Many of the histologic images and the tables are from MacSween s Pathology of the Liver (5 th Edition). Other images were used from an online source called PathPedia.com. A few images from other sources are present. The slides with algorithms were made by me. The following is a summary to go with the slides from the talk. Slide 2. The adequacy slide shows cores of varying size. 16 gauge cores are marked with (A). The Journal of Hepatology recommends 16 gauge cores. Our radiologists don t do 16 gauge biopsies. We request 18 gauge core biopsies measuring at least 3 cm long or adding up to 3 cm in toto. Smaller gauge biopsies are discouraged! Slide 7 demonstrates acute pericholangitisis with neutrophils around proliferating bile ducts. Slide 8 demonstrates acute lobular hepatitis with hepatocyte injury and swelling seen in association with a mononuclear cell infiltrate. Slide 9 is a higher magnification of the same process including a few areas of early acidophil body formation. Slide 10 demonstrates bridging necrosis with a few areas of residual hepatocytes. Slide 11 and 12 are to remind us that if serologies done within the first month of viral infection the antibodies may not be present yet. Hepatitis C virus RNA will be positive as early as two weeks and should be considered if a viral hepatitis is suspected. Slide 13 demonstrates an acute injury pattern consistent with steatohepatitis. The heavy neutrophilic infiltrate and neutrophil satalitetosis around the hepatocytes may be seen in ethanol related injury (see later discussion on differential of steatohepatitis). Slide 15 when looking at injury patterns focus on the location of the injury and the type of inflammatory cell present. Remember that bile duct reactions are limited to having an injured appearance, duct proliferation or ductopenia. Slide 17 when examining medical liver biopsies it is easiest to rule out or rule in the presence of steatosis. If it s steatosis only (not steatohepatitis) characterize as mild to moderate or marked. Steatohepatitis grade and stage will be discussed. Remember when there is steatosis with dense portal lymphoid aggregates consider hepatitis C virus infection. Hepatitis C virus genotype type 3 can cause steatosis. Slide 18 demonstrates an intermediate power view of a liver biopsy with steatosis. At this magnification there is also some degree of inflammation with ballooning degeneration and reactive changes. Slide 19 shows a higher magnification demonstrating necroinflammatory infiltrates and Mallory s hyaline.
Note: Mallory s hyaline (alone) is not diagnostic of ethanol-related injury. If monitoring for abstinence, Mallory s hyaline may take up to a year to clear. Slide 20 demonstrates the sinusoidal fibrosis with chicken wire or spider web configuration. Slide 21 demonstrates a similar sinusoidal fibrosis but also early bridging fibrosis. In steatohepatitis the fibrosing process begins in the pericentral vein area and extends into the sinusoids and then to the portal areas. Slide 22 the Brunt system for grading steatohepatitis. The column on the right labeled inflammation incorporates the information from the columns below (lobular inflammation and portal inflammation). Note that in mild steatohepatitis there is little to no inflammation in the portal areas. Slide 23 is the Brunt system for staging. The staging system is a 1 4 system similar to staging of fibrosis in HCV and others. ***My typical differential diagnosis for steatohepatitis (in the last paragraph of the micro): The differential diagnosis includes toxic/metabolic injury (including ethanol, drugs, over the counter substances), diabetes and obesity, among others. Clinical correlation is required. Alcoholic and non-alcoholic steatohepatitis have overlapping features and it s better for the clinician to sort out if the patient is drinking or not. Slide 25 demonstrates pericholangitis and is the same slide from earlier in the talk. If significant edema is also present the patient may be septic. Slide 26 demonstrates ascending cholangitis with a large collection of neutrophils associated with a disrupted bile duct. Residual epithelial cells are presented at the arrow. (These patients are sick) Slide 27 demonstrates a dense lymphoid aggregate within a portal area and the adjacent bile duct with intraepithelial lymphocytes and mildly injured epithelium. Just above the bile duct is a granuloma. These features are consistent with primary biliary cirrhosis. Slide 28 demonstrates and injured bile duct with an irregularly spaced nuclei, nuclear drop out and periductal fibrosis with an onion skin pattern (PSC). Slide 29 demonstrates a portal area with artery and vein but no bile ducts (circular area of fibrosis) consistent with ductopenia. Slide 30 demonstrates an image of ERCP and a corresponding diagram. PSC typically involves larger and intermediate size bile ducts. Since the liver biopsies come from the periphery of the liver the typical onion skin lesion is not seen often. Slide 31 shows the typical finding of acute pericholangitis consistent with intrahepatic and/or extrahepatic biliary obstruction. Any process that causes biliary obstruction can have this pattern. This would include tumor leading to obstruction, stricture, stones and PSC (and occasionally drugs).
Slide 32 delineates processes that cause lobular injury and/or interface injury. Slide 33 is an intermediate magnification view of a core biopsy with dense portal lymphoid infiltrates. The lobules look relatively normal. Slide 35 demonstrates piecemeal necrosis with the limiting plate delineated by a line. Slide 36 demonstrates acidophil bodies. Acidophil bodies are seen in hepatitis C virus infection, autoimmune hepatitis and drug reactions. Primary biliary serosis and primary sclerosing cholangitis should not have acidophil bodies. Slide 37 demonstrates early fibrous septate. Slide 38 demonstrates the ground glass cytoplasm in a chronic hepatitis B virus infection. The ground glass appearance is due to accumulation of HBV surface antigen within the cytoplasm. Slide 39 demonstrates the central nucleus with a slightly pink hue and is termed sanded nucleus. This is due to accumulation of the hepatitis B virus core antigen within the nucleus. To my knowledge we have not seen a case of acute hepatitis B virus infection in our practice in the years that I have been here. Most of the hepatitis B virus patients were infected long ago and may have a biopsy now to evaluate for fibrosis. Slide 40 demonstrates a core biopsy with dense portal lymphoid inflammation. Focal piecemeal necrosis is present. There may be a possible poorly formed granuloma centrally. Slide 41 demonstrates a bile duct with a few intraepithelial lymphocytes and mildly injured appearance (irregular nuclear spacing). A few poorly formed granulomas are adjacent to the duct. Slide 42 is a good contrast between a relatively normal bile duct (far right side) with uniform nuclei completely encircling the lumen vs to the left is an injured duct with irregularly spaced and irregularly shaped nuclei, intraepithelial lymphocytes and adjacent granuloma. Slide 43 demonstrates interface hepatitis. Slide 44 demonstrates lymphoid inflammation within the lobule in a case of primary biliary cirrhosis. Note there are no acidophil bodies (should not be seen with PBC). Slide 45 and 46 demonstrate cirrhosis with a regenerative nodule. Slide 47 there is some overlap between autoimmune hepatitis and primary biliary cirrhosis. Both processes may be ANA and SMA positive. However, PBC should be AMA positive and autoimmune hepatitis would have other antibodies listed on the left. Of course, PBC has bile duct lesions where autoimmune hepatitis has interface and lobular hepatitis. Slide 48 demonstrates portal infloid infiltrates with interface hepatitis and lobular hepatitis. Slide 49 is a higher magnification demonstrating a similar pattern.
Slides 50, 51 and 52 are progressively higher magnifications demonstrating high numbers of plasma cells. Note the early acidophil body in slide 52. In autoimmune hepatitis plasma cells should be present in clusters and sheets. Groups and clusters of plasma cells are present in the lobules. I found that if I have to count the plasma cells it may not be autoimmune hepatitis unless the patient has been treated recently with steroids. If you consider special stains to identify the plasma cells do not use CD138 as it also stains the hepatocytes. Kappa/lambda may be a consideration. Slide 53 demonstrates bridging necrosis which may be seen in a severe case of autoimmune hepatitis. Slides 54, 55, and 56 are tables that are clinical colleagues would use for deciding whether or not a patient has autoimmune hepatitis. Slide 57 demonstrates an eosinophil rich infiltrate within a portal area and slide 58 demonstrates a portal granuloma. Eosinophils and lobular granulomas often come to mind when thinking of drug reaction in the liver. However, in slide 59 we see marked acute hepatitis with bridging necrosis which may also be seen in drug related injury. The next several slides containing tables (slides 60 65) are to remind us of the many faces of drug related hepatitis. Slide 61 demonstrates toxicities that are either direct or indirect as well as post immunological hypersensitivity. Slide 62 lists the targets of drug induced injuries. Slide 63 lists drugs that can lead to syndromes resembling autoimmune hepatitis. This includes circulating antibodies similar to those seen in pure autoimmune hepatitis. Slide 64 describes various cholestatic injuries caused by drugs. Slide 65 I think is the most important. It lists the hepatotoxic herbal remedies that are commonly available at health food stores. The column on the far right describes the type of liver injury ranging from elevated LFT s to acute liver failure (!) Because of the many different types of injuries drugs can cause they are a consideration in almost any injury pattern which is summarized in slide 66. Slides 67 69 demonstrates findings in venous outflow obstruction. Slide 67 demonstrates red cell extravasation into the hepatic cords which is related to increased pressure within the liver. Blood outflow is decreased but blood inflow is not. Slide 68 demonstrates pericentral vein fibrosis and atrophy of the adjacent hepatic cords. Pericentral vein fibrosis occurs as the process becomes chronic. Slide 69 is another demonstration of sinusoidal dilatation with atrophy. Sinusoidal dilatation and atrophy and without red cell extravasation is not entirely specific. Slides 71 73 show a few different images from Wilson s disease. The changes may range from nuclear clearing (slide 70) which may be seen in diabetes to steatosis (slide 71) to significant parenchymal injury with the hepatocyte ballooning and parenchymal necrosis (lower right corner). Slide 73 demonstrates
obvious cirrhosis. In any young patient with significant liver disease Wilson s should be a consideration. Appropriate serologic and urinary testing could be recommended. Quantitative copper on the cores could be performed. In my experience by the time the routine medical liver stains have been made the remaining tissues in the core is sometimes insufficient for copper studies. Note: In cirrhotic livers copper, iron and alpha-1-antitrypsin accumulate at the periphery of regenerative nodules because the materials cannot be effectively transported out of the area due to fibrosis. Slide 74 and 75 hemochromatosis. In slide 74 you see a periportal predominant distribution of the iron with lower concentrations as we proceed toward the central vein. Earlier in the disease process the iron accumulation is periportal. Often there will be iron within the biliary epithelium. In this picture the periportal iron accumulation has a linear distribution this is due to the intracytoplasmic location of the iron (slide 75) the iron granules accumulate on the biliary side of the cell and have a linear appearance at intermediate and low power sometimes likened to train tracks. When hemochromatosis is a consideration there is typically enough liver tissue present in the paraffin block after routine medical liver stains for quantitative iron studies (in contrast to quantitative copper studies). Slide 76 and 77 are images of alpha-1-antitrypsin. PAS stain with diastase digestion is helpful because some variants have rather small globules (1 3 micron range). We generally do not see a lot of alpha-1- antitrypsin deficiency cases. Slide 78, 79, and 80 are algorithms for abnormal liver functions tests based on the focus on of the injury. Biliary injury (increased alk. Phos, GGPT, bilirubin with or without mild elevations in AST and ALT) If there is biliary injury associated with neutrophils (pericholangitis) obstruction or sepsis is the most likely injury. However, any process that causes intrapatic or extrapatic biliary obstruction including PSC is in the differential diagnosis. Periductal fibrosis and ductpenia is seen in PSC. However, as I mentioned the most common finding is pericholangitis. Periductal granulomas can be seen with PBC and infection. Biliary injury associated with lymphocytes is predominantly seen with PBC. Hepatitis C virus also has intraepithelial lymphocytes without significant biliary injury. Remember drugs can cause biliary injury and remain in the differential. Slide 79 correlates with the pattern of lobular and interface activity. Interface/lobular injury (increased AST and ALT with or without increased alk phos) Interface and lobular plasma cells in sheets and groups are seen in autoimmune hepatitis. Dense lymphoid inflammation mixed with fewer plasma cells and lobular acidophil bodies suggest hepatitis C virus infection. The same dense lymphoid infiltrates with plasma cells, biliary injury and no acidophil bodies suggest primary biliary cirrhosis. Lobular granulomas may be seen in drug reaction, infection and reaction to foreign material (IV drug abuse). Neutrophils or mixed inflammation in the lobules associated with fat is seen in steatohepatitis. Remember drugs can cause features of autoimmune hepatitis and chronic hepatitis (PBC/HCV).
Slide 80 is redundant and should have been left out. Patient Cases: Case 1 Slide 81 has intermediate power view demonstrating steatosis with little portal inflammation. Slide 82 shows steatosis with ballooning degeneration, necroinflammatory infiltrates and reactive changes. The portal area contains sparse inflammation. Slide 83 demonstrates sinusoidal fibrosis with a chicken wire pattern and early septa emanating to the portal area (stage 2 fibrosis). Diagnosis: steatohepatitis grade 1 2 and stage 2. Case 2 Slide 84 demonstrates dense portal lymphoid infiltrates with a relatively normal appearing bile duct and focal piecemeal necrosis (bottom center). Slide 85 demonstrates piecemeal necrosis at higher magnification. Slides 86 and 87 demonstrate acidophil bodies. This pattern of dense lymphoid or lymphoplasmacytic portal inflammation with piecemeal necrosis and acidophil bodies strongly suggests Hepatitis C virus infection. This patient was Hepatitis C virus positive. Case 3 Slide 88 demonstrates an acute lobular hepatitis with hepatocyte injury and a mononuclear cell infiltrate. Slide 89 demonstrates extensive parenchymal necrosis with bile duct proliferation and reactive changes. Note: there are no hepatocytes between the central vein and the proliferating bile ducts. Slide 90 is a reticulin stain demonstrating residual hepatocytes on the upper left and mid right side of the field. Centrally there is reticulin collapse and toward the bottom there is hepatocyte dropout without reticulin collapse. Slide 91 this patient is a mid 20 s male with negative hepatitis serologies, no medications, and autoimmune serologies are negative. I told the Hepatologist this is either an acute viral hepatitis (prior to seroconversion) or drug/toxin injury. I recommended they discuss with the patient any over the counter substances that he may have taken.
Slide 92 the patient and his girlfriend were taking a liver detox herbal supplement that lead to his acute hepatitis. Interestingly, his girlfriend had no symptoms or abnormal LFT s. Diagnosis: Drug/toxin related injury. Case 4 There is portal inflammation with interface hepatitis. An early acidophil body is present centrally in the right 1/3 of the image. Slide 94 demonstrates dense groups of plasma cells at the interface and small groups of plasma cells in the lobules. Diagnosis: Autoimmune hepatitis. Case 5 (a recap from earlier). Dense portal lymphoid inflammation (slide 95). Slide 96 demonstrates biliary injury with intraepithelial lymphocytes and a few small poorly formed granulomas. Diagnosis: PBC. Last slide. At first glance the histology may seem similar. With a little practice you are able to spot the differences. Summary: Dense portal lymphoid or lymphoplasmatic infiltrates with or without piecemeal necrosis and acidophil bodies raise the differential diagnosis of Hepatitis C virus infection and autoimmune hepatitis (should be plasma cell rich). Don t forget about drugs. Lobular hepatitis with acidophil bodies can be seen in hepatitis C virus infection, autoimmune hepatitis and drug related hepatitis but not PBC. Biliary injury with intraepithelial lymphocytes and periductal granulomas are highly suggestive of primary biliary cirrhosis. Don t forget about drugs. Acute pericholangitis is consistent with intrahepatic or extrahepatic biliary obstruction, including PSC. If PSC is a consideration the clinician may consider MRCP or ERCP to look for the typical beaded strictures of the intrapatic and extrapatic biliary system. Don t forget about drugs. Note: Mallory s hyaline (alone) is not diagnostic of ethanol-related injury. If monitoring for abstinence, Mallory s hyaline may take up to a year to clear.
***My differential diagnosis for steatohepatitis (in the last paragraph of the micro): The differential diagnosis for steatohepatitis includes toxic/metabolic injury (including ethanol, drugs, over the counter substances), diabetes and obesity, among others. Clinical correlation is required. Alcoholic and non-alcoholic steatohepatitis have overlapping features and it s better for the clinician to sort out if the patient is drinking or not. I found that if I have to count the plasma cells it may not be autoimmune hepatitis unless the patient has been treated recently with steroids. If you consider special stains to identify the plasma cells do not use CD138 as it also stains the hepatocytes. Kappa/lambda may be a consideration.