOMEN, (INAUDIBLE) REFERENCE VALUES IN IRON REPLETE WOMEN. AND FOLATE REPLETE WOMEN. AND THEY CURRENTLY WORK QUITE WELL WITH WHO REFERENCES P >> TWO MORE QUESTIONS. >> THANKS VERY MUCH. GREAT PRESENTATION. COUPLE OF COMMENTS, WHEN IT COMES TO HEMOGLOBIN RESPONSE TO IRON SUPPLEMENTATION, WE HAVE HEARD TODAY WE MIGHT NEED TO BE CAREFUL ABOUT THAT BECAUSE IN PREGNANCY AND INFANCY THEY'RE PRIMED TO RESPOND EVEN IF NOT DEFICIENT TO BEGIN WITH, SO THAT'S SOMETHING WE HAVE TO BE CAREFUL. IN TERMS OF CORROBORATION WITH FERRITIN, YOU EXPLAINED IN YOUR ANSWER LOOKING FOR INTERACTIONS IN FERRITIN AND AFFECT OF INTERVENTION BUT TO ESTABLISH A CUT OFF YOU HAVE TO DO THE INTERACTION AT VARIOUS LEVELS OF BASELINE FERRITIN. SO YOU NEED TO STUDY WITH A WIDE OPERATING INCOME AT DIFFERENT LEVELS IN ORDER TO DO THAT. SO NOT SURE EXISTING TRIALS WILL SATISFY THAT REQUIREMENT. >> THAT'S TRUE. SO I THINK ALSO MANY TRIALS HAVE NOT CAREFULLY MEASURED FUNCTIONAL OUTOUTCOMES THAT ARE IMPORTANT DISCUSSED ALREADY. SO THAT IS AN IMPORTANT PROBLEM. BUT I THINK WHAT I WOULD SAY IS THAT YOU CAN TRY AGE LATE BETWEEN. SO YOU WOULDN'T INFORM EVERYBODY FROM ONE STUDY FROM THE OTHER AND HOPE -- DEVELOP PUNITIVE THRESHOLD FROM ONE TYPE OF STUDY AND CHECK TO SEE WHAT IT WAS LIKE WITH ANOTHER STUDY. FOR EXAMPLE. >> IT MIGHT REQUIRE AN INDIVIDUAL PATIENT ANALYSIS, YEAH. >> LAST QUESTION. >> (INAUDIBLE) HOPKINS. IN THE GLOBAL LITERATURE THERE'S INDICATOR CALLED LOW HEMOGLOBIN AND DELIVERY BELOW 100-GRAMS PER LITER. THAT COMES OUT OF THE OBSTETRIC LITERATURE BEING A REAL INDICATOR BECAUSE OF THE IDEA THAT IF SOMEONE IS GOING TO HAVE A CESAREAN DELIVERY AND HEMOGLOBIN IS BELOW 100, IT IS A RISK TO THE PATIENT TO HAVE A CESAREAN DELIVERY AND MAY REQUIRE TRANSFUSION AFTER DELIVERY TO RESTORE HEMOGLOBIN CONCENTRATION. SO I WANT TO POINT THAT OUT BECAUSE THE LITERATURE IS ALSO FAIRLY CLEAR THAT IF WE VIEW THAT COMPONENT LIKE 110 AT THE END OF PREGNANCY, WE'RE TRYING TO REDUCE IRON SUPPLEMENTATION, I'M TALKING GLOBALLY, THAT THE RESULTS ARE NOT SO CLEAR, PEOPLE QUESTION IT. BUT WHEN YOU LOOK AT INDICATOR LIKE CAN YOU RAISE WOMEN ABOVE 100 BY END OF PREGNANCY, THOSE RESULTS ARE REALLY FAIRLY CLEAR. ABOUT 80% EFFICACY IN DOING THAT. AND REDUCING THE NUMBER OF WOMEN FOR WHICH THERE IS OBSTETRIC DECISION MAKING TO BE DONE. SO I WOULD ARGUE THAT THAT IS A CLEAR MAYBE NOT TO THE PATIENT, CLEAR FUNCTIONAL OUTCOME RELEVANT FOR THAT PARTICULAR CASE. THANK YOU. >> THANK YOU VERY MUCH. WE'RE NOW MOVING TO WHAT IS SORT OF A PANEL DISCUSSION BUT NOT A PANEL YET. WE HAVE TWO TEN MINUTE PERSPECTIVES. THE FIRST FROM MICHAEL GEORGEIFF ON PROTECTING AND DEVELOPING BRAINS. >> THIS PICKS UP NICELY FROM WHAT SANT-RAYN WAS TALKING ABOUT AND THE FIRST PANEL. WHAT TOM WAS TALKING ABOUT IS THIS IDEA THAT WE GIVE AN EXAMPLE, MAYBES, BECAUSE THAT'S WHAT I DO, WE CAN ACCOUNT FOR TWO OF THE THREE POOLS IF YOU WILL OF IRON. BETWEEN HEMOGLOBIN, RED CELLS, MOST OF IT IN THE BABY, BABIES OF ANY MAMMAL INCLUDING HUMAN ARE BORN WITH LARGE IRON STORES, KATE TALKED ABOUT THAT. BUT THE SYMPTOMS THAT YOU'RE WAITING FOR -- RESPOND TO COME FROM A SMALL POOL, LESS THAN 8% TOTAL IRON IN A BYE-BYE IS FOUND AT THE TISSUE LEVEL. WHETHER BRAIN OR HEART, STILLCAL MUSCLE BUT THOSE ARE THE SOURCES TO FIND SOME BIOMARKERS THAT TALK ABOUT HOW RESPONSE TO THERAPY OR RESPONSE TO DIAGNOSIS OR THOUSAND MAKE DIAGNOSIS IS RELATED TO CERTAIN BIOMARKERS, I WILL CONCENTRATE ON THE BRAIN, I WANT TO PROPOSE A COUPLE OF DIFFERENT -- THESE ARE IDEAS, NOT READY FOR PRIME TIME BUT MAYBE GOING FROM MEASUREMENTS THAT TELL US SOMETHING RELATIVE TO A POPULATION, BUT MAY OR MAY NOT BE RELEVANT PHYSIOLOGICALLY. SO THE PROBLEM IN OUR FIELD IS THAT BABIES DON'T DIE OF IRON DEFICIENCY AND WE DON'T GET BRAIN BIOPSIES. WHEN I WROTE THIS IN AN ARTICLE ONCE, SHE SAID THIS IS NOT UNFORTUNATE, IT'S A GOOD THING THAT BABIES DO NOT DIE, SHE'S RIGHT. SO WHAT I HAVE DONE OTHER IT'S IMPORTANT FOR US FROM THE STANDPOINT OF TRYING TO UNDERSTAND BEHAVIORAL ELECTROPHYSIOLOGIC RESPONSES THAT CAN BE MEASURED IN HUMAN, HOW THEY RELATE TO MODELS. IF WE LOOK AD TODDLER WITH IRON DEFICIENCY, ANEMIA OR TODDLER WITH NON--- THE RATES REPORTED ACROSS THE WORLD FROM DEVELOP TO DEVELOP TO DEVELOPING COUNTRIES, WE HAVE NO CLUE WHAT THEIR BRAIN IRON LOSS IS. WE HAVE BABIES BORN TO IRON DEFICIENT ANEMIC MOTHERS WHATEVER THE CUT OFF IS, WHERE FETUS BECOMES AT RISKER THIS IS RARE IN THE UNITED STATES, THOUGH INNER CITY POPULATIONS ARE AT RISK MORE COMMON IN DEVELOPING COUNTRIES. WE HAVE NO IDEA OF BRAIN IRON LOSS. THERE ARE BABIES WHO HAVE BEEN IDENTIFIED, 50% OF INFANTS WHO ARE GROWTH RESTRICTED AT BIRTH, SMALL FOR GESTATIONAL AGE WILL HAVE FERRITINS CORED BLOOD FERRITIN BELOW THE FIFTH PERCENTILE FOR THE POPULATION. SO IN A NEWBORN, THE AVERAGE FERRITIN IS 137. THE 5TH PERCENTILE IS AROUND 40. 25th PERCENTILE IS 75. THOSE DATA COME FROM ANY NUMBER OF STUDIES LARGEST ACTUALLY IS FROM CHINA BUT THEY CORROBORATE EACH OTHER. AGAIN MORE COMMON IN THE DEVELOPING WORLD. HERE WE WERE FORTUNATE TO GET A COHORT OF INTRAUTERINE GROWTH RESTRICTED BABIES THAT DIED WITHIN A DAY OF BIRTH. THEY COULDN'T REDISTRIBUTE THEIR IRON IN SPITE OF WHATEVER ILLNESS, BRAIN IRON, WE WERE SHOCKED TO SEE THAT THERE WAS 33% REDUCTION IN BRAIN IRON CONCENTRATION. SIMILARLY I TALK INFANTS OF DIABETIC MOTHERS. IEGR GROWTH RESTRICTED ONES WILL BE SUPPLY SITE PROBLEM, HEALTHY MOTHER BUT LOUSY DELIVERY SYSTEM. HERE IN THE DIABETIC MOTHER YOU MIGHT HAVE A MOM WHO IS DEFICIENT BUT BABY WHO HAS AN IRON DEMAND THAT IS -- OR FETUS WITH IRON DEMAND BEYOND PLACENTAL ABILITY TO TRANSPORT IN THAT CONDITION. THERE WE SEE 40% REDUCTION IN BRAIN IRON LOSS. SO WHAT THAT MANAGES TO DO AT LEAST IS TO ANCHOR SOME OF OUR MODELS. THEN THE OTHER GROUP THAT I DEAL WITH SINCE I'M A NEONATOLOGIST IS PREMATURE INFANTS, THEY HAVE NOT ACEDED IRON IN LAST TRIMESTER WE BLEED THEM DOWN BEFORE WE TRANSFUSE THEM BACK UP. SO THEY ARE REALLY CHRONIC IN NEGATIVE IRON BALANCE UNLESS SUPER SICK AND HAD MULTIPLE RED CELL TRANSFUSIONS. AGAIN, WE'RE TRYING TO DO THIS STUDY, IT'S DIFFICULT TO DO, IS THERE'S PLENTY OF AUTOPSIES THAT COULD BE ACCESSED BUT NO PUBLISHED STUDIES WHAT THE BRAIN IRON LOOKS LIKE THROUGH GESTATION. MUCH LESS WHAT HAPPENS TO THAT BRAIN IRON OVER A 6 TO # WEEK HOSPITAL STAY. I'M ONLY SHOWING YOU THIS, NOT TO GO THROUGH IT BUT TO SAY THAT IT'S UNKNOWN, THEREFORE WHEN THE BRAIN BECOMES DEFICIENT IN THIS PROCESS, YET WE KNOW FROM MANY IN THE ROOM HAVE DONE, A CERTAIN DEGREE OF DEFICIENCY IN THE BRAIN IN ANIMAL MODELS WILL CAUSE NEURAL BEHAVIOR NEUROANATOMICAL, NEUROMETABOLIC AND NEUROPHYSIOLOGIC PROBLEMS. SO I WAS STUNNED WHEN I JOINED THE BOND GROUP TO HEAR THE FOLLOWING. CONCEPT. THAT STILL IN ADULT MEDICINE, YOU IDENTIFY IF PROBLEM OF IRON DEFICIENCY ANEMIA AND YOU TREAT THE ANEMIA AND THE PROBLEM IS RESOLVED BECAUSE ANEMIA IS RESOLVED, PROBLEM SOLVED. AND THE COROLLARY TO THAT OF COURSE THEN IS THIS SCREENING FOR IRON DEFICIENCY IF IT APPLIES IN CHILDREN. SCREENING FOR IRON DEFICIENCY BY HEMOGLOBIN CONCENTRATION WORKS. AND BASED ON WHAT I SHOWED YOU BEFORE AND OTHERS HAVE TALKED ABOUT IS THAT THE THINKING IS THAT MAYBE IT'S NOT SO NEW, ANEMIA IS AT LEAST IN YOUNGSTERS TOWARD END STAGE, EVIDENCE OF BRAIN IRON BEFORE RED CELLS, AND THAT'S NOT ALL THAT BAD. EXCEPT FOR THE SECOND SHOE THAT DROPS WHICH ARE THE DATA THAT SHOW AT LEAST IN MODELS ONCE THE BRAIN IS DEFICIENT IN THE PERINATAL NEONATAL POSTNATAL PERIOD, YOU CONFER A RISK OF LONG TERM NEURAL BEHAVIORAL PROBLEMS IF THAT WERE NOT THE CASE YOU CAN COME BACK TO THIS AND SIMPLY GIVE THE IRON BACK. THE BRAIN GETS BETTER, EVERYBODY GOES HOME HAPPY. THIS IS THE PROBLEM, ONCE THE BRAIN IS DEFICIENT, THERE'S LONG TERM IMPAIRMENT AND THERE'S PLAUSIBLE BIOLOGICAL MECHANISMS I MENTIONED IN TERMS OF EPIGENETICS AND IN TERMS OF CRITICAL PERIODS OF NEURAL DEVELOPMENT WHERE IF YOU DON'T BUILD THE BRAIN RIGHT WITH PROPER SUBSTRATE YOU DON'T HAVE SCAFFOLDING THEN TO BUILD RIGHT AT LEAST THROUGHOUT CHILDHOOD. SCREENING SHOULD HAVE MARKERS ON BRAIN HEALTH AND NOT HEMOTOLOGY. TWO EXAMPLES HOW THAT MIGHT WORK. IN EXAMPLE ONE, GOING INTO THE FUTURE, THE THING WE LIKE TO HAVE IS ACCESSIBLE, MEANING NOT DOING BRAIN BIOPSY OR SPINAL TAP OR GETTING INTO THE CNS. A SERUM, SALIVA, A URINE, SOME BODY FLUID OR CELLS WHERE YOU CAN HAVE A MARKER THAT IS A READ OUT OF BRAIN IRON DEPENDENT FUNCTIONAL STATUS, A BIOINDICATOR I BELIEVE THAT WILL BE CALLED. THE SECOND WOULD BE TO CORRELATE OR UNDERSTAND WHEN CONVENTIONAL PRE-ANEMIC SERUM MARKERS, FERRITIN PICK YOUR FAVORITE ONE, WITH A KNOWN RELATIONSHIP TO BRAIN IRON DEPENDENT FUNCTIONAL STATUS, THAT'S NOT BEEN DONE EITHER. FIRST CASE. WE HAVE BEEN WORKING WITH SOME GROUP IN WISCONSIN, WHERE THERE'S A COLONY OF NON-HUMAN PRIMATES THAT BECOME SPONTANEOUSLY IRON DEFICIENT. WHY THEY DO THAT IS INTERESTING, THIS IS CHRIS'S GROUP AND PART OF PROJECT GRANT WITH BETSY LOZOFF. WHAT CHRIS DID WAS HE OBTAINED SERUM AT TWO MONTHS, SERUM IN SPINAL FLUID, AND FOUR MONTHS AND HEMOTOLOGIES AT ALL TIME POINT. YOU CAN SEE THESE MONKEYS THE IRON DEFICIENT ONES BECOME IRON DEFICIENT AT TWO NEITHER WERE ANEMIC OR MAYBE A TREND TOWARDS SOME MICROCYTOSIS AN ONLY AT SIX MONTHS THEY DECLARE IRON DEFICIENCY. YET, METABOLITES THAT INDEX KREBS CYCLE AND ENERGY METABOLISM, AND WE LOOK SPECIFICALLY HERE AT THE CITRATE PYRUVATE RATIO, WERE ELEVATED IN THE CSF AND THE SERUM IN THE PREANEMIC SO WE SEE THE EFFECT IN THE BRAIN AND PARALLEL EFFECT IN ACCESSIBLE BODY FLUID MEANING SERUM. IN FACT THERE WAS A TREND TOWARD THAT OF TWO MONTHS, IT'S DIFFICULT TO TAP MONKEYS AND THEY DID NOT TAP AT TWO MONTHS THAT'S THE IDEA GOING FORWARD. THAT'S AN EXAMPLE OF SOMETHING REFLECTING IRON DEPENDENTS METABOLIC PROCESS THAT IS OCCURRING IN HIGH ENERGY CONSUMING BRAIN AS WELL AS IN MUSCLE AND HEART AND PROBABLY REST OF THE BODY WHERE WE CAN GET PARALLEL INFORMATION, START TO DEVELOP MARKERS THAT INDEX A FUNCTIONAL IRON DEPENDENT OUTCOME. BY THE WAY, IN THAT STUDY WE LOOKED AT PERCENT ITBC AND FERRITINS ON THOSE ANIMALS. AND ALTHOUGH THEY ALSO STARTED TO DROP BEFORE ANEMIA, NOT SURPRISINGLY, THEY DID NOT BEAR A DIRECT RELATIONSHIP, A CORRELATIVE RELATIONSHIP TO WHAT WAS GOING ON IN THE BRAIN. THE SECOND POSSIBILITY IS TO LINK SERUM FERRITIN TO BRAIN, MODELS SHOW THE LOSS OF STORAGE CAPACITY IS A THRESHOLD AFFECT FOR LOSS OF BRAIN IRON IN NEWBORNS. AND THE OBSTACLES IS IMPLEMENTATION TALKED ABOUT, IT'S UNKNOWN IF THE THRESHOLD EXISTS ONLY IN NEWBORNS OR ALSO IN OLDER CHILDREN WITH POSTNATAL IRON DEFICIENCY AND HOW YOU WOULD KNOW. WE'RE DOING THIS FROM AUTOPSY MATERIAL. IT'S ALSO UNKNOWN WHAT THAT THERE SHALL HOLD VALUE WOULD BE IF THAT DOES EXIST IN CHILDREN AND IS THE ACUTE PHASE PROBLEM. MERE IS COMPARISON OF MODEL IN SHEEP AND FROM ACTUAL AUTOPSY MATERIAL. AND THEN FERRITIN. WHAT YOU CAN SEE HERE ON THE X AXIS, BRAIN IRON ON THE Y AXIS. AND AS FERRITIN FALLS, THESE ARE INDIVIDUAL CASES, AS THE LIVER IRON BECOMES LOWER AND LOWER AND LOWER, AND BY THE WAY HEMOGLOBIN WAS HIGHER AND HIGHER IN THESE INFANTS, THERE WAS A POINT IN WHICH THE BOTTOM FALLS OUT. AND WE MODEL THAT IN SHEEP WE FOUND A VERY SIMILAR RELATIONSHIP. WE WERE ABLE TO USE SHOWED THAT THAT ESTIMATED FERRITIN WHERE THAT CUT OFF IS ABOUT 40 MICROGRAMS PER LITER. WE USE THAT THEN IN AN ELECTROPHYSIOLOGICAL STUDY STUDYING NEWBORN MEMORY ON DAY ONE OF LIFE. SHOW BABIES LESS THAN 40 INDICATING HIPPOCAMPAL DISEASE. SO IN SUMMARY, BRAIN CAN BE IRON DEFICIENT BEFORE RED CELLS, THE PRACTICAL BIOMARKER, HEMOGLOBIN MAYBE LEAST SENSITIVE TO INDICATE ABNORMAL BRAIN PHYSIOLOGY DUE TO IRON DEFOR SCHISM WHAT'S NOT RESOLVED, DOES THIS MEAN BEFORE, IF SO, WHAT BIOMARKER INFORMS US OF BRAIN ID, BEFORE RED CELLS ID. THEN THE THRESHOLD RESPONSE FOR LOSS OF BRAIN IRON HEPATIC IRON FERRITIN CONCENTRATION EXISTS IN FETUS AND NEWBORN, WHAT'S UNRESOLVED DOES IT EXIST IN WHOLE THROUGH CHILDHOOD, IF SO AT WHAT FERRITIN CONCENTRATION. [APPLAUSE] >> THE PLAN IS THAT DR. GEORGEIFF WILL JOIN US IN FEW MOMENTS SO THE LAST TEN MINUTE SPEAKER, NANCY KREBS. >> THANK YOU. I WANT TO ADD MY THANKS TO CHRIS AND PATSY FOR INVITING MEMO TARTS PATE IN THIS CONFERENCE. I THINK I'M SORT OF BRINGING BACK TO THE NEGATIVE FRONT LINE OF CLINICAL PRACTICE, BECAUSE I'M ON MANY PHONE CALLS DISCUSSING THIS SESSION, IT WAS ALMOST OVERWHELMING THE CHECKS COMPLEXITIES OF THIS, SO I'M GOING SAY WE DO KNOW SOME THINGS I THINK ABOUT IRON STATUS IN CHILDREN. IN THE U.S.. SO TO COME BACK TO OUR ONE FIRST TALK THIS MORNING ABOUT THE PREVENTIVE SERVICES TASK FORCE, A COUPLE OF LIMITATIONS TO POINT OUT, AND THIS IS LIMITATIONS NOT OF THE PROCESS BUT OF THE DATA, THAT THESE WERE BASED ON SCREENING FOR TODDLERS AND INFANTS IN THE U.S. AND THE AGE RANGE WAS 6 TO 24 MONTHS. BUT THEY USED IRON DEFICIENCY ANEMIA WHICH AS WE HAVE BEEN HEARING ALL MORNING IS THE WORST CASE AND PRIORITIZES THE HEMATOLOGIC EFFECTS, NOT THE BRAIN LINKED BIOMARKERS. SO THAT REALLY WAS MAYBE THE TIP OF ICEBERG. AND ALSO NOTING THERE'S NO DISTINCTION FOR REPEATING MODE. I WILL ARGUE I THINK THAT IS INCREDIBLY IMPORTANT SO WE WANT TO REALLY KNOW WHAT'S GOING ON WITH IRON DEFICIENCY WE HAVE TO DISTINGUISH WHO WE TALK ABOUT IN THE U.S. POPULATION. SO RECENTLY THIS YEAR, (INAUDIBLE) PULLED TOGETHER THE NHANES DATA FROM 2007 TO 10 IN 1 TO 5-YEAR-OLDS SO I REPLICATED THAT HERE. FROM WHEN YOU LOOK AT THE GROUP, THE PERCENT OF IRON DEFICIENT ANEMIA IS 1.1%. FOR IRON DEFICIENCY WAS 7%. LOOK AT ONE TO TWO-YEAR-OLDS IT'S ACTUALLY A BIT OF A DIFFERENT STORY. ANEMIA WITH HEMOGLOBIN LESS THAN 11, IT'S 5.4% SIGNIFICANTLY HIGHER THAN THESE -- THE WHOLE GROUP AND IRON DEFICIENCY WAS UP TO 13.5%. I WOULD NOTE, THIS IS IN ONE THE TWO-YEAR-OLDS WE DON'T HAVE DATA IN LESS THAN ONE-YEAR-OLDS AND AS I WILL SHOW YOU THERE'S A LOT OF IRON DEFICIENCY IN LESS THAN ONE-YEAR-OLDS. SO THE OTHER POINT AT LEAST IN THIS REPORT THERE WERE NO DIETARY DATA IN HOW INFANTS ARE FED. SO I WAS THINKING WHAT IS MY IMPRESSION WE HAVE MORE IRON DEFICIENCY THAN THE DATA SUPPORT, JUST A SKEWED CLINICAL POPULATION OR WHAT? WE LOOK BACK AT STUDIES IN DENVER COOING RANDOMIZE CONTROL TRIALS AND ONE WAS EMPHASIS ON ZINC FOR SOME BUT NEVERTHELESS ZINC AND IRON TRAVELED TOGETHER IN SAME FOODS AND CERTAINLY FOR BREAST AND INFANTS THEY HAVE SIMILARITY. SO I I LOOKED AT THE RESULTS FOR THOSE TRIALS AND WE HAVE TENDED TO USE A FERRITIN LEVEL OF 15 AS A CUT OFF FOR IRON DEFICIENCY THAT'S WHAT'S RECOMMENDED AND (INAUDIBLE) WROTE CHAPTER SO WHAT MORE DO I NEED. AND IN SOME CASES WE HAVE USED TWO MARKERS. OVER THREE STUDIES WE HAVE DONE, THESE ARE IN PARENTHESES, IT'S ABOUT 38 DOWN TO ABOUT 30% WITH LOW FERRITINS. IRON DEFICIENCY, I PULLED THESE TOGETHER, THE AVERAGE WAS 3 #%. THAT -- 3 #%. THAT'S 31%. THAT'S NOT INSIGNIFICANT IF WE BELIEVE EFFECTS ARE ON THE BRAIN AT LEVELS WE SEE. THESE ARE INFANTS WE KNOW BREAST FEEDING STATUS IS THERE IN OUR TRIALS BECAUSE THEY ARE COMMITTED TO REALLY EXCLUSIVELY BREAST FEEDING NO FORMULA AND THEN WE HAVE MODIFIED IN SOME CASES THE COMPLIMENTARY FEEDING REGIMENS. I WOULD NOTE THAT THERE'S TWO OTHER GOOD GOOD STUDIES OF INFANTS LOOKING SPECIFICALLY AT BREAST FEEDING. ONE WAS BY (INAUDIBLE) IN IOWA AND PUBLISHED IN 2009 IN WHICH HE FOLLOWED INFANTS FROM ONE MONTH UP TO 24 MONTHS, I HAVE OVERALL DATA IN 12 TO 24 MONTH AGE RANGE AND HE SAW OVERALL THIS WAS 37% IRON DEFICIENT BUT WHEN HE LOOKED AT THOSE HE DIDN'T GET IRON FORTIFIED CEREAL OR ADDITIONAL IRON SUPPLEMENT, SO JUST FED AD LIBBED AT PARENT DISDISCRETION. HE HAS A FERRITIN CUT OFF OF TEN. SO A FAIRLY IMPRESSIVE NUMBER. THIS IS LOOKING AT NHANES DATA FROM 1999 TO 2002, THEY USED A CUT YOU HAVE OF 7 AND THEIR LEVEL OF LOAFER TEN WAS 18% IN THE 12 TO 24 MONTH OLD GROUP. SO WHEN LOOKING ACROSS THE INFANTS THERE'S A LOT OF FORMULA FED INFANTS SO LOOKING JUST AT BREAST FED INFANTS WE HAVE HIGHER NUMBERS. SO HOW MANY INFANTS MIGHT THIS BE IN THE U.S.? IF CDC SAYS THAT REPORTING THIS THEY TRACK EVERY GRIER, 27% ARE STILL BREAST FED AT 12 MONTHS SO THAT'S OVER A MILLION INFANTS, WE SAID 30% MIGHT BE IRON DEFICIENT, THAT IS HUNDREDS OF THOUSANDS OF INFANTS, WHAT DO YOU CALL THIS, 30, 25% N WE'RE NOT TALKING SMALL NUMBERS OF INFANTS BEING FED THE WAY WE SAY AND NOT CATCHING THE FACT THEY ARE -- MANY ARE IRON DEFICIENT. RISK FACTOR? SITTING ON THE PHONE CALL YOU THINK WE DON'T KNOW ANYTHING. WE COULD BE PARALYZED BY THE COMPLEXITIES OF THIS, I WAS BEING FLIPPANT WHEN WE KNOW MORE THAN NOTHING SO WE ACTUALLY KNOW A LOT AND AT SOME POINT WE HAVE TO SAY WE KNOW RISK FACTORS HERE. PREDOMINANCE HAS LED TO REDUCTION IN IRON DEFICIENCY AND ANEMIA ACROSS THE POPULATION. THE TRADE OFF IS BREAST FEEDING SO ALL THE BENEFITS OF THAT. THIS IS Q1 FACTOR WE HAVE IMPROVED ON BUT THERE'S BEEN COST TO THAT. THE TRADITIONAL EMPHASIS ON IRON DEFICIENCY ANEMIA MEANS THAT PEDIATRICIANS REALLY SCREEN ONLY WITH HEMOGLOBIN. SO AGAIN, WE ARE MISSING LOWER PART OF THE ICEBERG. SO THE RISK FACTORS AS WE HEARD ALREADY TODAY ARE LOW BIRTH WEIGHT, SGA LATE PRETERM INFANTS, INFANTS WITH RAPID WEIGHT GAIN AS BETSY POINTED OUT, MANY GAINING MUCH MANUFACTURE RAPIDLY THAN USED TO AND BIRTH WEIGHT HIGHER. BOYS AT HIGHER RISK THAN GIRLS, NOBODY SAID THE ANSWER TO WHY THAT IS BUT WE SEE THAT IN OUR STUDIES IN DENVER AS WELL. AND INFANTS INSULIN RESISTANT MOTHERS ARE A HUGE POPULATION NOW, MANY DON'T BREAST FEED SUCCESSFULLY SO IN THIS SENSE WE HAVE SEEN MANY BUT IT ALTERS THE IRON HOMEOSTASIS FOR THE MOTHERS AN PUTS INFANTS AT SOME RISK. THEN SO I THINK BOTTOM LINE HERE IS BREAST FEEDING IS ASSOCIATED WITH INCREASE RISK. AND WHAT I SEE CLINICALLY -- THIS IS BACKED UP BY OBSERVATIONS FROM TRACKING THE CDC HAS DONE, IS THERE ARE FAMILY DIETARY BELIEVES ON -- THAT DRIVE HOW COMPLIMENTARY FEEDING CHOICESES ARE MADE AND THIS INFLUENCES THE RISK. SOMEWHAT LIKE I THINK WHAT ZEIGLER WAS SEEING IN IOWA WHEN LEFT TO DEVICES MANGO IS THE FIRST FOOD, IS A REAL BELIEF IN FRUITS AND VEGETABLES ARE THE BEST THING BECAUSE THAT'S WHAT WE SAY TO EVERYONE AND YET FOR BREAST AND INFANTS NOT DELIVERING NUTRIENTS TO BECOME LIMITS IN BREAST MILK. THEN THE FACT IS THAT WE DON'T SCREEN BEYOND HEMOGLOBIN. WHAT I INCLUDED HERE IS INTERESTING STUDY PUBLISHED FROM CANADA, WHICH THEY DID A PRACTICE BASED STUDY WHICH THEY TRACKED A NUMBER OF VARIABLES INCLUDING FERRITIN AND LOOK AT OVER 1600 INFANTS AND LOOK AT RELATIONSHIP OF BREAST FEEDING TO THE DEVELOPMENT OF IRON DEFICIENCY, WHAT YOU CAN SEE IS THEY FOUND SIGNIFICANT CUMULATIVE INCREASING PROBABILITY OF IRON DEFICIENCY WITH DURATION OF BREAST FEEDING. AND THEY ACTUALLY SAID FOR EVERY ADDITIONAL MONTH OF BREAST FEEDING 5% INCREASE RISK OF DEVELOPING IRON DEFICIENCY. THAT WAS DEFICIENCY NOT ANEMIA. SO CLINICIANS DILEMMA AND PUBLIC HEALTH CHALLENGES ARE WHO AND HOW WE SHOULD SCREEN CLEARLY ONE SIZE DOESN'T FIT ALL, WE HAVE TO GET TO THE PREVALENCE OF IRON DEFICIENCY. TO HONE ON ON AT LEAST NINE MONTHS, THERE'S SOME DEFICIENT BEFORE NINE MONTHS BUT CERTAINLY AFTER THAT THE RATES DO SEEM TO BE GOING UP. IF YOU HAVE MIXED BREAST FEEDING AND FORMULA FEEDING, I CATEGORIZE THAT AS NO MAN'S LAND BECAUSE YOU DON'T KNOW WHAT THE BALANCE IS IN GENERAL. BUT I DON'T THINK THEY'RE OUT OF THE WOODS ESPECIALLY PRIMARILY BREAST FED ONLY SMALL ENOUGH FOR FORTIFIED FORMULA. ONCE PAST THE FIRST YEAR, MOST NO FORTIFIED FORMULA TIMES SEVERAL MONTHS, DOESN'T TAKE LONG SCREENING IRON DEFICIENCY, OUR CRITERIA WITHIN FORMULA FOR THREE MONTHS AND WE SAW LOTS OF IRON DEFICIENCY IN TODDLERS WHO HAD BEEN PREVIOUSLY FORMULA FED AND DIET HISTORY, WHAT ARE TRIGGERS FOR RISK AND SCREENING? LIMITED COMPLIMENTARY FOODS, FASIS ON FRUITS AND VEGETABLES MANGOS WHICH IS ARE NOT GOING TO DO IT. NEITHER IS AVENUE QUAY DOE. PROCESS FOODS AND SO CEREALS SO AS WE -- AS MEDICAL COMMUNITY HAVE CHOSEN IRON FORTIFIED CEREAL AS THE MAIN VEHICLE TO DELIVER IRON MANY FAMILIES ARE SAYING WE DON'T LIKE ALL THIS HYPERPROCESSED FOOD SO THEY'RE NOT GETTING THAT SOURCE THAT WE NEED AND AGAIN THIS IS BACKED UP BY NATIONAL SURVEYS. SO THE LAB TEST WE DON'T HAVE RECEPTOR ATP IN CEREAL SETTING, SOMETIMES USE FED RATE SO ONE ARTICLE NOTED THAT IN TEN YEARS AGO IN EFFORTS TO INCREASE IF EFFORTS TO INCREASE BREAST FEEDING DURATION ARE SUCCESSFUL THE EFFORTS TO PREVENT IRON DEFICIENCY WILL HAVE INCREASING IMPORT AND I THINK WE ARE CLEARLY SEEING NOW THAT WE ARE REALLY NOT ADDRESSED THIS POPULATION. SO SO I BELIEVE WHAT RELATE TO BRAIN FUNCTION AND BEHAVE I DON'T RECOLLECT, AND DO WE HAVE IT RIGHT, ARE WE OVERDIAGNOSING DEFICIENCY OR THIS IS WHAT (INDISCERNIBLE) LOOKING FOR? RESEARCH GAPS PREVALENCE IRON DEFICIENCY IN HEALTHY BREAST FED INFANTS IN DEVELOPED COUNTRIES AND SYSTEMATIC EFFECT ON ASSESSMENT OF FUNCTIONAL OUTCOMES, RECOMMENDATIONS TAILORED TO PREVENT IRON DEFICIENCY IN THIS GROUP WHICH REINFORCE IT IS 12 TO 24 MONTHS INITIATIVE NOW DOING A BETTER JOB TAILORING OUR ADVICE. PAUSE PLUS -- [APPLAUSE] >> IF WE CAN ASK THE SPEAKERS FROM SESSION 2 TO COME UP TO THE FRONT PAM. -- PANEL. THOSE IN THE AUDIENCE IF YOU HAVE SOME QUESTIONS FEEL FREE TO COME TO THE MICROPHONE. I WILL REITERATE A LITTLE BIT WHAT I MENTIONED AT THE BEGINNING WHICH IS THAT WE WERE GOING TO BEGIN WITH SORT OF THE CLASSIC WAY OF THINKING ABOUT IRON WHICH IS ALWAYS BEEN IRON DEFICIENCY BUT THAT I WANTED TO PUT ON THE TABLE THAT THIS WAS A LITTLE BIT EVOLUTION THROUGH A THOUGHT PROCESS. THAT IS, I WOULD LIKE THE PANEL TO THINK ABOUT TRYING TO DETERMINE STATUS OTHER THAN ANEMIA OR DEFICIENCY, IN OTHER WORDS WHAT ARE THE KINDS OF THINGS WE NEED TO THINK ABOUT IF WE'RE TRYING TO FIGURE OUT ADEQUACY AND EVEN A LITTLE BIT EXCESS. THOSE ARE FAIR QUESTIONS FOR SOME HEMOTO LOGICAL MEASURES. AND ALSO TO MENTION SOMETHING WE WERE TALKING ABOUT AT LUNCH AS WE START TO MOVE TOWARDS WHAT THE TASK FORCE WAS INTERESTED IN, MAKING SURE THE HEMOTO LOGICAL MEASURES IN FACT LINKED IN SOME WAY TO A HEALTH OUTCOME, HOW ARE THOSE KINDS OF THINGS DONE AND WHAT DO YOU DO IN TERMS OF MEASURES. SO LET ME ASK FIRST ABOUT THIS CONCEPT OF ADEQUACY, MORE ADEQUATE, LESS ADEQUATE AND EXCESS. ANY THOUGHTS ON THAT? WE SPENT TIME ON DEFICIENCY BUT IT IS A CONTINUUM, STATUS IS A CONTINUUM. SO ARE WE STUCK WITH ANEMIA, IS THE ONLY WAY WE CAN THINK ABOUT THESE MARKERS OF STATUS? ANYBODY? >> I WANTED TO FOLLOW-UP ON WHETHER WE CAN USE FERRITIN AS AN EXAMPLE OR IRON DEFICIENCY, I KNOW YOU WANT THE GET TO ADEQUACY BUT IF WE CAN USE DEFICIENCY AS NOT ADEQUATE, NOT DISCUSSING RISK YET, I THINK WHAT PARMINDER SHOWED AND SIGNIFICANCE OF INFLAMMATION ON FERRITIN MAKES ME WONDER AS A CLINICAL LABORATORIAN HOW MUCH WE CAN TRUST FERRITIN AS MEASURE OF IRON DEFICIENCIES OR IF YOU WILL, INADEQUACY. >> ANYBODY ELSE? >> ONE THING THAT I MENTION TOWARD THE END, I GUESS IT'S NOT JUST DEFICIENCY FOR EXAMPLE OR REPLEASE BUT YOU ALSO HAVE A HOMEOSTATIC FEEDBACK SO WE KNOW THAT -- IT INCREASES IRON ABSORPTION TO ACHIEVE OPTIMIZE HOMEOSTASIS. I WONDER IF THERE'S WAY WE CAN USE THAT CIRCUIT TO HELP INFORM US BECAUSE IT ENTAILS US TRY TO BE ACHIEVED PHYSIOLOGICALLY, THE TWO WAYS THAT CAN BE DONE IS USING THOSE PARAMETERS TO HELP US UNDERSTAND FERRITIN BETTER OR OTHER BIOMARKERS BETTER BUT ACTUALLY IF HEPSADEN WAS DISCOVERED EARLIER AS A BIOMARKER USED FOR IF 1960s, '70s, WE WOULDN'T BE HAVING A MEETING NOW TO SAY LET'S START USING FERRITIN. I WONDER WHETHER USING HEPSADIN ITSELF BECAUSE YOU KNOW WHAT WILL HAPPEN POTENTIALLY. >> I KNOW IF WE HAD IT BACK THEN WE WOULDN'T PUT 12.8 -- 12-MILLIGRAMS OF METER IN FORMULA BECAUSE THAT WAS THE HISTORY CURRENTLY. WAS BASED ON THE IDEA THAT MANY ARE DISCONTINUING FORMULA FITTING FEEDING AND WE WANT TO LOAD THEM UP TO -- IN ORDER TO SKATE THROUGH THE SECOND HALF NOW WE KNOW THAT'S NOT HOW THE SYSTEM WORKS. >> I THINK THAT IF I HAD A CHOICE OF HEPSADIN IT WOULD BE GREAT. IF I HAD A CHOICE OF MARKERS AND WHEN BEING A NEONATOLOGIST I WOULD LICK TO KNOW WHAT A KID STARTS WITH. YOU HAVE A HEMOGLOBIN AFTER IT SETTLES OUTPOST DELIVERY, YOU HAVE A FERRITIN AND T 2% OF THE TOTAL BODY AARON ACCOUNTED FOR, YOU SHOULD HAVE A GOOD IDEA IF THIS CHILD IS ENTERING LIFE WITH THE ABILITY TO SKATE THROUGH WITH NO IRON SUPPLEMENTATION FOR TWO TO FOUR MONTHS, SMALL AMOUNT OF SUPPLEMENTATION OR WHATEVER. SO I'M CHANNELING WHAT KAY TALKS ABOUT WHICH IS AGA BABY WITHOUT THOSE RISK FACTORS BORN WITH NORMAL STORAGE WITH THE -- WE CALL IT APPROPRIATE CORD CLAMPING NOW, IF YOU CUT IT EARLY THAT'S PREMATURE BUT WHAT PEOPLE ARE CALLING DELAYED CORD CLAMPING, ADD THAT PIECE IN THERE, THEY GROW BLOOD VOLUME MEANING BODY AT A RATE ALONG THE WHO CURVE, FAIR AMOUNT OF IRON THERE TO WORK WITH. THAT WOULD BE WHAT I WOULD LIKE TO KNOW. JOKINGLY SAY TO PARMI, WE SCREEN FOR ALL SORTS OF RARE DISEASES IN NEWBORN SCREENING AND HERE YOU HAVE A HIGH INCIDENCE ENVIRONMENTAL DISEASE AND WE'RE NOT LOOKING AT IF YOU ADD THAT FACT WITH WHAT BETSY TOLD YOU FROM MICROPHONE, MANY POSTNATAL IRON DEFICIENCY STUDIES MAYBE EXPLAINED BY A PRENATAL COMPONENT, SEEMS LIKE WE SHOULD BE LOOKING EARLY AND TAKING ACCOUNT OF WHAT THAT KID STARTS. >> AND ON THAT -- LET ME MAKE SURE PEOPLE IN THE AUDIENCE ARE COMING TO THE MICROPHONE IF THEY HAVE QUESTIONS, I WANT TO FOLLOW-UP ON THAT BUT I DON'T WANT TO PUT YOU ON THE SPOT BUT YOU HAVE TOLD US YOU'RE NOT AN IRON EXPERT YOU ARE INSTEAD PLASMA VOLUME EXTENSION, AS YOU LISTEN TO THIS, DID YOU WANT TO ADD ANYTHING IN TERMS OF PLASMA VOLUME SINCE MOVING FROM INFANTS AND BACK TO THAT, AS FAR AS PREGNANCY? >> I WOULD JUST SAY THAT AS I HAVE BEEN LEARNING A LITTLE BIT MORE ABOUT THE POTENTIAL ROLE OF HOMO CONCENTRATION AND SOME OF THE -- WE HAVE KNOWN FOR A LONG TIME HEMOCONCENTRATION WAS IMPLICATED IN THE PATHOGENESIS ON ADVERSE PREGNANCY OUTCOMES. IT WAS NEW TO ME AS I WAS PREPARING FOR THIS PRESENTATION THERE HAVE BEEN INDICATORS THAT ACTUAL IRON SAW MR. E MENNATION PRE-DISPOSE TO PREECLAMPSIA AND ADVERSE PREGNANCY OUTCOMES, I MAYBE OVERSTATING THAT BUT THERE HAS BEEN A STUDY THAT ALLUDED TO THAT AND I FIND THAT PERSONALLY FASCINATING. IF ANYBODY ELSE HAS ANY OTHER KNOWLEDGE OR THOUGHTS ABOUT ONGOING RESEARCH FOR THAT, I WOULD BE VERY INTERESTED. BECAUSE IF THAT WERE THE CASE, THAT COULD BE CHANGES THE PARADIGM WHAT THE GENESIS OF PREECLAMPSIA IS RATHER THAN VOLUME CONTRACTION, PRECIPITATING BY ACCESS OF IRON. SO IF ANYBODY HAS ANY THOUGHTS I WOULD BE INTERESTED TO KNOW. >> TAKE PLACEBO CONTROL STUDIES, OF HEALTHY PREGNANT WOMEN, GIVEN PLACEBO TO ONE GROUP, IRON TO THE OTHER GROUP, NONE OF THIS STUDIES SHOWN INCREASE INCIDENCE PREECLAMPSIA, SINCE WE INTRODUCED IN DEN MARK GENERAL IRON SUPPLEMENTATION 66-MILLIGRAM OF IRON FROM WEEK 40 THERE'S NO RISE IN PREECLAMPSIA. WE DON'T SAY HEMOCONCENTRATION WE SHOULD SAY HIGH HEMATOCRIT IN THIS GROUP OF HEALTHY WOMEN. AND IT INCREASES THE TRANSPORTATION ACTUALLY IF YOU HAVE A HIGH BENEFIT. SO YOU SHOULDN'T MIX THEM TOGETHER. PREECLAMPSIA IS A DISEASE FOR ITSELF AND I DON'T KNOW IF IRON SUPPLEMENTATION, WILL AUGMENT THE PREECLAMPTIC SYMPTOMS, I DON'T KNOW. >> AM I RIGHT? >> THIS SECTION WAS DEVOTED TO MEASURING AND SCREENING AND I WOULD HIKE TO ASK A GENERAL QUESTION, THE RECOMMENDATIONS IN 2006 AND 2015 WOULD THAT BE EVIDENCE FOR SCREENING WITH INSUFFICIENT -- DOES ANYONE ON THE PANEL HAVE ANY IDEA HOW TO AVOID HAVING A SIMILAR MEETING IN 2027? >> YOU'RE NOT ALLOWED THE CRAWL UNDER THE TABLE. YOU HAVE THE ANSWER. >> I GUESS I'M BIASED. I THINK ALEX THIS MORNING HIT THE NAIL ON THE HEAD AND PREVENTATIVE TASK FORCES HIT THE NAIL ON THE HEAD OVER AND OVER. WE HAVE TO PROVE WE CAN CATEGORIZE PEOPLE AS DEFICIENT, B WE HAVE TO TREAT THEM AND C WE HAVE TO SHOW THERE'S CHANGE IN OUTCOMES, THAT'S HOW WE PREVENT HAVING THE SAME MEETING. THAT SAID I HAVE A LOT OF NIH FUNDING. CHEERS TO EVERYBODY HERE. >> THE OTHER ISSUE NUTRITION AS WE WERE LIKE MEASURING LIKE THE PEOPLE WHO ARE DEVELOPING THESE COST EFFECTIVE METHODS TO MEASURE IRON STATUS, WE'RE FOCUS ON HEMOGLOBIN, FOCUSING ON THE WRONG INDICATOR, I HAVE I WAS AT A CLINIC IN GEORGIA, MEASURING HEMOGLOBIN, MOVING TO FINGER DEVICE, I THINK WE'RE IN THE COMMUNICATING WHAT THE DATA WE NEED IN ORDER TO BEST UNDERSTAND WHO IS AT RISK AND WHO IS SUFFICIENT, I THINK THAT WILL BE A FIRST STEP. >> I WOULD THINK THE MEETING WILL CONTINUE TO BE HELD EVERY FIVE TO SEVEN YEARS UNTIL PRIMARY RESEARCH IS DONE TO ADDRESS THE UNDERLYING PROBLEM. SO THERE'S ACTIVE RESEARCH PROGRAM IN IRON AND DEVELOPING COUNTRIES, THERE HAS BEEN BUT MOST OF THAT IS DEDICATED TO -- GOING TO GET MYSELF IN DEEP TROUBLE NOW MEASURING HOMOGLOBIN AND FERRITIN SHOWING IRON IMPROVES IT. SOME HAVE LOOKED AT DEVELOPMENT BUT NOT MANY. WE HAVE SOME PAUCITY OF DATA THERE. AND IN DEVELOPED COUNTRIES THE LITERATURE FOR WHAT IS CONSIDERED EVIDENCE BY EVIDENCE -- PROPER FORMAL RCT OF IRON INTERVENTIONS, IS REALLY THIN, WHAT THE REVIEW SHOWED. I GETS IF YOU TALK TO USPS TASK FORCE CHANGING YOUR MIND THEY NEED TO SEE SOMETHING THEY HIKE WHICH IS HIGH QUALITY TRIALS AND THAT'S THE WAY TO ADDRESS QUESTIONS. I THINK AND YOU CAN WORK BACKWARDS FROM THERE -- NOT SURE YOU NEED TO NECESSARILY HAVE A TRIAL OF SCREEN POPULATIONS VERSUS UNSCREEN POPULATIONS, PUREST WAY OF ANSWERING THE QUESTION BECAUSE WE ARE NOT EVEN AT THE STEP BEFORE THAT WHICH IS NECESSARY HI WHAT HAPPENS IF YOU -- IN A DEVELOPED POPULATION WHAT HAPPENS ON THESE FUNCTIONAL OUTCOMES. >> I THINK YOU WERE NEXT. I HAVE A QUESTION I'M ALMOST AFRAID TO ASK BUT MICHAEL AND BETSY, SOME YOU HAVE CAN ASSIST WITH THIS, MORE ASSUMPTION THAT FERRITIN MORE AT BIRTH IS BETTER YOU NEED MORE FERRITIN AND THAT'S A POSITIVE THING. IN YOUR STUDIES FOUND IN DIABETIC P BABIES FERRITIN WAS ASSOCIATED WITH HEMOGLOBIN AT BIRTH. WE'RE SEEING THE SAME THING IN OUR OTHERWISE HEALTHY NEONATE SPACE ON CORED BLOOD SAMPLES. BABIES THAT HAVE HIGH FERRITIN HAVE LOW HEMOGLOBIN, HIGH HEMOGLOBIN HAVE LOW FERRITIN. THOSE SITUATIONS GOING FOR HIGH FERRITIN IS NOT AN OPTIMAL SITUATION SO NOT SURE IF WE'RE SEEING SOMETHING STRANGE ABOUT THE TIME WE'RE TAKING SAMPLES IN CORED BLOOD OR INVERSE ASSOCIATION IS PRY YOUR TIDESSED BY HEMOGLOBIN, SOME OTHER NUTRIENT SOME OTHER ISSUE IS CONSTRAINED, THE ABILITY TO USE IRON FOR HEMOGLOBIN AND GET STUCK IN FERRITIN OR KIND OF OTHERS HAVE SEEN THIS, OTHER DATA SETS OR EXPLORED IT BUT IT'S SOMETHING WE SEE NON-ANEMIC BABIES, AND ANEMIC BABIES. >> YOU'RE DESCRIBING MAY WELL BE CHRONIC INFLAMMATION, WHO KNOWS WHAT'S GOING ON IN THOSE PREGNANCIES AND BEGS THE QUESTION IF IT'S NOT USED FOR HEMOGLOBIN IS IT AVAILABLE FOR BRAIN DEVELOPMENT IS ALSO THE ANEMIA OF INFLAMMATION. INTERESTING TO BRING THAT UP WHEN I FIRST GOT THE FIELD OF CHORED BLOOD FERRITIN, IT WAS A PAPER FROM GOLDENBERG SHE PUBLISHED THAT 300 KIDS ANDY VIEDED UP BY QUARTILES IN TERMS OF CORED FERRITINS. EVERYBODY REMEMBERS, I REMIND EVERYBODY THE KIDS IN QUARTILE DO WORST AT SCHOOL AGE. THE SECRET IS THE KIDS HIGH QUARTILE ALSO DID NOT DO AS WELL AS THE MIDDLE TWO QUARTILES. THEY DIDN'T DO ADS POORLY AS THE LOW QUARTILE. THAT'S AN INTERESTING THING. YOU WILL TALK, I THINK KAY WILL TALK ABOUT THIS. SO RIGHT. IN THE UNUSUAL STATE WHY WOULD YOU HAVE A LOW HEMOGLOBIN IN A NEWBORN AND HAVE HIGH FERRITIN. I DON'T SUSPECT -- >> THEY DON'T SEEM TO HAVE -- >> I'M GOING TO BE HERETICAL. THIS CONFERENCE IS ABOUT SCREENING AND SUPPLEMENTATION AND IRON REPLETE PREGNANT WOMEN A LOT OF DISCUSSION TODAY IS FOCUSED ON INDICATORS OF DEFICIENCY AND THINKING OF DEFINING DEFICIENCY AND IF WE LOOK AT ANEMIA, WE'RE GOING TO MISS OUT ON BRAIN DEFICIENCY IN THE FETUS OR NEWBORN. THAT'S NOT A NEGATIVE COMMENT, I THINK IT'S AN IMPORTANT ONE. BUT I DIDN'T HEAR ANY DISCUSSION ALTHOUGH THERE WAS AN INTRIGUING SLIDE THAT SAYS I'M NOT GOING TO TALK ABOUT THESE BUT WHERE ARE THE INDICATORS OF POTENTIAL HARM BECAUSE I THINK THE QUESTION TO BE ADDRESSED HERE IS THERE SOMETHING WRONG WITH WHAT I CONSIDER TO BE CURRENT PRACTICE WHICH IS A RECOMMENDATION THAT ALL WOMEN RECEIVE SOME SORT OF IRON SUPPLEMENTATION DURING PREGNANCY REGARDLESS OF INITIAL IRON STATUS IN A POPULATION LIKE THE U.S. THE BULK OF WOMEN MAY BE CONSIDERED IRON REPLETE AT THE BEGINNING OF PREGNANCY BUT WE DO THINK THAT BY THE END OF PREGNANCY IF THEY DON'T HAVE IRON SUPPLEMENTS THEY MAYBE IRON REPLETE. SO WHAT ARE OUR MARKERS, OUR INDICATORS OF POTENTIAL HARM THAT WE MIGHT THINK ABOUT? AND I FORGET WHO HAS THE SLIDE WITH SOME POTENTIAL BIOMARKERS. YOU I APPRECIATE HEARING IF THOSE ARE REASONABLE FOR PREGNANCY. >> ONE THING I WOULD SAY IS, MAYBE I DIDN'T MAKE THE POINT THERE, THE REASON I SHOWED THE BRAIN IN HEMOGLOBIN IS I DON'T WANT PEOPLE TO THINK THAT JUST BECAUSE YOU'RE NOT ANEMIC YOU DON'T HAVE POTENTIAL PHYSIOLOGIC PROBLEMS OF POTENTIAL IRE DEFICIENCY. I THINK THE SAME STUDY HAS TO BE DONE ON THE OTHER END WHICH IS WHAT YOU WERE SAYING, IF YOU GIVE IRON WHAT ARE BIOMARKERS OTHER INDICATORS OF HEALTH YOU MIGHT BE CAUSING TOXICITY AS WELL. WHAT WOULD THOSE BE? MICHAEL ZIMMERMAN WILL TALK ABOUT THAT. >> I MIGHT AS WE PREPARE FOR THE WORKSHOP, WE DIDN'T SEE A LOT OF MARKERS FOR SOMETHING OTHER THAN TOXICITY. IN OTHER WORDS, WHAT IS SORT OF A SUPER IRON LEVEL, THERE'S ADEQUACY MAYBE ADEQUACY THE LACK OF ANEMIA, IS THAT ADEQUACY? ARE THERE STAGES OF ADEQUACY, WHAT SIGNALS EXCESS AS OPPOSED TO WHAT SIGNALS TOXICITY? THAT'S PART OF THE QUESTION. I THINK LAURA IS ALLUDING TO. IN SOME WAY. I SUPPOSE SOME WAYS THE SILENCE GOES TO THE FACT, WELL, WE'RE HAVING THE WORKSHOP BUZZ WE DON'T HAVE THOSE THINGS AND WE WANT TO TALK ABOUT THAT. >> IS HEPSIDEN A POTENTIAL MARKER IS THERE A TITRATION EFFECT ON PLATEAU CAN WE USE THAT TO AT LEAST ADEQUACY? IS THAT WHAT YOU WERE SAYING BEFORE? >> I WOULD SAY IT COULD BE USED, I CAN SEE IT BEING USED AS WAY OF SAYING WHO COULD -- WHO SHOULD YOU GIVE IRON TO OR WHO WOULD RESPOND TO YOU GIVING THEM IRON. IF YOU'RE SUFFICIENT YOU'RE NOT GOING TO ABSORB IN THEORY, IF INFLAMED IT'S HIGH, YOU WON'T ABSORB IT. IF IT'S LOW. AND THAT'S BEEN USED THIS TRIALS. >> I WANT TO BE ABLE TO -- MARY ANN AND KEVIN. >> SO IT'S FASTKED WITH THE STEM CELLS, THAT'S ONE AREA THAT'S FAIRLY NEW IN STUDY. AND RIPE FOR PICKING. WE DON'T HAVE A LOT OF INFORMATION, WE DON'T HAVE A LOT OF INFORMATION WE CAN STUDY EPIGENETIC MARKS NOW, BUT WHAT WE NEED ARE BETTER STUDIES, BIGGER STUDIES OR FOCUS STUDIES TO ASK THE QUESTION. SO THERE'S A LOT OF EVIDENCE FOR OXIDATIVE STRESS. THAT'S CLEARLY THE PATHWAY YOU WANT TO EXPLORE. BUT LOOKING AT AVAILABLE EVIDENCE, THERE'S IN THE A LOT OUT THERE SO YOU HAVE TO SAY WE NEED THE EVIDENCE TO THIS IS A PRIORITY AREA. TOMORROW STUDY AS BETSY FORMULA FEEDING STUDY HIGH LEVELS, YOU HAVE THE SAME, IT'S A U SHAPED CURVE. SO WHAT HIGH IRON MIGHT DO, TO SUPPRESS SO YOU NEED THE SESSION INEFFECTIVE FEEDBACK. IRON LOADING INDUCE OWN ANEMIA. IT'S IMPORTANT TO RECOGNIZE THAT IN THE DATA AS WELL. SO I THINK SOMEBODY ASKED ME THE QUESTION, I DIDN'T FIND ANY OF THIS IN THE LITERATURE FOR TOXICITY IN PREGNANT WOMEN. BUT THE REEL QUESTION ARE THESE HINTS, A FEW HINTS IN HUMAN STUDIES AND HIGH END OF IRON SUPPLEMENTATION. YOU MAY UNCOVER THESE AFFECTS AND THE LARGE DATA BODY OF DATA IN ANIMAL STUDIES WHICH SHOW A CLEAR ASSOCIATION WHEN YOU LOAD ANIMALS DURING THIS PERIOD OF LIFE YOU WILL SEE BEHAVIORAL EFFECTS. SO YOU CAN'T HAVE TOO MUCH BRAIN IRON. >> I DON'T HAVE A HORSE IN THIS RACE. >> KEVIN GO AHEAD. >> HELPING PEOPLE THINK OUTSIDE THE BOX, I COMING FROM A COMPLETELY DIFFERENT TANGENT WHICH IS TO ASK NAIVE QUESTION AND HOPE IT ENCOURAGES PEOPLE TO THINK DIFFERENTLY THAN THEY'RE ACCUSTOMED. I JUST WANT TO REFLECT OVER THE COURSE OF TODAY, I LEARNED THAT VAST AMOUNT ABOUT ISSUES LIKE PRIORITIZATION AND HOMEOSTASIS AND I HAD SOME OTHER INKLINGS ABOUT BEFORE. PHYSIOLOGICAL CHANGES THAT OCCUR THROUGH PREGNANCY WITH SPIKE IN SOME THINGS AT CHILDBIRTH AND ALL THROUGH INFANCY IRON STATUS IS NOT ONLY A LIVELY MOVING TARGET. GO WE INTEND TO GET A VIEW OF THIS WITH A POINT MEASURE. EVEN THOUGH THERE'S A WELT OF DIFFERENT IRON STATUS MARKERS WE'RE MEASURING TYPICALLY AT A POINT IN TIME, IT'S LITTLE BIT LIKE THE THREE BLIND MEN AND THE ELEPHANT. AND I GUESS TO TURN THIS FROM A COMMENT INTO A QUESTION, TO EXPERTS WHO KNOW BETTER THAN I DO SHOULD WE LOSE ALL HOPE AT THIS POINT? OR IS THERE -- ARE WE DREAMING THE UNREACHABLE DREAM OR IS THERE >> I THINK WE SHOULD NOT LOSE HOPE. BUT I THINK ACTUALLY IT'S NOT THAT BAD BECAUSE -- SO I THINK -- HEPSAD iN IN MY VIEW IS AN EXCELLENT POTENTIAL BIOMARKER BUT I ALSO DON'T RAY LAY EXPECT THAT EVERY LAB IN THE U.S. IS TRAILING THE UK AND UNDEVELOPED COUNTRIES HAVE IT AVAILABLE IN NEXT DECADE. IT WOULD HAPPEN BUT WILL TAKE A MANUFACTURER WILL RUN WITH IT, I'M NOT AWARE OF WHAT'S HAPPENING. I THINK IT COULD BE A REALLY GREAT BIOMARKER BUT THE THING WITH FERRITIN, THERE'S TWO PARTS, MOST CLINICALLY TRAINED PEOPLE ARE FAMILIAR WITH FERRITIN, THEY RECEIVE A FERRITIN OF X AND THEY KNOW IN THEIR GUT WHAT IT MEANS WHERE THIS RUNS INTO TROUBLE IS WHERE YOU HAVE GUIDELINES AND SYSTEMATIC PROTOCOLS PEOPLE MUST FOLLOW, YOU HAVE TO REFER SOMEONE IF YOU GET THIS ANSWER AND YOU'RE NOT ALLOWED TO THINK AND IN THOSE CONTEXT THAT'S WHERE HAVING I THINK A DETAILED APPRECIATION OF WHAT THESE VALUES REALLY MEAN IS MOST IMPORTANT. I THINK THE TYPE OF STUDY THAT GET US TO UNDERSTANDING NOT JUST FERRITIN BUT ALL BIOMARKERS WHAT THEY REALLY MEAN IN A BUNCH OF CONTEXT AND WITH THE SERIES OF GOLD STANDARDS IS ONLY -- IT'S NOT CATASTROPHICALLY TECHNICALLY COMPLICATED STUDIES, THEY ARE ACHIEVABLE AND WE CAN GET THEM ALL DONE IN ONE SET OF STUDIES. >> WE HAVE ABOUT ONE OR TWO MINUTES LEFT. SO -- >> WANT THE MAKE A COMMENT ABOUT -- I THINK WE SHOULD ADVOCATE FOR INCLUDING TWO MORE BIOMARKERS IN THE STUDY. ONE IS HEPSIDEN, ONE IS NTBI. THE CAVEAT -- AND ALL THESE HAVE TO BE INTERPRETED IN CONTEXT. THE CAVEATS ARE APART OF THE MASS IN TERMS OF ASSAYS AVAILABLE RIGHT NOW, BEING PHI YOU ARE FIGURED OUT. THE OTHER ONE IS DYNAMIC MARKER INFLUENCED BY DIFFERENT THINGS SO IT WILL ABSOLUTELY HAVE TO BE INTERPRETED IN CONTEXT. AND THE SECOND ONE IS THE NTBI, NON-TRANSFER RENE IRON, WHICH MAYBE RELEVANT FOR IRON SUPPLEMENTATION IF LOW DURING PREGNANCY, ONCE WOMEN TAKE IRON SUPPLEMENTS THERE MAYBE CONSTANTLY SPIKENING THE SERUM, THAT'S SHOULD BE MEASURED TO UNDERSTAND HOW THAT AFFECTS CENTRAL TRANSPORT AS WELL SO THOSE TWO BIOMARKERS ARE VERY IMPORTANT TO DEVELOP. >> 30 SECONDS. >> COMMENT WAS ABOUT HIGH IRON AND EARLY EFFECT THAT'S COMING FROM A (INDISCERNIBLE) 21 YEAR FOLLOW-UP. THAT IS IRON FORTIFIED FORMULA OFF THE SHELF IN THE UNITED STATES. DELETE THE CONCEPT OF PATHOLOGICALLY HIGH IRON. THAT'S WHAT ALL THE KIDS IN THE U.S. HAVE QUOTE GOTTEN. SO I KNOW WE'LL HAVE A CHANCE TO TUCK MORE. >> WONDERFUL. THANK YOU, VERY MUCH, THIS WAS EXTREMELY USEFUL PRODUCTIVE AND THOUGHTFUL. COME ON BACK IN 15 MINUTES AND WE'LL CONTINUE. SO I'LL TALK WHILE YOU'RE STILL GETTING YOUR SEATS, BY THE TIME YOU HAVE DONE THAT, IT WILL BE TIME FOR THE FIRST PRESENTATION. I'M PAUL COATES, WE MET BEFORE, AND I'M THE MODERATOR FOR THIS SESSION ON IRON STATUS OF PREGNANT WOMEN AND YOUNG CHILDREN, FOCUSED ON DEVELOPED COUNTRIES. A SERIES OF FOUR BRIEF PRESENTATIONS FOLLOWED BY A MODERATED DISCUSSION. THAT SHOULD BRING US TO THE END OF THE DAY. IT'S LONG, IT'S BEEN INTERESTING, MOST OF YOU ARE STILL AWAKE, THAT'S GOOD TO NOTE. LET ME START BY INTRODUCING ZUGUO MEI WHO WILL TALK IRON STATUS AND THE PREVALENCE OF IRON ADEQUACY AND INADEQUACY FROM THE NHANES STUDY. >> GOOD AFTERNOON. MY PRESENTATION GIVE YOU OVERVIEW OF PRESENCE OF QUAD SY AND INADEQUACY FROM NHANES DATA FOR YOUNG CHILDREN, KNOP PREGNANT WOMEN AND PREGNANT WOMAN. SO THE TITLE IS TALKING ABOUT ADEQUACY AND INADEQUACY, IN REALITY IRON DEFICIENCY. AND IRON DEFICIENCY AND ANNEALIA. IN THE U.S. WE HAVE -- INTRODUCE THE SESSION TO WITH USE OF TOTAL BODY IRON WHICH IS A -- (INDISCERNIBLE) IN 2003 BASED ON THE RATIO OF SERUM TRANSFER RENNES RECEPTOR TO SERUM FERRITIN. SO THE INCREASE IS PRESENTED HERE. SO SINCE PEOPLE SAW THOSE SLIDES TODAY I'M NOT GOING TO SAY TOO MUCH, THE ONLY THING I WANT TO FOCUS THE RELATIONSHIP FOR TOTAL BODY IRON IS THE TOTAL BODY IRON FOR THE (INAUDIBLE) REPRESENT STORAGE AND VALUE INDICATED TISSUE IRON DEFICIENCY. SO THAT SUGGESTS THAT THE CUT OFF IS LESS THAN ZERO. THE OBJECTIVE IS FIRST TO EXAMINE THE DISTRIBUTION OF TOTAL BODY IRON. IN THE THREE YOUNG CHILDREN, WOMAN, NON-PREGNANT WOMEN, PREGNANT WOMAN IRON DEFICIENCY TO REPLEASE. THE SECOND PREVALENCE OF ANEMIA AND FINALLY FINALLY IDENTIFY RESEARCH GAPS. SO THE DATA WE USED IS FROM THE NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY FOR THREE POPULATION IN ORDER TO GET THE ADEQUATE SAMPLE SIZE COMBINE DATA TOGETHER FOR CHILDREN WE HAVE TO COMBINE 80 YEARS DATA FROM 2003 TO 2010 GAUZE NARROW AGE OF 12 TO 23 MONTHS TO GET A FOR NON-PREGNANT DATA WE NEED 2007 TO 2010 TO GATHER 34, 38 SAMPLE SIZE, FOR PREGNANT WOMAN WE HAVE TO COMBINE YOU CAN SEE THE DATA SETS BECAUSE BETWEEN O 2011 TO 2015, LACK OF FUNDING WE DON'T HAVE IRON MEASURE. FIRST EXAM TOTAL BODY DISTRIBUTION BY GROUP ALSO IRON DEFICIENCY ANEMIA, AND THE STRATIFY BY SOME SOCIO ECONOMIC AVAILABLE FOR EACH TARGET POPULATION. FOR ALL THOSE POPULATION, STRATIFY BY AGE, AND ALSO FAMILY INCOME. FOR CHILDREN BY GENDER, FOR NON-STRATIFY WE -- FOR PREGNANT WOMAN WE STRATIFY TRIMESTER. SO FIRST I'LL FRIEND DISTRIBUTION OF TOTAL BODY IRON. FIRST IS FOR CHILDREN, IN DISTRIBUTION BUT ALSO IF YOU USE LESS THAN ZERO AS CUT OFF FOR IRON DEFICIENCY, THE AREA UNDER THE CURVE IS PERCENTAGE OF IRON DEFICIENCY. SINCE WE DON'T HAVE A CUT OFF FOR IRON DEPLETION OUR HIGH IRON STORE GOOD MARKER OR IRON REPLEASE OR HIGH IRON STORE IN SEPARATION SCALE THEN CHARACTER THE PREVALENCE SO THE ENTIRE DISTRIBUTION IS HERE. HERE IS NON-PREGNANT WOMAN, THIS MEANS IN GENERAL NON-PREGNANT WOMAN HAVE HIGHER IRON STORE COMPARED TO CHILDREN. FOR PREGNANT WOMAN YOU CAN SAY OVERALL THE DISTRIBUTION IS SHIFTED TO THE LEFT COMPARED TO NON-PREGNANT WOMAN. THAT MEAN IT IS MORE PREGNANT WOMAN CLASSIFIED AS IRON DEFICIENCY. THE PROBLEMS OF IRON DEFICIENCY ANEMIA FOR CHILDREN OVERALL WE GOT ABOUT 15%. IRON DEFICIENCY ANEMIA IS ONLY ABOUT 2% BUT EVEN THOSE BUZZ SMALL SAMPLE SIZE, THE ESTIMATION IS UNSTABLE BASED ON CRITERIA WHICH IS A RELATIVELY (INAUDIBLE) MORE THAN 30%. FOR NON-PREGNANT WOMAN THE PREVALENCE OF IRON DEFICIENCY IS ABOUT 10%. MORE THAN 5% ARE IRON DEFICIENCY ENEMIA. FOR PREGNANT WOMAN OVERALL WE GET ABOUT 16%. BUT ONLY LESS THAN 3% ARE IRON DEFICIENT ANEMIA. THAT'S THE OVERALL. HERE I WILL PRESENT EACH POPULATION BY STRATIFICATION. SO FOR CHILDREN WITH STRATIFY GENDER, AGE GROUP, RACEETH IN ETHNICITY, FAMILY INCOME THAT'S THE PREVALENCE OF IRON DEFICIENCY. SO EACH STRATIFICATION THERE'S NO STATISTICAL SIGNIFICANCE BETWEEN BOY AND -- BETWEEN TWO AGE GROUP AMONG THREE -- SO FAMILY INCOME. BUT ALL THE IRON DEFICIENCY ANEMIA IS UNSTABLE O SO WE CAN'T MAKE ANYTHING UNDER IRON DEFICIENCY ANEMIA FOR YOUNG CHILDREN. FOR NON-PREGNANT WOMAN WE OBSERVE MOST MEXICAN AMERICAN NON-HISPANIC BLACK HIGHER PREVALENCE OF IRON DEFICIENCY COMPARED TO HISPANIC TO WHITES, WOMAN WITH GREATER OR EQUAL TOO HIGH PREVALENCE OF IRON DEFICIENCY WITH PARODY LESS THAN TWO. NO BETWEEN FAMILY INCOME AND AMONG AGE GROUP, THAT'S IRON DEFICIENCY, IRON DEFICIENCY ANEMIA WE OBSERVE THE SAME PATTERN. FOR PREGNANT WOMAN WE ALSO OBSERVE BOTH MEXICAN AMERICAN NON-HISPANIC BLACK HAVE HIGHER IRON DEFICIENCY COMPARED TO NON-HISPANIC AN WHITES. MOSTLY IMPORTANT YOU CAN SAY BY TRIMESTER THE PREVALENCE OF IRON DEFICIENCY IS MORE THAN DOUBLED. SO -- FIRST TRIMESTER IRON DEFICIENCY IS ABOUT 5%. SECOND TRIMESTER INCREASE TO OVER 12% BY THIRD TRIMESTER IT'S OVER 27%, EACH TRIMESTER IS SIGNIFICANTLY HIGHER COMPARED TO THE PREVIOUS TRIMESTER. THAT'S MOST -- BETWEEN FAMILY MCOR AMONG AGE GROUP. ALL IRON DEFICIENCY ANEMIA STRATIFICATION FOR PREGNANT WOMAN BASED ON CDC AND CHS CRITERIA IS UNSTABLE. SINCE U.S. IS ONLY COUNTRY I USE TOTAL BODY IRON TO DEFINE IRON DEFICIENCY, IN ORDER TO COMPARE WITH OTHER RESULTS SO WE CALCULATE PREVALENCE OF IRON DEFICIENCY SIMPLY USING 7 FERRITIN. SO IF YOU USE TOTAL BODY IRON AS I TOLD YOU, THE IRON DEFICIENT RATES FOR CHILDREN IS ABOUT 15 PERCENT. IF YOU HAVE FERRITIN LESS THAN 12 WE ALMOST GET THE SAME PREVALENCE FOR THIS YOUNG GROUP. BUT HOWEVER NON-PREGNANT WOMAN TOTAL BODY IRON GET ABOUT 10%. FERRITIN LESS THAN 5 YOU GET ALMOST 16%. FOR PREGNANT WOMAN IF YOU USE TOTAL BODY IRON THE IRON DEFICIENCY RATES ARE ABOUT 16%. IT FEELS CERTAIN FERRITIN LESS THAN 15 THE PREVALENCE ALMOST DOUBLED. SO IT'S ALMOST 32%. FOR PEOPLE COMPARE WITH OTHER DEVELOP COUNTRIES USE FERRITIN HERE IS THE RESULT IN THE U.S. DATA. IN SUMMARY CHILDREN OVERALL PREVALENCE OF DEFICIENCY IS ABOUT 15%. IRON DEFICIENCY ANEMIA IS LOW BUT RESULT IS UNSTABLE. WE DIDN'T OBSERVE SIGNIFICANT DIFFERENCE IN THE PREVALENCE OF IRON DEFICIENCY IN AGE GROUP, GENDER, RACE ETHNICITY OR FAMILY INCOME IN CHILDREN. FOR NON-PREGNANT WOMAN THE OVERALL PREVALENCE OF IRON DEFICIENCY IS ABOUT 10%. IRON DEFICIENCY ANEMIA IS 5%. BOTH NON-HISPANIC BLACK AND MEXICAN AMERICAN HAD HIGHER PREVALENCE OF IRON DEFICIENCY AND IRON DEFICIENCY ANEMIA THAN NON-HISPANIC WHITE. WOMEN WITH PARODY GREATER THAN 2 HAS HIGH PREVALENCE OF IRON DEFICIENCY AND ANEMIA,COMPARED TO WOMAN -- THERE'S NO SIGNIFICANT DIFFERENCE IN IRON DEFICIENCY ANEMIA IN AGE GROUPS FOR FAMILY INCOME. FOR PREVENIENCE ABOUT 16% IRON DEFICIENCY ANEMIA IS LESS THAN 3%. NON-HISPANIC BLACK AND MEXICAN AMERICAN HAVE HIGHER PREVALENCE COMPARED TO LUNG HISPANICS OR WHITES. THE THIRD TRIMESTER HAS THE HIGHEST COMPARED TO THE SECOND AND FIRST. SO IN TERMS OF RESEARCH GAP ON THE RESEARCH LEADS ASSESS IN THE BEGINNING THERE'S LOW CUT OFF FOR IRON REPLEASE OR HIGH IRON STORE BASED ON TOLT BODY IRON. I ALSO FROM SESSION 2 YOU LEND FROM P,RMY EVEN WITH INFORMATION IS LOWER, STILL HAVE A IMPACT ON FERRITIN AND TFR AND TOTAL BODY. SO IN ALL THE RESULT WE DIDN'T COME FOR INFORMATION INFECTION. ALSO BASED ON SOME LIMITED DATA SUGGEST IRON DEFICIENCY TOTAL BODY IRON LESS THAN ZERO MAY NEED FURTHER ITERATION. SOME ARGUE IT LESS LESS THAN ONE. OR TWO. SO WHAT THEY'RE TALKING ABOUT BUT DEFINITELY THE CUT OFF ALSO NEEDS TO BE REVISITED. THANK YOU VERY MUCH. >> THANK YOU VERY MUCH. [APPLAUSE] >> WE'LL MOVE STRAIGHT ON TO THE NEXT PRESENTATION BY KIM O'BRIEN FROM CORNELL WHO WILL TALK OTHER DATA THAT REVEAL POPULATION RELATED IRON STATUS IN THE UNITED STATES AND CANADA. >> THANK YOU FOR INVITING ME (INAUDIBLE). SO WHEN THEY WANT TO DO THIS -- DIFFICULT AS IT MAY SEEM THANKS TO COMPREHENSIVE REROW WE HAD ON LONGITUDINAL CHANGES ON IRON STATUS ACROSS GESTATION, 12 LONGITUDINAL STUDIES WERE IDENTIFIED BY THE TASK FORCE THAT COMPARED IRON SUPPLEMENTATION TO NO SUPPLEMENTATION IN DEVELOPED COUNTRIES HOWEVER ONLY THREE OF THOSE STUDIES WERE CARRIED OUT IN NORTH AMERICA ALL THREE WERE FROM THE UNITED STATES. TWO OF THOSE THREE STUDIES FOCUSED ON HIGHER RISK POPULATION, THOSE WERE LOWER SES WOMAN, WOMAN WITH HIGHER PARODY O AND MINORITY WOMAN. AS WE HEARD FROM DR. MEI, THE U.S. HAS CROSS SECTIONAL DATA FROM PREGNANT WOMEN ON NHANES STUDY. CANADA HAS NO NATIONAL OR CROSS SECTIONAL DATA LOOKING AT IRON STATUS IN THEIR PREGNANT WOMEN, TWO SURVEYS CHECKED HEMOTO LOGICAL DATA, THEY ONLY HAD SMALL NUMBERS OF PREGNANT WOMEN IN THOSE STUDIES AND NO DATA WERE PUBLISHED LOOKING AT THAT POPULATION. SO THIS BRINGS US TO THE QUESTION THAT ANDY MENTIONED EARLIER, WHERE THE REFERENCE DATA COME FROM TO LOOK AT THE CUT OFFS THAT ARE USED TO ESTABLISH ANEMIA IN NORTH AMERICAN WOMEN. THESE CUT OFFS COME FROM THIS PAPER THAT WAS PUBLISHED IN '88, '89 BY CENTERS FOR DISEASE CONTROL. THE DATA INDICATED ON THIS TAME, THIS IS LOOKING AT THE FIFTH PERCENTILE CUT OFF IF YOU FALL BELOW THIS YOU HAVE ANEMIA, THESE POPULATION GROUPS WERE FOUR STUDIES UNDERTAKEN IN FINLAND, SWEDEN AND UNITED KINGDOM. SOME MIGHT BE INTERESTED TO KNOW REPEAT BIOPSIES OF THE STERN NUMBER RADIO ISOTOPES GIVEN TO LOOK AT ABSORPTION SO THEY WERE COMPREHENSIVE STUDIES BUT THESE WERE LIMITED IN SIZE. THESE WERE ISSUES THAT MAY IMPACT RELEVANCE TO CURRENT CUT OFF WE UTILIZE TO DEFINE ANEMIA ACROSS PREGNANCY. SMALL STUDY POPULATIONS FROM 32, 36 WOMAN TO 267 AND IN TOTAL, ONLY 400 UTILIZED TO INFORM THE GUIDELINES. THE RACIAL COMPOSITION OF THE STUDY WAS NOT MENTIONED BUT CAN BE ASSUMED TO BE PREDOMINANTLY CAUCASIAN AND NOT REPRESENTATIVE OF THE CURRENT MINORITY POPULATION OF NORTH AMERICA. PRE-PREGNANCY BMI SPECIFIED IN ONLY TWO OF FOUR STUDIES AND IN THOSE TWO AVERAGED 21-KILOGRAMS PER METER SWEARED. HALF U.S. WOMAN ENTER PREGNANCY OVERWEIGH OR OBESE AND CANADIAN WOMAN OVERWEIGHT OR OBESE. WOMEN IN REFERENCE STUDIES RECEIVE SUPPLEMENTAL IRON THAT RANGEDED FROM 65 TO 200-MILLIGRAMS PER DAY SO HIGH END OVER 7 TOMB HIGHSER THAN THE RDA OF 27-MILLIGRAMS PER DAY, THOSE ARE THE DATA UTILIZED GUIDELINE IT IS FIFTH PERCENTILE FLOW BIN CUT OFF. THROW LONGITUDINAL RECENT LE CARRIED OUT IN OTHER POPULATION TO LOCK HEMOTO LOGICAL CHANGES ACROSS GESTATION. THE FIRST IS LONGITUDINAL PREGNANCY AND BIRTH COHORT FROM ALBERTA CANADA, KINDLY SHARED UNPUBLISHED INFORMATION FROM THIS STUDY TO LOOK AT HEMOGLOBIN IN THIS LARGE COHORT THAT IS ALSO FOLLOWING CHILDREN OUT TO AGE 3. I ALSO WANT TO DISCUSS DATA FROM TWO OTHER U.S. POPULATIONS OF PREGNANT WOMAN LONGITUDINAL DATA, THE STUDY WOMAN CARRYING MULTIPLES SO 83 WOMAN AND 156 OF 183 NEONATES AT BIRTH USING CORED BLOOD. THE SECOND IS LONGITUDINAL STUDY OF PREGNANT ADOLESCENTS, 176 ADOLESCENTSES AND 193 BABIES. MULTIPLES NOW COMPRISE THREE AND A HALF PERCENT OF U.S. BIRTH SO THIS IS OTHERWISE HEALTHY POPULATION. AND PREGNANT ADOLESCENTS, 7% OF THE U.S. OBSTETRIC POPULATION IS DEFINED AS PREGNANT TEEN 19 YEARS OF AGE AND UNDER D. THESE COHORTS GIVE ADDITIONAL OPPORTUNITIES TO LOOK AT ANEMIA ACROSS GESTATION RELEVANT TO THOSE CDC CRITERIA I SHOWED YOU. TO LOOK AT CORRELATION BETWEEN IRON STATUS BIOMARKERS AND HEMOGLOBIN AND THEIR PREDICTIVE ABILITY TO IDENTIFY THOSE AT RISK OF ANEMIA AT TERM. WHAT I'M NOT GOING TO MENTION IS THOSE COHORTS ALSO LET US LOOK AT MATERNAL IRON STATUS AND NEONATAL IRON STATUS AT BIRTH WHICH IS VITALLY IMPORTANT. 20% OF THE TEEN BABIES WERE ANEMIC AT BIRTH AND 12 TO 17 MULTIPLE BABIES WERE ANEMIC AT BIRTH USING A CLIA CERTIFIED LAB TO DIAGNOSE THAT AS A CORED HEMOGLOBIN UNDER 13-GRAMS PER DECALITER. THESE ARE THE DATA FROM THE APRON STUDY COMPARED TO NHANES DATA, DR. MEI SHOWED US FROM THIRD TRIMESTER WOMAN, THOUGH THIS WAS LOW RISK POPULATION THEY TOOK SUPPLEMENTS ACROSS PREGNANCY, 70% HAD UNDERGRADUATE OR HIGHER DEGREE. 40% HAD DEPLETED FERRITIN IN THE THIRD TRIMESTER OF PREGNANCY AND BIRTH 5% OF WOMAN HAD ANEMIA. LOOK IN THE TEENS AND MULTIPLES 40% WOMAN HAD ANEMIA. HOWEVER ONLY 20% HAD DEPLETED FERRITIN OR IRON DEFICIENCY. I THINK THIS BRINGS UP THE CONCERN OF LOOKING AT FERRITIN AS MARKER OF IRON STATUS THAT DELIVERY WHEN YOU HAVE INFLAMMATION. WE SAW SIGNIFICANT INCREASES IN HEAPSIDEN AND IRL 6 AND CRP AT DELIVERY. THIS MARKER IS NOT NORMALLY MEASURED DURING PREGNANCY, THIS IS JUST LOOKING AT CORRELATIONS WHEN THIS GROUP IS DIVIDED TO THOSE THAT REMAINS NON-ANEMIC AND THOSE THAT DEVELOPED ANEMIA, BLACK ASTERISKS, RED ANEMIC WITH INCREASING ASTERISK AND SIGNIFICANCE. WHAT WE FOUND IS ERYTHROPOI TIP WAS ASSOCIATED WITH IRON STATUS MARKERS NEARLY ALL OF THEM AND NON-ANOMIC GROUP AND ALL OF THEM IN THE ANEMIC GROUP. RELEVANCE EPO WAS NOT SIGNIFICANTLY ASSOCIATED WITH IL-6 OR CRP. SO IT WASN'T IMPACTED BY INFLAMMATION. WOMAN WHOSE EPO CONCENTRATIONINGS OVER 27th PERCENTILE HAD THREEFOLD RISK AT TERM AND EPO EXPLAINED MAJORITY OF THE CHANGE IN SERUM HEMOGLOBIN AND SERUM TRANSFER RECEPTOR FROM PREGNANCY TO DELIVERY. SO JUST TO CONCLUDES, THERE WERE MANY GAPS IN KNOWLEDGE LOOKING AT FACTORS THAT IMPACT RESPONSE TO SUPPLEMENTATION NO NORTH AMERICAN WOMAN, IT'S VERY IMPORTANT WHEN ASSESSING DEGREE OF RESPONSE THAT YOU CONSIDER BASELINE MATERNAL IMMUNOLOGICAL STATUS BUT THAT IS KNOWN TO IMPACT IMPACT OF ABSORPTION OF IRON, IT INCREASES AS IRON STORES GO DOWN BUT IT'S NEVER CONSIDERED IN ANY STUDIES IS HEME IRON AND WE HAVEN'T HEARD MUCH ABOUT THAT TODAY BUT WE KNOW FROM STABLE ISOTOPES STUDIES IN PREGNANT WOMAN IT'S ABSORBED NOT IMPACTED ADVERSELY BY INHIBITORS AND ALSO IS NOT REGULATEDDED IN RESPONSE TO MATERNAL IRON STORES. WE ALSO HAVE DATA TO SHOW MORE HEME IRON IS TRANSFERRED TO THE FETUS. SO CONSIDERING HEME INTAKE EVALUATING RESPONSE TO CHANGE IS VERY IMPORTANT. WE KNOW THREE HORMONES REGULATE IRON HOMEOSTASIS AS DR. NETIT TOLD US IT WAS IDENTIFIED, THERE ARE NO NORMATIVE DATA TO DATE ON ERYTHROPOIETIN, NOT KNOWN THE DEGREE WHICH IT MAY DAMPEN DOWN HEAPSIDE NEXT PRODUCTION IN ANEMIC WOMEN. THEY TALKED ABOUT THE NEED THE THINK IRON SUPPLEMENTATION BEYOND PREVENTION OF ANEMIA BUT LOOKING AT OPTIMAL LEVELS OF IRON TO SUPPORT FETAL DEVELOPMENT AND CONSIDERING NOT JUST PREGNANT WOMAN BUT THIS DYAD, INTAKE NEEDS TO BE SUFFICIENT TO MAINTAIN MATERNAL HOMEOSTASIS AND OPTIMIZE FETAL DEVELOPMENT AND BIRTH OUTCOMES AND THE IRON ENDOWMENT OF BIRTH. SO I ENDED TWO MINUTES EARLY. [APPLAUSE] >> LET'S CONTINUE IRON STATUS OF WOMEN IN DEVELOPED COUNTRIES AND DR. NILS MILMAN WILL TALK EXPERIENCE IN EUROPE. >> HELLO, UNITED STATES. THANK YOU FOR THE INVITATION TO CROSS UPON AND TELL YOU ABOUT THE IRON SITUATION IN EUROPE. EVERYBODY KNOWS HAMLET HAS 200 YEARS IN I DON'T KNOWBERG THIS YEAR SO I WONDER IF HAMLET HAD NEOFATAL BRAIN. IRON DEFICIENCY. AND KILLED ALL HIS FAMILY. MY JOB IS TO TALK ABOUT IRON USE AND I HAVE INCLUDED DIETARY IRON INTAKE IN PRE-MENOPAUSAL AND PREGNANT WOMEN IN EUROPE. FERRITIN IS I WILL CALL RELIABLE MARKER BIOMARKER FOR BODY IRON AND WHAT DID WE DO WHEN WE DIDN'T HAVE FERRITIN? IT WAS A HUGE STEP FORWARD IN THE EARLY '70s. AND ACCORDING TO TO SOME PAPERS SOME FERRITIN IN ADULTS AND ONE MICROGRAM PER LITER CORRESPOND TO 7.5-MILLIGRAM IMMOBILIZABLE IRON. THAT'S MEAN AS FERRITIN OF 30 YOU HAVE MOBILIZABLE IRON. APPROXIMATELY 2 TO 5-MILLIGRAM. HOW WOULD YOU FIND IRON STATUS? I HAVE USED THE FOLLOWING DEFINITIONS IN WOMEN, IRON OVERLOAD AS YOU CAN SEE THAT IS MOSTLY 200, ABOUT 200 BUT SOME WERE OVER 110, ENOUGH FOR PREGNANCY WITHOUT TACKING IRON SUPPLEMENT, IF FERRITIN IS ABOVE 70 MICROGRAM PER LITER, IRON REPLETE WHEN YOU HAVE BONE MARROW IRON FERRITIN ABOVE 30 MICROGRAM PER LITTER AND SMALL OR DEPLETED IRON STORES LOWER. IRON DEPLETION, 15 MICROGRAM PER LITER AND IDA IS OF COURSE HEMOGLUE BIN BELOW EXIT THE LIMIT AND WE USE THE WHO LIMIT HERE SO MOST USE FERRITIN BELOW 15 OR BELOW 12 MICROGRAM PER LITER TO DEFINE IRON DEFICIENCY ANEMIA. THE MAIN TA SUBSTITUTION IN WOMEN OF REPRODUCTIVE AGE IS PRIMARILY MENSTRUAL BLOT AND IRON LOSSES. WOMEN HAVE (INAUDIBLE) FOR 35 -- 37, 37 YEARS MEN STREW WEIGHS AND THAT'S WHY THEY HAVE A POOR IRON STATUS THAN MEN. IRON STATUS IN WOMEN ARE INCREASING AND REACHES A LEVEL OF MEN AFTER CERTAIN YEARS. THE SECOND ONE VERY IMPORTANT IS DIETARY INTAKE. ABSOLUTE MILLIGRAM RATIO BETWEEN HIM AND NON-HEME IRON AND VERY IMPORTANT CONTRIBUTOR IN EUROPE IS DONATION ACTUALLY. THE PREVALENCE OF ANEMIA BY WHO HERE YOU CAN SEE THE PREVALENCE OF OF ANEMIA IN EASTERN EUROPE IS HIGHER THAN WESTERN EUROPE. ALL TOGETHER PREVALENCE OF 20% IN EUROPEAN WOMAN. WHICH IS QUITE IMPRESSIVE. I HAVE PICKED THE STUDIES OF AVAILABLE IRON STATUS IN EUROPEAN COUNTRIES AND THIS IS IN NON-PREGNANT WOMEN OF REPRODUCTIVE AGE, YOU CAN SEE THE MEDIAN FERRITIN ACTUALLY IS QUITE LOW AND YOU HAVE MEDIAN FERRITIN AROUND 30, THAT MEANS 50% OF THE WOMEN FERRITIN BELOW 30 WITH SMALL OR DEPLETED IRON STORES AND LOW BONE MARROW IRON. ID FREQUENCY RANGES FROM 10% TO 32% AND FREQUENCY OF IDA AS YOU CAN SEE IRON DEFICIENCY ANEMIA IN THESE APPARENTLY WELL HEALTHY WOMAN RANGING FROM 3 TO 7%. I SAW FROM THE AMERICAN STUDIES IS VERY RARE. A FEW PERCENT. SO THE CONCLUSION IS ACTUALLY THAT AMONG WOMEN IN EUROPE 40 TO 50% HAVE SMALL OR DEPLETED IRON RESERVE. FERRITIN BELOW 30. APPROXIMATELY 23% HAVE IRON DEFICIENCY AND 4% HAVE IRON DEFICIENCY ANEMIA. HOWEVER, DON'T DESPAIR. ACTUALLY 20 TO 30% OF WOMEN OF REPRODUCTIVE AGE HAVE A FERRITIN ABOVE 70 MICROGRAM PER LITER AND THAT IS ENOUGH TO COMPETE PREGNANCY WITHOUT IRON SUPPLEMENTS. WE SHOULD BEAR THAT IN MIND IN FURTHER DISCUSSION. ONLY ONE TO TWO PERCENT HAVE DEFINITE IRON OVERLOAD. IF WE LOOK AT THE PREVALENCE IN ANEMIA, IN PREGNANT WOMEN YOU CAN SEE HERE WE HAVE THE SAME PATTERN HERE HIGHER IN EASTERN EUROPE THAN WESTERN EUROPE AND HIGHER FREQUENCY ANEMIA OF 25%. SO IRON STATUS IS IN PREGNANT WOMAN IS NOT VERY WELL STUDIED IN EUROPE, THERE IS A FEW STUDIES THAT EXAMINE IRON STATUS IN PREGNANCY WITHOUT SUPPLEMENTS AND WE CANNOT PERFORM STUDIES TODAY ACTUALLY DUE TO ETHICAL REASONS. SO WE HAVE TO ESTIMATE IRON STATUS FROM EARLIER PLACEBO CONTROL STUDIES AND CROSS SECTIONAL STUDIES. AND I TRIED TO DELINEATE SOME OF THESE STUDIES HERE, TODAY'S STUDY PLACEBO IRON DEFICIENCY, 30% OF IRON DEFICIENCY ANEMIA AROUND 21%. IF WE CAN GIVE IRON YOU CAN SEE THE FREQUENCY OF IRON DEFICIENCY AND IRON DEFICIENCY ANEMIA GOES DOWN. IT IS THE SAME PATTERN WITH ALL MASS BOW CONTROL STUDIES. THEY HAVE BEEN REVIEWED IN A COCHRAN REVIEW AND THE PRESENT WAS CLEAR -- THE PATTERN WAS CLEAR, IT SHOWED ALL IRON STATUS PARAMETERS WHEN THEY HAD IRON TREATMENT AND IRON STATUS IN PLACEBO TREATED PREGNANT WOMEN ACTUALLY. SO IN NON-IRON TREATED WOMEN, 50% ON THE -- IRON DEFICIENCY ACCORDING TO OUR CRITERIA AND 20% HAVE IDA AND HIGH IN THE LATE THIRD TRIMESTER. IN THE IRON SU IMPLEMENT AROUND 30% AROUND ID IDA, IN 4 TO 5% WHICH IS ACCEPTABLE. DETERMINE IRON STATUS IN WOMEN IS DIETARY IRON INTAKE. VERY DIFFICULT TO COLLECT FROM THE NUMBER OF EUROPEAN COUNTRIES AND THE PATTERN IS QUITE SIMILAR. THE IRON INTAKE IS LOW. THE ESTIMATED MEDIAN OR MEAN IS 20.5-MILLIGRAM PER DAY. MEN HAVE HIGHER INTAKE THAN WOMEN, AND THE RECOMMENDED IN EUROPEAN COUNTRIES FROM 15 TO 20-MILLIGRAM PER DAY. AS YOU CAN SEE MOST WOMEN ABOUT 80 TO 85% OF THE WOMEN, THAT DON'T MEET DIETARY RECOMMENDATIONS CONCERNING IRON. WHAT HAPPENS WHEN THE WOMAN BECOMES PREGNANT? NOTHING, KEEPS EATING THE SAME TYPE PATTERN, IRON INTAKE IS (INAUDIBLE). WE NORMAL RECOMMENDED INTAKE OF NON-PREGNANT WOMEN IN EUROPE. SO GENERAL PATTERN IN PRE-MENOPAUSAL WOMEN AROUND 80 TO 95% HAVE IRON INTAKE BELOW RECOMMENDED INTAKE. THE SAME PATTERN IS SEEN IN PREGNANT WOMAN AND I SHOULD ADMIT 100% HAVE INTAKE BELOW 27-MILLIGRAM PER DAY RECOMMENDED BY YOUR INSTITUTE OF MEDICINE IN TWO OR ONE AND APPROVED BY NATIONAL INSTITUTES OF HEALTH. IN 216. WE ALSO LOBBY IN THE EUROPEAN COUNTRIES, ICE WAY NORWAY SWEDEN DENMARK, WE HAVE COMMON NUTRITION BOARD FOR ALL COUNTRIES WHICH MAKES NUTRITION RECOMMENDATIONS THERE ARE ACCOMODATIONS FOR PRE-MENOPAUSAL WOMEN 16 PER DAY AND PREGNANT 15-MILLIGRAM PER DAY PLUS IRON SUPPLEMENTATION 40-MILLIGRAM PER DAY FROM EARLY PREGNANCY TO DELIVERY. IRON PROPHYLAXIS. IRON PROPHYLAXIS IS AROUND 20 TO 30% SO I'M FIGHTING FOR INDIVIDUAL IRON PROPHYLAXIS AND STILL BEING DISCUSSED WITH HEALTH ONE OR TWO YEARS. WE HAVE RESENT EUROPEAN GUIDELINES WITH EUROPEAN FOOD SAFETY HERE THEY RECOMMEND 16-MILLIGRAM PER DAY PRE-MENOPAUSAL WOMEN AND ALSO TO PREGNANT WOMEN. AND THEY HAVE SUPPLEMENTATION FOR IRON SUPPLEMENTS, THIS IS THE ENGLISH GUIDELINES WHO COMES UP HERE THIS IS BASED ON -- THEY DON'T NEED TO IRON SUPPLEMENTATION PREGNANCY BASED ON CONCEPTION OF IRON ABSORPTION INCREASES DOCTORSICALLY DURING THE SECOND AND -- DRASTICALLY DURING THE SECOND AND THIRD TRIMESTER BUT LOOK AT THE STUDIES, AND THEY ARE MADE ON WOMEN WHO ARE DEEPLY IRON DEFICIENT. THIS IS BEING ADDRESSED FOR STANDARDIZATION OF FERRITIN AND COMMON (INAUDIBLE) LARGER COHORT STUDIES TO SEE HOW IRON STATUS ACTUALLY IN PREGNANCY AND HEALTHY WOMEN, WE HAVE TO LOOK AT INDIVIDUAL IRON SUPPLEMENTATION, CALLING FOR FERRITIN OR TBI WHO AND HOW MUCH IRON AND WE SHOULD ALSO SOME DAILY, ALTERNATELY SUPPLEMENT AND I WOULD LIKE TO SEE CONSENSUS ON RECOMMENDATION FOR DIETARY IRON INTAKE BETWEEN EUROPE AND UNITED STATES. THANK YOU WE HAD -- FOR WONDERFUL SEMINAR. >> THANK YOU VERY MUCH. WE'LL MOVE RIGHT ON AND HAVE A DISCUSSION ON IRON STATUS OF YOUNG CHILDREN IN EUROPE. BYILY DREY VAN DER MER WE. -- BY, LIANDRE VAN DER MER WE. GOOD AFTERNOON. LAST PRESENTATION OF THE DAY. I WILL ONLY BE TEN MINUTES. TO RECAP THE SPECIFIC OBJECTIVES OF THE TALK WAS TO DESCRIBE IRON STATUS IN EUROPEAN CHILDREN AND IDENTIFY RHESUS RESEARCH GAPS, KNOWLEDGE GAPS IN RESEARCH. DURING LATE INFANCY AND EARLY CHILDHOOD IRON REQUIREMENTS ARE HIGHER THAN ANY OTHER PERIOD IN LIFE. BUT BY THIS STAGE IRON STORES FROM BIRTH ARE DEPLETED, AND IRON INTAKE FROM IRON RICH FOODS ARE INSUFFICIENT. SO THEREFORE, IRON DEFICIENCY IS COMMON DURING THIS AGE AND IS A GLOBAL PROBLEM AS WE ALL KNOW ALSO IN THE DEVELOP WORLD SUCH AS EUROPE. NEVERTHELESS IN EUROPE SEVER CITY AND PREVALENCE OF IRON DEFICIENCY IS NOT CLEARLY DEFINED. THIS WAS THE RATIONALE FOR MY COLLEAGUE DR. ERSON WHO COULDN'T BE HERE TODAY TO DO THE SYSTEMATIC REVIEW THAT LED US TO BE INVITED AND FORM THE BASIS OF MY TALK. THIS REVIEW LOOKED AT THE AVAILABLE DATA ON IRON STATUS AND FOUND IT WAS NOT THAT MUCH BUT ALL THE DATA, MORE RECENT DATA WERE INCLUDED. IN THE INTEREST OF TIME AND BECAUSE CHRISTINE TAYLOR ALREADY TOUCHED ON IT, I WON'T PRESENT INTAKE DATA, ONLY THE IRON STATUS DATA. THIS REVIEW FOCUSED SPECIFICALLY ALSO ON IRON DEFISH AND IRON DEFICIENCY ANEMIA, NOT IRON DEPLETION SO TO MATCH CLOSELY WHAT THE OBJECT IS OF THE WORKSHOP, I ALSO WILL PRESENT SOME DATA THAT WE HAVE FROM A RANDOMIZED CONTROL TRIAL THAT WAS RECENTLY CONDUCTED IN WESTERN EUROPE, BASELINE RESULTS HAVE BEEN PUBLISHED SO THIS WILL HOPEFULLY GIVE SOME IDEA ON IRON REPLEASE SO THE SYSTEMATIC REVIEW LITERATURE RESEARCH WAS PERFORMED INCLUDED FROM SEVERAL COUNTRIES, 15 COUNTRIES APPROXIMATELY OF WHICH 20 STUDIES DEVELOPED IRON STATUS RATHER THAN IRON INTAKE. IN THE SUBGROUP OF THOSE COUNTRIES WE DID A MORE IN DEPTH ANALYSIS USING AN APPROACH CALLED NEUTRAPLANET WHERE YOU LOOK AT THE NUTRITIONAL CONTEXT OF THE COUNTRY. THE RANDOMIZED CONTROL TRIAL WAS PERFORMED IN GERMANY NETHERLANDS AND UNITED KINGDOM, THAT INCLUDED 325 HEALTHY CHILDREN MOSTLY ELEVATED CRP LEVELS AGE BETWEEN 12 AND 36 MONTHS. THE AIM OF THE STUDY WAS TO LOOK AT THE AFFECT OF CONSUMING SPECIFIC FORMULA FOR YOUNG CHILDREN VERSUS COW'S MILK ON IRON AND VITAMIN D STATUS ON 20 WEEKS OLD SEDIMENTATION. SO THE RESULTS OF THE REVIEW IT WAS FOUND THAT JUST AS WE HAVE HEARD TODAY THE WHOLE DAY, A LOT OF VARIOUS (INAUDIBLE) WERE APPLIED. IRON DEFICIENCY, IRON DEFICIENT ANEMIA HAD A BIG IMPACT ON ESTIMATES ACROSS THE COUNTRIES AND MADE THE COMPARISONS ACROSS COUNTRIES COMPLICATED. FOR INSTANCE ONE STUDY ESTIMATED IRON DEFICIENCY USING SERUM FERRITIN TEN VERSUS 15 AND BY THESE DIFFERENT ESTIMATES FOUND PREVALENCE OF IRON DEFICIENCY OF ONE (INAUDIBLE) VERSUS 20 IN THE SAME POPULATION. THE DIFFERENT HAD A MASSIVE IMPACT ON NOW ESTIMATES. IN ORDER TO SUMMARIZE AND SIMPLIFY IN ONE SLIDE THE SIREN STATUS WE FOUND IN 20 DIFFERENT COUNTRIES, I HAVE ONLY SELECTED THE MOST REPRESENTATIVE OF STUDIES TO PUT UP ON THE SLIDE. IF YOU LOOK AT THESE VALUES, IN ORDER OF INCREASING PREVALENCE OF IRON DEFICIENCY, YOU SEE THAT THERE'S SOME STUDIES PREVALENCE OF UNDER 10% BUT STUDIES THAT ALSO FOUND PREVALENCE OF 20, 30, 40% IRON DEFICIENCY. SO THERE WAS A LARGE VARIATION, LOOK AT THE TWO STUDIES THAT LOOK AT EUROPE, PREVALENCE IN GIRLS AND THIS WAS IN BOYS. 13 TO 18% PREVALENCE WHICH CONFIRMS IS COMMON IF EUROPE. IN TERMS OF RISK FACTORS IN THE CHILDREN 6 TO 12 MONTHS COMING FROM A VULNERABLE SITUATION WAS IS A RISK FACTOR AS WELL AS CONSUMING COW'S MILK IN THE FIRST YEAR OF LIFE AND IN THE OLDER CHILDREN IS COW MILK CONSUMPTION WAS A MAIN RISK FACTOR ESPECIALLY HIGH VOLUME OF COW'S MILK. MAINLY FOR IRON DEFICIENCY. IN ANEMIA IN WESTERN AND NORTHERN EUROPE IT WAS VERY LOW UNDER 5%. HOWEVER IN EASTERN EUROPE THE PREVALENCE WAS MUCH HIGHER. I HAVE ONLY SHOWED THE MOST REPRESENTATIVE STUDIES BUT FOR THE LESS REPRESENTATIVE STUDIES YOU SEE FOR EASTERN EUROPE THE PREVALENCE IS MUCH HIGHER, REALLY ECHOS WHAT NILS MILMAN SAW IN THE PREGNANT WOMAN. THERE WE SAW VALUE VALUES OF 8 TO 53% PREVALENCE OF IRON DEFICIENCY, IT WAS QUITE COMMON. IN THE RANDOMIZED CONTROL TRIAL IRON DEFICIENCY 13% AN ANEMIA 4%. PREVALENCE INCREASE QUITE DRAMATICALLY AT THE END OF THE INTERVENTION FROM 13% TO NEARLY 30%. THAT WAS A MASSIVE REDUCTION WHICH IS EXPLAINED BY THE FACT CHILDREN GREW OLDER DURING THE INTERVENTION PERIOD SERUM FERRITIN LEVELS ARE KNOWN TO DROP DURING THE SECOND YEAR OF LIFE. AND ALSO BY THE FACT THAT AT BASELINE HALF CHILDREN WERE CONSUMING FORMULA FORTIFIED MILK AND MANY RANDOM ICIZED TO COW'S MILK SO FERRITIN LEVELS WOULD DROP. IN THE YOUNG CHILD FORMULA GROUP IRON DEFICIENCY DIDN'T CHANGE THE PREVALENCE. WHICH TO US WAS SAYING THAT IT COUNTER ACTED THE AFFECT OF GROWING OLDER. IN TERMS OF IRON REPLEASE AND EXCESS STORES THERE WERE NOT A LOT OF DATA AVAILABLE BUT THESE ARE THE DATA FROM THE RANDOMIZE CONTROL TRIAL THAT ACQUIRED NICELY PLOTTED FOR EVERY SUBJECT FERRITIN LEVELS VERSUS AGE BASELINE. THE LINE SHOWS HOW THE OLD -- IN THE OLDER CHILDREN SERUM FERRITIN IS SLIGHTLY LOWER THAN IN THE YOUNGER CHILDREN. THE MEAN SERUM FERRITIN WAS 29. AND WE USE THEM ARBITRARY CUT OFF TO DEFINE REPLETE IRON STATUS AND I HEAR TODAY THAT'S PERFECTLY LEGAL. SO ABOUT 17%, 72% -- ABOVE 17 MICROGRAMS PER LITER, 72% OF CHILDREN. SO THAT'S QUITE COMMON IN THIS POPULATION OF WESTERN EUROPEAN CHILDREN. THE DEFINITION OF STORES IS NOT VERY CLEAR, I DID SHOW 95 -- 95 PERCENTILE OF 58 MICROGRAMS PER LITER. SO ONLY 5% OF CHILDREN HAD LEVELS HIGHER THAN 58 MICROGRAMS PER LITER AND THE HIGHEST LEVEL MEASURED WAS 97. SO IN TERMS OF LEVELS RANGES THAT I HAVE SEEN TODAY NONE OF THESE CHILDREN WERE REALLY HAVING AN IRON OVERLOAD OR EXCESS IRE STORES. AT THE END OF THE INTERVENTION DIDN'T HAVE THE RESULT SHOW RESULTS IT'S COMPLICATED BY THE INTERVENTION BUT IT WAS A SIMILAR PICTURE AND ALSO IN RECENTLY PUBLISHED STUDY FROM WESTERN URINE AND IRELAND, SIMILAR PICTURE 95 PERCENTILE WAS ALSO AROUND THIS AMOUNT. IN SUMMARY IRON DEFICIENCY IS STILL COMMON IN EUROPE, ANEMIA PREVALENCE IS VERY LOW IN WESTERN EUROPE BUT MUCH HIGHER IN EASTERN EUROPE. THE PREVALENCE OF IRON REPLEASE DATA LIMITED SHOW HIGH PREVALENCE IN WESTERN EUROPE IF YOU USE THE CUT OFF THAT WE DID. THE PREVALENCE OF EXCESS IRE STORES NOT A LOT TO SAY ABOUT THAT BECAUSE DATA ARE LIMITED AND IT'S NOT EASY TO KNOW WHICH DEFINITION TO USE. BUT IN OUR RANDOMIZE CONTROL TRIAL IN WESTERN EUROPE, VERY WELL NOWISHED CHILDREN, THE HIGHEST STORES WERE 58 TO HUNDRED MICROGRAMS PER LITER. AND ALSO IN SUMMARY, THE DIFFERENT CUT OFFS AND DEFINITIONS APPLIED REALLY DID INFLUENCE ESTIMATE AND COMPLICATED THE COMPARISONS, MAYBE THAT'S ONE OF THE BIG CONTRIBUTING FACTORS TO THE MASSIVE VARIATION WE SAW. IN THE DIFFERENT COUNTRIES. THE KNOWLEDGE GAPS IN RESEARCH NEEDS I HAVE IDENTIFIED OF COURSE WE NEED CONSENSUS AND IDEALLY INTERNATIONAL HARMONIZATION ON THE DEFINITIONS AND CUT OFFS FOR IRON STATUS. AND DIETARY IRON REQUIREMENTS. THINK IT'S VERY IMPORTANT TO DEVISE EFFECTIVE STRATEGIES TO MEDIATE NOT OVEREXCEED IRON REQUIREMENTS. IN THE EUROPEAN CONTEXT THE RANDOMIZE CONTROL TRIAL AND ANOTHER STUDY I DIDN'T HAVE TIME TO SHOW SHOWED THAT THE YOUNG CHILD FORMULA HAD QUITE A GOOD EFFECT ON PREVENTING IRON DEFICIENCY BUT ALSO PREVENTING UNWANTED SEARCH IN IRON LEVELS. BUT FURTHER RESEARCH IS NEEDED TO ESTABLISH THIS KIND OF INTERVENTION AND DEVELOP OTHER STRATEGIES FOR MEETING THIS GOAL. I PROPOSE WE NEED TO CLARIFY EFFECT OF IMPROVED IRON STATUS ON CLINICAL OUTCOMES LIKE NEURAL DEVELOPMENT AND HEALTH AND THEN WE NEED TO LOOK AT DIFFERENT FORTIFICATION LEVELS OF INFANT FORMULAS AND ALSO DIFFERENCE AGES IN THE U.S. 0 TO 12 MONTH WITH THE SAME FORTIFICATION LEVELS, IN EUROPE DIFFERENT CUT OFFS SO I THINK FOR THESE WE NEED TO KNOW WHAT IS IDEAL FORTIFICATION LEVEL FOR DIFFERENT AGE APPROPRIATE FORMULAS. FORMULA FED, THE IMPACT CAN BE VERY BIG AND HAVE A LASTING INFLUENCE ON HEALTH. SO IT'S CLEARLY QUITE AN IMPORTANT RESEARCH NEED AND THEN AS MANY PEOPLE HAVE MENTIONED TODAY MY FINAL PROPOSAL IS TO RESEARCH NOVEL IRON STATUS INDICATORS SPECIFICALLY IN CHILDREN. THANK YOU VERY MUCH. [APPLAUSE] FROM >> MAY I ASK OUR FOUR SPEAKERS TO NOT WANDER TOO FAR INSTEAD COME BACK UP TO THE TABLE AND INITIATE A BIT OF A DISCUSSION. JUST AS A REMINDER THE DRILL IS THE SPEAKERS HAVE A BRIEF OPPORTUNITY TO ENGAGE ONE ANOTHER IN A CONVERSATION WHILE THE REST OF YOU ARE THINKING ABOUT THE QUESTIONS THAT YOU WOULD LIKE TO ASK COME UP TO THE MICROPHONE OR IF YOU'RE ON THE PHONE MAKE YOUR QUESTIONS KNOWN AND WE'LL BE HAPPY TO SEE THEY GET ANDED. DO THE SPEAKERS HAVE ANY COMMENTS TO MAKE COMMENTS OR POINTS OF CLARIFICATION THEY WOULD LIKE TO SEE? IT'S ALL CLEAR. WHILE THERE'S STILL DECIDING, I ENCOURAGE PEOPLE TO COME UP. (OVERLAPPING SPEAKERS) >> WHY WOMEN ARE IRON DEFICIENT DURING PREGNANCY, CERTAIN PERCENTAGE. HOW MUCH COULD POSSIBLY DIAGNOSTIC PHLEBOTOMY CONTRIBUTE? I'LL NOT A CLINICIAN SO I'M ASKING CLINICIANS OR WOMEN WHO ARE PREGNANT AND WERE BLED REPEATEDLY THROUGH DIFFERENT DIAGNOSES, HOW MUCH BLOOD IS REALLY TAKEN IN ONE ML OF RED BLOOD CELLS IS ONE MG OF IRON. >> WOMEN WOULD HAVE GLUCOSE TOLERANCE TESTING DONE AND THEN TESTED FOR ALPHA FETAL PROTEIN SO THOSE ARE ONLY I THINK THE TWO MANDATORY TESTS THAT MOST PREGNANT. WOMEN WOULD HAVE AND MINIMAL AMOUNTS OF BLOOD, THEY SHOULDN'T REQUIRE -- IT SHOULDN'T BE CONTRIBUTING TO FALL. >> HI. THIS IS (INAUDIBLE) FROM CDC. I HAVE A COMMENT FOR DR. MILMAN, THANK YOU FOR SHARING THOSE WONDERFUL SLIDES YOU PUT TOGETHER REVIEWING THE LITERATURE IN EUROPE, IN PREGNANT WOMEN, I WAS ACTUALLY STRUCK BY A COUPLE OF THINGS, ONE WAS I WANT TO MAKE SURE I UNDERSTOOD THIS CORRECTLY BECAUSE THEY WERE VERY QUICK AND I WANT TO MAKE SURE I GOT YOUR MESSAGE DIRECTLY. SO I STATED WHAT I THOUGHT YOU STATED IF IT'S WRONG PLEASE CORRECT ME. I THINK YOU STATED THAT IN THE RANDOMIZE CONTROL STUDIES THAT YOU SUMMARIZE WHEN WOMEN GOT IRON MOST OF THEM DID NOT DEVELOP ANEMIA. VERSUS THE ONES WHICH DID NOT GET IRON, MANY OF THEM SAVE 50% IS THE NUMBER I GOT UP TO 50% GOT ANEMIA. I THINK IF THAT IS TRUE THAT'S QUITE AN IMPORTANT MESSAGE FROM YOUR PRESENTATION BECAUSE IT IS SAYING INVEST AT LEAST IN EUROPE WHAT YOU SUMMARIZE WOMEN RECEIVING BENEFITS DRASTICALLY AND ANEMIA RATES WENT DOWN AND WE KNOW ANEMIA IS A MAJOR PREDICTOR FOR PREGNANCY OUTCOME SO I WANTED TO CONFIRM THAT FIRST WITH YOU IF I UNDERSTOOD IT CORRECTLY. >> ALL PLACEBO CONTROL STUDIES SHOW UNIFORMLY THAT IRON DEFICIENCY WAS INCREASING DURING PREGNANCY AND REACH MAXIMUM TRIMESTER AND THE SAME WAS TRUE FOR IRON DEFICIENCY ANEMIA. AND OF COURSE THE NEED FOR IRON INCREASES DURING PREGNANCY. AND THE STATUS HAS BEEN COMPILEDDED IN IN THE COCHRAN REVIEW ACTUALLY AND THEY FOUND EXACTLY THE SAME RESULTS SO BUT IF YOU SUPPLEMENT WITH IRON, DEPENDING ON WHEN IN PREGNANCY YOU START AND DEPENDING ON THE DOSE, YOU USE, YOU WILL SEE DRAMATIC REDUCTION IN IRON DEFICIENCY AND IRON DEFICIENT ANEMIA. ONGOING WAS TO GIVE ENOUGH IRON OR AS LITTLE IRON AS POSSIBLE. SO WE HAD THE SAME FREQUENCY OF IRON DEFICIENCY ANEMIA IN PREGNANT WOMEN AS WELL HAD IN HEALTHY PRE-MENOPAUSAL WOMEN. THAT WAS AROUND 40-MILLIGRAMS. SO I'M TAKING BETWEEN -- THIS HAS BEEN IMPLEMENTED NOW IN THE DENMARK FOR ABOUT FIVE, SIX YEARS. BEFORE WE USED HIGH DOSE OF IRON 66-MILLIGRAM THAT WE SHOWED IN THE STUDY, 14-MILLIGRAM WAS ENOUGH. THE RIG STUDY THAT WAS MADE WITH (INDISCERNIBLE) IRON, VERSUS -- IT IS PRODUCED HERE IN THE UNITED STATES. AND WHICH WOULD GIVE US 25-MILLIGRAM OF IRON DURING PREGNANCY AND STILL PREVENT IRON DEFICIENCY AND IRON DEFICIENCY ANEMIA. MY HOPE IS THAT WE WILL IN THE FUTURE IN ONE OR TWO YEARS BECAUSE ASSOCIATION OF OBSTETRICS AND GYNECOLOGY, HAVE MADE A REFERENDUM ON HOW TO WORK OUT THE IRON STATUS DURING PREGNANCY AND WE WILL RECOMMEND THAT THEY HAVE IRON SCREEN, FERRITIN WHEN THEY HAD MIXED UP THE FIRST TIME AND YOU CAN STRATIFY WHETHER THEY SHOULD HAVE IRON SUPPLEMENT OR NOT. AND WHICH GOES THEY SHOULD HAVE. IF YOU HAVE FERRITIN ABOUT 70, IN ORDER TO GIVE IRON SUPPLEMENTS ACTUALLY, IT CORRESPONDS TO IRON STORES AROUND 500-MILLIGRAM AND WE HEARD IN THE BEGINNING OF THE -- THAT'S WHAT'S NEEDED FOR PREGNANCY IF YOU HAVE IRON STATUS OF FIVE HUNDRED MILLIGRAM YOU CAN DO WITHOUT IRON. >> POINT TO TAKE BACK HOME TO U.S. WHAT YOU PRESENTED IN EUROPE, THE SAME, JUST TRYING TO EXTEND DISCUSSION ON IRON SUPPLEMENTATION DURING PREGNANCY BUT WHAT I WAS ASTOUNDED BY WAS SO MANY WOMEN BENEFITED IF THEY DIDN'T GET IRON 50% STAY ANEMIC WHICH IS NOT WHAT WE WANT. SO COMING BACK TO THE U.S. ZUGUO'S PRESENTATION HAS THESE ARE THE WOMEN WHO MAY BECOME PREGNANT, AND MAY GOEN TO ANEMIA, 5% HAVING ANEMIA. ONE THING DR. MILMAN LAST QUESTION AND I WILL LEAVE. WHAT WAS THE RANGE OF ANEMIA IN THESE WOMEN THAT YOU SUMMARIZE LITERATURE ABOUT. >> THE FREQUENCY OF ANEMIA IS PRE-MENOPAUSAL WOMEN, IN DENMARK IS AROUND 4%. WE HAVE MADE SEVERAL STUDIES SHOWING THE SAME FIGURE. WE HAVE FOLLOWED IRON STATUS DURING THE LAST 15 YEARS IN WOMEN AND IT HAS NOT CHANGED. IRON STATUS IN PRE-MENOPAUSAL WOMEN HAVE BEEN LOW FOR MANY YEARS. IF YOU GO BACK TO VERY OLD PHLEBOTOMY STUDIESES IN THE 30s THEY HAD AROUND 300-MILLIGRAM OF IRON AND IT'S THE SAME TODAY. SAME SITUATION ACTUALLY NOT CHANGED VERY MUCH. CONCERNING IRON NUTRITION. >> THANK YOU. >> ONLY THING MAYBE TO ADD IS SERUM FERRITIN IS THE ONLY INDICATOR THAT'S MEASURED, IT MAYBE IMPORTANT TO INCLUDE AN INFLAMMATORY MARKER JUST TO CAPTURE THE INDIVIDUALS THAT MIGHT HAVE ACUTE INCREASE IN FERRITIN FROM SOME OTHER INFLAMMATORY PROCESS AT THE TIME THE SAMPLE IS TAKEN ESPECIALLY IF YOU GO TO ONE MEASURE AT THE BEGINNING, IF IT'S NOT GOING TO BE CHECKED AGAIN. >>NA'S QUITE RIGHT ACTUALLY. SO THEY HAVE A SAMPLE TAKEN THE FIRST PRENATAL VISIT FOR HCV AND HIV AND I DON'T KNOW A LOT OF THINGS. SO FAR THE NATIONAL BOARD OF HEALTH HAS REJECTED AND THE CLAIM THAT IT'S TO COSTLY BUT IT'S NOT TOO COSTLY. THE WOMEN HAVE A BLOOD SAMPLE ANYWAY, BUT THAT'S RIGHT. WE SHOULD INCLUDE (INAUDIBLE) ALSO. >> DR. ZIMMERMAN. >> IN PREVIOUS ANALYSIS OF NHANES USING THE OLDER INDICATORS FOR IRON STATUS, BMI WAS PREDICTOR OF IRON DEFICIENCY ACROSS ALL AGE GROUPS, I WAS WONDERING IF YOU LOOK AT BMI AS PREDICTOR OF IRON DEFICIENCY USING THE NEW IRON STATUS MARKERS. >> IN THIS WE DIDN'T LOOK AT IT BUT A GROUP OF PEOPLE IN OUR TEAM LOOKING AT THIS BUT DIDN'T REPORT. >> DR. VALENTINE. >> TWO COMMENTS. INTERESTING IN THE NHANES WORK TO LOOK AT DIET PATTERNS IN THE FOOD VARYING VERSUS IRON STATUS TO SEE HOW DIETARY PA ATTORNEY INFLUENCES INTAKE, THAT COULD BE INFLUENCED. AND ALSO BE INTERESTING TO LOOK HOW THE FORM OF IRON USED IN SUPPLEMENTAL IRON WILL IMPACT BECAUSE VARIOUS FORMS HAVE DIFFERENT BIOAVAILABILITIES AND WONDER WHETHER COMPARING TO HEME IRON AND WHETHER YOU HAVE WITH VITAMIN C STATUS HOW IT IMPACTS HOW IRON STATUS IS BEING CHANGED DURING THE COURSE OF PREGNANCY THAT MIGHT SHIFT AS WELL. >> COMMENTS. IN THE PAPER WE STRATIFY THE DATA WE HAVE TO THE DIETARY (INAUDIBLE) PARTICULARLY ON SUPPLEMENT QUESTION. SO PARTICULARLY IN THE RESULT WE SHOW PREGNANT WOMAN HAVE HIGHER IRON DEFICIENCY BUT A DEFICIENCY ANEMIA COMPARED TO NON-PREGNANT WOMAN. THE IRON DEFICIENCY RATES IS LOWER THAN COMPARED TO PREGNANT WOMEN BUT IRON ANEMIA IS HIGHER. FOR THE PREGNANT WOMAN SINCE WE DIDN'T ADJUST FOR INFORMATION, BUT IF BASED ON REGRESSION MODEL YOU PRESENT JUST PREGNANCY ALONG ITS INFORMATION STATUS, BUT WE ALSO OBSERVE IN OUR -- WE PUBLIC A PAPER AND SEVERAL BEFORE BY OTHER PEOPLE, WE IN TRIAL IN CHINA OBSERVE RELATIONSHIP BETWEEN GESTATION AGE AND CRP. SO CRP INCREASE WITH GESTATION AGE. IF WE ADJUSTED THOSE BACK MAYBE BY EACH TRIMESTER THE PREVALENCE WOULD BE DIFFERENCE. >> INTERESTING POINT RAISE. IN MANY STUDY THERE'S A LARGE DISCONNECT. YOU BROUGHT UP BETWEEN IRON DEFISH IS AND ANEMIA. YOU CAN'T CAPTURE, THERE'S A DOGNA MT. LITERATURE THAT HALF IRON DEFICIENCY ANEMIA FROM IRON BUT OFTENTIMES IN THESE STUDIES USING THE CUT OFFS THAT WE HAVE AT PRESENT, HALF ISN'T CAPTUREDDED BY IRON DEFICIENCY, OTHER NUTRIENTS LIKE HAVE IT MINUTE D INTERACT WITH EPO AND HAVE BEEN ASSOCIATED WITH ANEMIA IN THESE POPULATIONS SO TRYING TO FIGURE OUT BEST CONCENTRATION OF NUTRIENT DEFICIENCIES TO CAPTURE OTHER POSSIBLE CAUTIONS OR INTERACTIONS THAT MIGHT IMPACT WOMAN'S RESPONSE TO IRON SUPPLEMENTATION IS IMPORTANT. >> I HAVE A QUESTION FOR ZUGUO. DO YOU SEE THAT SHOULD BE ADJUSTED FOR OR DO YOU SEE THIS THAT AS HIGH RISK GROUP THAT SHOULD BE FOCUSED ON? >> I'M NOT SURE WE SHOULD BE ADJUSTED FOR BECAUSE WE USE THE SAME CUT OFF, IF YOU USE A DIFFERENT ONE YOU CAN CALCULATE THE PREVALENCE. IT'S ALL ABOUT THE CUT OFF. SONAL BIOLOGY NOT SURE THAT PEOPLE STILL ARGUING THE DIFFERENTLY IN TERMS OF IRON SO I'M NOT SURE. WHICH WAY. YOU ADJUST FOR OR HAVE A DIFFERENT CUT OFF. >> MY QUESTION DO YOU WANT A DIFFERENT CUT OFF OR SAY THIS IS POTENTIALLY HIGHER RISK GROUP? >> I THINK RIGHT NOW IDENTIFY HIGH RISK GROUP TO ME IS REASONABLE. >> MAYBE DR. DOWY WILL TALK ABOUT THIS BUT THE EWE SHAPE DISTRIBUTION AND ADJUST DOWNWARDS IN AFRICAN AMERICANS IT BETTER CAPTURES THOSE AT RISK AT BOTH END OF THE SPECTRUM. WHEREAS IF YOU USE THE SAME HEMOGLOBIN CUT OFF, IT -- YOU DON'T FIND THE SIGNIFICANT EFFECTS AT BOTH ENDS SO THERE SEEMS TO BE SOME PREDICTIVE BENEFIT ADJUSTING DOWNWARD AND CAPTURING WHO IS AT RISK FOR BOTH ENDS. (INAUDIBLE). (OFF MIC) >> COULD YOU REPOET THAT? IT WON'T BE CAPTURED. -- REPEAT THAT. >> THE QUESTION IS BECAUSE MY RESULT PRESENT TOTAL BODY IRON SO THE QUESTION IS, FERRITIN OR TFR USE OBSERVE THE SAME PATTERN. I THINK IN THE PREVIOUS PUBLICATION WE USE STFR WE ALSO OBSERVE THE MEXICAN AMERICAN AND HISPANIC HAVE HIGHER PREVALENCE IRON DEFICIENCY. >> SOUNDS LIKE A FOLLOW-UP COMING. >> I UNDERSTAND ON THE HEMOGLOBIN, THERE'S GENETIC VARIANT IN THE AFRICAN AMERICANS THAT LEAD TO PERHAPS A REASON FOR THE HEMOGLOBIN TO BE LOWER BUT I DON'T THINK THAT APPLIES TO FERRITIN OR TFR. THAT WAS MY QUESTION. >> I DIDN'T MEAN TO INSINUATE FOR THOSE TWO MARKERS THAT IT SHOULD BE SHIFTED. I THINK THE WHOLE ISSUE OF WHAT ARE THE GENETIC DETERMINANTS OF IRON HOMEOSTASIS IS A VERY FASCINATING ONE. MICHAEL ZIMMERMAN HAS A PAPER SHOWING A SHARED ENVIRONMENT YOU CAN ONLY CAPTURE 30% VARIATION IN IRON ABSORPTION USING THE MARKERS THAT WE HAVE CURRENTLY. SO HEPSIDEN FER TEN, OTHER BIOMARKERS WHAT'S CAPTURING THE REST VARIABILITY IN IRON ABSORPTION I THINK IS REALLY IMPORTANT QUESTION TO ALSO HELP IDENTIFY WHO IS GOING TO BENEFIT MOST, IS IT GENETICS, IS IT A SHARED ENVIRONMENT, IN YOUR PAPER, THERE'S UNKNOWN QUESTIONS. >> I GET TO SHARED ENVIRONMENT QUESTION. ONE DIFFERENCE IN EUROPE VERSUS THE U.S. IS FOOD FORTIFICATION PROGRAM. SO ALWAYS LOOKING AT END POINTS RATHER THAN INTAKES. I HAVE SEEN MANY NUMBERS FLASH BEFORE ME BUT IT SEEMS IF I WALK AWAY, I'M GOING TO THINK TO MYSELF THE PREVALENCE OF IRON DEPLETION IRON DEFICIENCY ANEMIA PRETTY MUCH RATES ARE THE SAME. WITH OR WITHOUT IRON FORTIFICATION AND BASICALLY THE SAME DIET. AM I MISCONCEDING SOMETHING FROM THE INFORMATION PRESENTED? I WANT TO COMMENT ON THAT, WHETHER THE FORTIFICATION PLAYS A ROLE IN ANY OF THESE OUTCOMES. >> WE HAD IRON FORTIFICATION UNTIL 1995, 15-MILLIGRAM PER KILOGRAM AND THAT WAS IMPORTANT -- FORTIFY WITH DOES CARBONATE. SO OFFICIALLY IRON STATUS AFTER THE FORTIFICATION HAS BEEN WITHDRAWN AND THAT WAS NO DIFFERENT IN IRON STATUS IN WOMEN. IN MEN ACTUALLY. WE ALSO MEASURED THE IMPACT OF MULTI-SLIGHT MINUTE MULTI-MINERAL TEMPLATES BECAUSE IN THIS POPULATION STUDY THERE WAS 40% TAKING SOME KIND OF SUPPLEMENT. ALSO CONTAINING IRON, USUALLY BETWEEN 14 AND 15-MILLIGRAMS OF IRON. THERE WERE NO DIFFERENCE ON IRON STATUS THOSE TAKING SUPPLEMENTS AND THOSE NOT TAKING SUPPLEMENTS. AND THAT IS FINE. SOME (INAUDIBLE) VITAMIN TABLET SO IT IMPAIRS ABSORPTION OF IRON. NO ABSORPTION STUDIES ON THESE TABLETS. IT HAD -- WE LOOKED AT THE END OF THE SCALE, WE LOOK AT THE PERSON HAVING VERY HIGH FERRITIN. BECAUSE THEY HAD PROBABLY HAD SOME KIND OF HEMOCROW MATOSIS AND THEY WERE HIGHER WHEN THEY TOOK MINERAL SUPPLEMENTS. SO IT HAD AN EFFECT IN ONE END OF THE SCALE AND ALSO IN THE LOW END OF THE SCALE THOSE TAKING IRON SUPPLEMENTS HAD LOWER FREQUENCY OF IRON DEFICIENCY. IN THE OUTSKIRTS IT WORKS BUT NOT FOR THAT GREAT PART OF THE POPULATION. THERE WAS NO DIFFERENCE. I DON'T THINK ANY COUNTRY IN EUROPE HAVE IRON FORTIFICATION. IT WAS APAN DONNED BY THE EUROPEAN COMMISSION. SO WE ARE EQUAL NOW. ABANDONED. >> THE THANK YOU VERY MUCH. LET ME TURN THE PODIUM NOW OVER TO PATRICK STOVER. >> I WOULD LIKE TO THANK PAUL AND THE PANELISTS FOR ANOTHER ABSOLUTELY EXCELLENT SESSION. I HAD BEEN ASKED TO QUICKLY SUMMARIZE, WE ARE PAST OUR TIME. AND I THINK AT LEAST WHAT I HEARD TODAY IS THAT AT LEAST IN THE MORNING WE STARTED TALKING COMPLEXITY OF IRON HOMEOSTASIS. AND NOT ONLY IS IT COMPLEX IN ITS OWN RIGHT BUT THEN WE HEARD ALL THE MODIFIERS OF IRON HOMEOSTASIS WHETHER IT BE INFLAMMATION, INFANT AGE, THE MICROBIOME, GENETICS, DIABETES AND PREGNANCY ON TOP OF THAT. SO THIS IS AN EXTRAORDINARILY COMPLEX SYSTEM. ON TOP OF THAT WE LEARN THE COMPLEXITY IS INDIVIDUALIZED TO DIFFERENT TISSUES. THAT IS NOT ALL TISSUES DEAL WITH THE HOMEOSTATIC RESPONSE TO IRON EQUALLY. AND BECAUSE OF THAT WE GET TISSUE SPECIFIC DIFFERENCES NOT ONLY IN HOW IRON IS METABOLIZED AND WHAT IRON PHYSIOLOGY AND HOMEOSTASIS IS BUT THAT WE CAN GET TISSUE SPECIFIC SENSITIVITIES TO DIFFERENCES IN IRON STATUS. ON TOP OF THAT, AGAIN, WE LEARNED HOW IRON INTERACTS WITH OTHER NUTRIENTS THAT CAN AFFECT STATUS GIVING A POTENTIAL INKLING INTO WHAT CONCERNS OF EXCESS MIGHT BE BUT WE DID HEAR FROM NANCY KREBS WHO TOLD US U WE CAN'T GET LOST IN ALL COMPLEXITY. WE DO KNOW A LOT AND GIVES A BASIS TO MOVE FORWARD. SO MOVING FORWARD IN WHAT I WOULD LIKE ALL OF YOU TO THINK ABOUT FOR TOMORROW IS WE HEARD THE WORD MEANINGFUL MENTIONED SEVERAL TIMES. THAT IS WHAT ARE THE MEANINGFUL CLINICAL AND FUNCTIONAL OUTCOMES THAT WE CARE ABOUT THAT WOULD BENEFIT PATIENT? WHAT ARE THOSE OUTCOMES HOW DO WE PRIORITIZE THOSE, WHICH ARE THE MOST SENSITIVE AND WHAT ARE THE CRITICAL WINDOWS ASSOCIATED WITH THAT SENSITIVITY. ONCE WE KNOW WHAT THOSE MEANINGFUL CLINICAL OUTCOMES WHAT THEY ARE, WHAT ARE THE MEASURES WE NEED TO TIE TO THOSE? SPECIFICALLY WE HEARD A LOT OF TALK ABOUT HA SWEET SPOT, FOR SOME CLINICAL OUTCOMES, THERE WAS RISK BOTH WITH INSUFFICIENCY AND WHAT MEASURES MATTERS OF DEFICIENCY, WE HEARD THAT TODAY. THEY'RE NOT PERFECT, BUT WE CAN WORK WITH THOSE. SOMEONE IS REPLETE. AND WHETHER SUPPLEMENTED OR WHEN THEY ARE REPLETE. OF COURSE WHAT WERE MEASURES OF EXCESS. WE HEARD ABOUT EXCESS WE HEARD THE FACT THERE'S TWO CATEGORIES OF DECEMBER, THERE CAN BE ACUTE RESPONSE TO EXCESS BUT ALSO CAN BE READ OUTS OF EXCESS THAT ARE HIDDEN, THAT IS THAT DON'T MANIFEST UNTIL LATER IN LIFE, THESE CAN BE ASSOCIATED ALSO WITH CRITICAL WINDOWS. THAT IS DEFICIENCY OR EXCESS IN A WINDOW CAN GIVE YOU DEVELOPMENTAL DEFECT, STRUCTURAL PROBLEM IN WIRING OR NOT ENOUGH CELLS THAT MAYBE YOU CAN MEASURE BY MRI BUT THERE CAN ALSO BE AFFECTS THAT DON'T MANIFEST LATER IN LIFE THAT ARE DUE TO PROGRAMMING. AND WE HEARD THE WORD EPIGENETICS USED AND THERE ARE NEW ASSAYS COMING OUT THAT ARE BEGIN AGE TO TELL US WHAT'S GOING ON IN THE GENOME. BECAUSE IF THERE WAS INSULT THAT HAPPENED AT A PERIOD OF TIME THAT DOESN'T MANIFEST UNTIL LATER IN LIFE THAT SIGNATURE IN THE GENOME AND WE'RE GETTING BETTER BEING ABLE TO IDENTIFY THOSE. WHETHER THEY BE DIFFERENCES IN MUTATION OR IN SOME SORT OF EPIGENETIC SIGNATURE BUT WE HAVE TO THINK ABOUT WHAT ARE THE APPROPRIATE MEASURES TO GET AT THIS IDEA OF EXCESS SO WE KNOW WHETHER TO SUPPLEMENT REPLETE OR NOT. IN THE ACUTE STATE AND IN THE LONG TERM THIS WAS THE RISK LABOR IN LIFE. THEN WE HEARD ABOUT NEED TO HAVE RELIABLE MEASURES, THERE'S A LOT OF PEOPLE WHO KNOW ABOUT THAT. IN THIS ROOM. BUT ONE THING I LEARN THAT WE DON'T HAVE RELIABLE MEASURES MR. BILL ENDS UP IN A BLENDER AND THE GHOST OF RICHARD NIXON OVERSHADOWS, WE DON'T WANT THAT TO HAPPEN. SO WITH THAT WE WILL CONTINUE TOMORROW. BUT WE REALLY HAVE TO THINK ABOUT THE PRIORITY OF CLINICAL OUTCOMES AND WHAT ARE THE MEANINGFUL MEASURES. THE ONLY LAST ANNOUNCEMENT IS TOMORROW FOR SESSION 5 PANEL ONE IF YOU COULD GO THROUGH G-2 TO MEET WITH YOUR GROUP TO MEET FOR TOMORROW AND IF YOU ARE IN PANEL 2 PLEASE GO TO G-1. SO WE CAN ORGANIZE FOR TOMORROW. THANK YOU ALL VERY MUCH AND THE SESSION TODAY IS CLOSED. [APPLAUSE]