During this 20-25 minute pre-recorded lecture, Dr. Stephen Ward discusses the topic of liver pathology. This in-depth review will provide an update on this topic for your clinical practice as well as supplement your learning for the ABIM Gastroenterology and Hepatology boards. CME pre-requiste of live Q & A webinar, 8th Annual Mount Sinai Intensive Board Review in Gastroenterology & Hepatology on Oct 13. Hi I'm Stephen Ward. I'm a liver pathologist at Mount Sinai Hospital and I'll be reviewing liver pathology with you today. I'll begin with a brief review of normal liver histology. I will then go over nine case based multiple choice questions and end with a list of some take home points. Since this is a prerecorded video, I will just pause briefly between presenting the question and going over the answer, but if you need additional time please feel free to pause the video. We'll get started with a review of the normal liver histology. The liver is composed predominantly of parasites that are arranged in one or two cell thick tropical it with intervening sinus oil spaces through here. So the pink cells here are the parasites and the white space here. The sign of social spaces and interspersed our portal tracks and central venables and the porter tracks consist of portal vein, branch, paddock artery, branch and branch of the bile duct. And functionally the liver is can be divided into lobbying rules which consists of a portal track. The intervening parasites and the draining central venial. So the blood comes into the liver from the hill um through the portal vein and through the paddock artery. The blood then percolates through the sinus soil spaces between the parasites and the parasites. Meanwhile metabolized and detoxify the blood when the blood then eventually reaches the central genial and empties into uh the inferior vena cava out of the liver. Meanwhile the liver is also producing bile and bile is um transported in the opposite direction through can molecular spaces which are not readily uh seen under normal conditions. So the bible is transported um towards the portal track, eventually draining into the Baltic branch and eventually draining out of the liver through the highland. And the liver can be also divided into different zones based on their proximity to the portal tractor central venue Zone one Parasites are the parasites around the portal track Zone three are the parasites around the central manual. And then the parasites in the intervening spaces are considered zone too. And by examining where the injury or where the abnormality is um based on the lob, you'll or whether it's evolving the portal track or central manual or parasites or pile dock. We can learn a lot about what is going on in the liver. And so we will use these clues uh when evaluating uh liver specimens. So we'll get started on the cases in case one is a 61 year old woman with elevated alkaline phosphate is mild elevation of S. A. L. T. And a normal billy Rubin. She underwent a liver biopsy which is shown here and the question is, what is this lesion right here for duck lesion, productive onion, skin, fibrosis firing granuloma or mallory tank body. So this is an example of a florida duct lesion uh and basically the consists of granuloma. This reaction to a bile duct. So these pale staining uh cells here are history sites forming a granuloma and they're attacking the bile duct here and this floor duck lesion is essentially pathan demonic for primary biliary cholangitis. So briefly, primary biliary cholangitis is an autoimmune disorder affecting the small and dramatic ball talks usually affects middle aged women as an insidious onset with fatigue kuraitis and eventually john does so logically. Most cases are positive for antibiotic Andrea antibodies and often have elevated serum I. G. M. The liver biopsy can show inflammation of the portal track with bile duct damage and Baldock loss. But if you see a floor duct lesion that as I mentioned earlier is essentially path a demonic from for PBC Case to this is a 42 year old man with elevated alkaline phosphate tastes and elevated S. T. and LT and normal Billy Rubin. And this patient underwent reception for a highly klinger carcinoma. But then this uh vision was identified. Um So what what is this lesion is therefore duck lesion, periodontal onion skin, fibrosis, vibrant ring granuloma or peace building a crisis. And this is an example of perry ductile onion skin fibrosis. We have the Baldock branch in the center and it's basically surrounded by this laminated uh huh onion skin like fibrosis. And so this can be seen in primary sclerosing cholangitis, which is what this patient did have. Um So primary sclerosing cholangitis usually occurs in young men has a strong association with inflammatory bowel disease often presents with abdominal pain, fatigue apparatus and Jonah's um The diagnosis is generally made on imaging and you get the characteristic beads on a string pattern basically um representing areas of all training sclerosis and dilatation of the um bulldogs. So the biopsy will show um fiber obliterate fiber obliteration of bile ducts often with this onion skin type character fibrosis. However, this feature is not specific for primary sclerosing cholangitis, but one other point for primaries. Closing cholangitis has also demonstrated this this case presentation. Uh These patients are at increased risk for Colangelo Carson. As I mentioned, The onion skin fibrosis is not specific because there is also and uh the entity of secondaries grossing cholangitis. So this basically shows very similar histological features. Two primary sclerosing cholangitis. But there's another underlying cause. Could be infectious. Ischemic, neo plastic or mechanical. Um So again this the onion skin fibrosis is not a thematic for primary sclerosing. Cool entrance. And here's since this was one of the answers and the multiple choice questions, I just want to show an example of a fiber and ring granuloma. These are classically associated with Q. Fever. They consist again of a granuloma. So with history sites um they often have a little fat droplet in the center and then they have this ring of fiber and around. Yeah, I'm sorry, just an example of a fiber. Mhm. Next case Case three. This is a 38 year old woman with elevated trans am illnesses, liver biopsy was done before the serology results were back which of the following uh neurologic markers is most likely to be elevated. So p anca anti double stranded DNA anti mitochondrial antibody or hepatitis B surface antigen. And I'll give you a little hint this is a large portal track and cure as well. Mhm. So in this case we would expect to see an elevated anti double stranded DNA. So this is what we're seeing is a portal based uh inflammation. And here we can't really tell what the type of cells they are. But we can see that they're expanding the portal tracks and um and basically going out into the lob. You'll as well, so that that is a process we call interface hepatitis. When it spills out into the lob, you'll and when we go higher power we can see that many of these cells are plasma cells. They have an e centric nucleus with a little clearing um around the around the nucleus. And uh and then uh more pale cytoplasm elsewhere. So, a plasma cell um as I've shown there but its morphology can often be seen a little better on on a smear. But again, it's characterized by e centric nucleus with this little clearing called a Hoff and then, you know, the remaining cytoplasm around here. Mm. So and these are characteristic of these findings are characteristic of autoimmune hepatitis. So autoimmune hepatitis is a disease. Autoimmune disease of the liver with the parasite directed inflammation, usually with prominent plasma cells usually affects middle aged women and they have a varied clinical presentation can be asymptomatic elevations and trans am bonuses and can also on the other end of spectrum need to fulminate liver failure. And they often show elevations in any one of these uh uh huh factors here. Uh anti nuclear antibodies is the least specific but anti smooth muscle and body double stranded DNA. And um some of these others can also be seen. These patients also often have elevated serum I. G. Mm case four. Um so this is a surgical specimen, this a 28 year old woman with no known underlying liver disease was found to have a 4.5 centimeter mass in the left lobe of the liver and she underwent reception which of the following is most likely the most likely diagnosis based on the gross findings is that peta cellular carcinoma, hemangioma, vocal modular hyperplasia or Colangelo carcinoma. This is an example of focal modular hyperplasia. And the clue here is that it has a central radiating scar here. And another helpful fact feature is that the background liver is also non psoriatic. Actually, you might even see there's even another uh focal natural hyperplasia here as well. So, the features of focal hyperplasia. They're generally welcome circumscribed lesion with a central radiating scar. They usually occur in young women with no underlying liver disease. And these are actually non neo plastic vascular lesions and they have a benign course. And so I'm showing obviously the pathology here. But this central radiating scar is also seen on radiology. And so you know, this diagnosis is often made made on imaging. I'll just show you some gross examples of some of the some of the other answers. This is uh an example of what a peta cellular carcinoma might look like. Um so these are also often well circumscribed lesions. They're generally relatively soft. They usually arise in older patients, usually in the setting of underlying liver disease, often with cirrhosis. So you can see some modular liver in the background here and this of course, is a malignant neo plasm human ngoma. Um these uh have a characteristic spongy appearance. They would be very bloody when first removed that can show areas of sclerosis or high lionization like these areas here and sometimes the whole region become can become sclerosing and uh we can call that's gross, starts grossing hemangioma. These generally have a good clinical course, but uh, but there are vascular tumors and they can rupture and cause bleeding. The Klan joke carcinoma is also usually well circumscribed lesion, but unlike competitor carcinoma, this is usually a firm lesion um due to the desmond play asia within the lesion and usually the liver is non psoriatic. Um and of course this is also another malignant neo plasma moving on to case number five. This is 65 year old man with hepatitis C and cirrhosis and was found to have a five centimeter mass in the right lobe of the liver and underwent resection. And this is uh um slide from the tumor. What is the diagnosis here is in a panic cellular carcinoma, hemangioma calandra carcinoma or metastatic carcinoma. This is an example of hypothesis cellular carcinoma. And the key here is that it's a bile producing tumor. So not all of Peninsular carcinomas will produce bile, but if you do see bile production, it's a very good sign that it's uh this is a pet, a sailor carcinoma. Um and we'll go over some of the other options here. So, padded cell carcinoma is a malignant primary tumor with a pot of cellular differentiation. Some of these tumors are by all producing. Um So when present, that's essentially pathan demonic. For cellular carcinoma, it uh Minnesota carcinoma is often seen in the setting of chronic liver disease with cirrhosis. Um Though we are seeing more cases arising in the absence of cirrhosis, especially the setting of hepatitis B and C. And hepatitis. And these tumors can be very heterogeneous even within the same tumor nodule. But I probably said they're carcinoma is like the more well differentiated um types. They kind of recapitulate the normal liver. And they often maintain that Trebek Euler architecture. But here's some examples of uh just some showing uh some heterogeneity of metastatic carcinoma. So on this one, you can still see the tribeca architecture um somewhat mimicking the normal liver architecture. But these other ones you'd be kind of hard pressed to to see the underlying liver architecture, but some of them can be cleared uh cell variants. Some can have uh standard apathetic looks. Some can be a more poorly differentiated, more well differentiated. But I think um you know, for board review purposes um bio production would be the key feature in making a diagnosis of testicular carcinoma. Here's an example of the histology of a hemangioma. It basically consists of uh vascular spaces often filled with blood but just lined by very bland cells. And this is the most common primary liver tumor. And it's benign. Kalandia carcinoma is a gland forming tumor. Um and basically uh with biliary differentiation. So this produces musician rather than bile. It often has a dismal plastic fiber optics trauma, which gives it that firm appearance and feel on gross examination. And it can be very difficult to differentiate and in some cases from metastatic tumors. So, you mean it has the chemical stains can be helpful, but even with stains it can be difficult to differentiate from pancreatic biliary or gastric primary. Just show a couple examples, like I would say this example in the center here is almost indistinguishable morphological from a Colangelo carcinoma. Just this gland forming to North Lauderdale Malaysia. Here's an example of colorectal carcinoma metastatic deliver, which has a lot of uh dirty necrosis in the center. And here's an example of uh thyroid carcinoma metastatic deliver. And here you can actually see the thyroid globulin information within the tumor. But we can, as I mentioned before use immune system chemical stains to uh to help identify the origin of these tumors. We've got the case six. This is a 19 year old woman who presented to the emergency room in liver failure and underwent liver transplantation, One of the most likely ideology of the liver failure, chronic hepatitis C, four minute autoimmune, hepatitis, large bile duct obstruction or acetaminophen toxicity. So here's a lower power here and then this is a higher power here and again, I'll give you a little help here. So here is the portal tracked and here is the central venial and here is a higher view of the central venue. Mhm. And here actually is a portrait. This is an example of acetaminophen toxicity. And so this is characterized by predominantly zone three uh necrosis. So again the perry vehicular uh necrosis. And also it's characterized by generally not much associated inflammation. You just kinda have necrotic to parasites. Um beginning and kind of spreading out from the Zone three region with relative sparing of the perry portal areas. Mm hmm. Um So this can be due to intentional or unintentional overdose of acetaminophen. Uh the toxicity is actually due to the metabolite Um Nike uh genocidal 16 can be used to minimize the impact of toxicity. And as I showed it can lead to a parasite or necrosis with minimal information general beginning in the Peri vehicular zone three regions. So chronic hepatitis C would show inflammation and fibrosis. But without zonal necrosis and generally portal based information, autoimmune hepatitis can cause permanent liver failure with extensive parasite and necrosis but usually has more inflammation. And you would also expect to see plasma cells especially a large bile duct obstruction would show coast assist dr reaction and bile duct injury. But you wouldn't expect to see zonal necrosis. Okay. Seven. There's a 65 year old man with chronic hepatitis C. And a parasite of carcinoma who underwent liver transplantation. Grandmothers were seen in the parasites that were positive on pearls prussian blue. So here is the H and E. We can see these Granules and then they light up bright blue on pearls Prussian blue stain. So what additional tests should be considered genetic testing for hemochromatosis or logic testing for hepatitis B virus. Copper quantification or genetic testing for up to one anti trips and deficiency. Mhm. So the correct answer is genetic testing for hemochromatosis. So the pearls prussian blue is an iron stain. And so we're basically staining the iron within the parasites here. So you can get iron deposition in the parasites for many different reasons. Uh There are many different like secondary causes of iron deposition like for example patients undergoing multiple blood transfusions. But one thing to consider is a primary um or hereditary hemochromatosis and this is inherited on his own or resistive recessive disorder of iron metabolism most commonly due to mutations in the HIV gene. Most patients are northern european ancestry and they have variable presentation with weakness, evidence of liver disease, cardiac dysfunction, diabetes and skin hyperpigmentation. Moving on to Case eight, this is a 68 year old man who underwent a liver transplantation for presumed alcoholic liver disease. And these globules were seen in the parasites which are positive for P. A. S. Staying following diabetes treatment. So here we see the pedal sites along septum here and the parasites contain these variable variably sized highland globules and they are positive for ps following diabetes treatment. So again, what additional tests would be considered testing for human chemical ketosis, Hepatitis B copper qualification or genetic testing for ALFA one anti trips and efficiency. So the answer here is genetic testing for Alpha one anti trips and deficiency. So these globules are actually uh miss formed alpha one anti trips and proteins that are accumulating in the liver. They're basically misfolded proteins that cannot be secreted from the liver. And they accumulate inform these globules and they are positive for P. A. S. Uh even after a day's taste treatment. So, if you want any trips and efficiency is also and autism a recessive genetic disorder is characterized by mutations in the and Sir pin A one gene uh alpha one. Any trips and protein is synthesized mainly in the liver. It's a protease inhibitor. So it inhibits neutrophils proteus is thus protecting the host tissue from non specific injury secondary to inflammation mutations result in defective secretion of the molecule. And so the protein folds abnormality and basically becomes insoluble and trapped within the parasites and deficiencies characterized by lung disease like emphysema and chronic liver disease. And last question case nine, a 40 year old man has liver biopsy for elevated liver enzymes. What is are the possible cause or causes of this liver histology, obesity, alcohol drugs or all of the above? The answer here is all of the above. So this is an example of Seattle hepatitis. So on lower power we can see um this is uh central genial. So we're in the zone three region we can see um extensive fat deposition with macro vesicular cyanosis. Me and these parasites are expanded by large vacuole containing in fact. And as we look around, in addition to the fat um droplets, we also see these balloon to parasites. So these parasites that have this kind of finally articulated um cytoplasm here and so if we just have just the fat deposition, we would just call ketosis. But when you have ballooning degeneration that now makes its data hepatitis and basically all these conditions can lead to Seattle hepatitis so Seattle hepatitis is fat deposition within the parasites with associated inflammation, especially ballooning degeneration of parasites. And the fat deposition is often zonal usually zone three pair of annular region as we saw in this example. So there are many causes of Seattle hepatitis, alcoholic Seattle hepatitis. Um Non alcoholic hepatitis generally associated with obesity metabolic syndrome. And then there are many drugs that can cause Seattle hepatic pattern. So chemotherapy associates, Seattle hepatitis is sometimes referred to as cash. Um And deodorant is uh notorious mimic of alcoholic Seattle hepatitis, but many other drugs that a lot of patients are on, such as methotrexate, cortical steroids and others can also lead to Seattle hypothetic pattern. Just here, just showing a couple examples that may suggest um uh alcoholic liver disease as a cause. Um one of the features is uh will be uh terms uh satellite toast this. So basically you have a balloon parasite here and it's surrounded by neutrophils and also and here we see Mallory denk islands. Um Somali Jenkins can be seen really any cause of Seattle hepatitis, but but if they are very prominent that is somewhat suggestive of alcoholic liver disease. So I will just end here with some take home points the floor duck lesion, the grain luminous inflammation of the bile ducts is essentially path a demonic for primary biliary cholangitis. However, the paradoxical onion, skin fibrosis, which we see often in primary sclerosing cholangitis, but this is not specific for this entity. Autoimmune hepatitis is characterized by portal chronic inflammation with plasma cells focal natural hyperplasia is characterized by a central scar, generally in a nonce erotic liver. A bible producing tumor in the liver um is pat cellular carcinoma, a gland forming tumor in the liver. It could be claimed to a carcinoma. It could be a metastasis. acetaminophen toxicity generally leads to zone three necrosis and pearls. Prussian blue um stains for iron alFA one. Any trips and deficiency leads to variably sized highland gobbles and the perry portal parasites. And these goggles are positive with ps sustain following diabetes treatment and uh finally, Seattle hepatitis can be due to metabolic syndrome, alcohol drug or other causes as well. So I'll end here and thank you very much.