Liver Fibrosis: Past, Present, and Future

December 06, 2021

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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.