Good evening, everybody. I am Jim Jai, the current president of Florida Society of Pathologists, and today we are very honored and fortunate to have Dr. Murti Krishna as our speaker for our statewide webinar. Dr. Murti Krishna graduated from LLRM Medical College in India, followed by residency in anatomic and clinical pathology at Long Island College Hospital, New York, and the University of Massachusetts Medical Center. Following residency, he did a fellowship in GI pathology at Mayo Clinic, Rochester, Minnesota, and currently Dr. Krishna is the consultant pathologist at Mayo Clinic, Florida, and associate professor in Mayo Clinic College of Medicine and Science. And I have the honor and the pleasure to work with him at a daily base, and Dr. Krishna is my go-to guy in GI, liver, and other things too. And he has very, very solid diagnosis skills. He's very seasoned, but not old. Seasoned, but not old. And one comment about FSP. FSP stands for Florida Society of Pathologists. This is our own organization. FSP has done a great job in advocating our value of pathologist work and try to prevent a fight against any adverse regulations legislated by Tallahassee. So if you are not a member yet, please join us. And last year, we reversed $15 million on the professional part of the CP from the Medicaid. And without further ado, Dr. Krishna. Thank you, Dr. Jai, for that generous introduction. And I want to thank the Florida Society of Pathologists for this invitation to present and for everybody joining in this evening. One of the special thanks to Ms. Amber Nays for making this presentation easier for me, helping me with some of the technical details. But anyway, I'm really happy to be here. I was just, when I accepted the invitation, I put some thought into how I should do this. And given that liver pathology is not a very common type of specimen or pathology that you know, people generally do, it's really a small minority of the specimens. I was wondering how I should do this. And on top of that, I just wanted to make it such that it's interesting and it helps people. And on top of that, 7pm is not really a very ideal time for many people to join a presentation like this, and especially liver pathology. So hopefully, everybody will benefit from this. So my title today, the subject of my talk is just a sort of a broad sweep of liver pathology, focused on patterns, pattern recognition, and the clinical correlations that go with the patterns. So goals of my presentation today, briefly, to understand the various histologic patterns, as I said, and within that context, to recognize more specific changes or specific names given to this, these patterns when applicable, and formulate etiologic differential diagnosis based on histology. And I emphasize the last point very carefully, because after all, the review has to be focused trying to help our clinical providers establish, or our goal should be to guide them to reach an etiologic understanding of the liver problem the patient has. So that's what we would try to do. And I have no conflicts of interest to declare for this presentation. And before I go into the discussion of the patterns, I just wanted to briefly cover the basic histology of the liver, because without understanding the normal, it's more difficult to appreciate the abnormal. So here is a sort of a media magnification of histology of what looks like a relatively normal liver. And turn the laser pointer on here. So highlighting the, or showing the most basic unit of liver, the microscopic anatomy. The liver comprises of about, estimated people say, about 50,000 units called lobules or SNI, depending on which terminology one wants to use. In the older, more traditional understanding and concept of the microscopic anatomy, the, we used to say that there is a central vein. We actually still say that there is a central vein and there is a portal tract. The central vein, as the name implies, is the center of the unit. And the unit is called the lobule. And so the zone closest to the vein here, the central vein, is referred to as central lobula. The zone closest to the portal tract is referred to as the periportal zone, and then the zone in between the mid zone. Now, as understanding evolved, it became more appropriate to call the center of this unit, call this unit an acinus, the most basic unit, an acinus, and the center of the unit, a portal tract, mainly focused on the hepatic arterial supply. So if we use that, we call the zone closest to the portal tract zone one, the mid zone, zone two, and the central lobular zone, as it relates to the central vein, zone three. So this is the more current terminology. There's nothing wrong with using the older terminology as long as one is able to evaluate and convey the information that we histologically interpret. You see here there's another portal tract. Just a word of caution that portal tracts can sometimes be sectioned longitudinally, and so this should not be interpreted as a band of fibrosis. I think that the best way to look at this one is to make sure that the structures within this tract are also showing a longitudinal or linear profile so that it really confirms that it's been longitudinally sectioned. Just a close-up of a portal tract. This is a small portal tract. There is a bile duct, a single bile duct. Not too far from that, very close to that, is the hepatic arteriole. They generally exist together. So if we want to locate the bile duct, and if it's possible, one would try to locate the arteriole and then look for the bile duct somewhere close to it, particularly in portal tracts that are inflamed. So the portal vein here is larger. The stroma of the portal tract has collagen, a few inflammatory cells. Importantly, there is a zone of periportal hepatocytes that is a continuous zone, and it is called the limiting plate, so the limiting plate of hepatocytes. It's very important in evaluating liver biopsies, and damage or inflammation-related injury to this particular zone usually precedes the process of fibrogenesis arising and extending from the portal tract. Also, as you see here on the left side, is a couple of arrowheads that point to bile ductules. These should be very rare, very few under normal conditions, normal histology. These are the smaller duct structures that communicate bile from the canals of herring to the bile ducts. That's how the bile drains out. So that's the sort of the basic histology. And just a little bit about how one can approach evaluation of a liver biopsy. So, and I think generally speaking in pathology, there are two approaches. One is to look at a biopsy first blindly. So you pick up a slide and you put it under the microscope and see what pattern or what type of injury or what combination of changes are there at first glance, and then sort of take it from there and read further into the other details. The other approach is starting from the point of knowing the clinical information. So one would do the review of the medical record, including clinical notes, lab results, imaging studies. And then in that context, with that understanding and knowledge, look at a slide and see whether the histology fits with the clinical picture. Either way is fine. I generally like to look at the biopsy first blind, and then look at the notes and try to then review and modulate my thoughts on the changes to come to a conclusion. With either way, the interpretation that we render should always reconcile the morphology and the clinical information together. So that combination of histology and information from the patient's medical record should be the way one gives a final conclusion on the biopsy. And then, so what is an adequate liver biopsy? It really depends on what one is looking for, the clinical context. Generally speaking, about 2 centimeters, 10 to 15 tracts. So for example, a biopsy that is done to evaluate for like fibrosis stage or grade or whether there is ductopenia or not, loss of ducts, that probably needs more portal tracts. And a biopsy that is post-transplant, rule out rejection, really does not need that many tracts. But a word of caution, a core biopsy is generally better to evaluate liver pathology, especially when one is looking for a diffuse process like grading and staging of hepatitis. A wedge biopsy may sometimes be obtained by the surgeon for whatever reason. They have access to the abdomen. They see some abnormality in the liver, or for example, fairly common to obtain a liver biopsy at the time of cholecystectomy or a procedure that is laparoscopic, otherwise for something else. Wedge biopsy is not that great because the biopsy can often have nonspecific changes under the capsule, particularly fibrosis. So a core biopsy is always better. Also, nowadays, we get biopsies obtained with ultrasound guidance. Really, that's not the primary reason for them for doing endoscopy. They are there to do something else, US of the pancreas, or look at the stomach, upper endoscopy, and obtain a liver biopsy. And that can often be actually pretty generous, but my experience is that it's quite fragmented, and so really not the best specimen. So some basic questions. My first couple of slides are a little bit wordy, and I promise I have many pictures to show, so it's coming up. So important things to keep in mind. What is the reason for the biopsy? So is it basically looking for abnormal LFTs? Very importantly, the clinical colleagues are generally more aggressive obtaining a liver biopsy when they think that there could be a clinical condition that can be managed. And for example, the patient may have, you know, they're looking at the possibility of autoimmune hepatitis, and that can be treated and the disease managed. Or quite often, they actually already know what the disease process is, or they have a very good idea. They have a confirmation with the biopsy, and they are looking for the activity. How much ongoing damage is there? And one thing to note is that nowadays, a lot of the biopsies are done for staging. Because actually, they often have a pretty good understanding of what the patient has. So the patient may have had an ultrasound, it shows fatty liver, and the patient has a metabolic syndrome, and so on and so forth. So they have a pretty good idea. They're trying to determine the stage. And sometimes the biopsy is a follow-up for a condition like autoimmune hepatitis when they want to know whether the patient has responded appropriately to treatment. So clinical context, as I mentioned earlier, is very important. And for pathologists who also look at allograft biopsies, the clinical context may be different, the questions may be simple, but very often in the allograft setting, one could have a combination of things. One could have a biliary obstruction, one could have a rejection with it, and a recurrence of hepatitis, etc. And if an allograft biopsy is obtained, particularly in a clinical setting when there is a concern for rejection that's difficult to treat or very aggressive, there may be a need for ruling out an antibody-mediated rejection. And in that context, obtaining a piece of liver tissue and freezing it to perform immunofluorescence for C4D becomes very important. So getting back to the overall theme, I have identified multiple patterns here that I'm going to go through, mostly with pictures, and see how I can walk through the process of recognizing patterns and correlating with clinical etiologic associations. So the first pattern is hepatitis. It's very common. And the hepatitis pattern can be, as we all know, mixed portal and lobular, that's very common, or portal or mostly lobular. So most of the time it's mixed, maybe heavy on the portal tracts or heavier in the lobules, but generally the inflammation is in both areas. There may be associated findings, as we know. For example, there may be a background of fatty liver. And then in that context, one has to sort of try to understand whether the primary process is fatty liver disease or hepatitis, or there are two different things going on, because fatty liver disease can exist as a background finding very often. It's fairly common nowadays. Or more specific findings, such as in an immunocompromised patient, CMV infection, or in a patient who has a hepatitis, it could be a mixture of primary biliary cholangitis and autoimmune hepatitis. So those are things that come to mind, but there can be associated findings. So hepatitis can exist by itself, but there can be things that go with it that may be related or not related. The second pattern is biliary. I'll discuss that, show some slides. And the biliary pattern includes ductal disturbances, proliferation, duct loss, and more specific biliary diseases. Another pattern is necrosis, common causes, drugs, ischemia. And then there is a category of vascular abnormalities and related liver changes that I will also discuss. And the regenerative pattern is something that we often see. It's really not, most of the time, it's not very specific. It basically indicates a disturbance of the liver, whether it's in association with inflammation or purely. What I'm referring to is a mostly regenerative pattern, past inflammation, past injury, in which setting the liver has regenerated or recovered from that particular injury. But there is at least one specific entity that I will go through. Then lastly, steatosis and steator hepatitis. That is a relatively common histology. I will spend perhaps a little bit of time in that, but not too much. So as I said, is there a predominant pattern or a mixed pattern? So that's very important to recognize or at least raise that possibility in the diagnosis or description or as a comment. So the hepatitis pattern is really defined as the presence of inflammation and or hepatocellular injury. And hepatocellular injury is most commonly seen as ballooning or hydrophobic change of the hepatocytes. The cytoplasm becomes rarefied, accumulation of fluid, and also necrosis. So these two things often exist with inflammation, but there can be very minimal inflammation. One may sometimes see just ballooning and either individual hepatocyte necrosis or what we call spotty necrosis, a clump or cluster of hepatocytes. And as I mentioned, other findings can be seen with a hepatitis. Inflammation or a hepatitis, quote unquote, hepatitis pattern can be, I guess, seen fairly commonly, and inflammation by itself can be seen in multiple settings or with multiple causes as well. So the degree of injury in a hepatitis is expressed as grade, and the degree of scarring which results as a result of this injury is expressed as stage. The grading and staging was originally designed in the setting of chronic hepatitis, so that's the most relevant setting for which the grade and stage is used, but it can be used otherwise as well, as long as it's used as a communication tool with the provider so that the clinicians can understand. So hepatitis patterns have various causes, infection, drug, immune reaction. So autoimmune hepatitis, you know, I mentioned, alluded to before. Alloimmune hepatitis is seen in the transplant setting. It's sort of not a well-defined entity, but sometimes in post-transplant liver biopsies, there is really no clear-cut etiology, but there is a hepatitis. Usually it's a mild hepatitis. So alloimmune means basically an immune reaction towards the allograft. And as I mentioned, I sort of seem to be repeating this hepatitis as a concurrent process with something else. A common example would be a fatty liver with hepatitis that is disproportionately, the inflammatory process is disproportionately more than the extent of stereohepatitis that one would expect. So here is an example, so getting to some pictures here. Here is an example, a good example of portal and lobular hepatitis. So one can see a fairly dense inflammatory infiltrate in the portal tract that is actually extending out beyond the confines of the portal tract. And then in addition to that, we see very brisk inflammation within the lobule. Here's a central vein, just for reference, or the terminal hepatic venule. And the terms acute and chronic hepatitis is used clinically. And the question is whether we should use those terms histologically as well in pathology reporting. And really it's very difficult to tell in many cases. The only way one can, so chronic hepatitis clinically is defined as a disease process or abnormalities in liver tests that actually exceed six months. So the liver problem exists for at least six months or so. In other words, chronic actually indicates a long-term process or that has been there for a while. The only way we can tell that a process has been chronic is by observing the presence of fibrosis. Now, the presence of fibrosis doesn't necessarily indicate it's been more than six months or even longer, but what it tells is that the process of injury has been there for a while. So I am very careful and very selective when I use the word chronic. And I use that only in cases where there is convincing clinical evidence, which basically is clinical evidence, clinically chronic, or I can document with a trichrome state that there is a well-established process of fibrosis. Acute hepatitis is, again, a clinical terminology. I try not to use that terminology. One can say portaled lobular hepatitis and leave it as such. I don't think the clinicians would make a big deal out of that. The important thing they would be looking for is whether there is any evidence of chronicity. And therefore, they would want to have a trichrome stain done and reported on the case. If there is no fibrosis, they're pretty happy, which means that if the disease has been there for a while, it hasn't led to a high-stage process. And how much description should we include in the report? It depends. One can describe as much as one wants. It is encouraged, particularly for trainees, and it is also encouraged when one wants to communicate some finer information to the providers. But one thing we all should do is to make sure that the conclusion or the bottom line is clearly indicated. Whether it's a more specific diagnosis or not, sometimes I think a lot of the clinical colleagues don't read the report that much in detail. I've covered this. For instance, histologically, here is a higher magnification that shows a mixture of lobular hepatitis and periportal hepatitis. This is an interface region, and I would not be able to tell whether this was an acute process or a chronic process. If I had good evidence that there is fibrosis, then I would be able to perhaps say that. On the other hand, this is a well-established chronic hepatitis, evidenced, of course, by inflammation, but in addition to that, there is bridging fibrosis. A little more specific, we hardly see this now, but this is an example of hepatitis C and a more specific, not entirely specific, but a very strong correlation with chronic hepatitis C. One could mention that, but it would also be appropriate to actually confirm the presence of fibrosis with a trichrome stain. Hepatitis C generally tends to, in the chronic phase, form this lymphoid nodules in the portal tract. Another more specific example here of hepatitis is the autoimmune hepatitis. Excuse me. So, the autoimmune hepatitis has some characteristic features, at least a majority of autoimmune hepatitis cases. So, this is a fairly inflamed portal tract with some interface hepatitis here, and the important thing to note here on higher magnification is the presence of plasma cells. So, there are numerous plasma cells. Here is another example, sort of a medium magnification. There is fairly dense portal and lobular inflammation here as well. So, a good example of autoimmune hepatitis. Autoimmune hepatitis can also be acute. It is essentially a diagnosis of exclusion and generally presents with a lot of lobular inflammation, not much portal inflammation, but there's a picture of very active hepatitis without fibrosis and with necrosis as well. So, here is an example of the trichrome stain. In that particular case, the slide that I just showed, you can see that the trichrome stain does not show any fibrosis even in areas of necrosis. For comparison, this is a portal tract which has the darker staining, blue staining collagen as a native collagen as an internal control. So, very interesting, more recent scenario here, checkpoint inhibitor hepatitis, a little more specific in terms of the etiology, but again, the histologic changes are not really specific. So, it is well established that checkpoint inhibitor therapy can cause hepatitis, liver injury. I think it was initially recognized and even now recognized to be more severe with anti-CTL A4 treatment, a little less severe in cases of anti-PDL1 or PD1. But in a more aggressive case, there is a lot of inflammation, central lobular necrosis, which seems like, according to literature at least, is not relatively less in cases that are PD or anti-PD or anti-PDL1. But this is also data in evolution, and I think we'll probably have a clearer idea. So, many of these patients, some of these patients may be on other medications as well, so it gets a little blur. Very briefly, this is not, I'm not here to discuss in detail this grading and staging. There have been multiple systems that have been used historically, and we can see here that there, the main recognized, or the majority of the grading schemes came about in the last in the last 30, 40 years. And initially, we used to have this entity, two entities called chronic persistent hepatitis and chronic active hepatitis. They quickly became out of favor because the chronic persistent and chronic active hepatitis were both being considered as disease entities rather than patterns of inflammation. So, after that, there was this hepatitis activity index, which was established in 1981, modified in 1995. Those are more elaborate systems. Many places use those, particularly the modified system now, but it's more often more appropriate in a research setting. These are basically tools of communication that are used between the pathologists and the clinicians, for the clinicians to understand the process more clearly. The simpler systems were established by Shoyer, 1991, Ludwig, Batts-Ludwig system, which is what we use at Mayo and the Metavira system. So, the simpler systems are, of course, as the name implies, easier to use. Very importantly, whichever system one decides to use, hopefully one of the newer systems, whichever system one decides to use should be used in a reproducible way, and it should be clearly understood by the clinical colleagues who provide patient care. So, there is no confusion. One caveat I wanted to mention when evaluating, I actually already mentioned that the wedge biopsy is not very good for evaluating diffuse diseases of the liver, diffuse abnormalities, and here's the histologic example of a case, it's actually a wedge biopsy. You can see that there is a V-shaped area right here. Part of it is actually an elongated portal tract, and the other side here is a fibrous septum, which actually is really a non-specific subcapsular process. You can see the deeper areas of the tissue really do not have any fibrosis. So, imagine if a core biopsy needle went through this area, one could easily overstage. Another thing to keep in mind for hepatitis, neoplastic processes. So, all lymphocytes are not benign. This is an example of a lymphoma, and we did a CD3 and actually a CD5, well, a panel of stains, but the CD5 and CD20 stains were fairly strongly positive, so this is a B-cell lymphoproliferative disorder, either CLL, SLL, small lymphocytic lymphoma, or it actually even could be mental cell. Another word of caution, autoimmune hepatitis can be mimicked by a plasma cell proliferative disorder. So, here's a dense plasma cell infiltrate, and it is eating into the lobule, and when we did the kappa and lambda stain in this particular biopsy, it was kappa-restricted. So, one should always keep in mind when it's a dense plasma cell infiltrate. So, hepatitis also includes cholestatic hepatitis, or what we call bland cholestasis. They're related, and most common etiologies for these are drugs, and there is a whole list of drugs here on the right-hand side. We fairly commonly see this in the post-transplant setting with patients on Vectrin, but there are multiple other drugs that can cause that. Granulomatous hepatitis. I won't say too much, but sarcoid is a fairly, I guess, characteristic histology. One should always exclude infections. This is also a picture of granulomatous hepatitis. So, this actually was a case of sarcoidosis, where granulomas were also larger in other areas, but what I wanted to say is that the granulomas can be of variable size, but they're well-formed and sarcoid-like, but here's a list of etiologies. So, that's a long list, and I don't think anybody would be surprised. Sarcoids really stands out, multiple drugs, including foreign material, especially with IV drug use, infections, neoplasms, idiopathic in about 10% of cases. So, moving on to the biliary pattern. Biliary pattern can be due to obstruction. It can be due to inflammation of the bile ducts, or it can be with duct loss, or what we call ductopenia. So, an acute biliary outflow impairment or obstruction is characterized by a lot of portal tract edema with bile duct and ductula proliferation. You can see that here as well. That is a more acute process. There is a lot of edema. So, I'm using the word acute and chronic here. Perhaps I would be pretty careful when I report this. I think it seems to be acute, but I don't want to create a sort of a clinical diagnosis of acute, but histologically acute sort of obstruction has a good correlation with portal tract edema. And then here's a chronic, which is a more fibrotic process. There is a septum, there is a duct, which is more specific for obstruction. Ductal abnormalities or tortuosity or branching of the duct is more specific than ductula reaction, which is often proliferating, which is often seen in chronic obstruction, but is less specific. So, in contrast to obstruction here in chronic rejection, and this comes up in cases of allografts, liver allografts, chronic rejection has duct damage and duct loss, but you see very few ductular elements here at the periphery. So, that's one of the things that actually is helpful in distinguishing the two entities. So, here is an example of end-stage biliary disease. You cannot say it's ductopenic. So, the ducts are supposed to accompany the arteriole. The ducts are gone, and all I can say is that this is an end-stage biliary disease with a pre-characteristic ductopenic histology. Ductular reaction is not very specific. The reaction happens whenever the interface region of the liver or the portal tract, the interface region between the portal tract and the hepatic therancoma gets disturbed or injured. There is a ductular reaction. So, this is a hepatitis with ductular reaction. So, it's important to look at the ducts to just make sure that the ducts are also abnormal. This is a nonspecific ductular reaction, just to emphasize that, you know, if we just focus on the ductular proliferation, we can get misled. Ductular proliferation in an area of liver necrosis with subsequent fibrosis. So, one entity I want to mention briefly is this thing called, the entity called cholangitis lenta. Also, people have called this an ICU liver. This is a picture that sort of overlaps with biliary obstruction or a biliary pattern and also a cholestatic pattern. So, there is a lot of cholestasis here in the lobule. The important thing to note is that the bile duct here is relatively normal or not very abnormal, and the cholangioles or the ductules at the periphery are filled with bile. So, this is very characteristic, the inspecited bile in the ductules at the periphery of an enlarged portal tract. In the setting, most commonly of a patient who is very sick in ICU with systemic sepsis. So, there is a strong association with sepsis. Here is another example. Duct which looks relatively preserved, cholangiola cholestasis in addition to cholestasis within the lobule. So, this cholangiola cholestasis should catch one's attention. So, more specific examples, primary sclerosing cholangitis, we are all, I think most of us are familiar with this, an obliterative fibrosing lesion of the bile duct. Most cases of PSC are mixed small duct and large duct, and in 10% of the cases, the disease process only involves small ducts. So, a liver biopsy, it can be very helpful if we see this characteristic lesion, onion skinning or obliterated lesion in the smaller ducts, that would help the clinicians a lot because the imaging studies of the cholangiogram would, in these cases, really not be abnormal. Example of primary biliary cholangitis, previously called primary biliary cirrhosis. We all are familiar with this. There is a granulomatous reaction that is centered around the bile duct. I'm showing more typical examples here. So this is really very obvious, bile duct, epithelioid histiocytes forming a granulomatous reaction or a granuloma around the bile duct. And in some cases, and this may be one reason why the patient has a biopsy, because AMA, if a patient is AMA positive and has an appropriate clinical enzymatic picture of liver enzyme abnormalities, then it is not always necessary to do a biopsy for confirming PBC. If there is any doubt, they will do a biopsy, and quite often they're actually also looking for the presence of autoimmune hepatitis in association with that so-called overlap. And because autoimmune hepatitis can be managed with steroids as an additional means of treatment for these patients. So here is a picture of how these diseases overlap or are interconnected. So PBC, primary biliary cholangitis, is mostly AMA positive. A small minority are AMA negative. They look similar, physiologically. They both overlap with autoimmune hepatitis, more classic PBC. PSC can overlap with autoimmune hepatitis as well. And then there is this more recently recognized cholangiopathy as part of the IDG4-related disease process. I thought it was a nice pictorial that shows the interrelation between these entities. So a new thing that should not escape our attention, liver injury with COVID-19. So hepatitis has been described, which really is a mixture of inflammation and injury, cholestasis, that is deemed to be due to COVID-19. However, it is not very certain how much of the changes, of the hepatitic changes, is entirely because of COVID-19, the virus itself. Because these patients are generally fairly sick on other medications as well. So it's a little difficult to sort that out. More specific has been the observation of cholangiopathy. So I'm going to focus on that particular portal track. So the COVID cholangiopathy has been described. Many cases have been on imaging look like PSC with a beaded appearance. And in our case here, this is one of our patients, the finding was mostly in small ducts. So there is this very disorganized appearance arrangement of the biliary epithelium. This was a very diffused process. And again, on the right-hand side here, some bile ductules, very abnormal looking. So we were able to document this abnormality in the biliary ducts and ductules, which was a diffused process. So vascular problems in the liver. I'm switching gears here, moving on to the next category. So vascular problems can be due to hepatic artery or due to portal vein. This is a picture that shows the relationship between the structures, extrahepatic and within the liver. So most of the blood comes in through the portal vein and most of the oxygen comes in through the hepatic artery. And then within the vascular patterns, I wanted to discuss, touch upon just a couple of things, changes that are prehepatic related to portal vein. You can have portal vein thrombosis that if it's very abrupt and acute, it can lead to ischemic damage. So can the occlusion of hepatic artery. Then there are intrahepatic causes that can be divided into presinusoidal, just the occlusion at the level of the portal tract. Sinusoidal is mostly, it has to do with cirrhosis when there is destruction of the sinusoidal structure and obstruction. Then there is an entity in the post sinusoidal category as well that I wanted to touch upon. Posthepatic is mostly venous outflow picture or congestive liver, congestive hepatopathy. So here's a picture of ischemia with centrilobular necrosis or drop out of the hepatocytes, pretty bland with minimal inflammation, patient generally with flow, hepatic arterial flow problem. Here is a more abrupt necrosis. So it's a very acute onset coagulative necrosis in a patient who is hypertensive or has hepatic artery thrombosis. Now the thing that I wanted to focus on a little bit is the presence of portal hypertension in the absence of cirrhosis. And that's a dilemma that the clinicians are hoping that we would help them resolve. Falls in the category of non-cirrhotic portal hypertension. Two entities are there that one should really try to see if one can establish a diagnosis. Hepatoportal sclerosis is the obliteration of the portal vein within portal tracts. This is a fibrotic obliteration, etiologically not very clearly understood, but has been associated with things that cause endothelial damage or thrombosis, association with chemotherapy, et cetera. So here's a scar and a tiny lumen of the portal vein. Here's a trichrome stain that shows the scar, fairly clear that there's no portal vein. The other entity that I wanted to touch upon is the, within the non-cirrhotic portal hypertension is the nodular regenerative hyperplasia. So this is different from focal nodular hyperplasia. This is a diffused process that also results in portal hypertension. This is a very difficult diagnosis to make on a biopsy. Here is a biopsy, not a very good example, but you can see some faint lobularity or lobulation rounded nodularity of the liver parenchyma. Reticulin stain is very important. One would see curvilinear or curved or linear zones of compressed reticulin. And again, as I said, this is not a very good example, but the nodular regeneration can be best appreciated of the stain. And sometimes it's impossible. So what they end up doing is if really they need to establish the diagnosis, they can do a wedge biopsy, a bigger piece of liver tissue. And here's an example, just an H&E stain, nodular regenerative hyperplasia. So this category of venous outflow impairment or congestive hepatopathy is when the blood flow out of the liver is impaired. So you see sinusoidal dilatation is the main finding due to elevated pressure in the sinusoids. Another example, sinusoidal dilatation. So if one sees this, one should raise that possibility. Another example, otherwise the liver looks fine, architectural changes, but the most prominent finding is sinusoidal dilatation. I would mention that the central vein is open. There is an entity which is within the liver itself that causes this picture, and one can attempt to make the diagnosis histologically. This entity called sinusoidal obstruction syndrome, which was previously called venal occlusive disease, and this is caused by occlusive lesions first lose matrix with edema and some cellular elements and eventually becoming fibrotic. As you can see here, there is a tremendous dilatation of the sinusoids due to the increased pressure and impairment of the outflow. More chronic setting, this particular central vein has been occluded, actually is beginning to get re-canalized here, and the central vein that was there is sort of outlined by the two arrows from both sides. So this is a chronic case, and this is really a tough situation clinically. Reticulin stain again helps. You can see the area where the central vein was, and now it's got this reticulin deposition, so it's occluded, and here's a trichrome stain. So causes of sinusoidal obstruction syndrome, so once we have sinusoidal dilatation and a picture of venous outflow impairment, since we have the liver, we don't know what's going on beyond the liver, but we have the liver tissue, we should try to make sure that there is no, there are no occlusive lesions in the central veins, and reticulin stain would be fairly important in that setting. Causes are multiple, very strong association with chemotherapeutic agents, and some other things that I think mainly the reason is the underlying mechanism is damage to the epithelium. One interesting scenario is when we have venous outflow impairment picture, congestive hepatopathy. I have had cases where, for the first time, I found the presence of amyloid, so the idea that the venous outflow impairment could possibly be, well, quite often, if it's extrahepatic or beyond the liver, it is due to a heart problem, but a heart problem can also be due to amyloid deposition, and at the least, one should look for clinical information on whether the patient has a condition that predisposes to amyloidosis, systemic amyloidosis, such as a light monoclonal protein. And lastly, I'm just going to touch upon this, because this itself is a sort of a longer topic of discussion, it's fairly common, most of us see this, steatosis and steatohepatitis. Steatosis is just a presence of fat without indicators of injury or inflammation, steatohepatitis is presence of fat, which, with indicators of injury, the most, perhaps the most specific being ballooning injury of the hepatocytes, inflammation, malarie dengue, malarie hyaline bodies, and this is a distinction that may become important, not always, steatohepatitis versus steatosis. So, it is the hepatitis part, the activity part that leads to progressive fibrosis, initially deposition of collagen in the pericynosoidal space of these. So there are grading systems for this, commonly used as a brunt grading system, and importantly, one has to have the features of the ITIS part, the steatohepatitis part, of course, it has to have steatosis as well. It's a system that's not that easy to use, but a lot of people use it, it's a simple four-tier grading system. And here's the staging of the fibrosis in that, so no fibrosis, only Zone 3 or pericynosoidal fibrosis is a Stage 1. If you have Zone 3, pericynosoidal plus portal or periportal is 2, and then 3 and 4 is more advanced fibrosis. So here is a slide that shows steatohepatitic fibrosis. Why I'm showing this is that about a third, 20-30% of end-stage livers are cryptogenic, and many of these are probably end-stage steatohepatitis without evidence of activity now, but just has fibrosis. And if you did a trichrome stain, and if you see a pericynosoidal pattern of fibrosis, that's a good indicator that this was most likely related to prior steatohepatitic injury. And another thing comes in the differential diagnosis, which also could have pericynosoidal fibrosis, but we can actually distinguish the two most of the time. So in steatohepatitic fibrosis, there is this chicken wire collagen, Type 1 collagen deposition in a pericellular distribution. The other thing that leads to pericynosoidal fibrosis is venous outflow impairment, a topic that I just discussed a few minutes ago. So a patient may have cardiogenic process or pressure-related changes in the liver that leads to a picture of venous outflow impairment or histologically dilatation of the sinusoids, and that often results in a pericynosoidal fibrosis. The difference here is that this has just the sinusoidal fibrosis, maybe with fat or maybe without fat, but here you see the presence of sinusoidal dilatation. So that's an important clue as to what has caused the sinusoidal fibrosis. So in summary, I think I've gone a few minutes over. Just to emphasize, recap the points I made in a lot of slides, a liver biopsy is best evaluated with understanding of the clinical information. So that's very important. The pattern recognition is very critical in liver biopsies, and that should be the initial assessment when evaluating a liver biopsy. Clinical patterns and etiologies are possible together, and one word of caution is that when the liver looks like a hepatitis and if it looks very florid, there may be a neoplastic process that one may need to rule out. Thank you all for your attention, and I'm happy to take questions or entertain comments as well. Thank you. Thank you. Thank you, Marty. As always, I always enjoy and learn so much, although some of the material I learn from your daily work is still refreshing, and I love the approach that your pattern recognition and the clinical correlation. So any comments and questions from our audience? You can... I'm not sure we can hear them. Hey, Amber, how can we know that we have questions coming in? Either you can speak or put in chat, is this how we work? Yes. Anybody has questions, please type them into the chat box. Marty, while we're waiting for questions, I have a question that I know we put the morphological finding and the clinical finding correlation, but have we ever seen or how often do we see the morphological changes that don't correlate with clinical finding very well? What will you do at that point? That can happen. I think clinicians are very good in doing their groundwork before they send the patient for a biopsy, and they go by the labs and the imaging studies, so they are sometimes surprised when they are very certain that the patient has, for example, cirrhosis, and for whatever reason, because they don't have a very clear cardiology, they do a biopsy and it's actually not cirrhotic, so that's surprising, and we have had cases where it actually avoided liver transplantation, so in cases where it's not cirrhotic, the patient does have some synthetic function or it's fairly well-preserved, they can do shunts. In fact, there are cases where if they did a transplant, they would get penalized for a non-cirrhotic, or the indication was not very good. I have had cases where they were predicting a liver disease and the liver was full of tumor in the sinusoids, whether this was actually, there was a renal cell carcinoma I saw not too long ago that was just permeating the sinusoids, and there are cases where there is a lymphoma that's permeating or a leukemia that's permeating the sinusoids, so it is not very common. They have generally a good idea, more than 50% of the biopsies nowadays are done with a pretty good idea from the clinical side of the process. What they want to know is how active it is and what the stage is, so that's very important for them. Because when we do these conferences and we look at these biopsies and talk about this hepatitis or whatever changes are there, the last question they ask is, you know, show us a trichrome stain or what is the stage. Yeah, thank you, thank you, yeah, you're right, sometimes you see, quote unquote, surprise, that's the value of a pathologist and then they can treat the patient, manage the patient more accurately, and thank you, we want to thank you Dr. Vandekrishna for your expertise and your contribution to our FSP education series, and with that I want to say thank you for your attendance and have a great evening everybody.

liver pathology

clinical correlations

liver diseases

liver biopsies

liver injury patterns

histological features

chronic hepatitis

clinical correlation

diagnosis

patient management