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GOOD AFTERNOON.
WELCOME TO TODAY'S CLINICAL
CENTER GROUND ROUNDS FEATURING
THIS YEAR'S JOHN LAWS DECKER
LECTURE.
IT'S 50561.
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TODAY'S PRESENTATION IS THE 20TH
ANNUAL JOHN LAWS DECKER MEMORIAL
LECTURE AS PART OF OUR
CONTEMPORARY CLINICAL MEDICINE
SER
SERIES.
TODAY WE HONOR THE LEGACY OF
DR. JOHN DECKER WHO SERVED AS
NIH CLINICAL DIRECTOR IN 1983 TO
1990.
DURING DR. DECKER'S TENURE
INCLUDES THE CLINICAL USE OF
MAGNETIC IMAGES AND MARSHALLS OF
RESOURCES FOR AIDS RESEARCH.
I'M HONORED AND PLEASED TO
WELCOME THE DECKER FAMILY TODAY
TO INCLUDE MR. DAVID DECKER, THE
SON OF DR. DECKER AND HIS
GRANDSONS IAN AND TOMAS.
WELCOME.
THANK YOU FOR BEING HERE.
I WOULD NOW LIKE TO TURN THE
MICROPHONE OVER TO MR. DAVID
CARAMEL, SENIOR HAVE THE AND
CHIEF GROWTH AND OFFICER FOR
REMARKS ON BEHALF.
>> THANK YOU, DR. BURKLOW.
WELCOME EVERYBODY.
MY NAME IS DAVID CARAMEL.
I'M DELIGHTED TO WELCOME YOU TO
THIS MILESTONE JOHN LAWS DECKER
MEMORIAL LECTURE FEATURING THE
2024 DISTINGUISHED CLINICAL
TEACHER AWARD, DR. DAVID KLE
KLEIKLEI
KLEINER.
DR. KLEINER, WE LOOK FORWARD TO
YOUR PRESENTATION.
THE FNIH IS PROUD TO HAVE BEEN
PARTNER OF THIS IMPORTANT
LECTURE SINCE 2003 WHEN THE NIH
BEGAN RECOGNIZING THE LATE
CLINICAL CENTER DIRECTOR JOHN
LAWS DECKER ANNUALLY THROUGH
THIS CLINICAL CENTER GRAND ROUND
LECTURE SERIES.
AT THAT TIME THE FAMILY OF
DR. DECKER WORKED WITH THE FNIH
TO ESTABLISH THE E MEMORIAL
FUND IN HONOR OF THEIR LATE
FATHER.
DURING HIS LIFETIME DR. DECKER
WAS AN OUTSTANDING TEACHER WHO
STRIVED TO CONNECT SCIENTIFIC
COMMUNICATIONS AROUND THE WORLD
TO ACCELERATE IMPORTANT
RESEARCH.
THIS IS THEIR AND OUR WAY OF
EXTENDING HIS LEGACY.
I ALSO WANT TO THANK THE DECKER
FAMILY FOR YOUR GENEROSITY AND
INSPIRED VISION IN ESTABLISHING
THE DECKER MEMORIAL FUND.
I'M PLEASED THAT DR. DECKER'S
SON DAVID AND GRANDSONS IAN AND
TOMAS ARE HERE TODAY.
AND OTHER MEMBERS OF THE FAMILY
ARE JOINING ONLINE, I BELIEVE.
THE FNIH IS PROUD OF OUR LONG
STANDING COLLABORATION WITH YOU
AND THE CLINICAL CENTER TO
RECOGNIZE INNOVATIVE
ESTABLISHMENTS.
-- ACCOMPLISHMENT.
WE INVITE YOU TO EXPLORE THE
MANY PARTNERSHIPS FORMED IN THE
INNOVATIVE SCIENTIFIC THINKING
THAT IS SUPPORTED THROUGH OUR
PROGRAMS.
I THINK IT'S UP THERE AS WELL.
OUR WEBSITE IS FNIH.ORG.
SO NOW I'LL TURN THINGS BACK TO
DR. BURKLOW.
THANK YOU FOR JOINING US FOR
THIS EVENT AND PLEASE ENJOY THE
20TH.
>> [APPLAUSE]
>> THANK YOU MR. CARAMEL.
AND TO THE DECKER FAMILY, THANK
YOU VERY MUCH.
WE EXTEND OUR GRATITUDE FOR YOUR
CONTINUING SUPPORT.
EACH YEAR THE NIH CLINICAL
FELLOWS SELECT A HIGHLY REGARDED
MENTOR TO RECEIVE THE
DISTINGUISHED CLINICAL TEACHER
AWARD.
DR. DECKER WAS AN INSPIRING
LEADER AND MENTOR SO IT'S VERY
APPROPRIATE THAT THE AWARDEE
DELIVER THE ANNUAL DECKER
MEMORIAL LECTURE.
BEFORE INTRODUCING TODAY'S
SPEAKER AND A 2024 DISTINGUISHED
CLINICAL TEACHER AWARDEE I'D
LIKE TO TURN THE PODIUM OVER WHO
COCHAIRS THE CLINICAL COMMITTEE
TO ANNOUNCE THE WINNER OF THE
2025 DISTINGUISHED CLINICAL
TEACHER AWARD.
>> HI EVERYONE.
I'M THE CLINICAL FELLOW
COMMITTEE CO-CHAIR.
WE'D LIKE TO THANK DR. BURKLOW
FOR HIS ON GOING SUPPORT TO
FELLOWS AND IMPORTANT FOR
MENTORING AT NIH.
I'M HONORED TO ANNOUNCE THE
WINNER OF 2 -- 2025 AWARD.
THEY SET AND ACHIEVE GOALS,
ANTICIPATE ROADBLOCKS AND OVER
COME OBSTACLES.
ALL RIGHT.
SO ALL INDIVIDUALS NOMINATED FOR
THIS YEAR'S AWARDS DESERVE
RECOGNITION AS OUTSTANDING
CLINICAL MENTORS.
I'D LIKE TO THANK ALL THE
NOMINEES FOR THEIR COMMITMENT TO
TRAINING CLINICAL INVESTIGATORS
AT NIH AND THEIR OVER ALL
CONTRIBUTION.
EACH YEAR THE AWARD IS DECIDED
BY THE VOTE OF FELLOWS AND
PRESENTED TO AN INDIVIDUAL WHO
HAS IDEALS OF TEACHER AND
RESEARCHER.
HERE ARE A FEW WORDS ABOUT THIS
YEAR'S AWARDEE.
A DEDICATED TEACHER WHO DEVOTES
TIME AND EFFORTS TO SHOW US
CASES AND GIVE US EXPOSURE TO
THINGS BEYOND THE DAYS IN
DAY-TO-DAY SESSIONS. HE HAS A
PLACE OPEN AT 4:00 P.M.
HE HAS AN EXTENSIVE CASE ARCHIVE
COVERING VARIOUS SURGICAL
SUBSPECIALTIES AND PROVIDES A
SLIDE SHOW SESSION TO HELP US
OUT IF IN THE FIELD.
HE'S A WORLDWIDE KNOWN AUTHOR
WITH GREAT IMPACT IN THE FIELD.
HE'S CONTRIBUTED TO THE
LITERATURE WITH LOTS OF
INKNOWTIVE PAPERS.
HE RECEIVED CONSULTATION CASES
NOT ONLY AROUND THE U.S. BUT
ALSO ALL OVER THE WORLD.
NOT LIMITED TOO BUT INCLUDING
COUNTRIES SUCH AS PR, VIETNAM
AND TURKEY.
SO PLEASE JOIN ME IN C
CONGRATULATING OUR 2025
DISTINGUISHED CLINICAL AWARD
WINNER.
>> [APPLAUSE]
>> CONGRATULATIONS DOCTOR.
NOW I'D LIKE TO TURN THE MIC
BACK OVER TO DR. BURKLOW TO
INTRODUCE DOCTOR KLEINER, OUR
2024 WINNER.
>> THANK YOU DR. ZEQUAY.
WELL DESERVED.
SO WE SEEM TO HAVE RUN ON HERE
IN PATHOLOGY AND TEACHING SO I
GUESS THAT'S A GOOD THING.
I'M NOW HONORED TO INTRODUCE
TODAY'S TEACHER AND RECIPIENT OF
THE 2024 DISTINGUISHED TEACHER
AWARD.
DR. DAVID KLEINER.
HE EARNED HIS DEGREES AT SAINT
OLAF COLLEGE AND UNIVERSITY OF
CHICAGO WHERE HE EARNED HIS PHD
IN CHEMISTRY AND MEDICAL DEGREE.
DR. KLEINER IN TERMS OF
RESIDENCE D -- RESIDENCY.
AT THE NCI HE'S NOW A SENIOR
PHYSICIAN, DIRECTOR OF
LABORATORY INFORMATION SYSTEM
AND CHIEF OF THE POSTMORTEM
SECTION WITH EXPERTISE IN
PATHOLOGY.
HIS INTERNATIONALLY RECOGNIZED
RESEARCH HAS FOCUSED ON CHRONIC
LIVER DISEASE AND DRUG-INDUCED
INJURY AND LIVER CANCER.
WITH ATTENTION TO ASSESSING HIS
RESPONSES TO THERAPY.
HE IS A KEY PATHOLOGIST FOR THE
NATIONAL INSTITUTE FOR DIABETES,
THE NON ALCOHOLIC STEATOTIC
HEPATITIS NETWORK, DRUG INDUCED
LIVER NETWORK AND HEPATITIS B
RESEARCH NETWORK.
A RESEARCHER AND SCHOLAR HE'S
AUTHORED OR CO-AUTHORED OVER 500
PEER REVIEWED ARTICLES, BOOK
CHAPTERS AND EDITORIALS WITH A
FOCUS OF DRUG UNDEUCED LIVER
INJURY AND HEPOTITIS.
DR. KLEINER IS A VALUED TEACHER
AND MENTOR WHO BRINGS HIS
PASSION TO THE MICROSCOPE.
INSPIRING HIS MANY CURRENT AND
PAST FELLOWS AND RESIDENTS IN
PATHOLOGY.
THE TITLE OF DR. KLEINER'S
PRESENTATION TODAY IS STEATOTIC
LIVER DISEASE FROM FIRST
DESCRIPTION TO FIRST DRUG
APPROVAL THROUGH THE EYES OF THE
PATHOLOGIST.
PLEASE JOIN ME IN RECOGNIZING
OUR SPEAKER AND THE WINNER OF
THE TEACHER AWARD, DR. DAVID
KLEINER.
>> [APPLAUSE]
>> THANK YOU.
THANK YOU TOO TO THE DECKER
FAMILY.
I OVER LAPPED A LITTLE BIT WITH
DR. DECKER AS -- WHEN HE WAS THE
CLINICAL DIRECTOR OF THE
CLINICAL CENTER BUT ONLY FOR A
FEW YEARS AND I WAS ONLY JUNIOR
AT THE TIME.
SO I DON'T THINK I ACTUALLY EVER
MET HIM.
SO ON WE GO.
SO I HAVE FINANCIAL CONFLICTS OF
INTEREST RELEVANT TO THIS
PRESENTATION, WHICH I'M SURE
MANY IN THE AUDIENCE CAN ALSO
SAY.
SO THIS IS AN EDUCATIONAL TALK.
SO THERE ARE SOME OBJECTIVES.
THERE WILL NOT BE A QUIZ.
SO I'M GOING TO REVIEW THE
PATHOLOGY OF THIS STEATOTIC
LIVER DISEASE AND THE SCORING
SYSTEM THAT WE DEVELOPED FOR USE
AND RESEARCH AND CLINICAL
TRIALS.
ESPECIALLY HIGHLIGHT SOME OF THE
CONTRIBUTIONS OF THE NETWORK
THAT I BELONG IN -- BELONG TO
AND THAT THE NIDDK SPONSORED.
AND A LITTLE BIT ABOUT THE
HISTORY WHICH SPANS 45 YEARS OF
TIME.
I'VE GOT ABOUT THAT MANY MINUTES
SO I CAN ONLY HIT THE
HIGHLIGHTS.
I DO WANT TO TAKE ONE SLIDE TO
EXPLAIN A NEW NOMENCLATURE THAT
WAS INTRODUCED IN 2023.
WE HAVE CHANGED THE NAME OF THIS
DISEASE BUT MOST OF THE PAPERS
AND THINGS THAT I WILL REVIEW
REFER TO THE OLD NAME, SO NOW
THIS DISEASE IS CALLED METABOLIC
DYSFUNC
DYSFUNCTION STEATOTIC LIVER
DISEASE.
USED TO BE CALLED NON ALCOHOLIC
LIVER DISEASE.
THE STEATOHEPATITIS VERSUS NON
ALCOHOLIC STEATOHEPATITIS.
THE ABBREVIATIONS ARE AT THE
BOTTOM THERE AND NASH OR MASH.
I WILL MOSTLY USE THE NAFLD AND
NASH FOR THIS TALK.
WHY IS THIS SO IMPORTANT?
I THINK IT'S IMPORTANT WHEREVER
WE STUDY DISEASE TO UNDERSTAND
WHY A DISEASE IS PARTICULARLY
IMPORTANT.
AND I THINK THIS MAP SHOWS THE
SIGNIFICANCE OF THIS DISEASE.
THIS IS AN INCIDENTS MAP
COVERING MOST OF THE RWORLD.
NOT SURE WHY THEY LEFT OUT PARTS
OF THE WORLD BECAUSE IT'S BEEN
COVERED BY AUTHORS IN PREVIOUS
PAPERS.
WHAT YOU CAN SEE A NEARLY A
THIRD OF PEOPLE IN THE WORLD ARE
AFFECTED BY STEATOTIC LIVER
DISEASE.
IT'S A STAGGERING, REALLY
STAGGERING NUMBER.
IT'S RELATIVELY EVENLY
DISTRIBUTED WITH SOME HIGH
POINTS, LATIN AMERICA
PARTICULARLY AFFECTED.
IT'S NOT SHOWN ON THIS BUT SUB
SAHARAN AFRICA HAS A LOWER
INCIDENT.
IT'S ABOUT 15%.
BUT EVERYWHERE ELSE IT'S ABOUT
30%.
MORE SIGNIFICANTLY IS THAT THE
CRITICAL PART OF THIS DISEASE
WHERE IT BECOMES FIBROTIC AND
PROGRESSES THE STEATOTIC IS A
SIXTH OF THOSE.
YOU CAN SEE THOSE NUMBERS UP ON
THE PANEL OVER HERE ON THE
RIGHT.
THE NASH PREF -- PREVALENCE
NUMBERS.
THEY VARY FROM 4.5% TO 7% OF THE
POPULATION.
DOWN BELOW WE SEE THE END
EFFECTS OF THOSE.
MORTALITY, CARDIAC SPECIFIC
MORTALITY OF FATTY LIVER DISEASE
IS 4 PER THOUSAND.
SO .4%.
CANCERS ARE ALSO RELATED TO THIS
DISEASE AT ABOUT .3% OF
PATIENTS.
AND LIVER SPECIFIC DEATH IS
SLIGHT DLY -- WELL, 1 TO 2%. TS
IS A REALLY IMPACTFUL DISEASE
AND ONE THAT WE NEED TO PAY
QUITE A BIT OF ATTENTION TO IT.
THIS SHOWS THE TIME COURSE
THOUGH DESPITE THE FACT THAT A
THIRD OF THE POPULATION OF THE
WORLD IS AFFECTED.
THIS IS A VERY SLOW DISEASE.
SO IF YOU START WITH 100
PATIENTS WITH NAFLD, OVER THE
COURSE OF 20 TO 30 TO 40, 50
YEARS ONLY 5 OF THOSE PATIENTS
WILL DEVELOP CIRRHOSIS WHICH IS
REALLY THE STAGE THAT WE WORRY
ABOUT.
A COUPLE OF THOSE WILL
DECOMPENSATE AND THEN WE MIGHT
END UP WITH LIVER
TRANSPLANTATION OR DEATH RELATED
TO CIRRHOSIS.
THEN MOST OF THESE PATIENTS WILL
NEVER DEVELOP THAT AND THEY WILL
DIE WITH THE DISEASE RATHER THAN
FROM IT.
AND IT'S IMPORTANT FOR US TO TRY
AND UNDERSTAND THE NATURAL
HISTORY OF THE DISEASE SO WE CAN
FOCUS ON THE PEOPLE WHO ARE
REALLY GOING TO SUFFER.
SO I'M A PATHOLOGIST.
WE'RE GOING TO TALK ABOUT
PATHOLOGY.
TO UNDERSTAND ABNORMAL, YOU
FIRST HAVE TO UNDERSTAND NORMAL.
SO NORMAL ADULT LIVER, I SWIPED
THE PICTURE FROM THE NIDDK
WEBSITE, IT'S ABOUT 3 TO 4
POUNDS, RIGHT.
ABOUT 2% OF YOUR BODY WEIGHT.
THAT'S NORMAL.
YOU CAN SEE OVER ON THE GRAPH ON
THE SIDE THAT IT STARTS OUT
PRETTY SMALL, ABOUT 70 GRAMS, A
FEW OUNCES.
THEN AS YOU GROW UP THROUGH
PUBERTY IT ATTAINS NEARLY ADULT
SIZE BY THE TIME YOU'RE A
TEENAGER.
BUT WE'RE GOING TO DEAL WITH THE
MIC
MICROSCOPIC.
YOU SEE A PHOTO MICRO GRAPH OF A
NORMAL LIVER.
I EXPECT MANY IN THE AUDIENCE
HAVE NOT LOOKED AT HISTOLOGY
SINCE MEDICAL SCHOOL OR NEVER
ENCOUNTERED IT.
SO A BRIEF REVIEW.
THIS IS A STAIN.
THE PURPLE CIRCLES ARE ALL CELL
NUCLEI.
THEN THE PINK IS THE PSYDOPLASM.
YOU CAN SEE THE EDGE.
THAT'S THE CELL BOARD PER --
BORDER.
SO THIS SHOWS THE NORMAL
ARCHITECTURE OF THE LIVER WHICH
IS SIMPLE.
BLOOD FLOWS IN THROUGH TWO
VESSELS, THE PORTAL VEIN WHICH
COMES FROM THE GUT AND THE
ARTERI
ARTERIES, I'LL SHOW YOU A
PICTURE IN A MINUTE FLOW THROUGH
THE SITES TO THE CENTRAL VEIN.
SO THE BLOOD COMES IN, GETS
FILTERED, PROCESSED AND THEN OUT
REPACKAGED AND COMES OUT OF THE
LIVER OVER THERE.
I'M OBVIOUSLY OVER SIMPLIFYING A
LOT.
THEN BILE DRAINS OUT OF THE
LIVER THROUGH THE BILE DUCT
WHICH IS OVER IN THE PORTAL
AREA.
SO HERE'S A BIGGER PICTURE.
SO WE SEE CENTRAL VEIN OVER HERE
ON THE LEFT.
VERY WELL DEFINED, FEW RED BLOOD
CELLS IN THE MIDDLE AND THEN
PATASITES ALL AROUND.
AND THEN THE LARGE PORTAL AREA,
THE LARGE PORTAL VEIN AND A
COUPLE OF ARTERIES AND BILE DUCT
UP TO THE UPPER RIGHT.
OKAY.
THE OTHER STAIN THAT I'M GOING
TO SHOW YOU IS A MASAN STAIN,
WHICH IS A STAIN WE USE TO
HIGHLIGHT COLOGIN.
THIS IS NORMAL.
THE BLUE IS THE COLLAGEN.
YOU CAN SEE IT IN THE PORTAL
AREA QUITE NICELY.
I DON'T HAVE A CENTRAL VEIN OR
THERE MIGHT BE ONE DOWN HERE IN
THE FAR LEFT CORNER BUT THERE'S
JUST A THIN RIM OF COLLAGEN
AROUND THAT VEIN.
NOW YOU'RE FULLY ACQUAINTED WITH
THE PATHOLOGY OF THE LIVER, OR
THE NORMAL.
SO WE ARE GOING TO TALK ABOUT
PATHOLOGY.
THERE'S FOUR STAGES OF STEATOTIC
LIVER DISEASE WHICH IS IMPORTANT
FOR UNDERSTANDING WHAT IS GOING
ON HERE.
THERE'S THE FAT, THE STEATOSIS,
WHICH IS INSIDE.
THERE'S INFLAMMATION, THE
HEPATITIS COMPONENT OF THIS
DISEASE.
SO CLUSTERS OF INFLAMMATORY
CELLS IN THE PORTAL.
AND THEN THE BALLOONING INJURY
WHICH IS IMPORTANT TO, IT IS A
SWELLING DUE TO INJURY TO THE
ORGAN AND THE MEMBRANES OF THE
SITE.
AND THEN FIBROSIS, WHICH IS THE
SCARRING.
SO I'LL SHOW YOU ALL THESE
THINGS.
SO THIS IS WHAT STEATOSIS LOOKS
LIKE.
THE LIPID IN THE CELLS DISSOLVED
OUT WHEN WE PROCESS THE CELLS TO
LOOK AT THEM UNDER THE
MICROSCOPE.
IT LOOKS LIKE THESE EMPTY HOLES.
THOSE ARE NORMALLY LIPID FILLED
AND WITHIN THE PATASITES.
YOU CAN BARELY SEE THE PLASM
BECAUSE THE FAT IS TAKING UP SO
MUCH ROOM.
IT CAN LOOK ALMOST LIKE TISSUE
THAT YOU MIGHT FIND IN THE
ABDOMEN OR UNDERNEATH THE SKIN.
IT USUALLY NEVER GETS THAT BAD
BUT IT CAN.
THEY CAN BE DIFFERENT SIZES.
YOU CAN HAVE BIG VACULES OR
LITTLE BUT THEY ARE ALL LIPID.
WE HAVE THE INFLAMMATION.
ON THE LEFT PANEL YOU SEE
LOBULAR INFLAMMATION.
THEY POINT TO LITTLE CLUSTERS OF
INFLAMMATORY CELLS.
YOU SEE LITTLE INCLUDCLUSTER HE
HERE.
THEY ARE THE MOST COMMON
INFLAMMATORY CELLS.
ON THE RIGHT YOU CAN SEE A
PORTAL AREA AND ALL THE CELLS
INSIDE THE PORTAL AREA ARE ALL
MOSTLY INFLAMMATORY CELLS.
SO YOU CAN HAVE PORTAL
INFLAMMATION OR LOBULAR
INFLAMMATION.
THE BALLOONS G.
THE YELLOW INDICATING BALLOON
CELLS.
IT'S ALL MESSED UP. IT'S CLUMPY
AND STRANDY.
I HAVE THE BLUE AREA UP ABOVE
THAT POINTS TO THIS BIG CELL
WHICH IS THE MALLOY-DENK BODY.
THESE ARE CLUMPS OF PROTEINS
WHICH ARE AN IMPORTANT
CHARACTERISTIC OF THESE
BALLOONED SITES AND THEY HELP US
IDENTIFY THEM.
OKAY.
SO NOW COMPARING THE NORMAL
AGAINST THE OTHER.
THIS IS ALL HAPPENING ALL AT
ONCE HERE ON THE RIGHT.
YOU CAN SEE THE FAT AND YOU SEE
THE BALLOONING AND THE
INFLAMMATION AND IT'S ALL MIXED
TOGETHER.
AND THEN COMPARED TO WHAT THE
PANEL ON THE LEFT, WHICH IS ALL
NORMAL.
SO QUITE A LOT IS HAPPENING IN
THESE LIVER BIOPSIES.
AND THERE'S ALSO A LOT OF
FIBROSIS.
THE NORMAL IS ON THE LEFT.
NORMAL PORTAL AREA.
SEE ALL OF THIS STRANDING IN
BETWEEN THE CELLS?
MAKING THESE CONNECTIONS.
CUTTING THE CELLS OFF FROM ONE
ANOTHER.
THIS IS THE FIBROSIS THAT
HAPPENS IN STEATOHEPATITIS.
IT FORMS THESE NETWORKS OF CO
COLLAGEN THROUGH THE CELLS AND
THEY DROP OUT AND STEATOSIS.
A LITTLE BIT OF HISTORY.
BACK IN 1980 WE HAVE A LANDMARK
PAPER FROM THE MAYO CLINIC.
LUDWIG PUBLISHED A PAPER, NOT
TOPLINE JOURNAL BY THE ONE BUT
ONE THAT PRODUCED REALLY
RESPECTABLE PAPERS THAT
DESCRIBED THIS PATHOLOGY.
NOW THIS PATHOLOGY HAD BEEN
DESCRIBED BEFORE BUT HIS
CONTRIBUTION, ONE OF HIS MAIN
CONTRIBUTIONS WAS TO GIVE IT A
NAME.
ANYONE, ANY PERSON WHO HAS AN
ILLNESS THAT DOES NOT HAVE A
NAME WILL TELL YOU HOW IMPORTANT
A NAME IS FOR TREATING A DISEASE
AND SOLVING THE PROBLEM.
SO HE CALLED IT STEATOHEPATITIS.
IN PARTICULAR THIS PATHOLOGY IS
VERY SIMILAR TO WHAT YOU SEE IN
ALCOHOLIC HEPATITIS, HE CALLED
IT NON ALCOHOLIC
STEATOHEPATITIS.
THAT'S WHERE OUR STORY BEGINS.
NOW MY PART IN THIS STORY REALLY
DOESN'T PICK UP UNTIL 18 YEARS
LATER WHEN THE NIDDK CONVENED A
WORKSHOP ON NON ALCOHOLIC
STEATOHEPATITIS IN 1998.
THESE WERE MOST OF THE SPEAKERS.
SO I'M IN THERE SOMEWHERE.
I HAD MORE HAIR THEN.
I WAS TASKED WITH GATHERING THE
PATHOLOGISTS.
SO AROUND ME ARE THE
PATHOLOGISTS WHO HAD PUBLISHED
ON THIS TOPIC BEFORE.
SEVERAL OF WHOM BECAME MY
MENTORS.
ONE OF WHOM, DR. ELIZABETH
BRUNT, WHO IS STANDING HERE,
BECAME A CLOSE COLLEAGUE FOR
MANY SUBSEQUENT YEARS.
THEN EVERYBODY ELSE ON HERE IS
PRETTY MUCH A HEPATOLOGIST.
YOU CAN SEE THE BALANCE HERE.
ONE PATHOLOGIST AND ONE
HEPATOLIGIST.
THIS WAS A LITTLE BIT MORE
BALANCED.
FROM THAT WORKSHOP GREW THE NASH
NETWORK. THIS IS THE TIMELINE.
IT'S STILL GOING ON TODAY
ALTHOUGH WE'RE CLOSING OUT THE
NETWORK.
WE'VE KIND OF ACCOMPLISHED MOST
OF OUR GOALS.
YOU CAN SEE THAT WE'VE DONE
QUITE A LOT.
SO FUNDING STARTED AROUND HERE.
WE'VE DONE FIVE CLINICAL TRIALS
AND WE'RE FINISHING A SIXTH NOW.
WE DID A HUGE NATURAL HISTORY
STUDY.
AS ONE OF THE CO-LEADERS OF THE
PATHOLOGY COMMITTEE, WE
REGULARLY REVIEWED THE CASES
THAT CAME INTO THE NETWORK.
SO AS OF THE END OF LAST YEAR
WE'D ACTUALLY REVIEWED ALMOST
7,000 BIOPSIES AND SCORED THEM
AS I WILL DESCRIBE.
SO WE'VE DONE QUITE A LOT.
SO WHEN THIS NETWORK FORMED THEY
FORMED A PATHOLOGY COMMITTEE, IT
WAS ONE PATHOLOGIST FROM EACH OF
THE CLINICAL CENTERS AND THEN
ME.
AND OUR FIRST GOAL WAS TO CREATE
A SCORING SYSTEM THAT COULD BE
USED TO TRACK THE PATHOLOGY IN
THESE PATIENTS.
THAT'S REALLY IMPORTANT BECAUSE
WE DIDN'T HAVE IMAGE ANALYSIS
BACK THEN.
AT LEAST NOT IN ANY WAY THAT WE
COULD USE.
AND SO WE NEEDED TO TAKE THE
IMAGING OR THE PICTURES THAT I
SHOWED YOU AND TURN THEM INTO
NUMBERS SO WE COULD PUT THEM
INTO A DATABASE AND ANALYZE
THEM.
SO THAT WAS OUR JOB.
AND SO WE GATHERED.
THIS WAS THE FIRST CENTRAL
PATHOLOGY MEETING ACTUALLY TO DO
-- TO LOOK AT CASES.
BUT WE HAD MET BEFORE AND IT WAS
PRETTY MUCH THE SAME GROUP.
SO, AGAIN, YOU SEE BETH BRUNT
HERE IN THE MIDDLE.
MOST OF THESE PEOPLE ARE THE
PATHOLOGISTS THAT FORMED THE
CORE OF THAT FIRST GROUP.
THEN WE HAVE STATISTICAL HELP
FROM OUR DATA COORDINATION
CENTER AT JOHN HOPKINS AND JOHN
HOPKINS PI WHO PLAYED A BIG PART
AS ONE OF THE LEAD HEPATOLOGISTS
IN THE NETWORK.
WE WROTE THIS PAPER.
WE MET HERE IN THE BASEMENT
ACTUALLY ON THE OTHER SIDE OF
THIS WALL TO TALK ABOUT WHAT
COULD WE LOOK AT IN THESE --
WHAT DID WE THINK WE COULD
RECORD.
I ASKED ALL OF THE PARTICIPANTS
TO CONTRIBUTE THREE CASES AT
LEAST.
ONE THAT THEY THOUGHT WAS
DEFINITELY STEATOHEPATITIS, ONE
THAT WAS NOT, NO ONE WOULD AGREE
THAT IT WAS AND THEN SOMETHING
IN BETWEEN.
SO WE REVIEWED THE CASES AT A
MULTI-HEAD MICROSCOPE, KICAME U
WITH A SCORING SYSTEM,
CIRCULATED THE CASES TWICE TO DO
THE OBSERVER VARIABILITY STUDIES
AND THEN PUBLISHED.
SO IT'S BASICALLY A METHODS
PAPER.
IT KIND OF EXPLODED ON US.
IT WAS PICKED UP BY A LOT OF
OTHER PEOPLE WHO FOUND IT VERY
USEFUL.
SO THAT WAS WONDERFUL, THAT WAS
PART OF OUR GOAL.
WE ALSO USED IT FOR THE NETWORK.
THIS IS THE SCORING SYSTEM.
I AM NOT GOING TO GO THROUGH
THIS.
SO BE THANKFUL FOR THAT.
THE THINGS IN ORANGE WERE THE
THINGS THAT WE STARTED OUT WITH.
EVERYTHING ELSE IN WHITE WE
ADDED LATER ON.
SOME OF THE THINGS DROPPED OUT
WITH TIME.
AS I SAY, I'M NOT GOING TO GO
THROUGH WITH IT BUT I AM GOING
TO TELL YOU ABOUT THE THREE OR
FOUR MOST IMPORTANT THINGS.
SO WE CAME UP WITH SOME CORE
ELEMENTS. THESE CAME OUT OF
STATISTICAL ANALYSIS THAT WE DID
THAT ULTIMATELY TURNED INTO A
COMPOSITE SCORE.
BUT WHAT WE -- WHAT TURNED OUT
TO BE MOST IMPORTANT WAS A
MEASURE OF STEATOSIS, WHICH IS A
VERY SIMPLE LOW POWER
EXAMINATION OF THE BIOPSY AND
HOW MUCH THE LIVER SEEMED TO BE
INVOLVED BY THE FAT.
LOBULAR INFLAMMATION.
AGAIN, WE WERE FOCUSING ON THESE
LITTLE SITES OF INFLAMMATION AND
COUNTING THEM, ESTIMATING THEM
REALLY, IN A 20X FIELD.
SO IN THE MICROSCOPE A
PARTICULAR OBJECTIVE TO SEE HOW
MANY AVERAGED ACROSS THE WHILE
BIOPSY.
AND THEN THE BALLOONING WHETHER
WE DIDN'T SEE ANY OR WHERE WE
FOUND THEM EASILY AND THEY WERE
BIG OR WHERE THERE WERE ONLY A
FEW OR THEY WERE HARD TO FIND.
SO VERY SIMPLE SCORE.
WE ALSO SCORED THE FIBROSIS OR
STAGED THE FIBROSIS.
EVERYTHING FROM NO FIBROSIS UP
TO CIRRHOSIS WHICH WAS A STAGE
FOUR.
YOU CAN SEE A LITTLE BIT OF
EARLY FIBROSIS IN THE TOP PHOTO
AND A MORE EXTENSIVE ONE LIKE
THE ONE I SHOWED BEFORE. THIS
IS CIRRHOSIS DOWN AT THE BOTTOM
WHERE YOU CAN SEE BIG BANDS OF
COLLAGEN AT THE BOTTOM.
WE GOT DONE, PRESENTED TO THE
COMMITTEE.
THE STATISTICIAN SAID THIS IS
WONDERFUL BUT WE CAN'T USE A
SINGLE SCORE TO DETERMINE
WHETHER OR NOT SOMEBODY IS
CHANGING THEIR DISEASE OR
RESPONDING TO TREATMENT OR
WHATEVER.
SO WE HAD TO COME UP WITH A
COMPOS
COMPOSITE.
MY RESPONSE TO THIS WAS SORT OF
AS YOU SEE THE BOWLS OF FRUIT
THERE, YOU HAVE LOTS OF
DIFFERENT FRUIT IN THE FIRST
BOWL AND OTHER KINDS OF FRUIT IN
THE SECOND BOWL.
HAS THE SECOND BOWL IMPROVED OR
REGRESSED?
WELL, YOU HAVE BAA -- BANANAS IN
THE SECOND BUT NOT THE FIRST.
THE GRAPES ARE DONE.
IF -- ARE GONE.
IF THE GRAPES ARE THE PROBLEM
THINGS ARE BETTER NOW.
THAT IS THE WAY I FELT ABOUT IT
BUT I WAS OVERRULED AND IT'S
PROBABLY JUST AS WELL.
WHAT WE DID WAS DID A
STATISTICAL ANALYSIS ON ALL OF
THESE FEATURES THAT WE LOOKED
AT.
WE SAW WHAT WAS MOST RELATED TO
WHAT WE THOUGHT WAS
STEATOHEPATITIS.
WE CAME UP WITH FOUR THINGS,
STEATOSIS, LOBULAR, INFLAMM
INFLAMMATION.
THESE WERE RELATED TO THE
SEVER
SEVERITY.
YOU CAN SEE THE PERCENTAGE OF
CASES THAT WE CALLED DEFT NIT --
DEFINITE STEATOHEPATITIS GOING
UP.
SO WE CREATED THIS SCORE, THIS
ACTIVITY SCORE WHICH WAS -- WE
JUST ADDED THESE THINGS
TOGETHER.
SO INSTEAD OF GRAPES AND BANANAS
AND APPLES, WE HAVE FRUIT,
STEATOSIS PLUS LOBULAR
INFLAMMATION BLUE BALLOONING
SCORE WENT FROM 0 TO 8.
NOW THE STATISTICIANS WERE
HAPPY, THEY COULD SEE A CHANGE
OVER AN 8-POINT SCALE.
OVER ON THE RIGHT IS A GRAPH
SHOWING HOW THE SCORE TRANSLATED
INTO WHAT WE -- WHAT OUR
DIAGNOSIS WAS.
SO HIGH SCORE THINGS ALMOST
ALWAYS GOT CALLED STEATOTIC OR
STEATOHEPATITIS -- CALLED
STEATOHEPATITIS.
IT'S THE HUMP IN THE MIDDLE
WHERE WE CALLED IT BORDERLINE OR
SUSPICIOUS.
IT HAD ALL OF THE FEATURES BUT
NOT ALL OF THE FEATURES.
SO THOSE WERE KIND OF IN THE
MIDDLE.
WE DID NOT ADD THE FIBROSIS
BECAUSE IT'S MORE OF AN OUTCOME.
WE FELT THAT THE ACTIVITY WAS
CREATING THE FIBROSIS.
WE DIDN'T WANT TO MIX IT ALL
TOGETHER.
WE DID WANT TO KNOW WHAT ALL OF
THIS MEANT.
SO A COUPLE OF YEARS LATER, SO
NOW 2011, WE PUBLISHED A PAPER
LOOKING AT ALL OF THE BIOPSIES
THAT WE HAD SCORED THUS FAR, AT
LEAST IN ADULTS.
YOU CAN SEE THE GRAPH, WHICH
LOOKS VERY SIMILAR TO THE
PREVIOUS ONE NOW LOOKS CLEANER.
WE DON'T HAVE SO MUCH NOISE DOWN
HERE OR UP HERE.
EVERYTHING, YOU KNOW, GOES TO
STEATOHEPATITIS.
WE STILL HAVE THIS HUMP IN THE
MIDDLE OF THESE BORDERLINE
CASES.
BUT WHAT WE FOUND WAS THAT THE
SCORE THAT WE CREATED WAS MORE
ASSOCIATED WITH ALT.
YOU CAN SEE THAT UP ABOVE.
SO WE DIVIDE THE SCORES INTO A
SCORE OF 5 OR GREATER VERSUS 4
OR LESS VERSUS THE DIAGNOSIS
THAT WE GAVE IT.
AND THE SCORE WHEN WE PUT BOTH
IN THE MODEL, THE SCORE COMES
OUT TO BE MORE SIGNIFICANT AND
HAVE A HIGHER ODDS RATIO OF, YOU
KNOW, DETERMINING WHICH HAS THE
HIGHER ALT.
AND THEN WHEN YOU LOOK AT
DIABETES AS A DIAGNOSIS, SO THE
DIABETICS IN OUR POPULATION, THE
SCORE DIDN'T MATTER SO MUCH.
IT WAS NOT EVEN STATISTICALLY
SIGNIFICANT.
BUT THE DIAGNOSIS WAS.
SO WE WERE SEEING THINGS IN THE
BIOPSY THAT WENT BEYOND THE
SCORE.
SO WE COULD HAVE MILD CASES,
WHICH WERE STILL STEATOHEPATITIS
AND HIGH SCORE CASES THAT WERE
NOT.
SO THAT'S WHY THE SCORE WAS A
LITTLE BIT DIFFERENT FROM THE
DIAGNOSIS.
SO WE MAINTAINED THAT DIFFERENCE
ALL THE WAY THING.
THE IMPORTANT THING WAS TO USE
THIS SCORING SYSTEM IN CLINICAL
TRIALS AND STUDY DISEASE
PROGRESSION.
WHOOPS.
SO THE NASH CRN DID SIX CLINICAL
TRIALS.
YOU CAN SEE THEY ARE ALL
ABBREVIATIONS HERE.
WE DID TWO IN ADULTS AND TWO IN
CHILDREN THAT HAD PRE AND POST
TREATMENT BIOPSIES SO YOU COULD
SEE WHAT WAS HAPPENING TO THESE
PATIENTS.
WE HAD ANOTHER PEDIATRIC STUDY
THAT HAD A STUDY ENTRY BIOPSY
ONLY AND THEN MOST RECENTLY OR
ON GOING STUDY ONLY HAS A ENTRY
BIOPSY AND ACTUALLY THAT WAS
MADE OPTIONAL AFTER WE STARTED
ENROLLING.
I AM ONLY GOING TO TALK ABOUT
ONE OF THESE.
I'M GOING TO TALK ABOUT THE
FLINT TRIAL, WHICH WAS THE
SECOND ADULT TRIAL WE DID. IT'S
A SIMPLER TRIAL.
THIS WAS TO TEST THE DRUG
OBETICHOLIC.
IT WAS ONLY ADULTS.
THEY HAD TO HAVE STEATOHEPATITIS
AND BIOPSY OR THAT DIAGNOSIS HAD
TO BE THERE AND THE SCORE HAD TO
BE FOUR OR GREATER.
SO WHAT WE WERE TRYING TO DO WAS
GET THE MORE SEVERE DISEASE
PATIENTS TO SEE CHANGE.
THEY COULDN'T HAVE CIRRHOSIS SO
THAT WAS AN EXCLUSION.
YOU CAN SEE THE OTHER DETAILS.
IF -- THE BIOPSY HAD TO BE DONE
AT LEAST THREE MONTHS, NO LONGER
THAN THREE MONTHS BEFORE
TREATMENT AND THEN A SECOND
BIOPSY AFTER 72 WEEKS OF
TREATMENT.
AND THE PRIMARY ENDPOINT, THE
MAIN POINT WAS TO SHOW
HISTOLOGIC IMPROVEMENT.
THE SCORE HAD TO DROP BY TWO
POINTS AND THE FIBROSIS COULDN'T
BE COURSE.
SO THIS IS THE SCHEMATIC OF THE
STUDY DESIGN.
SO PATIENTS GET ENROLLED, GOT A
LIVER BIOPSY, RANDOMIZED TO ONE
OF THESE TWO THERAPIES AND THEN
TREATED FOR 72 WEEKS AND CAME
OUT THE OTHER END, GOT ANOTHER
BIOPSY AND FOLLOWED FOR ANOTHER
24 WEEKS.
THIS IS THE DIAGRAM THAT SHOWED
YOU HOW THE PATIENTS FLOWED IN
NUMBERS.
IT WAS A LITTLE COMPLICATED
BECAUSE WE HAD SORT OF AN EARLY
STOP.
SO OUT OF THE 345 PATIENTS THAT
WERE ASSESSED, 62 WERE
INELIGIBLE FOR ONE REASON OR
ANOTHER.
SO WE RANDOMIZED.
ABOUT HALF EACH AND PLACEBO.
SOME PATIENTS DIDN'T GET A BUY
OLE -- BIOPSY IN THE END AND
ASSUMED TO NOT HAVE IMPROVED.
THEN THE DATA SAFETY AND
MONITORING BOARD ACTUALLY
DETERMINED THAT WE HAD REACHED
AN ENDPOINT BEFORE EVERYONE HAD
GONE THROUGH THE TRIAL SO WE
DIDN'T DO THE LAST 64 BIOPSIES.
IN TEND WE HAD 192 BIOPSIES ON
ONE SIDE, 98 ON THE OTHER.
WE INCLUDED THESE EXTRAS AND NOT
IMPROVED.
SO HOW DID WE DO?
WE HIT OUR ENDPOINT.
SO THERE WAS AN IMPROVEMENT IN
THE SCORE OF GREATER THAN 2
POINTS.
YOU CAN SEE DOWN HERE 21% OF THE
PATIENTS ON PLACEBO AND 46% OF
THE PATIENTS WHO GOT TREATED.
THAT WAS HIGHLY STA
STATISTICALLY SIGNIFICANT.
THAT WAS A PERSISTENT FINDING.
10 TO 20% OF PATIENTS GET BETTER
ON THEIR OWN.
THAT HAS TO DO WITH A
COMPLICATED NATURAL HISTORY OF
THIS DISEASE AND SOME OTHER
FACTORS.
BUT IT DOES SEEM TO BE A REAL
PHENOMENON.
MAKES EVERYTHING HARDER.
AND WHEN YOU LOOKED AT THE
INDIVIDUAL COMPONENTS, SO NOT
ONLY THE COMPOSITE SCORE BUT ALL
THESE INDIVIDUAL FEATURES, WE
ALSO SHOWED IMPROVEMENT .
SO THE STEATOSIS GOT BETTER,
INFLAMMATION GOT BETTER,
BALLOONING GOT BETTER.
YOU CAN SEE THE PATIENTS
IMPROVED.
DOWN BELOW IS THE SCORE.
ON STEATOSIS ON AVERAGE DROPPED
.8 POINTS COMPARED TO .4 OF
PLACEBO ACROSS THE BOTTOM THERE.
FIBROSIS ALSO IMPROVED. SO THAT
WAS REALLY A BIG BONUS.
SO WE HAD 35% OF PATIENTS
IMPROVING ON DRUG AND 19% ON
PLACEBO AND THAT WAS
SIGNIFICANT.
ONE THING THAT WE DIDN'T SEE IS
THAT PATIENTS DIDN'T RESOLVE
THEIR STEATOHEPATITIS.
SO WE COULD STILL DETECT THAT
THIS WAS THERE AT THE SECOND
BIOPSY IN MOST OF THE PATIENTS
WHICH TO ME TELLS ME THAT WE'RE
DAMPENING THE ACTIVITY OF THE
DISEASE BUT NOT MAKING IT GO
AWAY COMPLETE.
IT WAS HAVING ENOUGH AN EFFECT
THAT WE WERE SEEING FIBROSIS
IMPROVE
IMPROVEMENT.
SO IT IMPROVED THE FEATURES OF
NASH INCLUDING FIBROSIS. IT WAS
ASSOCIATED WITH SOME SIDE
EFFECTS THAT WAS SEVERE IN SOME
PATIENTS.
IT DID CAUSE AN ELEVATED TOTAL
AND LDL CHOLESTEROL BUT
DECREASED HDL CHOLESTEROL.
THAT WAS PLANNED FOR FUTURE
CLINICAL TRIALS TO LOOK AT THAT
MORE CAREFULLY.
BUT THIS TRIAL, WHEN THIS TRIAL
SORT OF WENT PUBLIC, THIS IS
WHEN THE PHARMACEUTICAL
COMPANIES REALLY GOT INTERESTED
AND SORT OF DATES FROM THIS
TIME.
AFTER THAT THERE WERE LOTS OF
CLINICAL TRIALS.
MOST OF WHICH USED HISTOLOGIC
ENDPOINTS AND THIS SCORING
SYSTEM TO EVALUATE THE CHANGES.
THE OTHER STUDY I WANT TO POINT
OUT HERE IS IN LONGITUDINAL
STUDY WE DID.
WE HAD A LOT OF PATIENTS
ENROLLED, A LOT OF PATIENTS WITH
PAIRED BIOPSIES WHO HAD NOT BEEN
TREATED IN BETWEEN.
SO WE GATHERED ALL THOSE
BIOPSIES TOGETHER AND ANALYZED
THEM.
EVERYONE WHO HAD A BIOPSY AT
LEAST A YEAR APART AND THAT WERE
NOT TREATED IN A CLINICAL TRIAL
IN BETWEEN.
SO AGAIN A COMPLICATED CONSORT
DIAGRAM.
THE MOST SPOIMPORTANT THING AT
END AFTER ELIMINATING EVERYTHING
THAT WOULDN'T FIT OUR
DEFINITIONS WE HAD DATA ON 464
PATIENTS AND CLINICAL DATA TO GO
WITH THAT ON 219.
SOME BIOPSIES WERE WAY BEFORE
THE NETWORK STARTED SO THEY
DIDN'T HAVE CLINICAL DATA.
SO WHAT DID WE FIND.
SO THERE WERE A LOT OF FINDINGS
IN THIS STUDY BUT I'M GOING TO
FOCUS ON THE HISTOLOGIC ONES.
IF YOU JUST LOOK AT THE
HISTOLOGY YOU CAN SEE BASELINE
AND CHANGES OVER TIME IN BETWEEN
THE TWO BIOPSIES.
THE THINGS THAT CAME OUT AS
SIGNIFICANT WERE BASELINE
BALLOONING AND PORTAL
INFORMATION AND CHANGES IN
CHANGING AND PORTAL
INFLAMMATION.
MOST OF THESE THINGS WERE
SIGNIFICANT EXCEPT LOBULAR
INFLAMMATION ODDLY ENOUGH DIDN'T
COME OUT AS A SIGNIFICANT
FINDING IN THIS ANALYSIS.
BUT WE COULD SAY IF YOU KNOW
WHERE THE BASELINE IS WHICH
PATIENTS ARE LIKELY TO DO WORSE
OVER THE NEXT FEW YEARS.
IF YOU KNOW THEN SOME CLINICAL
THINGS ABOUT THOSE PATIENTS, YOU
COULD SAY, YOU KNOW, WHO WAS
REALLY GETTING BETTER OR WORSE.
WE ALSO USED THE COMPOSITE
SCORE, WHICH DIDN'T HAVE SO MUCH
SIGNIFICANCE ON REGRESSION.
I THINK PARTLY BECAUSE IT WAS
THE MALLORY-DANK BODY IS A GOOD
SURROGATE FOR BALLOONING AND
DECREASED THE IMPORTANCE OF THE
OTHER CHANGES IN THE NASH.
PROGRESSION, IT DID MAKE A
DIFFERENCE AT BASELINE.
AND THEN CHANGES WERE
SIGNIFICANT.
SO ACTIVITY UP, ACTIVITY DOWN,
FIBROSIS EITHER IMPROVES OR
WORSENS.
IT'S TRUE WITH THE DIAGNOSIS
TOO.
THIS IS KIND OF A COMPLICATED
GRAPH.
BUT WHAT I WANT YOU TO FOCUS ON,
SO THE STAGES ARE DOWN HERE.
SO CIRRHOSIS IS AT THE RIGHT.
NO FIBROSIS IS AT THE LEFT.
SO BLUE OR DARK PURPLE I GUESS
IS GOOD.
AND RED IS BAD.
THEY ARE ALL STACKED UP NICELY,
RIGHT.
SO IF YOUR DIAGNOSIS GETS WORSE,
FROM FATTY LIVER DISEASE TO
NASH, THIS BLUE BAR GOES ALMOST
TO NOTHING.
MEANS THAT EVERYBODY GETS
FIBROSIS AFTER ABOUT FOUR YEARS.
THAT SOME PATIENTS GET -- MOVE
INTO ADVANCED FIBROSIS.
IN IN MIDDLE CATEGORY HAVING
BORDERLINE FEATURES INTO
STEATOHEPATITIS, THERE ARE A LOT
OF PEOPLE THAT DEVELOP
CIRRHOSIS.
IF YOU JUST GO FROM FATTY LIVER
TO A BORDERLINE DIAGNOSIS, EVEN
THEY GET WORSE.
SO THERE'S PROGRESSION WHEN THE
DISEASE GETS WORSE THE FIBROSIS
GETS WORSE.
THAT MAKES SENSE.
BUT THIS WAS REALLY THE FIRST
LONGITUDINAL BIOPSY-BASED STUDY
TO SHOW THAT.
AND THEN THIS IS THE FINAL GRAPH
I'M GOING TO SHOW ON THIS.
DISEASE ACTIVITY IN STAGE RUN IN
PARALLEL.
SO THE CHANGE IN THE NASH SCORE,
WHATEVER CONTRIBUTES TO THAT
CHANGE RUNS MORE OR LESS IN LINE
WITH THE CHANGE IN THE STAGE.
SO STAGE IMPROVEMENT, NASH
IMPROVEMENT GO TOGETHER.
SO THIS WAS THE LARGEST PAIRED
BIOPSY STUDY.
IT'S STILL THE LARGEST PAIRED
BIOPSY STUDY.
I WENT THROUGH MOST OF THESE
OBSERVATIONS.
SO I'M GOING TO GO ON.
SO WE'VE HAD A COUPLE OF STUDIES
THAT HAVE COME OUT OF THIS THAT
HAVE RELATED TO FINDINGS OUTSIDE
PURELY THE AREA OF PATHOLOGY.
THIS WAS A GENOME WIDE
ASSOCIATION STUDY USING IMAGING
ON PATIENTS WHO WERE ENROLLED IN
THE DALLAS HEART STUDY.
THIS WAS NOT A BIOPSY STUDY.
THIS WAS A STUDY BASED ON MRI
IMAGING OF FAT.
THEY FOUND A POLYMORPHISM IN THE
DNA NEAR THIS GENE PNPLA3.
SO YOU CAN SEE THAT THAT LITTLE
DOT OUT ON THE END RIGHT HERE,
THAT'S THE ONLY SIGNIFICANT
POLYMORPHISM THEY FOUND ACROSS
THE WHOLE GENOME. THIS WAS THE
VERY FIRST STUDY OR ONE OF THE
FIRST AND MOST IMPORTANT
STUDIES.
SHORTLY AFTER THAT WE PUBLISHED
TWO -- THERE WERE TWO BIOPSY
STUDIES THAT CAME OUT OF THE
NETWORK.
BOTH CONFIRMING THIS AND
EXTENDING THOSE OBSERVATIONS NOW
INCLUDING HISTOLOGY.
I'M GOING TO TALK ABOUT THE ONE
DONE OUT OF THE NIH.
RAKMAN WAS THE PI ON THIS
PORTFOLIO.
WE LOOKED AT THIS, CONFIRMED IT
WAS PRESENT AND SPECIFICALLY THE
C TO G DIFFERENCE AT THIS POINT
IN THE GENOME AND THAT ACTUALLY
CORRESPONDED TO TO A CHANGE IN
THE AMINO ACID SEQUENCE OF THIS
PROT
PROTEIN.
WHEN YOU HAD TWO OF THEM WERE
MORE LIKELY TO HAVE STEATOSIS OR
MALLORY BODIES.
SORRY AND INFLAMMATION.
THOSE THREE IMPORTANT THINGS,
AGAIN MALLORY BODIES BEING A
SURROGATE FOR BALLOONING ALL
WENT UP IN PATIENTS WITH G
ALLEL.
ALL FLEE OF THOSE WERE
IMPORTANT.
THE GRAPH ON THE RIGHT SHOWS THE
PEDIATRIC POPULATION, WHAT AGE
AT FIRST BIOPSY, WHICH IS KIND
OF A SURROGATE FOR WHEN PEOPLE
PICKED UP THE DISEASE.
IF YOU WERE UNDER 9 AND GOT A
BIOPSY YOU WERE ABOUT 90% LIKELY
TO HAVE THIS G ALLEL.
SO PRETTY IMPORTANT MARKER.
WE'VE ALSO LOOKED AT
TRANSCRIPTOMICS.
THERE'S ARUN'S NAME AND MELISSA
CANTOS WAS A PATHOLOGIST WITH
THE NASH CRN.
SO SHE DID ALL THE SCORING FROM
THIS STUDY.
THEY WEREN'T BIOPSIES OUT OF THE
NETWORK.
THEY RELATED HISTOLOGIC TO GENE
CHANGES AND LOOKED AT A WHOLE
BUNCH OF GENE PATHWAYS.
YOU CAN SEE WHEN YOU PLOT THESE
GENE PATHWAYS THE SUMMARY SCORES
AGAINST THE NASH NAS OR FIBROSIS
STAGE YOU CAN FIND GENE PATHWAYS
THAT BECOME MORE ACTIVATED OR
REPRESSED AS THE SCORE GOES UP
OR DOWN.
SO THIS IS A REALLY SIGNIFICANT
FINDING THAT WE COULD SEE ALL OF
THESE GENETIC CHANGES,
TRANSCRIPTIONAL CHANGES THAT
RELATED DIRECTLY TO HISTOLOGY.
THEY CAME UP WITH MASTER SCORES
THAT ALLOWED THEM TO SORT OF
GAUGE ACTIVITY OR FIBROSIS JUST
BASED ON THE TRANSCRIPTION
PROFILE.
HOW ARE WE DOING?
I THINK WE'RE GOOD.
SO CLINICAL TRIALS FOR
STEATOHEPATITIS.
I MENTIONED THERE WAS THIS
EXPLOSION OF CLINICAL TRIALS.
NOW A LOT OF PHASE THREE TRIALS
ARE ONGOING.
IN THIS REVIEW ARTICLE, WHICH
WAS JUST WRITTEN LAST YEAR, THEY
HIGHLIGHTED FOUR DRUGS IN PHASE
THREE CLINICAL TRIALS, .
THE SECOND ONE IN THE IS SECOND
COLUMN HERE DLSH -- THERE'S MY
POINTER.
AND TWO OTHER DRUGS.
THE LAST TWO DRUGS WE'RE STILL
WAITING FOR THOSE TRIALS TO
FINISH, AT LEAST AT THE TIME OF
THIS WRITING.
WHAT I'M GOING TO SHOW YOU IS
THE DATA FROM ONE OF THE PAPERS.
THIS WAS JUST PUBLISHED IN THE
NEW ENGLAND JOURNAL.
AGAIN I WAS CIRCLE THE
PATHOLOGISTS WHO ARE TWO AND
THREE ON THIS PAPER.
THE SECOND PAPER -- OR SECOND --
THIRD AUTHOR, I'M SORRY, IS
CINDY GUY. SHE'S ALSO A
PATHOLOGIST IN THE NASH CRN.
AND PIER BEDOSA IS ONE OF MY
COLLEAGUES IN FRANCE WHO IS A
LEADER IN THIS FIELD, ALSO A
PATHOLOGIST.
SO THE HISTOLOGIC ENTRY CRITERIA
WAS THE SAME AS BEFORE,
STEATOHEPATITIS AND WASN'T
CIRRHOSIS.
AND THE HISTOLOGIC END POINT WAS
RESOLUTION OF THIS -- THAT
SHOULD BE WITHOUT FIBROSIS
WORSENING.
OH WELL.
OR IMPROVEMENT OF THE FIBROSIS
WITHOUT WORSENING OF THE SCORE.
AND THEY HIT THE TARGETS.
SO IT SHOWED A 30% RESPONSE RATE
IN TERMS OF NASH RESOLUTION WITH
NO WORSENING COMPARED TO 10% OF
THE PLACEBO PATIENTS.
ON THE FLIP SIDE OF THAT,
FIBROSIS IMPROVEMENT WITH NO
WORSENING OF THE NAFLD SCORE.
AGAIN A QUARTER OF THE PATIENTS
WITH 15% IN THE PLACEBO GROUP.
THERE WAS ANOTHER ENDPOINT THAT
THEY HIGHLIGHTED WHICH WAS DROP
IN THE NLDL CHOLESTEROL.
THEY ALSO HIGHLIGHTED A BUNCH OF
ADDITIONAL ENDPOINTS THAT WERE
ALL HISTOLOGIC THEY HIT AS WELL.
THESE WERE THE FIRST TWO.
TWO POINT IMPROVEMENT.
THEY HIT THAT MARK.
AND ANOTHER SIMILAR ONE, AGAIN,
A LITTLE BIT MORE STRINGENT, HIT
THAT MARK.
IMPROVEMENT OF EACH COMPONENT OF
THE SCORE, HIT THAT MARK.
IMPROVEMENT OF THE FIBROSIS BY
TWO STAGES, THAT WAS ALSO
SIGNIFICANT.
AND THEN NASH RESOLUTION AND
FIBROSIS IMPROVEMENT AND THEY
HIT THAT MARK.
SO EVERY SINGLE HISTOLOGIC
ENDPOINT THEY IDENTIFIED THIS
DRUG HIT.
SO IT'S VERY, VERY ENCOURAGENCO
THE FDA ALSO FOUND THIS
ENCOURAGING SO THEY APPROVED
THIS AS THE FIRST DRUG TREATMENT
FOR PATIENTS WITH LIVER SCARRING
DUE TO FATTY LIVER DISEASE.
SO THIS IS THE ANNOUNCEMENT OFF
THE FDA WEBSITE.
SO THIS IS THE SUMMARY.
SO 21 YEARS NASH CRN PATHOLOGY
COMMITTEE CONTRIBUTED TO THE
GREATER UNDERSTANDING OF THIS
DISEASE. THERE'S A LOT OF STUFF
OBVIOUSLY I DIDN'T HIGHLIGHT.
WE PUBLISHED 17
PATHOLOGY-FOCUSED PAPERS AND WE
MADE FUNDAMENTAL CONTRIBUTIONS
TO 136 OTHER.
MOST OF THE OTHER 136 NASH CRN
PAPERS INCLUDING THE FOUR
CLINICAL TRIALS, GENETIC
TRANSCRIPTOMIC STUDIES WHICH I
DIDN'T HAVE TIME TO COVER.
NON INVASIVE IMAGING AND
BIOMARKER STUDIES.
SOME OF WHICH ARE STILL GOING
ON.
AND WE ESTABLISHED THIS
EVALUATION METHOD FOR THE LIVER
BIOPSY THAT'S BEEN USED IN
LITERALLY HUNDREDS OF STUDIES
OUTSIDE THE NETWORK INCLUDING
THE STUDY THAT LED TO THE FIRST
FDA APPROVAL AS A TREATMENT FOR
MASH.
SO WHAT I HOPE YOU'VE LEARNED.
STEATOHEPATITIS, I COVERED THE
PATHOLOGY.
IT HAS A LOT OF DIFFERENT MICRO
SD
MICROSCOPIC CHANGES WHICH ARE
IMPORTANT.
WE CAN SCORE THOSE CHANGING
LOOKING AT THE SLIDES UNDER THE
MICROSCOPE WE CAN CORRELATE WITH
GEN
GENOMESTUDIES. IT'S BEEN USED
TO GAIN ACCELERATED APPROVAL FOR
ONE DRUG SO FAR AND I GUARANTEE
YOU THAT THERE WILL BE OTHERS.
SO LOTS OF PEOPLE TO THANK.
THESE ARE THE NASH CRN
PATHOLOGISTS SINCE WE STARTED
THE COMMITTEE.
YOU CAN SEE THERE'S BEEN SOME
CHANGE IN PERSONNEL AS PEOPLE
MOVED OUT OF ACADEMIC CENTERS
INTO OTHER PLACES.
I'VE HIGHLIGHTED TWO PEOPLE THAT
I REALLY COULD NOT HAVE DONE
THIS WITHOUT.
ONE IS ELIZABETH BRUNT, WHO WAS
MY STALLWARD CO-CHAIR FOR MANY
YEARS.
AND THEN CYNTHIA BAILEY WHO TOOK
OVER AFTER BETH RETIRED.
SO 73 MEETINGS.
ALMOST 7,000 CASES PLUS EXTRAS
ADDED TO THAT.
WE LOOKED AT CASES FROM ADULTS
AND CHILDREN WITH THE LARGEST
PEDIATRIC BIOPSY COHORT PROBABLY
IN THE WORLD IN THIS STUDY.
I DIDN'T COVER ANY OF THAT.
SO WE'VE ESTABLISHED -- IS
WE'VE ACCOMPLISHED QUITE A LOT.
AND THEN THE NATIONAL CLINICAL
RESEARCH NETWORK INVESTIGATORS
ARE ON THE LEFT HERE.
AND THE CURRENT MEMBERS OF THE
PATHOLOGY GROUP, THE DCC, COULD
NOT HAVE DONE ANY OF THIS WORK
WITHOUT OUR STATISTICIANS, JIM
AND ESPECIALLY PAT WILSON WHO
WERE AT EVERY SINGLE ONE OF OUR
SCORING MEETINGS.
AND THEN THE PROJECT SCIENTIST
FROM THE NIDDK.
I MENTIONED THE PATHOLOGISTS.
A LOT OF PATIENTS, GOT A LOT OF
BIOPSIES.
SO THANK YOU.
>> [APPLAUSE]
>> I WILL STAY HERE.
I CAN'T RUN AWAY.
UP THE STAIRS.
>> CAN YOU LOCK THE DOORS.
I JUST WANT TO SAY THANK YOU
AGAIN FOR SHARING WITH US YOUR
EXPERT
EXPERTISE. IT'S CLEAR TO ALL OF
US WHY YOU'VE BEEN SELECTED AS A
MASTER EDUCATOR.
AS A PEDIATRIC CARDIOLOGIST I
STOOD.
THANK YOU.
THANK YOU FOR YOUR IMPACT ON THE
WHOLE DISCIPLINE OF
STEATOHEPATITIS.
APPRECIATE IT.
THANK YOU VERY MUCH AND
CONGRATULATIONS.
>> THANK YOU.
>> [APPLAUSE]
>> OF COURSE THE ONLY PERSON
CRINGING IS [INAUDIBLE]
>> YOUR TURN NEXT YEAR.
>> I HAVE A QUESTION THAT CAME
IN WITHIN THE COMMUNITY.
EXCELLENT TALK.
WERE YOU ABLE TO FIND ANY
EVIDENCE OF HEPATITIS VIRUS?
>> SO ALL OF THE PATIENTS IN
THE NETWORK WERE EXCLUDED IF
THEY HAD A CO-INFECTION WITH ONE
OF THE HEPATITIS VIRUSES.
INTERESTINGLY IN REVIEWING THE
BIOPSIES OF COURSE WE FIND OTHER
THINGS.
WE FINED FI-- WE FIND THINGS.
WE SAID ONE THIS IS NOT
STEATOHEPATITIS, THIS IS
HEPATITIS C.
WE SENT A MESSAGE BACK TO THE
CLINIC.
SURE ENOUGH THE PATIENT HAD BEEN
TESTED AND NEGATIVE FOR HEN --
FOR HEP-C WHEN THEY ENTERED THE
STUDY AND WERE NOW INFECTED AND
POSITIVE.
SO WE DID HAVE THAT.
OTHERWISE THE PATIENTS WERE ALL
NEGATIVE.
>> DAVID, THANK YOU VERY MUCH.
INTERESTING TALK.
ELAINE JAFFEE.
>> I RECOGNIZE YOU.
>> YOU RECOGNIZE ME.
OKAY.
SO IS THIS A NEW DISEASE?
BECAUSE I DON'T REMEMBER HEARING
ABOUT THIS DISEASE WHEN I WAS A
RESIDENT UPTEEN YEAR AGO.
>> SO IT IS AND IT ISN'T.
SO IF YOU ACTUALLY GO BACK INTO
THE LITERATURE PRECEDING 1980 I
FOUND DESCRIPTIONS OF PATHOLOGY
IN DIABETES THAT DESCRIBED THIS
PATHOLOGY.
THEY JUST DIDN'T KNOW WHAT TO
CALL IT OR THEY DIDN'T HAVE A
NAME FOR IT.
WHICH IS WHY I POINTED OUT THE
IMPORTANCE OF NAMING SOMETHING.
BUT YOU'RE RIGHT.
THERE WAS NOT MUCH OUT THERE
UNTIL THIS WORKSHOP.
SO WHEN I DID -- I DID A
LITERATURE REVIEW BEFORE THE
WORKSHOP THAT I WENT OVER WITH
THE PATHOLOGISTS.
THERE WERE MAYBE 10 PAPERS OUT
THERE ON THE PATHOLOGY OF FATTY
LIVER DISEASE.
THAT CAME AFTER THAT SEMINAL
PAPER.
THERE WERE DESCRIPTIONS OF FATTY
LIVER BEFORE THAT.
SOME FAIRLY LARGE COHORT STUDIES
BUT THERE WAS ACTUALLY AN
ARGUMENT IN THE LITERATURES
WHETHER THIS WAS SIGNIFICANT OR
NOT OR WHETHER IT WAS NORMAL.
WE NOW KNOW THAT THAT'S NOT
TRUE.
THERE WAS A LOT OF DISBELIEF
THAT FAT IN THE LIVER HAD ANY
SIGNIFICANCE AT ALL.
>> BUT I MEAN YOU DESCRIBE --
DESCRIBING HIGH INCIDENTS.
>> BECAUSE WE'RE GETTING BIGGER
AND DIABETIC.
>> IS THIS ASSOCIATED WITH
CHANGES IN LIFESTYLE?
>> PEOPLE HAVE CORRELATED TO
THE EPIDEMIC OF DIABETES. IT'S
MAINLY AN ASYMPTOMATIC UNTIL YOU
GET TO ADMINISTRATIVE LEAVE --
TO ADVANCED LIVER DISEASE AND
HAVE PROBLEMS WITH CIRRHOSIS.
IT CAN FLY UNDER THE RADAR.
THE ENZYMES ARE NOT THAT
ELEVATED.
PHYSICIANS NOT AWARE OF THIS
DISEASE WILL SAY WE SEE THIS, WE
SEE A LITTLE BIT OF AN ALT
ELEVATION, DOESN'T MEAN
ANYTHING.
BUT, YOU KNOW, I THINK AS WE
BECOME MORE AND MORE AWARE OF
THE DISEASE AND IT'S POTENTIAL
CONSEQUENCES, YOU KNOW, PEOPLE
ARE LOOKING MORE, THERE ARE MORE
GUIDELINES OUT THERE, WHICH
DIDN'T EXIST 40 YEARS AGO.
>> THANK YOU.
>> I HAVE A QUESTION.
>> OKAY.
I'VE STUNNED EVERYONE.
>> WE HAVE ONE MORE.
>> OH.
>> YOU OBVIOUSLY RECOGNIZE ME
AS WELL.
SO YOU'VE GOT A REALLY HIGH
RESPONSE RATE IN YOUR PLACEBO
GROUPS IN THE CLINICAL TRIALS.
>> YEAH.
>> DO YOU THINK THIS IS DRIVEN
BY LIFESTYLE HABIT AS WELL?
>> SO I DIDN'T GO INTO IT IN
THAT LONGITUDINAL STUDY.
MORE PATIENTS GOT BETTER OVER
TIME THAN GOT WORSE.
MY THOUGHT -- AND THIS WAS NOT
JUST HISTOLOGIC NOISE.
SO THERE'S NOISE, I LOOK AT THE
SLIDE ONE DAY AND THINK IT'S
THERE, I LOOK AT IT ANOTHER DAY
AND THINK IT'S DIFFERENT.
THE SCORING ESPECIALLY CAN VARY
A LITTLE.
IT'S NOT JUST THAT.
BECAUSE OTHER THINGS CHANGE IN
THESE PATIENTS.
THEY LOSE WEIGHT, THEIR ENZYMES
CHANGE.
SO OTHER THINGS ARE CHANGING.
SO IT'S NOT ALL IN DAVE
KLEINER'S IMAGINATION.
BUT I THINK THAT TAKING GOOD
CARE OF PEOPLE, SEEING YOUR
PHYSICIAN ANNUALLY, GETTING THAT
ADVICE TO WATCH YOUR DIET, TO
LOSE WEIGHT, TO TAKE CARE OF
YOUR DIABETES, TO DEAL WITH
THOSE KIND OF PROBLEMS ACTUALLY
WORKS FOR SOME PERCENTAGE OF
PATIENTS.
SO THEY LOSE A LITTLE WEIGHT AND
THAT'S ENOUGH.
WHEN WE LOOKED AT WEIGHT CHANGES
RELATED TO THESE THINGS, YOU
DON'T HAVE TO LOSE MUCH WEIGHT.
ABOUT 10 POUNDS.
YOU'LL SEE CHANGES
HISTOLOGICALLY.
IT DOESN'T TAKE MUCH TO AFFECT
THAT.
SO WE DO SEE A SIGNIFICANT 10,
15% OF PATIENTS WHO GET BETTER
OVER THE COURSE OF THE CLINICAL
TRIAL.
>> JAY IS GOING TO ASK ME I'M
AFRAID.
>> JAY FROM CLINICAL CENTER.
ACTUALLY EVEN BEFORE THE
DISCOVERY OF HEPATITIS C AT THE
CLINICAL CENTER HARVEY ALTER
INTRODUCED ALT SCREENING OF
BLOOD DONORS AND WOULD EXCLUDE
SOMEONE WITH AN ELEVATED ALT.
WE DID BIOPSIES ON SEVERAL OF
THESE.
THE MOST COMMON DIAGNOSIS WAS
NOT CHRONIC HEPATITIS, IT WAS
FATTY LIVER DISEASE.
YES, THIS WAS KNOWN BUT IT
DIDN'T HAVE A NAME UNTIL THIS
GREAT PAPER BY LUDWIG THAT
SHOWED IT.
AS ALSO POINTED OUT IF YOU LOOK
AT THE PLACEBO GROUP THAT
IMPROVED, THEY LOST WEIGHT.
AS DAVID SAID IT'S NOT MUCH
WEIGHT.
WE HAD TROUBLE PUBLISHING THE
PAPER BECAUSE ALL THE OBESITY
EXPERTS SAID THAT'S NOT ENOUGH
WEIGHT LOSS TO ACCOUNT FOR
ANYTHING.
BUT WITH THIS LITTLE WEIGHT LOSS
IS HELPFUL.
AT LEAST FOR THOSE WHO AREN'T
TOO OVER WEIGHT.
>> THANK YOU.
DOCTOR KLEINER, THANK YOU AGAIN.
CONGRATULATIONS.
>> THANK YOU.
>> THE DECKER FAMILY INVITING
GUESTS UP TO THE MEDICAL BOARD
ROOM SO WE WILL SEE YOU THERE
MOMENTARILY.
>> THANK YOU.