Liver Fibrosis: Past, Present, and Future
December 06, 2021Information
December 2, 2021
Yale Pathology Grand Rounds
Dhanpat Jain, MD
ID7242
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- 00:04Well, good afternoon everyone
- 00:06and thank you for joining us
- 00:09today in pathology grand rounds.
- 00:11It is my great honor to introduce
- 00:14our grand round speaker today.
- 00:16Doctor Dhanpat Jain and I'd like
- 00:19to go into some detail about Doctor
- 00:22Jane and his many accomplishments.
- 00:25So Doctor Jane went to medical school at
- 00:28Mysore Medical College in Mysore, Karnataka.
- 00:31Sorry if I murder in the name India
- 00:34and did his pathology training at
- 00:36the Institute of Medical Education
- 00:38and Research at Chandigarh, India.
- 00:40Before coming to Yale in 1995,
- 00:44first as a GI pathology fellow.
- 00:48Recruited by Brian West,
- 00:49who many of you know.
- 00:52And this was only a year after
- 00:53I had joined the faculty in 1994
- 00:55as a GI and liver pathologist.
- 00:58When Dan Pat hit the scene as
- 01:00a GI pathology fellow,
- 01:01he was already a highly
- 01:04accomplished diagnostician.
- 01:05And we it was immediately recognized as a
- 01:09highly valuable asset to the department.
- 01:12He he joined the AP CP Anatomic and
- 01:16clinical pathology residency after his
- 01:19one year fellowship and that is was
- 01:22a four year residency at the time.
- 01:23However, when we had an opening on
- 01:27the GI faculty arrived sort of almost,
- 01:30you know.
- 01:31One year before he was to finish
- 01:33the CP component of his training.
- 01:35I and I think it was me convinced
- 01:38him to cut short his CP training
- 01:40to join the faculty.
- 01:42I basically begged him to do this and
- 01:44told John Morrow that chair at the
- 01:46time that this is what we needed to
- 01:48do and Dan Pat joined the faculty in 1999.
- 01:51The rest is history,
- 01:53so over the past 22 years,
- 01:55Dr.
- 01:55Jane has been and is a dynamic diagnostician.
- 02:00Outstanding educator,
- 02:01clinical researcher and thought
- 02:03leader in the field of GI and
- 02:07especially liver pathology.
- 02:08He has been a professor of pathology
- 02:11and internal medicine since 2013,
- 02:13and graciously accepted the
- 02:16directorship of both the program in
- 02:19GI Pathology and the GI pathology.
- 02:21Fellowship from me in 2000.
- 02:25In 2011,
- 02:26when I stepped back from those
- 02:28rules for a period of time.
- 02:30And he brought a vision and energy
- 02:33to the goals of our unit that was.
- 02:37Successful and exciting.
- 02:40With seemingly inexhaustible energy.
- 02:42Doctor Jane pursues excellence
- 02:44in all that he does,
- 02:46both in academic and administrative roles,
- 02:49to highlight some of his accomplishments.
- 02:52They include winning three
- 02:54teaching awards from Yale,
- 02:562 from pathology residents,
- 02:57and one from the clinical GI Fellows.
- 03:01He has been twice nominated
- 03:02for the David Leffell Award for
- 03:05Clinical Excellence very recently.
- 03:07He is well known for his diagnostic
- 03:10expertise being a go to person
- 03:13to whom to show difficult cases.
- 03:15And with respect to academic focus,
- 03:18has a love really for all things
- 03:20liver that is reflected in a body
- 03:22of work on the pathology of chronic
- 03:25liver diseases and tumors and
- 03:27especially on liver fibrosis,
- 03:28about which we will hear today.
- 03:31But in addition to this focus on liver,
- 03:34for which he's widely known,
- 03:36Dan Pat is that rare breed.
- 03:38Almost a throwback throwback to an
- 03:40earlier era in that he maintains his
- 03:44curiosity about all aspects of GI,
- 03:46medicine and pathology such that his
- 03:49publications and lectures span the entire
- 03:52breadth of inflammatory and neoplastic
- 03:55diseases of the entire GI tract.
- 03:57He is also widely successful
- 04:00collaborator with preeminent
- 04:02scientists at Yale and beyond.
- 04:04And he has taken on the organization
- 04:07and senior editorial duties
- 04:09of two major GI textbooks.
- 04:11As a recognized key opinion
- 04:13leader in liver pathology,
- 04:15Dr Jane has been an invited speaker
- 04:17in most continents and is soon to
- 04:19become the President of the Hans
- 04:21Proper Hepatic Pathology Society,
- 04:23as well as serving on the national
- 04:26newly formed National Accreditation
- 04:27Program for Rectal Cancer and serving
- 04:30as a member of the Cancer Committee
- 04:33of the College of American Pathology.
- 04:35He's also on the editorial Board of
- 04:37Human Pathology and numerous other
- 04:40prestigious pathology cancer journals.
- 04:42But just so you don't think he is all
- 04:44work and no play on a personal note,
- 04:46Dan Pat is also known for his
- 04:50sometimes sharp sense of humor.
- 04:54His many fun parties.
- 04:58And he's an excellent cook,
- 05:01and one of his hidden talents is painting,
- 05:04and I've had the privilege of seeing
- 05:05some of his works over the years.
- 05:09In addition to all of this though,
- 05:11Dan Pat has been a reliable,
- 05:14available and extremely hardworking
- 05:16colleague of mine for almost 3 decades.
- 05:20And in many ways we have grown up
- 05:23together establishing our careers and
- 05:25raising children at the same time.
- 05:28And for that I am very grateful.
- 05:31So without further ado,
- 05:33I now give you doctor Dhanpat Jain who
- 05:36will speak to us today on liver fibrosis,
- 05:39past, present and future.
- 05:43Thank you Maria for that really
- 05:46nice and elaborate introduction
- 05:48and the very kind remarks.
- 05:51It's been really a great honor
- 05:53and privilege to work with this.
- 05:55GI team here worked with you and
- 05:58and you know be a leader for the
- 06:01team of four past many years.
- 06:05And I also knew when I took up
- 06:08the leadership from you that
- 06:10you know this is something that
- 06:12is going to be challenging and
- 06:14and it was going to be hard.
- 06:17But having great colleagues and very
- 06:21talented team members made it all easy.
- 06:25And today when I look back,
- 06:28I feel this was one of the nicest
- 06:31things or fun thing that I was able
- 06:33to accomplish in my career so far so.
- 06:37With that I will start going
- 06:40into today's talk,
- 06:41which is about liver fibrosis and.
- 06:48OK, so today I'm going to talk about
- 06:52why if I process is so important in
- 06:55liver diseases and what are the best
- 06:58methods to assess the fibrosis with
- 07:00some historical perspective impact of
- 07:03various different etiologies on how
- 07:05we assess fibrosis in liver and the
- 07:08various methods of fibrous evaluation.
- 07:10Uh, we talked briefly about the
- 07:12end stage fibrosis or cirrhosis
- 07:14and assessment of its severity,
- 07:16and then also briefly talk about the
- 07:19progression of fibrosis and how do we
- 07:22assess regression in liver and towards
- 07:24the end I will touch upon some of the
- 07:28evolving technologies that are going to
- 07:31shape how the liver biopsy is might be.
- 07:35Perceived in future and what kind
- 07:36of role they will play in the future
- 07:40of hepatology and liver pathology.
- 07:43So the first thing is so why
- 07:46fibrosis so important?
- 07:47Liver right?
- 07:48Fibrosis occurs in virtually
- 07:50every tissue in every organ,
- 07:52but it is very very critical in terms
- 07:55of various chronic disorders in the
- 07:58liver and that is for a few reasons.
- 08:02I know that in the audience there
- 08:05are many people who are not aware
- 08:07of the nuances of liver Histology
- 08:09and liver diseases,
- 08:10so I will go over some of the very
- 08:13basics just to make sure that everybody
- 08:15understands some of the issues that
- 08:18I'm going to discuss about and some of
- 08:20the nuances of the liberal pathology.
- 08:22So here there's a Histology of normal
- 08:27liver which highlights couple few of
- 08:30the normal structures that are very.
- 08:33Critical in terms of understanding
- 08:35the pathophysiology of liberty
- 08:36says here you can see the central
- 08:38vein and the portal tracks at the
- 08:41corner of this imaginary hexagon,
- 08:43which is the functional unit of
- 08:46the liver and one of the key
- 08:49things to understand is that.
- 08:51Does blood supply of the liver
- 08:54comes through two major channels?
- 08:56The portal venous system and the
- 08:58hepatic artery which have the terminal
- 09:01branches in the portal track and
- 09:03these empty they're plugged into
- 09:04the hepatic sinus is where it goes
- 09:07through the entire liver lobule
- 09:09to finally reach the hepatic vein
- 09:11mills videos or the central vein,
- 09:13and then is drained through their padded
- 09:15veins into the inferior vena cava,
- 09:17and it is very critical that this
- 09:19blood flow occurs in this fashion.
- 09:22Any change in the hepatic blood
- 09:25flow can have severe.
- 09:28A functional derangements which
- 09:30are difficult to see just through
- 09:33normal routine Histology and and.
- 09:38This is illustrated here that has
- 09:41chronic liver disease progress.
- 09:45Liver that is injured is gradually
- 09:47replaced by fibrosis and this fibrosis
- 09:50takes place in a certain fashion
- 09:52and this depends on the etiologies.
- 09:55Here is depicted what happens typically in
- 09:58chronic hepatic disorders where the fibrosis
- 10:01typically starts from the pole tracks.
- 10:03These are the full tracks, the central veins,
- 10:05the fibrosis from the portal tracks
- 10:07extends into the lobular parent Kima,
- 10:10forming this kind of thin scepter
- 10:12which eventually formed bridges
- 10:13between portal tracks and then.
- 10:15From these bridges extend from
- 10:17pole tracks to Poltrack score.
- 10:19Tractor central vein.
- 10:20What we refer to as the bridging fibrosis
- 10:24and eventually this progresses to forming.
- 10:26This kind of hepatic nodules.
- 10:29Just surrounded this by 5 perceptor.
- 10:32Now. In this regard,
- 10:34it is very important to understand
- 10:36that while five processes occurring,
- 10:39there's certain loss of hepatic
- 10:40current time as well.
- 10:42But the functional derangement
- 10:43that occurs in this setting.
- 10:46Is far more than the quantitative
- 10:49loss of hepatic parenchyma.
- 10:51And why is that so?
- 10:53If one looks at a cirrhotic liver,
- 10:56the cross is shown here.
- 10:57It's a diffuse process, but.
- 11:00If you look at the amount of hepatic
- 11:01parent comma, there is still present.
- 11:04It is substantial.
- 11:05In fact,
- 11:05most of us know that you need only
- 11:07about 20% of the liver to sustain life.
- 11:11But once you develop cirrhosis,
- 11:13actually the functional derangements
- 11:15are much more severe and far
- 11:20more than what just the loss
- 11:22of parent comma can explain.
- 11:24And what is happening is that
- 11:26once this fibrosis is developing
- 11:27and one can see installing,
- 11:29these are the regenerative nodules of
- 11:31hepatocytes in a static current level
- 11:33which are separated by this receptor.
- 11:37So blood supply and blood flow changes,
- 11:40and as you can see here in this area,
- 11:42the blood flow which was taking place from
- 11:45the pole tracks towards the central way.
- 11:47Actually because of this fibrosis
- 11:49and formation 5 receptor is
- 11:52all diverted in the septum.
- 11:53Where most of the blood bypasses,
- 11:56the hepatic burn came out the lobby and
- 11:59now goes directly into the venous system,
- 12:03and this change in hemodynamics has severe.
- 12:10Impact on the function of the liver.
- 12:13This is shown here in three dimensions,
- 12:15where each of the cirrhotic nodules now
- 12:18has this vascular shunting of blood which
- 12:22is bypassing most of the nodule and going
- 12:25to the periphery and through this fibrous
- 12:28SEPTA into the hepatic venous system.
- 12:31So this functional aspect of the liver is
- 12:33difficult to assess on our routine Histology.
- 12:36What we assess is the fibrosis.
- 12:39And fibrosis in some sense,
- 12:42is the surrogate mass surrogate measure
- 12:44of this functional derangement that
- 12:46is occurring in the liver because of
- 12:48all the chronic disease progression.
- 12:51And this has been shown where back that
- 12:53as the fibrosis in liver increases,
- 12:56the portal pressures increase and the liver.
- 13:01Goes progressively from nofi process.
- 13:04Too early fibrosis and sources.
- 13:08Uhm, this was also shown that as you know,
- 13:12the fibrosis increase in the liver.
- 13:15There is increased in wedged hepatic
- 13:17venous pressure which is indirect measure
- 13:19of the portal. Pressure and and the.
- 13:24This has been shown by many other workers.
- 13:27That portal pressures are critical
- 13:29in predicting the prognosis.
- 13:31Oliver, so that's why the fibrosis
- 13:35in liver is very critical and for
- 13:38virtually all chronic liver diseases.
- 13:40This is probably the most
- 13:43important prognostic parameter
- 13:44is irrespective etiology.
- 13:45Certainly it is very important
- 13:47for viral not only hepatitis B
- 13:49repeat DSS and metabolic diseases,
- 13:51including Nash or alcoholic liver disease,
- 13:53but even for vascular disorders.
- 13:55We're made,
- 13:56I'm sure portal hypertension
- 13:58even without five process once
- 14:00fibrosis sets in the disease
- 14:02progresses even more rapidly.
- 14:05And as I explained.
- 14:07Development of fibrosis or this car
- 14:10certainly represents loss of hepatic friend,
- 14:14comma or functional reserve of the liver.
- 14:17But impact is far more because of
- 14:20the vascular shunting and hemodynamic
- 14:23alterations that are taking place.
- 14:25And this is sort of depicted in the
- 14:28various staging system that were developed
- 14:30for assessing fibrosis in liver.
- 14:33This is for chronic hepatitis,
- 14:36where as I mentioned earlier the fibrosis
- 14:38starts from pole tracks extending
- 14:40into periportal hepatic parenchyma.
- 14:42And then forming bridges and finally
- 14:45cirrhosis as this fibrosis progressing,
- 14:47the portal pressures are also increasing
- 14:50and at certain stage of the stage
- 14:53three late stage three or stage four
- 14:57you develop portal hypertension.
- 14:59Now this pattern of fibrosis.
- 15:00This is depicted here for chronic
- 15:03hepatitis varies from disease to disease.
- 15:05For example,
- 15:06if we talk about Billy disorders like
- 15:08primary skills in college, ID's or.
- 15:12Primary period cholangitis So if I
- 15:16process starts predominantly from the
- 15:17portal tracks and then forms portal portal,
- 15:20bridging scepter and progresses to
- 15:22cirrhosis whereas in Nash or or
- 15:25alcoholic liver disease the fibrosis
- 15:27tends to prefer the precentral regions
- 15:30in the early stages and that's why.
- 15:35You know many different staging system
- 15:37for this fibrosis have been developed
- 15:40which are more disease specific.
- 15:42There are many staging systems available
- 15:44for chronic hepatitis that are listed here.
- 15:47Similarly, they are staging
- 15:49systems for beauty diseases.
- 15:51For non alcoholic steatohepatitis.
- 15:53And even for alcoholic disease,
- 15:55which many people are not familiar
- 15:58with because the staging system was
- 16:00never used in clinical practice.
- 16:01But there is a staging system or
- 16:03even for alcoholic liver disease,
- 16:05and there are staging systems
- 16:07that have been recently proposed,
- 16:08forgiven congestive hepatopathy,
- 16:10and all these staging systems take
- 16:12various nuances of the specific disease
- 16:15entity and how the fibrosis progresses
- 16:18in this disease entity to account
- 16:22for the differences among themselves.
- 16:24So. Uhm?
- 16:28What this does is that now we have multiple
- 16:31different systems for assessing fibrosis,
- 16:33even from the same disorders.
- 16:35And if one looks at many
- 16:38of these staging systems,
- 16:39it is very clear that.
- 16:44While the advanced stages of all
- 16:46the systems are fairly similar,
- 16:48there are more nuances and differences in the
- 16:51earlier stages of the particular disease.
- 16:54But the practical problem remains that
- 16:56when you have multiple different systems
- 16:58to use in a clinical practice or trials,
- 17:00it becomes very difficult to compare
- 17:04reports from different places or compare
- 17:07different studies or compare clinical
- 17:10trials where people might have different
- 17:13staging systems in that particular study so.
- 17:17And while we are talking about this one,
- 17:19it was very clear that actually having
- 17:22a universal system for fibrosis in
- 17:24liver would be very, very useful.
- 17:28And we started the this work in one
- 17:31of our residents. Gabriel Lerner.
- 17:37Took on this project and I like his
- 17:39smile on the photograph here and
- 17:42this study was aimed at designing a.
- 17:47Fibrosing staging system taking key features
- 17:50from all the systems that are available.
- 17:53To make it applicable to any disease,
- 17:56irrespective etiology.
- 17:59And this is an ongoing project,
- 18:01and in this study actually we had
- 18:05one universal system which was the
- 18:08earlier draft of this staging system,
- 18:10and we applied this to many
- 18:14different disorders.
- 18:15We had the 10 cases of each.
- 18:18That is a B&C auto mean.
- 18:21Hepatitis primary schools,
- 18:23colleges, PVC,
- 18:24congestive hepatopathy,
- 18:25Nash and some cases with two two
- 18:30disorders at the same time and
- 18:32then stage these using the disease
- 18:36specific staging system and then
- 18:38using our proposed universal fibrosis
- 18:40scoring system and found that they
- 18:43function or or work almost in
- 18:46identical fashion in the initial.
- 18:48Analysis we did.
- 18:49We found only two cases where the
- 18:52staging systems gave a slightly
- 18:54different result,
- 18:54but when we looked at those
- 18:56cases more carefully,
- 18:57we realize that actually there was
- 18:59problem in our initial analysis and
- 19:01eventually there was no difference
- 19:03between how they were staged by the
- 19:06disease specific system and using our
- 19:08universal fibrosis scoring system.
- 19:10However,
- 19:11this is still a work in progress
- 19:13and we are still working with many
- 19:16different things on this project.
- 19:18And and the hopefully this will result
- 19:21in a manuscript soon and this is the
- 19:24sort of current draft that we have.
- 19:26We're hoping that this system will not
- 19:29only allow to develop an universal system,
- 19:31which is which can be used
- 19:33for a variety of disorders,
- 19:34but we'll also add certain additional
- 19:38features which will further enhance the
- 19:41staging of fibrosis in certain areas,
- 19:44particularly stage three and four,
- 19:46where subclassification of these stages can.
- 19:49Uhm,
- 19:49you know be clinically helpful
- 19:51and also get rid of some of the
- 19:53practical issues that we have in
- 19:55our routine clinical practice.
- 20:00However. When we look at this whole
- 20:04progression of fibrosis in liver,
- 20:06as I mentioned earlier,
- 20:08that increasing fibrosis in chronic
- 20:11liver disorders of various etiologies
- 20:14eventually leads to cirrhosis and cirrhosis.
- 20:18As all of you know,
- 20:20has been considered as the end stage
- 20:23liver disease for many decades,
- 20:26and it was thought that once you
- 20:28develop cirrhosis, that's it,
- 20:29and there is nothing else that can be done.
- 20:32And and the.
- 20:34There was no further sort of a disease
- 20:38severity classification understanding of.
- 20:41Process within this whole process.
- 20:45However, with time,
- 20:46the concept that cirrhosis may
- 20:48not be just one end stage disease
- 20:51started evolving and in this field.
- 20:56Doctor Lupe Garcia saw who
- 20:58is a very eminent liver,
- 21:01hepatologist at Yale,
- 21:03has been a pioneer who has really
- 21:06worked in this area and came up
- 21:09with this idea many years ago
- 21:11to me when I was a very junior
- 21:13and young faculty that you know.
- 21:18We understand that the clinical
- 21:20outcome of patients who have
- 21:22cirrhosis are very variable,
- 21:24not only between different technologies,
- 21:26but within the same ideology,
- 21:27so there must be different features
- 21:30within the CD cirrhosis which define
- 21:33something called mild and severe cirrhosis,
- 21:36and her idea was if there are clinical
- 21:40parameters which help us differentiate
- 21:42between mild and severe process,
- 21:43there must be logic features that can also
- 21:46help us differentiate between this smile.
- 21:48And see your form of cirrhosis and
- 21:51at that time this whole concept that
- 21:54cirrhosis is reversible was controversial.
- 21:58But with time this has become very
- 22:00clear that fibrosis can trigger
- 22:02reverse and cirrhosis can reverse.
- 22:05So this whole concept of understanding
- 22:08mild and severe variants of cirrhosis
- 22:12was critical and very important.
- 22:15And I have to mention that the
- 22:18loopy Garcia has been a great mentor
- 22:23for me and and the great collaborator
- 22:25and friend, who has been very,
- 22:27very instrumental in many of the
- 22:29studies that I'm going to show you.
- 22:31And and her insight and and her
- 22:33guidance has been invaluable.
- 22:35This work would not have been done
- 22:37without her help and guidance.
- 22:39So when we were talking about how to
- 22:42kind of divide cirrhosis into this mild
- 22:45and severe form and we came up with
- 22:47a variety of this logic features that
- 22:49we could look into and and then we
- 22:52designed this study with one of the.
- 22:55Medical students at that time,
- 22:56Satish Gola,
- 22:57who then went on to become a GI fellow
- 23:01and and now is a a gastroenterologist
- 23:04practicing in Mount Sinai, NY, and.
- 23:08In that study we looked at.
- 23:14Liver biopsy is that had the hepatic
- 23:17venous pressure gradient measurements
- 23:19available and looked at the variety
- 23:23of histologic features that included
- 23:26everything the the presence of inflammation,
- 23:28the presence of degree of
- 23:29status is the presence of iron,
- 23:31the presence of portal tracks,
- 23:32the loss of central veins,
- 23:34and characteristic of nodules.
- 23:36The fiber scepter and try to see which of
- 23:39these correlated with the HPG measurements.
- 23:43Which clinically has been shown to
- 23:46correlate very well with the severity
- 23:48of a liver disease and and then.
- 23:51In this regard,
- 23:52we'll talk a little more later on, but.
- 23:56Off 6 denotes portal hypertension,
- 24:00and it's been shown in studies that.
- 24:03He HPG of 10 is clinically
- 24:07significant portal hypertension,
- 24:08wherein if patients have HPV of 10
- 24:13they have significant worse outcomes
- 24:16and and chances to become so.
- 24:19In this particular study we started various.
- 24:23Use logic features and correlated
- 24:25them with the HPV measurements and
- 24:28after many things that we started,
- 24:30it turned out that. Uhm?
- 24:34So size of the nodules and the
- 24:37width of the scepter had the best
- 24:41correlation with the HPV measurements.
- 24:43In fact,
- 24:44most of the patients who have small
- 24:47nodules in liver biopsies or thick
- 24:50fibrous SEPTA had clinically significant
- 24:53portal hypertension, as shown here.
- 24:56And this is also shown here.
- 24:59And when we did the multivariate
- 25:01analysis of the many things,
- 25:03the nodule size and the septal thickness
- 25:06remain the only independent features
- 25:08that correlated with the clinically
- 25:11significant portal hypertension.
- 25:13So what does this mean and
- 25:14how does this look like?
- 25:15Well, on liver biopsy,
- 25:16this is what it is when you
- 25:18look at the liver biopsies,
- 25:19everybody will recognize.
- 25:21These are small nodules and
- 25:23these are large large nodules.
- 25:25So while this was obvious to us.
- 25:27While doing the study,
- 25:28and this is how we did it when we
- 25:31were trying to publish this paper,
- 25:33the reviewers asked us,
- 25:35you know.
- 25:36What does this mean in terms of
- 25:38actual size of the objects?
- 25:40So this is something we actually.
- 25:44Made rough estimates from and this
- 25:46is in fine print here that small
- 25:48nodules for us meant something which
- 25:50were less than about 1 millimeter
- 25:52in size and large nodules that
- 25:54were more than two millimeter size.
- 25:56And we took the width of needle
- 25:59biopsies which is about 1 millimeter.
- 26:01As a rough guide. And.
- 26:05Same thing for fibrous SEPTA here.
- 26:07Uh, this is a liver biopsy.
- 26:08Very big,
- 26:09very thin 5 receptor is a liver
- 26:11biopsy with very thick pipe receptor.
- 26:14Again based on our rough estimates
- 26:17set that there were less than .1
- 26:20millimeter where in the range of
- 26:22being thin scepter and those that
- 26:24were greater than .2 millimeters
- 26:27where considered acceptable and
- 26:29for the study required presence
- 26:31of more than 2/3 of the liver
- 26:33biopsy to have that feature either.
- 26:35Nodules,
- 26:35or the scepter to be considered
- 26:38predominantly acceptor or
- 26:39predominantly small notes if these
- 26:42were not fulfilled then these were
- 26:44considered mixed or intermediate.
- 26:46So.
- 26:46Why does this thing work out that
- 26:50the when you have small nodules
- 26:52or thick fibrous SEPTA,
- 26:54you have clinically significant
- 26:56portal hypertension and hence?
- 26:59So this is depicted here in a cartoon form.
- 27:02So if you can imagine a liver where you have.
- 27:06Progressive scarring shown by blue here and
- 27:09this brown represents the riscal hepatic
- 27:12comma which is broken up in nodules,
- 27:14which is what happens in cirrhosis.
- 27:17One can imagine that if this is
- 27:19happening in a very uniform way,
- 27:21all the modules will look like this.
- 27:24Shown here in this photograph as small
- 27:28nodules and here as large nodules and
- 27:30one can easily imagine that if all
- 27:33nodules were small or became smaller.
- 27:36The amount of hepatic turntable
- 27:38decrease and the distance between
- 27:40these nodules will also increase,
- 27:41which indirectly means the fibrous
- 27:43SEPTA which will be on the same
- 27:46token if the nodules are large.
- 27:48There's more hepatic parenchyma and
- 27:51less distance between adjacent nodules.
- 27:53However, as we all know,
- 27:55these are cartoons and this is a
- 27:58very schematic representation.
- 27:59In real life it doesn't happen
- 28:00like this in real life.
- 28:02What happens is something like this
- 28:04where the nodules are of variable size.
- 28:06One can have predominance
- 28:07of one particular type,
- 28:08but it's never very uniform and
- 28:10there's a lot of variability in how the
- 28:12scarring occurs in the liver, which.
- 28:15Makes assessment of these things
- 28:18in liver biopsies challenge.
- 28:20So.
- 28:21Based on our study,
- 28:23we had proposed that liver cirrhosis
- 28:25can be classified based on historic
- 28:28features into mild, moderate,
- 28:30severe or so called 484B and C.
- 28:34Based on the four four tiered staging system.
- 28:40Our study was very soon validated by
- 28:43another group from New Delhi or working
- 28:45on patients with chronic hepatitis B,
- 28:48and their results were
- 28:49virtually identical to ours,
- 28:51which was very satisfying to see that.
- 28:54Irrespective of whether to
- 28:56separate his B or C or alcohol,
- 28:58the nodule size and the septal width
- 29:01with predictive of severity of cirrhosis.
- 29:04Based on this study and some
- 29:06other work that I'll show later,
- 29:08we came up with a classification
- 29:11system of cirrhosis.
- 29:13Which is shown here where you
- 29:16could take any of these parameters
- 29:19and based on the presence of the
- 29:22feature you could give a score and
- 29:24then classify this as 484B or 4C
- 29:28and this had clinical correlates
- 29:30with the presence of either.
- 29:33Compensated cirrhosis or decompensate
- 29:35sources as well as portal pressures.
- 29:40Over a month.
- 29:43We realize that the while we're.
- 29:46We published this and this was a good study.
- 29:49Some of this work actually
- 29:51have been done earlier,
- 29:52and this sort of classification
- 29:56of cirrhosis into pile moderate
- 29:59severe was done by Lynette Group.
- 30:02In the year 2000 and and this was
- 30:06published only as an abstract form,
- 30:08so this was not widely recognized and
- 30:12we were certainly not aware of this.
- 30:16And the the principles were virtually
- 30:18similar to what we had come up with.
- 30:21The presence of nodules are the
- 30:23size of the nodules and with the
- 30:26scepter where critical in sort
- 30:28of classifying the cirrhosis.
- 30:30We eventually ended up publishing
- 30:32this a paper in 2006,
- 30:34and we're finding the
- 30:36classification somewhat in 2012.
- 30:38And now at least we have two
- 30:41systems of classifying cirrhosis.
- 30:44The one is the Linux system and and
- 30:46now I'm part of that group as well as
- 30:49well as the system that we developed
- 30:51here with collaboration with the Doctor,
- 30:54Lupe Garcia,
- 30:55and these two systems are shown here,
- 30:57and they're fairly similar in in in
- 30:59how they approach this whole issue.
- 31:01The only thing being that in Linux
- 31:05system the septal thickness was
- 31:07defined as broad when the size.
- 31:09Of the scepter was equivalent to the
- 31:11size of the nodules and very broad when
- 31:13it was greater than the size of nodules,
- 31:15which is a very subjective evaluation,
- 31:18and we know that the size of the
- 31:20nodules can vary within the liver
- 31:22biopsy and between liver biopsy.
- 31:24So to us it looked like there was
- 31:28more subjectivity involved in the
- 31:29Linux system then our system,
- 31:31which was somewhat more semi quantitative
- 31:33and we wanted to see how do these
- 31:36two systems compare and this work.
- 31:39Was undertaken by one of our residents,
- 31:42Maria Olavi or Carolina,
- 31:44who now is a fellow at Mayo Clinic
- 31:48and in this study we looked at.
- 31:51Fifty liver biopsy with thrusters
- 31:55which were randomly selected and these
- 31:57were evaluated independently by three
- 32:00pathologists that included a resident
- 32:02and associate professor and professor,
- 32:04just to see how experienced may
- 32:07affect this evaluation and the what
- 32:10it shows was that both systems
- 32:12were fairly compatible in terms of
- 32:17assigning the stage based on the
- 32:20logic features as stated. Uhm?
- 32:22Our system performs slightly
- 32:25better than the Linux system,
- 32:27largely because I think again some of the
- 32:30features were better defined in our system.
- 32:32But overall I think both systems perform
- 32:35fairly similar in sub classifying services.
- 32:38So in conclusion.
- 32:42We recognize that the the nodule size and
- 32:46the fiber swift are are predictive of HPV,
- 32:50gene liver and small nodularity and
- 32:54increasing fiber scepter with can
- 32:57predict development of clinical
- 33:00significance portal hypertension
- 33:01and based on these parameters can
- 33:04certainly be classified into a mild,
- 33:06moderate and severe stage.
- 33:08So when you're working with
- 33:10these nodules except.
- 33:11Wherever you look, you find those.
- 33:13So if you look at the sky,
- 33:15I could find nodules in the
- 33:16clouds and the scepter there.
- 33:18Or if you look from the sky into the ground,
- 33:20you could find nodules and
- 33:21the SEPTA even in the sand.
- 33:25However. Moving forward,
- 33:28I think the question that we were asking
- 33:30was in this particular study that we did.
- 33:32We correlated the stylistic features with
- 33:35the the hepatic venous pressure gradient,
- 33:38which correlate with prognosis
- 33:40of cirrhosis but.
- 33:42The next question or scandal is
- 33:44a Histology predictor.
- 33:45Prognosis of cirrhosis directly?
- 33:48And this was more or less the kind of
- 33:51question that we wanted to validate
- 33:52based on our initial study and the
- 33:54people who are familiar with the
- 33:56progression of chronic liver disease.
- 33:59Recognize that clinically,
- 34:01cirrhosis is divided into two stages,
- 34:04the compensated cirrhosis
- 34:06or decompensated process,
- 34:07and the reason being that once.
- 34:10You develop decompensation.
- 34:12The prognosis tends to be really
- 34:14bad and the progression of the liver
- 34:17disease or liver failure is rapid,
- 34:19so this was shown in different
- 34:21studies at the median survival
- 34:23of patients who have compensated
- 34:25cirrhosis is in excess of 12 years,
- 34:27whereas those who develop compensation,
- 34:30the median survival becomes around two years,
- 34:32which is a big difference.
- 34:35Uh,
- 34:35this was also shown by studies
- 34:38from here we're doctor Garcia was
- 34:42involved and the the presence of HPVG,
- 34:45which was less than ten,
- 34:47was also the significant negative
- 34:51predictive value that patients who had.
- 34:54No clinically significant
- 34:55portal hypertension,
- 34:56which is pressure measurement less than
- 34:5910 had in 90% chance of not developing
- 35:02clinical decompensation in a Fourier theory.
- 35:05So again signifying the importance
- 35:07of the pressure measurements and
- 35:09how this collects with the clinical
- 35:11spirit of the disease.
- 35:13So the question that we would ask was.
- 35:17Do the sample thickness and or the
- 35:19nodule size predict clinical development
- 35:21of decompensation in patients who
- 35:24have this logically proven cirrhosis?
- 35:26And this was a study that was
- 35:29undertaken with one of the GI Fellows
- 35:31on the clinical side Prithvi Cinema,
- 35:34Son,
- 35:34who is now a practicing
- 35:36gastroenterologist in the Boston
- 35:38area and in this study we looked at.
- 35:43Patients with the biopsy proven
- 35:46cirrhosis and followed them for
- 35:50development of the competition.
- 35:52There were 168 patients included of
- 35:56which 3043 developed decompensation
- 35:58and these biopsies were reviewed
- 36:00blindly without the knowledge
- 36:02of the clinical findings by two
- 36:04independent observers and many
- 36:06different things were assessed.
- 36:08But specifically,
- 36:09the sample thickness and the nodule size.
- 36:13And.
- 36:14The results showed that the septal
- 36:17thickness did predict a progression
- 36:19to decompensation in these patients,
- 36:22as shown here.
- 36:24The acceptor, as opposed to either the.
- 36:28Intermediate or thin SEPTA had a
- 36:31significant association with progression too.
- 36:36Decompensated, cirrhosis,
- 36:36and eventually when we did the
- 36:39analysis using thick persistent except
- 36:42and this became even more obvious.
- 36:45When he looked at the nodule size
- 36:48while the trends were similar,
- 36:50but the findings were not statistically
- 36:53significant and even when we studied
- 36:56the the small versus not small nodules.
- 37:01It was obvious that only after
- 37:0348 months the process started
- 37:06separating between these two groups,
- 37:08and while the reasons are not obvious to
- 37:10us or not very immediately clear to us,
- 37:13it is possible that in early stages,
- 37:15when the nodules is small,
- 37:17but the 5% are also very thin,
- 37:21probably there's no difference based
- 37:22on the nodule size as they sufficient.
- 37:25You know, parent, camel, reserved and and.
- 37:30Does not impact the overall process.
- 37:32However, it certainly validated our
- 37:35previous findings that you know,
- 37:38except on liver biopsies are associated
- 37:41with significantly higher rate of
- 37:43decompensation when compared with
- 37:44patients who do not have the acceptor.
- 37:47And as I mentioned,
- 37:48while this trend was seen with
- 37:49the small nodules,
- 37:50this was certainly not statistically
- 37:53significant in this regard, so.
- 37:55What does this all mean?
- 37:58Well.
- 37:59Well,
- 37:59uh,
- 38:00this certainly has some implications for
- 38:03patients who are being considered for
- 38:05treatment for a variety of disorders,
- 38:07or even transplantation.
- 38:09Some of the important considerations
- 38:11are that once these patients do
- 38:14show thick scepter on liver biopsy,
- 38:18this could allow initiation of non selective.
- 38:22Now even further investigation to
- 38:25prevent or delay the decompensation.
- 38:28Also,
- 38:28we know that these days you know some
- 38:31of the patients with cirrhosis can
- 38:34undergo resection of the liver cancers,
- 38:38and this is a very select group
- 38:40because we recognize that patients
- 38:41who are cirrhotic and develop
- 38:43particular carcinoma are,
- 38:44in general not good candidates for surgery
- 38:47because they tend to decompensate.
- 38:49But a subset of these patients who
- 38:51are probably having poorly or mild
- 38:54sources can undergo this reception,
- 38:56and in this regard.
- 38:59You find fix up down liver biopsy
- 39:01is probably that would be in control
- 39:03application for a search filter
- 39:05section of hypercellular carcinoma
- 39:06in the background of success.
- 39:08So those are the immediate kind of
- 39:11clinical implications that I can think
- 39:13of and I think more will probably come so.
- 39:17This is another view from Sky to
- 39:19show you how we can start seeing
- 39:21nodules and the five perceptor,
- 39:23and now the nodules are even colored.
- 39:26This is a photograph taken from
- 39:28the aircraft somewhere in the
- 39:30region of I think San Francisco.
- 39:35So as I mentioned earlier,
- 39:36this fibrosis which was considered earlier
- 39:41irreversible phenomena now is recognized,
- 39:43is actually dynamic process even
- 39:45within the liver and with effective
- 39:49therapy the fibrosis can progress.
- 39:52And now there are very effective therapies
- 39:56available for viral hepatitis B&C,
- 39:58which were not available or two decades ago,
- 40:01and this has changed the whole field.
- 40:03In trying to assess.
- 40:05How do we say this fibrosis is progressing?
- 40:09Or this is, you know,
- 40:11regressing and all the systems that I
- 40:13showed you earlier in terms of assessing
- 40:16fibrosis stage do not address this
- 40:18system of progression or regression.
- 40:21So, uh, this uh issue we
- 40:24had discussed in one of the.
- 40:27Reviews that we wrote for one of the seminars
- 40:31in particular topology and the Doctor,
- 40:35Garcia and Doctor Peter,
- 40:36producer who's from Europe who have done a
- 40:39lot of work in this area where my Co authors.
- 40:41So this is something which I'll
- 40:43illustrate by example here.
- 40:45So this is a process which is.
- 40:49Very obvious on Histology.
- 40:51These are cirrhotic not justify
- 40:53perceptor are very broad.
- 40:54So from my prior studies one could
- 40:57easily predict that this in this
- 40:59patient the the portal hypertension
- 41:01will be clinically significant.
- 41:02Portal hypertension or the measurement
- 41:04of the HPV will be greater than
- 41:0610 and here you can see a lot of
- 41:08inflammation while the cloud coloration,
- 41:10this fibrous SEPTA.
- 41:12However,
- 41:13once you treat this process and let's
- 41:15say this was something which was chronic
- 41:17hepatitis C which can be treated.
- 41:19A lot of things can happen and
- 41:23this can start looking like this.
- 41:26Where is fiber sector which is broad,
- 41:29can become thinner.
- 41:30The degree of inflammation decreases.
- 41:33The celebrity of this fiber sector decreases.
- 41:36And uh,
- 41:37the vascularity of this separate
- 41:39descriptions there's some restoration
- 41:41of the lobular architecture.
- 41:43There's some restoration of the zonal
- 41:46distribution hepatocytes in this thing.
- 41:49So from this cirrhosis,
- 41:51which is the severe untreated cirrhosis,
- 41:54one can progress to disconnect services,
- 41:57which is still cirrhosis.
- 41:58Still stage four.
- 42:00But it must work improved clinically
- 42:03and functionally.
- 42:04And.
- 42:06These features on progression,
- 42:07which were kind of
- 42:09recognized by many experts.
- 42:11They feel we're eventually
- 42:12put into a staging system,
- 42:14which I'm going to show.
- 42:16This is same thing shown on any sections.
- 42:19Again to illustrate that the cirrhosis
- 42:22which is severe and very active has this
- 42:25broad sector with a lot of inflammation,
- 42:27lot of buckler proliferation and
- 42:29vascular which is not obvious on either
- 42:32HIV sections or try constructions,
- 42:34and our routine Histology,
- 42:35but can be seen by other techniques
- 42:38that these things progress and receptor
- 42:40become like this where they're very thin,
- 42:43relatively acellular,
- 42:44relatively avascular, without any doctor.
- 42:47Information with some restoration
- 42:49of the lower popular architecture.
- 42:52So a group from Beijing, China.
- 42:57Studied the,
- 42:58you know,
- 42:59the features of regression in patients
- 43:02with chronic hepatitis B and in this group.
- 43:07Doctor Neal Tease who is a very eminent
- 43:10liver pathologist and have some yield
- 43:13connection because he worked here at
- 43:16Yale with Diane Kraus on stem cells
- 43:18and is a faculty in New York.
- 43:20Applied this concept of progression
- 43:22of high process to develop a scoring
- 43:24system and in this study they could
- 43:28using many different parameters.
- 43:31They showed that.
- 43:35Treatment of chronic hepatitis results
- 43:37in regression of this fibrous SEPTA.
- 43:40So just looking at this system,
- 43:42you know broadly what it is when you
- 43:45have this progressive fibrosis and they
- 43:47showed with all the features that had
- 43:49mentioned of sale lurdy, vascularity,
- 43:51the inflammation when you have more than
- 43:5350% of the fiber SEPTA in the biopsy,
- 43:56that is considered a predominantly
- 43:59progressive fibrosis or
- 44:01assigned escorpi when. You have.
- 44:05More than 50% sector showing regression
- 44:08features as I showed you earlier is
- 44:12you're considered a score of our.
- 44:14And if this was mix of this,
- 44:16it was considered indeterminate,
- 44:18and this was a highlighted or.
- 44:21This has been sort of referred to
- 44:24as the PIR score in various studies,
- 44:28and this is again illustrated herein
- 44:30from this paper that this is a patient
- 44:34with progressive fibrosis before treatment,
- 44:36which became progressive fibrosis,
- 44:40still cirrhosis but within the stage
- 44:42it has changed his character from.
- 44:44Progressive, too, regressive as shown here.
- 44:50And in this study they had paired
- 44:54biopsies in 71 patients where they
- 44:56looked at the pretreatment and
- 44:58posttreatment Histology and showed that
- 45:01many of these patients converted from
- 45:04Progressive 5 Percepta to regressive,
- 45:07high perceptive and of these
- 45:10more than half of the patient
- 45:12at least had improvement in one
- 45:15stage following treatment and.
- 45:20Almost half of the patients had
- 45:23significant improvement in the
- 45:24substage of cirrhosis fibrosis.
- 45:30So based on this study,
- 45:31the group proposed this PR scoring system,
- 45:35which has now been referred to as
- 45:38the Beijing System for classification
- 45:40of progressive or regressive
- 45:42fibrosis in liver diseases.
- 45:44And it is certainly conceptually
- 45:46very good and recognizes the
- 45:48dynamic nature of fibrosis.
- 45:49And, at least in this study,
- 45:51had shown good reproducibility with good
- 45:55inter and intra observer variation,
- 45:57primarily done on biopsies.
- 45:59And it was felt that since this
- 46:01didn't require any special stain,
- 46:03it was easy to apply and this
- 46:06was subsequently sort of.
- 46:08Bradley did on his very small study
- 46:12of A5 cases of chronic hepatitis C
- 46:17with autoimmune hepatitis where the
- 46:20patients were treated with directly
- 46:23acting antiviral agents and on paired biopsy,
- 46:26is they?
- 46:27Confirm that the progressive sectors
- 46:30can become regressive sectors,
- 46:31so very small.
- 46:33Study validating the findings
- 46:34from this page in classification.
- 46:36We also undertook this kind of a project
- 46:40of assessing the same findings in a
- 46:44subset of chronic hepatitis C patients,
- 46:47and this project was.
- 46:50Done with collaboration with a ROM Shelly,
- 46:53who was our fellow and then became a
- 46:56faculty here and now has disappeared with
- 46:59the dark side in in private practice.
- 47:03However, you know he was a very nice
- 47:05person to work with, a great guy and.
- 47:09This was a great study that we published and.
- 47:14In this study we had addressed many issues,
- 47:19but one of them was assessment of.
- 47:23So called regression of fibrosis in
- 47:25patients with chronic hepatitis C.
- 47:27Once we once they were treated
- 47:29with directly acting antivirals,
- 47:31which leads to.
- 47:35Cure of this viral infection with what's
- 47:38called sustained while response or SVR,
- 47:40where the viral load in purple blood
- 47:43becomes undetectable after the therapy.
- 47:45And this is shown histologically,
- 47:47why should what I showed you earlier from
- 47:49our study that the patients who had fibrosis,
- 47:52which was considered
- 47:54progressive on treatment,
- 47:56could become aggressive with the?
- 48:00Features that I mentioned earlier
- 48:02pending of the fibrous septal lack
- 48:04of cellularity lack of pallor,
- 48:07proliferation and decreasing inflammation.
- 48:09Same things shown in HD sections here.
- 48:13One of the things which we did
- 48:14realize in our study is that while
- 48:16these things sometimes are easier to
- 48:18evaluate on pipes because the amount
- 48:19of tissue that you see is blessed.
- 48:22On dissection specimens with you
- 48:24more to see you always find areas
- 48:27that put these things in.
- 48:29Little bit of question as to whether
- 48:32this really belongs to regressive or
- 48:35progressive or indeterminate category.
- 48:40And in this study,
- 48:42we had many other things that that overall,
- 48:45while we could see there were more,
- 48:48it's sort of progressive subtype
- 48:50patients who had achieved SVR in patients
- 48:53who are treated with antivirals.
- 48:56Overall,
- 48:56the difference between the PR score
- 48:59between untreated patients was not
- 49:01statistically significant and this
- 49:03still remains the same when we combine
- 49:06progressive with indeterminate
- 49:08category and compared.
- 49:09With the, uh, those with regression,
- 49:11and there are quite a few reasons for that.
- 49:14Once one of which I highlighted
- 49:17that the assessing
- 49:19the PR score on resection
- 49:20specimens were not easy,
- 49:22and also that the group that we have
- 49:25included both the explants and liver
- 49:27biopsies and and many of the patients
- 49:30have very severe advanced disease.
- 49:32So there was a selection bias
- 49:33in their patients.
- 49:34However, when we.
- 49:37Looked at a subset of patients
- 49:39where we had paired biopsies
- 49:40and we are only seven of those.
- 49:43It was clear that four of those seven
- 49:46patients did change their characters
- 49:48from progressive or indeterminate.
- 49:502 Progressive on treatment,
- 49:52so this certainly validated what has
- 49:56been shown earlier in the Beijing study
- 49:59and and the other from Mount Sinai in.
- 50:02In this study,
- 50:04we also sort of provided evidence that.
- 50:07Uh. Not only these patients clear
- 50:09the virus from parental blood,
- 50:10but if you look at the tissues
- 50:15by highly sensitive PCR.
- 50:18There is no evidence of residual
- 50:20virus in the tissues and this
- 50:23is an important finding because
- 50:27earlier it was controversial.
- 50:29If there was some degree of risk
- 50:33tool Oracle hepatitis C virus in
- 50:35tissues even after achieving.
- 50:37Clinical cure or so called SVR in
- 50:41this study the the viral PCR was
- 50:43done by using a highly sensitive
- 50:45essay at the CDC and at least we
- 50:48showed that in all the patients that
- 50:50had the clinically achieved SVR,
- 50:52there were no residual virus
- 50:55at the tissue level as well.
- 50:57Our uh,
- 50:58the other things that we also
- 51:01recognize from our study is that
- 51:04the progression of fibrosis may
- 51:06not occur uniformly in all patients
- 51:09and patients who may have very
- 51:11severe disease to start with.
- 51:14Either you may not see any
- 51:15regression or it may take long
- 51:17time and if patients who have.
- 51:20But I just infection for long period
- 51:22time or the ten years of duration.
- 51:24The regression again may not be obvious,
- 51:27or may or may not be seen and in
- 51:30this subgroup of seven patients,
- 51:32those who did not show any
- 51:34change to regressive fibrosis.
- 51:36All of them had hepatitis C infection
- 51:39for more than 1010 years of duration.
- 51:42Also,
- 51:43I think the process is slow
- 51:44and takes a long time,
- 51:46and in this study the the median
- 51:48follow-up was around about two years,
- 51:50so I think you need long term studies
- 51:54to assess what time or duration it
- 51:57takes for this regression to occur.
- 52:00So the other issues with hold
- 52:02this hypothesis is that what
- 52:04I've shown you is is all done on.
- 52:07Qualitative assessment of
- 52:09various features on Histology,
- 52:11and this is highly subjective and
- 52:13there is significant interobserver
- 52:15intraobserver variability.
- 52:16The question is,
- 52:17can we make it more objective and
- 52:19this was shown way back that if
- 52:21you assess just the fibrosis area
- 52:24using digital image analysis,
- 52:26there is a significant correlation
- 52:28with increasing fibrosis with the
- 52:31portal pressures and process and and
- 52:33the IT was also obvious that in in each.
- 52:37Fibrosis group there was still a high
- 52:40variability in the clinical subgroups,
- 52:43which again goes back to some of
- 52:46the issues of fibrosis in liver.
- 52:49So we also try to address this issue
- 52:52using some quantitative parameters with
- 52:54the one of the gastroenterologists
- 52:57from Thailand who was working with
- 53:00Doctor Garcia and now he's a guest role.
- 53:02Is that Alan practicing
- 53:04clinical gastroenterology?
- 53:06And in this study we looked at the
- 53:10fibrosis area by quantitative
- 53:12digital image analysis.
- 53:14The nodule size we counted the
- 53:16number of modules per millimeter
- 53:18of liberal biopsy again.
- 53:19Incorrectly looking at the size of the
- 53:22nodules and beat up the fibrous septum
- 53:24and the while assessing the fibrosis
- 53:26area using digital Amana Umagine,
- 53:29Alesis where you use the
- 53:31color for thresholding which
- 53:33was fairly straightforward.
- 53:35Assessing the nodule size and septal
- 53:38with was problematic and we took
- 53:41multiple measurements in each nodule.
- 53:45And and at the you know, uh,
- 53:47in the various 5 receptor
- 53:49across a liver biopsy,
- 53:51again calculating the mean and median.
- 53:54But as you can see,
- 53:55there are many areas where you could
- 53:58have drawn these measurements and
- 54:00that makes it somewhat challenging.
- 54:03However,
- 54:03as we expected the fibrosis area and
- 54:07the nodule site did have correlation
- 54:09with the HP VG and and the.
- 54:14This correlation was even retained
- 54:16once you even reached a clinically
- 54:19significant portal hypertension.
- 54:21That is,
- 54:22even patients who have clinically
- 54:24significant portal hypertension.
- 54:26If you increase the fibrosis area,
- 54:29the pressures continuously
- 54:30and keep on increasing.
- 54:35So this study kind of validated what we
- 54:38had shown earlier on subjective analysis,
- 54:41but we realized in this study that they were
- 54:44practical issues of measuring the nodule
- 54:46size and fibrous SEPTA, which was not.
- 54:50Ready for clinical use,
- 54:52but certainly validated our,
- 54:53you know earlier findings.
- 54:56This is around year 2009 and 10 I
- 54:59think at that time this technology was
- 55:02still evolving and UPMC had acquired
- 55:05the whole slide scanners and had the
- 55:08people working on various algorithm to
- 55:12assess histologically by automation,
- 55:14and we collaborated with UPMC to
- 55:17look at the same things where.
- 55:20Doctor Ahmed otherwise was our
- 55:23fellow at that time.
- 55:25Pursuing the project and we looked
- 55:27at the many things we looked at the
- 55:30fibrosis area we tried to sort of
- 55:32automate the nodule size and the
- 55:34diameter of nodule using computer algorithms.
- 55:37While it you know proved our prior
- 55:41kind of concepts, again,
- 55:43we recognize that the computer
- 55:45algorithms are not very good in
- 55:48identifying all the fibrosis,
- 55:49and we're missing nodules at times,
- 55:53and the estimation of the nodule size
- 55:56and the diameter was not perfect.
- 55:58And besides those examples,
- 55:59we know that there are many other
- 56:02areas where this is challenging,
- 56:03so this is another liver biopsy
- 56:05which shows many different sizes of.
- 56:07Modules and very different kind of SEPTA.
- 56:10And many times these things can
- 56:12be even more challenging where you
- 56:14have delicate fibrous SEPTA,
- 56:16and not just which are composed for
- 56:19virtually all only few hepatocytes.
- 56:21In addition to this,
- 56:23we recognize that the the significance
- 56:26of very central or sinusoidal file
- 56:29process is far more functionally than
- 56:31what it appears quantitatively and
- 56:34this is not captured by many of the
- 56:36other quantitative image analysis so.
- 56:41There are many challenges that prevent
- 56:43us from applying some of these things
- 56:46that we have learned from our liver
- 56:49biopsy analysis into automation.
- 56:51Another feature which is also
- 56:53difficult is that the liver biopsy
- 56:55has many normal 4 tracks that have
- 56:56lot of collagen or branching,
- 56:58or tracks that show fibrosis tissue.
- 57:01That again is easily recognized
- 57:04by Vista pathologist,
- 57:06but the image analysis it has
- 57:09to be done manually.
- 57:11So the issue is that the fibrosis
- 57:13assessment remains subjective and
- 57:15there's a lot of interobserver and
- 57:17interrupts or variability on top
- 57:18of that there is a lot of sampling
- 57:20issues with liver biopsy because
- 57:22liver box represents a very tiny
- 57:24sample of this huge liver and there
- 57:27are issues of both qualitative versus
- 57:30quantitative assessment of high process.
- 57:32So during this time while this is happening,
- 57:35many different noninvasive tests
- 57:37that assess the liberal globally
- 57:39have been developed which.
- 57:41Are gradually replacing and has replaced
- 57:43a blower biopsy in many settings.
- 57:46These tests are based on some
- 57:50psychological markers as well as
- 57:53imaging studies that evaluate liver
- 57:56stiffness and are are are kind of
- 57:59becoming so popular and so useful,
- 58:02and I'm sure that at some time
- 58:04they will completely replace you.
- 58:06Know,
- 58:06fibrosis and liver biopsies that
- 58:09people suspect that liver biopsy.
- 58:11May become extent and and the.
- 58:14Well, this may not happen exactly like this,
- 58:17but the people have seen a decline in liver
- 58:20biopsy is in in many different settings
- 58:23and in certain parts of the world where
- 58:26there is certainly a decline in the,
- 58:29you know liver biopsy now.
- 58:31So what one can do to liver biopsy to make
- 58:36it more informative so that you know we.
- 58:40Still do liver biopsy and
- 58:43get more information.
- 58:44That is not easily available
- 58:45from other weeds,
- 58:46so I know that I'm close to time,
- 58:48so I'll just quickly go over this thing and.
- 58:52Talk briefly about the
- 58:54the uh advanced Histology,
- 58:56which is something that Rick
- 58:58Torres has developed and he has
- 59:00already given a grand round,
- 59:02so I'm not going to kind of go over
- 59:04all the things that he has done,
- 59:06but what he has done is he has
- 59:09applied clearing of tissues and using
- 59:14multiphoton microscopy generated.
- 59:16Computer algorithms that can convert
- 59:19images acquired by multiphoton microscopy
- 59:22into equivalence mathematically,
- 59:24and this produces beautiful
- 59:27images that can be put on servers
- 59:30that can be accessed remotely.
- 59:32You can see these images have high
- 59:35quality of tissue Histology with
- 59:37great details and you can look at many
- 59:41multiple different levels you can use.
- 59:44Second,
- 59:44harmonic generation to look at the collagen,
- 59:46which is very important to assessment
- 59:48of fibrosis in liver as they showed.
- 59:50And you can look at these tissues
- 59:52in three dimension,
- 59:53which adds a certain level of
- 59:57advanced Histology which is not
- 59:59available with our routine methods.
- 01:00:02You can color this.
- 01:00:04Uhm?
- 01:00:06Find links in any color that you
- 01:00:08would like and to resemble any stain,
- 01:00:10and we also have started working on
- 01:00:13this using liberty and this work
- 01:00:15was done with all of you portal
- 01:00:18who was our fellow and in this
- 01:00:20study we just tried to look at you
- 01:00:22know how does the Histology done
- 01:00:24by this advanced Histology look or
- 01:00:27compared to traditional astrology,
- 01:00:29and our findings were that they
- 01:00:31look very good without any artifacts
- 01:00:33and the diagnosis can be made of.
- 01:00:36Significance of in one of the cases
- 01:00:38where you could study the levels,
- 01:00:40the fibrosis stage changed from
- 01:00:422 to cirrhosis.
- 01:00:43Based on this advanced three
- 01:00:46dimensional or multiple levels.
- 01:00:48Histology compared to the two
- 01:00:50dimensional strategy with two.
- 01:00:51So on top of this,
- 01:00:54if we don't add what is going on with
- 01:00:56the analysis of tissues by either
- 01:00:59mass spectrometry or ramen spectrometry,
- 01:01:02I think one can look at the chemical
- 01:01:05composition of various tissues
- 01:01:06that are either a batter sites or
- 01:01:09other components that goes beyond
- 01:01:12just DNA and RNA evaluation.
- 01:01:14This allows for quantitative
- 01:01:17analysis of various things,
- 01:01:19including lipids, proteins, metals.
- 01:01:21Nucleic acids at the very tissue level,
- 01:01:25which can be identified using
- 01:01:27probes or on two dimensional slides,
- 01:01:29will allows for insight to localization
- 01:01:31of those chemicals within tissues
- 01:01:34to the extent that is now almost
- 01:01:36at the cellular level,
- 01:01:38and I see the application of
- 01:01:41this technology
- 01:01:42in routine Histology.
- 01:01:44Advancing our knowledge in
- 01:01:46each area we are working with
- 01:01:48this company site to various.
- 01:01:50Sort of apply this technology
- 01:01:52to liver biopsies.
- 01:01:54They're already working on breast cancer.
- 01:01:56In our department,
- 01:01:58our work has been slightly delayed
- 01:02:01due to the COVID situation,
- 01:02:02but I'm very excited by
- 01:02:04collaboration with this company.
- 01:02:06Looking at, you know these new
- 01:02:09technologies in liver biopsies,
- 01:02:10so if you missed some of the
- 01:02:12things that I say that if you need
- 01:02:14more details we have addressed
- 01:02:15this in one of the reviews that
- 01:02:17we just recently published, so.
- 01:02:19Justin, in summary,
- 01:02:20I think Universal fibrosis system
- 01:02:22for assessing fibrosis and liver
- 01:02:24disease is desperately needed
- 01:02:26and it will be very useful when
- 01:02:29we can validate this system.
- 01:02:31I've shown you the subclassification
- 01:02:33cirrhosis.
- 01:02:33How it can be done and hopefully
- 01:02:36with advances in related fields.
- 01:02:39This will find more place in
- 01:02:42routine clinical practice.
- 01:02:44The evaluation of regression
- 01:02:46and progression of fibrosis.
- 01:02:48It is in a novel concept and it
- 01:02:51certainly requires some refinement
- 01:02:52before it can be used in practice,
- 01:02:55but this is almost there and I've
- 01:02:58shown you some quantitative image
- 01:03:00analysis that can be applied and
- 01:03:03with the availability of artificial
- 01:03:05intelligence and machine learning,
- 01:03:08this conservative advance our
- 01:03:10understanding and clinical
- 01:03:12use of liver biopsy.
- 01:03:15And the most exciting part of this is
- 01:03:17application of molecular pathology or
- 01:03:18chemistry at the tissue level or cell level,
- 01:03:21which is tremendous potential
- 01:03:22not only in the cancer field,
- 01:03:24but inflammatory,
- 01:03:25metabolic and infectious
- 01:03:26disorders of the liver.
- 01:03:28So with that,
- 01:03:29thank you very much for attention.
- 01:03:31I know I went a few minutes overtime,
- 01:03:33but I'll be happy to take any
- 01:03:36questions if there are any.
- 01:03:38Thank you,
- 01:03:39Dan Pat, thank you for that amazing tour and
- 01:03:43thank you for sharing this body of work.
- 01:03:46That's very deep in fighting in
- 01:03:49liver fibrosis and especially
- 01:03:51exciting technologies.
- 01:03:52At the end I I'll start.
- 01:03:55I think we can, you know take 5
- 01:03:57minutes for questions and I bet.
- 01:03:59There's a lot more than that.
- 01:04:00Well, I'll just start while
- 01:04:02people are collecting their their
- 01:04:04thoughts back to the size of the
- 01:04:06nodules in the fiber septien,
- 01:04:08a diagnostic liver biopsy.
- 01:04:11What are your thoughts as
- 01:04:12to when, if, or should this kind of
- 01:04:17information be provided in a biopsy report?
- 01:04:22I think this is a great question,
- 01:04:24and while the systems that
- 01:04:27I mentioned have been now,
- 01:04:29you know literature for many years.
- 01:04:33As you know, in clinical practice
- 01:04:35we really don't sign out for ABC,
- 01:04:38and I think this is largely due to the
- 01:04:41fact that in clinical practice the
- 01:04:43implications of that are still limited.
- 01:04:45But the areas where this is going to get
- 01:04:49important and the areas where it will find a.
- 01:04:52You know application is when
- 01:04:54treatment decisions are based on
- 01:04:56presence of early versus capacitors.
- 01:04:59For example hepatitis C right
- 01:05:01now everybody with cirrhosis
- 01:05:02gets treated with antiviral drugs
- 01:05:04because they're highly effective,
- 01:05:06but if one realizes that it's
- 01:05:08not beneficial in people who
- 01:05:10already have very advanced stage,
- 01:05:11whether you should treat them or you
- 01:05:13should take them straight to transplant
- 01:05:15all those issues will come up.
- 01:05:17Because as we saw in our study,
- 01:05:18when their patients with hepatitis C
- 01:05:20are very advanced, the regression.
- 01:05:22Is very little or minimal as
- 01:05:25I mentioned earlier,
- 01:05:27even patients who have
- 01:05:28hepatocellular carcinoma,
- 01:05:29for example the selection of patients
- 01:05:32based on early versus advanced cirrhosis,
- 01:05:35could be critical.
- 01:05:36And we don't do it right now.
- 01:05:37But I have tried this indirectly
- 01:05:40on some patients and I think
- 01:05:42that system does work.
- 01:05:44OK,
- 01:05:45well we'll wait for your cue.
- 01:05:48There's there's a couple
- 01:05:49of comments in the chat.
- 01:05:51Doctor Boyer is saying the
- 01:05:53reversibility of fibrosis depends
- 01:05:55to a certain extent on the degree
- 01:05:58of crosslinking of collagen.
- 01:05:59Is there any way to assess
- 01:06:01this histologically and how we
- 01:06:03all get to your question next?
- 01:06:06Sure, I think that's a great question.
- 01:06:07I think one of the things that people
- 01:06:11talk about the irreversible fibrosis is
- 01:06:14based on the fact that the the early
- 01:06:16fibrosis have less crosslinking and the
- 01:06:19advanced fibrosis more cross linking,
- 01:06:21which is probably indirectly
- 01:06:23reflected in our studies.
- 01:06:24As you know, more thick SEPTA, but.
- 01:06:28Truly, the functional assessment or the
- 01:06:31chemical assessment of this fibrosis
- 01:06:33has to be done by other techniques
- 01:06:36you know about histologically,
- 01:06:37people have used darker blue staining
- 01:06:40on trichrome stains as indirect
- 01:06:42measure of cross crosslet collagen,
- 01:06:44but that is a crude method only,
- 01:06:48so when I was showing about the
- 01:06:51chemical molecular pathology,
- 01:06:52I think these are some of the
- 01:06:55things that one can certainly
- 01:06:57assess to understand the you know.
- 01:06:59The whole nature of process.
- 01:07:03In the interest of time,
- 01:07:04I'll read how we use question patients
- 01:07:08with a paddle portal sclerosis.
- 01:07:10Can have bad clinical portal hypertension.
- 01:07:13And Pathologic exam often shows
- 01:07:16nodular regenerative hyperplasia,
- 01:07:17but not that many thick fiber spans.
- 01:07:21If any, how does your model
- 01:07:23tease out this population?
- 01:07:25How does fibrosis regression and then this
- 01:07:27might be a separate or same question?
- 01:07:30How does fibrosis regression correlate with
- 01:07:34HVPG slash clinical portal hypertension?
- 01:07:38And then a third. Also,
- 01:07:39how does it correlate with elastography,
- 01:07:41which is a global assessment so
- 01:07:44NRH in Portola Peppers, chlorosis?
- 01:07:47And then on aisle can repeat
- 01:07:50those questions so you can see it.
- 01:07:52Yeah, so I think that's a great question.
- 01:07:54So first thing conceptually,
- 01:07:56when you're talking about a part of portal
- 01:07:59sclerosis or non static profile process.
- 01:08:01In that setting you have portal
- 01:08:03hypertension even without five process.
- 01:08:05So it's all hemodynamics.
- 01:08:06So in that setting you know certainly
- 01:08:09we cannot apply what I was saying in
- 01:08:11terms of the five receptor or the nodule
- 01:08:13size because you don't see them and
- 01:08:15there's the whole thing about liver that.
- 01:08:18Deliver the hemodynamics is sticky feature
- 01:08:20and inhibited portal closes because
- 01:08:23of variety of things you have already
- 01:08:25deranged hemodynamics that leads to
- 01:08:27clinical significant portal hypertension,
- 01:08:29and the complications, however,
- 01:08:31was mentioning is that.
- 01:08:33In advanced Digital helper to
- 01:08:35portal sclerosis,
- 01:08:35you develop some partial modularity
- 01:08:37and what people call complete
- 01:08:40septic services in that setting.
- 01:08:42How one can apply this system?
- 01:08:44I don't know.
- 01:08:45It'll be an interesting thing to study,
- 01:08:48but it's also clear that once
- 01:08:51you develop fibrosis,
- 01:08:52even in that subgroup of patients,
- 01:08:54your progression is faster.
- 01:08:56So that's about the the the question of.
- 01:08:59You know a application of fibrosis and non
- 01:09:02static portal fibrosis or high particles.
- 01:09:04Closest.
- 01:09:05The other issue is how do these
- 01:09:08things you know?
- 01:09:10Oh behave or or assist on a clinical
- 01:09:12non invasive methods of fibrosis
- 01:09:14and these are the limitations of non
- 01:09:17invasive methods of high process.
- 01:09:19However again this is a whole
- 01:09:23separate discussion.
- 01:09:24In these patients there is evidence,
- 01:09:27support,
- 01:09:27hypertension which you can access
- 01:09:30by many means by other tests and the
- 01:09:33key thing is that both by clinical
- 01:09:36assessment as well as imaging
- 01:09:38assessment they don't have high costs.
- 01:09:40I really don't have fibrosis so this
- 01:09:43is one area where certainly there's
- 01:09:46a discordance between the fibrosis
- 01:09:48stage and clinical presentation
- 01:09:50of portal hypertension,
- 01:09:52but there's also a key towards the diagnosis,
- 01:09:54so I don't know if there are other
- 01:09:57limitations of elastography in the
- 01:09:59setting of idiopathic portal hypertension,
- 01:10:01but maybe Doctor boy or somebody
- 01:10:03else who knows more about this
- 01:10:05than me can answer this question.
- 01:10:08How I don't know if if we
- 01:10:11answered all your questions,
- 01:10:13but any further, how are any others?
- 01:10:15How you want to comment?
- 01:10:16Or are there any other further questions?
- 01:10:21Yes. So I I do see a comment by
- 01:10:24Joe Metric that the MALDI TOF or
- 01:10:27the multi technique can identify
- 01:10:29the crosslinking collagen,
- 01:10:30and that's what exactly I was
- 01:10:32mentioning that these techniques
- 01:10:34of mass spectrometry or or Rahman
- 01:10:37spectrometry will be able to answer
- 01:10:40the question of the actual chemical
- 01:10:42alteration that taking place at that level.
- 01:10:45So thank you Joe,
- 01:10:47I think you know that's
- 01:10:48absolutely right what you say.
- 01:10:52Well Dan pat. I want to
- 01:10:55thank you again for this really
- 01:10:59informative and engaging grand rounds
- 01:11:01and I know there was a very large
- 01:11:04audience and the vast majority of whom
- 01:11:07are hung out to the very end here.
- 01:11:10Thank you again, thank you everybody for
- 01:11:12attending and have a nice afternoon.
- 01:11:15Thank you all. Bye bye.