Liver biopsy interpretation

indications, techniques, special stains, approach to liver biopsy

1. Liver biopsy interpretation Presenter - Dr. Dhanya A N Moderator – Dr. Ramesh S T

2. Contents Indications of liver biopsy Lab investigations Techniques of liver biopsy Needles of liver biopsy Processing and staining Normal histology Approach to liver biopsy interpretation Interpretation of different pathological conditions

3. Indications of liver biopsy Make or confirm the diagnosis Assess the severity of liver damage Assess the prognosis of a given case Monitor the response to the treatment

4. Clinical and lab investigations History and general physical examination Lab investigation Liver function tests CBC Prothrombin time, aPTT Bleeding time Clotting time USG,CT, MRI

5. Liver function tests Hepatic integrity Serum aspartate aminotransferase Serum alanine aminotransferase Serum lactate dehydrogenase Biliary excretory functions Serum bilirubin Serum alkaline transferase gamma glutamyl transferase Hepatocyte synthetic function Serum proteins Coagulation proteins Serum ammonia

6. Techniques of liver biopsy Percutaneous - Transthoracic Subcostal Blind procedure I mage guided – USG, CT, MRI Plugged liver biopsy Gelatin, gel foam plugged

7. 2. Transvenous ( Transjugular ) Done in coagulation disorders or ascites P erformed in a vascular catheterisation laboratory with videofluoroscopy equipment and proper cardiac monitoring

8. 3. Laparoscopic liver biopsy T ransvenous liver biopsy is not available , I n patients who have a combination of a focal liver lesion and a coagulopathy.

9. Needles for liver biopsy B roadly classified into Suction needles Menghini , Klatskin , C utting needles Vim-Silverman , Tru -cut (commonly used) S pring-loaded cutting needles that have a triggering mechanism.

10. Vim silverman needle

11. Tru cut needle

12. Processing the sample Place on the filter paper Fix immediately Buffered formalin (routine) Alcohol (glycogen storage disorder) 2.5% buffered gluteraldehyde (for EM) Frozen sections (for fat) Fix overnight Take sections Stain

13. Special stains Masson trichrome , stains blue color to collagen and red color to hepatocyes H & E stain of hepatic lobule

14. Special stains Perls prussian blue for iron, heoatocytes have taken the blue stain PAS positive in glycogen storage right side and after treating it with diastase, left side

15. Special stains PAS+diastase for aplha1 antitrypsin deficiency Hapatocytes have taken magenta color Oil Red O stain highlighting fat globules in a frozen section of the liver.

16. Special stains Rhodanin stain for copper, hepatocytes have taken orange red color in the upper nodule Congo red stain orange-staining of vascular amyloid deposition, characteristic apple-green birefringence under polarized microscopy (inset)

17. Special stains Orcein stain for elastic fibres is positive in two portal tracts (P) but not in the intervening area of collapse. A necrotic bridge (arrow) is also negative. Inset: This contrasts with an elastic fibre -rich septum in chronic liver disease . P P Reticulin stain of micronodular cirrhosis Stains collagen

18. Adequacy of liver biopsy Biopsy length - > 1 cm At least 10 portal tracts should be seen Any amount of tissue that yields diagnosis Transjugular biopsy : smaller, thinner, fragmented tissue cores (4 fragmented cores) or at least 4-6 portal tracts Best is laparoscopic biopsy

19. Histology Lobular model 2-3 mm diameter lobule Hexagonal shape T he central hepatic vein (terminal hepatic vein) Portal tracts at the periphery Portal tract- portal vein, hepatic artery, bile duct

20. Conti.. Hepatocytes around central vein - centrilobular (zone3), portal tract - periportal (zone 1), in between mid zonal (zone 2) Hepatocytes – polygonal, central single nucleus, cells arranged in plates Sinusoids on either side of cell plate Sinusoids – lined by fenestrated endothelial cells P BD

21. Conti.. Space of disse – lies below the endothelial lining of sinusoids has stellate cells Kupffer cells- mononuclear phagocytic cells, on luminal side of sinusoids

22. Conti.. Bile canaliculi – seen in between hepatocytes, 1-2 𝛍 diameter, drain into canal of hering , in turn drain into bile duct

23. Acute Injury Response of liver parenchyma to acute injury Necrosis Hepatocytes swells Blebs are formed and carry out organelles out of the cell Cell rupture Macrophage infiltration at the site of necrosis Apoptosis Nuclear pyknosis , karyorrhexis Acidophilic bodies – councilman bodies

24. Disease process continues Spotty necrosis/ focal necrosis - Death of individual hepatocytes or small groups of these cells Confluent necrosis – widespread parenchymal loss, a zonal loss of hepatocytes

25. Bridging necrosis – necrosis link central veins to portal tracts or bridge the adjacent portal tract Panlobular and multilobular necrosis - confluent necrosis involving entire single lobules or several adjacent lobules respectively

26. Bridging necrosis p c

27. Panlobular and multilobular necrosis

28. Scar formation and regression Stellate cells – most important, myofibroblastic properties

29. Approach to liver biopsy interpretation Architecture Maintained Collapse Fibrosis Hepatocellular changes Necrosis apoptosis Cholestasis Canalicular Ductular Portal tract Inflammation Edema Bile ductular reaction Ductopenia Fibrosis Inflammatory infiltrate Neutrophils Eosinophil's Mononuclear cell

30. Acute viral hepatitis

31. Acute viral hepatitis Usually Pan lobular C entrilobular – hepatitis B, C Periportal – hepatitis A Hepatocytes – ballooning, pale granular cytoplasm or shrinkage, nuclear pyknosis – acidophilic bodies (Councilman bodies), Bilirubinostasis Mononuclear and lymphocytic infiltration Spotty necrosis

32. Acute viral hepatitis bridging necrosis . curved lines of necrotic debris and collapse extend from a portal tract to cetral venule . C P

33. Acute viral hepatitis multilobular necrosis Portal tract (arrow) can be identified but the parenchyma has been replaced by inflammatory cells, necrotic debris

34. Fate and morphological sequel of acute viral hepatitis Resolution Scarring Chronic hepatitis Cirrhosis Acute liver failure Hepatocellular carcinoma

35. Chronic hepatitis Classic causes of chronic hepatitis Hepatitis B, with or without HDV infection Hepatitis C Autoimmune hepatitis Drug-induced hepatitis – methotrexate, OCP, vitamin A, acetaminophin Chronic hepatitis of unknown cause

36. Chronic hepatitis The portal tract is heavily infiltrated with lymphocytes (H&E) Interface hepatitis - process of inflammation and erosion of the hepatic parenchyma at its junction with portal tracts or fibrous septa (H&E)

37. Chronic hepatitis Chronic hepatitis with lobular activity. Clumps of inflammatory cells, some of them associated with hepatocyte loss, extend through the parenchyma. The portal tract above is inflamed. (H&E .)

38. Chronic hepatitis B the central part of the cytoplasm has a homogeneous ground-glass appearance. Sanded nuclei – fine granular, eiosinophilic Cytoplasmic inclusions of HBsAg are present .

39. Chronic hepatitis C The portal tract is heavily infiltrated by lymphocytes, A lymphoid follicle with germinal center has formed 15-25% may have steatosis

40. Autoimmune hepatitis Female predilection Chronic progressive hepatitis with features of autoimmune diseases Genetic predisposition Associated with other autoimmune disorders Therapeutic response to immunosuppression

41. Autoimmune hepatitis Type 1 Any age (Middle aged to old age) Presence of antinuclear antibodies (ANA), anti smooth muscle actin antibodies (SMA), anti soluble liver antigen/liver- pancreas antigen( anti-SLA/LP), anti mitochondrial (AMA) antibodies Type 2 Children and teenagers Anti liver kidney microsome-1 antibodies

42. Autoimmune hepatitis Interface hepatitis Plasma cell predominates in the mononuclear inflammatory infiltrate

43. Autoimmune hepatitis Hepatocytes rosettes in areas of activity Confluent necrosis, parenchymal collapse Plasma cell infiltration seen ( characteristic )

44. Drug induced hepatitis

45. Conti..

46. N ecroinflammatory score for chronic hepatitis (HAI/ Knodell score)

47. Conti…

48. Grading for chronic hepatitis Minimal activity (grade 1). Inflammation is confined to the portal tracts and there is no interface hepatitis. The lobular parenchyma is quiescent Mild activity (grade 2 ). Focal interface hepatitis present (right periportal region) in addition to portal tract inflammation. A few lobular necroinflammatory foci are also seen at right

49. Grading for chronic hepatitis Moderate activity (grade 3). More extensive interface hepatitis is present than in grade 2, but involving <50% of the circumference of most portal tracts. Marked activity (grade 4 ). The portal tract is diffusely inflamed and shows extensive circumferential interface hepatitis. Similar changes affect virtually all portal tracts with this grade of activity, often with considerable lobular activity.

50. Cirrhosis Results from interplay between parenchymal damage, fibrinogenesis , fibrinolysis and hepatocellular regeneration Main Causes Hepatitis B, C, Alcohol abuse Biliary diseases Metabolic disorders Drugs, toxins Autoimmune hepatitis Venous out flow obstruction

51. Criteria for cirrhosis Fundamental Nodularity Fibrosis Relative Fragmentation Abnormal structure Hepatocellular changes Regenerative hyperplasia Pleomorphism Large-cell dysplasia (large-cell change) Small-cell dysplasia (small-cell change)

52. Classification based on size of the nodule Micronodule - < 3 mm causes - Alcohol, Metabolic, Hemachromatosis , Wilson's Disease Macronodule - > 3 mm causes – Viruses (B,C), Toxins, Poisoning Mixed – equal number of both nodules

53. Cirrhosis Cirrhosis: micronodular pattern. Nodules are of lobular size or smaller , reticulin stain Cirrhosis: macronodular pattern. Nodules are larger than 3 mm, reticulin stain

54. Fragmented sample Cirrhosis: fragmented sample. A specimen obtained by the biopsy method has broken into rounded fragments peripherally circumscribed by fibrosis, reticulin stain

55. Abnormal structures Cirrhosis: selective sampling. A nodule has been cored out of the connective tissue by the biopsy procedure, but a thin layer of connective tissue (arrow) has adhered to the nodule margin. (Needle biopsy, reticulin .) Cirrhosis: distorted reticulin pattern. The distortion has resulted from abnormal and irregular hepatocyte growth patterns. (Needle biopsy, reticulin .)

56. Hepatocellular changes Cirrhosis: hepatocellular regeneration. Liver-cell plates are two or more cells thick, indicating active growth. (Needle biopsy, H&E.) Cirrhosis: large-cell dysplasia , nuclei of the enlarged hepatocytes irregular in shape and vary greatly in size and staining intensity. Cells are multinucleated. The normal hepatocytes at right and in the upper left-hand corner. (Wedge biopsy, H&E.)

57. Hepatocellular changes Cirrhosis: small-cell dysplasia (small-cell change). The hepatocytes below and to the right have normal-sized nuclei, but their overall size is reduced. Nuclear– cytoplasmic ratios are therefore increased. (Needle biopsy, H&E.)

58. Assessment of cause for cirrhosis Pattern of nodules and fibrosis regular irregular Bile ducts Ductular reaction Ductopenia fibrosis Blood vessels Narrowing Ischemic changes Steatohepatitis Evidence of viral infection Abnormal deposits Iron Copper, copper-associated protein α1- Antitrypsin globules

59. Ishak score for Staging of fibrosis

60. Alcoholic liver disease 3 forms of alcoholic liver injury Hepatocellular steatosis Alcoholic hepatitis ( steatohepatitis ) Steatofibrosis

61. Hepatic steatosis There are large fat vacuoles in perivenular hepatocytes, displacing the nuclei to the edges of the cells. (Needle biopsy, H&E.)

62. Steatohepatitis Alcoholic steatohepatitis . Ballooning, necrosis,. Inflammatory cells, mainly neutrophils. contain densely stained Mallory bodies (arrows). Many hepatocytes contain large fat vacuoles. (Needle biopsy, H&E.) ASH cannot be differentiated from NASH Mallory bodies. The Mallory bodies in this example of steatohepatitis stain strongly for ubiquitin (arrows)

63. Steatofibrosis Micro nodules entrapped in blue-staining fibrous tissue . Fat accumulation no longer seen, burned out stage. ( masson trichrome stain)

64. Metabolic liver diseases Non alcoholic fatty liver disease Hemochromatosis Wilson disease 𝛂1 a ntitrypsin deficiency Glycogen storage diseases Gaucher’s disease Niemann –Pick disease

65. Non alcoholic fatty liver disease NAFLD is a group of conditions that have in common the presence of hepatic steatosis (fatty liver), in individuals who do not consume alcohol, or do so in very small quantities (less than 20 g of ethanol/week ) NAFLD Fatty liver NASH Fibrosis Cirrhosis Associated with metabolic syndrome

66. Non alcoholic fatty liver disease NASH predominantly mononuclear inflammatory cell in filtrate with both small and large fat droplets (H&E) Steatofibrosis prominent at portal region, extending along the sinusoids in a chicken wire pattern around the hepatocytes ( masson trichrome )

67. NAFLD Score

68. Hemochromatosis Excessive iron absorption, most of which is deposited in parenchymal organs like liver, pancreas, heart, joints, endocrine organs Normal iron pool 2-6 gm in adults 0.5 gm stored in liver (98% in hepatocytes) Disease manifestation appear when the iron load > 20gm

69. Hemochromatosis Mutations of TFR1, TFR2, HJV, HFE gene mutation lead to decrease production of hepcidin and increased absorption of iron and increased release into circulation Serum ferritin >1000 µg/L Transferrin saturation > 45% Serum iron > 150 µg/dl

70. Classification of hemochromatosis

71. Hemochromatosis Hepatocytes showing iron over load, stained blue color in perl’s prussian blue stain, note the inflammation characteristically absent .

72. Wilson disease A utosomal recessive disorder M utation of the ATP7B gene, I mpaired copper excretion into bile and a failure to incorporate copper into ceruloplasmin Copper accumulate in liver and later brain Serum ceruloplasmin < 20 mg/dl 24 hr Urine copper > 100 𝛍 g/dl Total serum Cu < 60 𝛍 g/dl

73. Wilson’s disease Fatty change, mild to moderate hepatocytic necrosis, with inflammatory infiltrate, intranuclear glycogen inclusions also seen. The upper nodule is strongly positive for copper, stained orange-red. The lower nodule is completely negative. (Wedge biopsy, rhodanine .)

74. Glycogen Storage Diseases A hereditary deficiency of one of the enzymes involved in the synthesis or sequential degradation of glycogen The liver is important in glycogen metabolism. Type 1( von Gierke ) is most common for liver – absence of glucose 6 phosphatase

75. Von Gierke disease type I glycogen storage disease, PAS positive and after treating with diastase hepatocytes are swollen and resemble plant cells ,the abundant glycogen displaces the organelles of affected cells to the periphery. Sinusoids are compressed . Slender periportal fibrous scars often develop

76. Gaucher’s disease A utosomal recessive disorders resulting from mutations in the gene encoding glucocerebrosidase Glucocerebrosidase - cleaves the glucose residue from ceramide . T he enzyme defect, glucocerebroside accumulates in phagocytes, kupffer cells

77. Gaucher’s disease Pale-staining, striated Kupffer cells containing stored lipid are present within sinusoids. The affected cells compress hepatocytes and sinusoids and may give rise to portal hypertension. Pericellular fibrosis is a common finding

78. Niemann –Pick disease L ysosomal accumulation of sphingomyelin due to an inherited deficiency of sphingomyelinase

79. Niemann –Pick disease accumulation of sphingomyelin in both hepatocytes and macrophages. The latter are greatly swollen, foamy and diastase–PAS-positive to a variable extent , Niemann –Pick disease may progress to cirrhosis

80. 𝛂1 - Antitrypsin deficiency A utosomal recessive disorder low levels of α 1 -antitrypsin Normal functions – inhibitors of protease, elastase , protease 3, cathepsin G which are released by neutrophils at the site of inflammation Mutated α 1 -antitrypsin protein abnormally folded inside the ER and lead to apoptosis of cell.

81. 𝛂1 - Antitrypsin deficiency Hepatocytes near periportal region contain mutated proteins, and stained magenta color for PAS+diastase . May also show steatosis , necrosis and fibrosis

82. Cholestasis diseases R efers to impairment of bile flow. In light microscope- bile pigment within bile canaliculi , hepatocytes and other sites . Bile is seen in the form of bile thrombi (bile plugs) in dilated canaliculi

83. Large bile-duct obstruction Causes in children Biliary atresia Cystic fibrosis Choledochal cyst Causes in adults Gall stones Malignancies of biliary tree, head of pancreas Stricture from previous surgery

84. Large bile-duct obstruction Dilatation intercanaliculi Portal tract edema Bile duct proliferation at the margin of portal tract Mild inflammatory infiltrate

85. Chronic bile-duct obstruction and biliary cirrhosis(secondary biliary cirrhosis) Bile duct obstruction persists, bile duct infarct and increasing fibrosis. Jigsaw puzzle shape

86. Primary biliary cirrhosis Autoimmune disease characterized by nonsuppurative , inflammatory destruction of small and medium sized intrahepatic bile ducts Antimitochondrial antibodies recognize E2 component of pyruvate dehydrogenase complex of mitochondrial membrane, Altered MHC II of bile ductal epithelial cells seen, causes autoactivation of T cells

87. Stages of primary biliary cirrhosis

88. Primary biliary cirrhosis Grannulomatous lesion surrounding bile duct with mononuclear cell infiltration Florid duct lesion

89. Primary biliary cirrhosis D uctular reaction with periportal hepatitis A lymphoid aggregate and a follicle with a germinal Centre (arrow )

90. Primary biliary cirrhosis Scarring; bridging necrosis, septal fibrosis There is extensive scarring with irregular nodule formation. Aggregates of lymphocytes mark the former sites of bile ducts

91. Primary sclerosing cholangitis I nflammation and obliterative fibrosis of intrahepatic and extrahepatic bile ducts, with dilation of preserved segments Immunological mediated injury to bile duct T cells in periductal region Autoantibodies to HLA-B8, MHC antigens pANCA can be noted in circulation O n cholangiographic demonstration of the characteristic beading of bile ducts May be associated with inflammatory bowel disease

92. Primary sclerosing cholangitis A bile duct undergoing degeneration is entrapped in a dense, “onion-skin” concentric scar

93. Cholestasis of sepsis By 3 main mechanism Direct effect of intrahepatic bacterial infection (abscess, bacterial cholangitis) Ischemia relating to hypotension due to sepsis ( when liver is cirrhotic) Response to circulatory microbial products (most common)

94. Cholestasis of sepsis Canalicular cholestasis – bile plug at centilobular canliculi , sometime associate with kuffer cell activity and mild poratl tract inflammation Ductular cholestasis – dilated canal of hering and bile ductules at the interface of portal tracts and parenchyma become dilate and contains bile plug

95. Biliary atresia Partial or complete obstruction of the lumen of the extrahepati biliary tree within the first 3 months of life Most common cause of neonatal cholestasis 2 types Fetal type (20%) Perinatal type (80%)

96. Cont.. Fetal form Malrotation of abdominal viscera Interruptured inferior vena cava Polysplenia Congenital heart disease Perinatal form Viral ( reovirus , rotavirus, CMV) Autoimmune reaction

97. Biliary atresia An expanded, inflamed portal tract at left contains many proliferated bile ducts, some of which are filled with inspissated bile.

98. Congenital hepatic fibrosis Autosomal recessive inherited condition Due to Ductal plate malformation P resents with hepatomegaly or portal hypertension, usually in childhood but occasionally in adults Associated with polycystic disease of kidney Misdiagnosed as cirrhosis

99. Congenital hepatic fibrosis Several portal tracts are interconnected by bridging fibrous septa containing ductal plate malformations. The fibrosis surrounds normal parenchyma with a terminal venule (short arrow) preserved in a central position. Inset: Higher magnification of the abnormal duct structures seen at lower left (long arrow).

100. Indian childhood cirrhosis H igh mortality affecting young Indian children (and Indian subcontinent) B rass- and copper-containing vessels used for milk-feeding - identified as sources of copper contamination Large amounts of copper and copper-associated protein accumulate in affected hepatocytes

101. Indian childhood cirrhosis Many liver cells are swollen ( centre ), and surrounded by fibrosis and mononuclear cells. Regenerating hepatocytes are organised into small clusters. Disease progress l/t micronodular cirrhosis (H&E .)

102. Granulomatous lesion

103. TB Granuloma Sarcoid Granuloma PBC Granuloma Fibrin Granuloma

104. Nodules and tumors

105. Hepatocellular adenoma Liver cells appear normal or contain fat vacuoles. Blood vessels but no portal tracts are seen within the lesion. (H&E .)

106. Focal nodular hyperplasia (FNH ) Central scar with arteriole, periphery shows fibrous septa with bile duct proliferation (arrow), surrounding the scar is the nodule consists of normal hepotocytes .

107. Nodular regenerative hyperplasia(NRH) This abnormal, nodular growth pattern is not accompanied by fibrosis and therefore differs from cirrhosis. The parenchymal nodules (N) are often adjacent to nodule (at left) or surrounding portal tracts. The intervening liver shows flattened and compressed liver-cell plates and/or sinusoidal dilatation (H/E) N N

108. Bile-duct adenoma This subcapsular tumour consists of closely packed well formed bile ducts set in a dense fibrous stroma . A dense collection of lymphocytes is seen at the edge of the lesion (bottom). (H&E .)

109. Hemangioma Locate beneath the capsule. Blood-filled spaces are separated by fibrous septa. A thick capsule is seen at right. ( H&E.)

110. Hepatocellular carcinoma Precursors of hepatocellular carcinoma Chronic cirrhosis Large cell dysplasia Small cell dysplasia Macroregenerative nodule Dysplastic nodule

111. Macroregenerative nodule This low-magnification view demonstrates the increased size of the nodule at left compared with the cirrhotic nodules at right.

112. Dysplastic nodule The dysplastic nodule at right shows hepatocytes arranged in pseudoacini , with a less cohesive growth pattern centrally. A cirrhotic nodule is present at lower left. Cells show nuclear atypia , (H&E)

113. Hepatocellular carcinoma Trabeculae -sinusoidal pattern, trabeculae are thicker and reticulin is often scanty or even absent, ( HandE ) Reticulin is scanty in this example. Reticulin stain

114. Hepatocellular carcinoma Adenoid pattern.

115. Grading of HCC Grade 1 (well differentiated) tumours have small, round nuclei prominent nucleoli almost similar to those of normal and cirrhotic liver. HandE Grades 2 show progressive alterations in nuclear contour, chromatin coarseness and hyper chromaticity

116. Conti.. Grade 3- more nuclear atypia compared to grade 2 and nuclear crowding is seen Grade 4 shows marked anaplasia with giant, multinucleated tumour cells and atypical mitotic figures

117. HCC - F ibrolamellar type Occur under the age of 30yrs, occur as single large, hard, scirrhous tumor.Tumor cells are well differentiated, shows oncocytic change, separated by parellel lamellae of dense collagen bundles.

118. Heptatocellular carcinoma Immunostaining Hep Par 1 (hepatocyte) Polyclonal CEA Cytokeratin 7/20 pair (−/− staining ) GPC-3/GS/HSP70 trio (recent and confirmative, any 2 + ve indicates HCC) Glypican - 3 (GPC-3) G lutamine synthetase (GS) H eat shock protein 70 (HSP70)

119. Hepatoblastoma Most common liver tumor of early childhood Occur at the age of 3yr 2 variants Epithelial – polygonal fetal or embryonal cells arranged in acini , tubules, papillary Mixed epithelial and mesenchymal – admixed with osteoid, chondroid , striated muscle

120. Hepatoblastoma Epithelial type - The tumour grows in cords of small hepatocytes with a ‘light-and-dark’ cells due to the admixed clear ( glycogenated ) and eosinophilic liver cells .( H & E.)

121. cholangiocarcinoma Malignancy of the biliary tree, arising from the bile duct within and outside of the liver Risk factors Chronic inflammatory conditions Primary sclerosing cholangitis Hepatolithiasis Fibropolycystic disease

122. Conti.. 2 types Intra hepatic Extra hepatic ( perihilar , klatskin tumor) Premalignant lesions – biliary intraepithelial neoplasias ( BilN ) Low grade BilN 1 and 2 High grade BilN3

123. cholangiocarcinoma There are islands of adenocarcinoma in the connective tissue, well formed glands lined by malignant tumor epithelial cells. Lymphovascular and perivascular invasions are common

124. Liver allograft rejection Acute cellular rejection Most common within one month, but can occur later Traid – portal inflammation, bile-duct damage & endothelitis Chronic rejection Occur after 6 months of transplantation

125. Host vs graft reaction Acute rejection- Heterogeneous portal inflammation consisting of lymphocytes, plasma cells and scattered neutrophils infiltrates the bile duct (between arrows) and the portal vein branch at top. (Needle biopsy, H&E.) Endotheliitis in acute rejection. An efferent vein shows lymphocytic infiltration of its wall. The endothelium is focally lifted off the underlying vein wall and partially destroyed. (Needle biopsy, H&E.)

126. Graft vs host reaction Chronic ( ductopenic ) rejection. An hepatic artery branch (arrow) is present in the portal tract but the corresponding interlobular bile duct has disappeared as a result of rejection. A sparse lymphocytic infiltrate remains. (Explanted donor liver, H&E.)

127. Vanishing duct syndrome Neonatal age Biliary atresia Alagalie syndrome Adult age PBC PSC Overlap syndrome Drug induced Chronic graft vs host rejection Idiopathic

128. Summary Acute severe liver injury and in advanced stages of fibrosis/cirrhosis – etiological diagnosis usually not possible Drug induced liver injury can present with any form of liver injury. Hence we cannot exclude if clinically suspected. Fibrosis with normal liver architecture – suspect congenital hepatic fibrosis

129. Summary Excess iron in liver is not always hemochromatosis. Infact most common cause is alcoholic cirrhosis Clinically suspected cirrhosis but no fibrosis on biopsy than look for NRH, and hepatic venous outflow obstruction Poorly differentiated HCC and cholangiocarcinoma difficult to differentiate – use IHC

130. References Theise ND. L iver and gall bladder. In: kumar , A bbas, Aster, Robbins and Cotran Pathologic Basis of Disease. 9 th ed. New Delhi: Reed Elsevier India Private limited; 2014. 185-263 Desmet VJ, Rosai J. Liver. In: Rosai J, Rosai and ackerman’s surgical pathology. 10 th ed. New Delhi: Reed Elsevier India Private limited; 2012. 857-942

131. Gill RM, Kakar s, Washington K. non neoplastic liver diseases and masses of the liver. In: G reenson JK, Hornick JL, Longacre TA, Reuter VE, Sternberg’s diagnositc surgical pathology. 6 th ed. China: Wolters Kluwer; 2015. 1663-1704 Lefkowitch HJ. SCHEUER’S Liver Biopsy Interpretation. 8 th ed . China: Reed Elsevier; 2010

132. Feldman M, Friedman LS, Brandt L. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 9 th ed. Philadelphia. Reed Elsvier ; 2010 Sanai FM, Keeffe EB. Liver Biopsy for Histological Assessment – The Case. AgainstSaudi J Gastroenterol . 2010 Apr-Jun;16(2):124-32

133. Schiff ER, Maddrey WC, Sorrell MF. Schiff’s Diseases of Liver.11 th ed. London: Wiley blackwell ; 2012.