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Liver biopsy interpretation

histopathology

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Liver biopsy interpretation

  1. 1. LIVER BIOPSY INTERPRETATION Dr. MAITHILI KULKARNI Guide Dr. J. K. KUDRIMOTI Dr. M. V. JADHAV
  2. 2. NON INVASIVE CLINICAL EVALUATION • Detailed history of hepatotoxins , source of infection • Physical examination • Battery of appropriate lab tests of liver function & integrity • Serologic tests for infectious agents & autoimmunity • Radiological studies
  3. 3. Four methods :- Percutaneous needle biopsy (transcut. Intercostal route), Usg & CT guided Bx Laparoscopy, Laparotomy, Transvenous route (Transjugular / transfemoral)
  4. 4. • The choice of one technique over another is based on availability, personal preference, and the clinical situation. Choice Of Technique
  5. 5. THREE TYPES OF NEEDLES :  Vim-Silverman’s needle,  Menghini’s aspiration biopsy needle,  ‘Tru-cut’ biopsy needle (modified Vim- Silverman’s) • Biopsy Gun / Biopter (modified Tru-cut needle)
  6. 6. INDICATIONS FOR LIVER BIOPSY  Diagnosis, grading, and staging of alcoholic liver disease, nonalcoholic steatohepatitis, or autoimmune hepatitis  Grading and staging of chronic hepatitis C or chronic hepatitis B  Diagnosis of hemochromatosis in index patient and relatives, with quantitative estimation of iron levels  Diagnosis of Wilson’s disease, with quantitative estimation of copper levels  Evaluation of the cholestatic liver diseases primary biliary cirrhosis and primary sclerosing cholangitis
  7. 7.  Evaluation of abnormal results of biochemical tests of the liver in association with a serologic workup that is negative or inconclusive  Evaluation of the efficacy or the adverse effects of treatment regimens (e.g. methotrexate therapy for psoriasis)  Diagnosis of a liver mass  Evaluation of the status of the liver after transplantation or of the donor liver before transplantation  Evaluation of fever of unknown origin, with a culture of tissue INDICATIONS FOR LIVER BIOPSY Continued …..
  8. 8. Contraindications to liver biopsy include the following: • Increased prothrombin time, international normalized ratio (INR) greater than 1.6 • Thrombocytopenia, platelet count less than 60,000 • Ascites (transjugular route preferred) • Difficult body habitus (transjugular route preferred) • Suspected hemangioma • Suspected echinococcal infection • Uncooperative patient
  9. 9. Complications of percutaneous liver biopsy  Pain – Pleuritic, Peritoneal, Diaphragmatic  Hemorrhage – Intraperitoneal, – Intrahepatic and/or sub capsular – Hemobilia  Bile peritonitis  Bacteremia  Sepsis and abscess formation  Pneumothorax and/or pleural effusion  Hemothorax  Arteriovenous fistula  Subcutaneous emphysema  Anesthetic reaction  Needle break  Biopsy of other organs :- – Lung, Gallbladder, Kidney, Colon
  10. 10. Interpretation of liver biopsy starts with gross examination of biopsy specimen Hand lens can be used • Cylinders of even color & thickness which not fragment easily- normal liver • Cirrhosis- Fragmented, irregular in caliber, obviously nodular • Nodular, no fibrous septa – NRH • steatosis - Yellow color, greasy sensation , float in fixative
  11. 11. Limitations  Sampling error – focal lesions (cysts , tumors ) can not be entirely excluded  Misdiagnosis – inadequate sample  Operative biopsies – hemorrhages , PMN infiltration  Artifacts –due to rough handling , poor fixation
  12. 12. Adequacy Of Sample • In general, a sample of • 1.5 cm in length • 1.2-2 mm in diameter and • contains at least 3 portal triads is considered adequate. This represents approximately 1/50,000th of the adult liver. • Adequacy depends on the disease process concerned. • In HCC, adequate if malignant cells are seen, amyloidosis, storage disorder
  13. 13. Gross Examination  Hand lens can be used  Fragmented, irregular in caliber, obviously nodular – Cirrhosis  Nodular, no fibrous septa – NRH  Yellow colour, greasy – float in fixative – steatosis  Rusty brown – genetic hemochromatosis  Slate gray - malaria,  Brown-Black - Dubin Johnson syndrome  Black – protoporphyria  Light tan to white foci – lymphoma carcinoma
  14. 14. Gross cont  Rusty brown –genetic hemochromatosis  Slate gray- malaria  Black or dark brown- Dubin Johnson syndrome  Black – protoporphyria  Deep red - cong  Light tan to white foci – lymphoma carcinoma
  15. 15. Processing Of specimen Excessive manipulation should be avoided USE OF FIXATIVE – FOR LIGHT MICROSCOPY- 1. Routinely - 10 % neutral formalin 3 hrs at room temp 2. For metabolic diseases which contain water soluble stored material – • Cystinosis GSD– alcohol • Mucopolysaccharidosis – Lindsays dioxane picrate 3. Frozen section – demonstration of lipids , immunohistochemisry FOR ELECTRON MICROSCOPY – minute pieces put into appropriate fixative like glutaraldehyde Uses – inborn error of metabolism, tumor of doubtful histogenesis, viral infection
  16. 16. SECTIONS TO BE TAKEN • 3 to 5 micron sections –consecutive sections • For special stains- Depending on clinical suspicion, no. of sections are taken • Serial or step sections – granulomas or tumor deposits ,parasitic egg,larva, Serial biopsies following liver transplant.
  17. 17. MICROSCOPY STAINS USED 1. H & E stain 2. Special stains H & E Stain • All fragments should be examined • Look for –architecture (Special stain is required) • Locating terminal hepatic venules – moving in direction of portal areas • Look at- portal tracts, Hepatocytes, Bile canaliculi, Sinusoids & their contents, Kupffer cells Abnormal deposits in spaces of Disse–amyloid, collagen
  18. 18. Normal portal tract and central vein
  19. 19. Special stains • Reticulin – structural changes , outlining areas of focal or zonal necrosis, • MT- • Pericellular fibrosis • New collagen formation • Changes involving blood vessel • Elastin – For recent collapse/fibrosis • Orcein – elastic tissue, hepatitis B surface Ag, Cu associated protein • PAS – complex CHO, glycogen (benign & malignant hepatocellular tumors) • D-PAS – to remove glycogen, 1 antitrypsin –DPAS positive • PAS – amyloid, starch, amoebae, pathogenic fungi, basement membrane of acinar ducts • PTAH – fibrin in (DIC & Eclampsia)
  20. 20. • Gomori methanamine silver – fungi • Prussian Blue :- Iron • Rhodanine :- Cu( ICC, Chronic cholestasis, wilson) • PTAH -> Fibrin • Van Gieson -stains Bile green • Congo red - Amyloid • AFB -> TB bacilli, schistosoma egg, hooklets in scolices of echinococcal cyst Special stains continued…..
  21. 21.  Warthin starry - Spirochetes, Leptospira, cat scratch bacilli  Geimsa -> Hematopoietic cells  Frozen – Oil red O -> Neutral Lipid  Bakers acid hematin with pyridine reaction -> Neimannpick
  22. 22. Liver, Wilson disease - High power This special stain (rhodanine stain) highlights the accumulation of copper in the hepatocytes of patients with Wilson disease.
  23. 23. Low power :  Quality of biopsy (size, staining),  Overall architecture,  Presence / absence of normal structures,  Pattern of injury,  Fibrosis and nodularity,  Gross area of necrosis or congestion
  24. 24. Medium & High power :  Portal tracts :  Presence of normal structures (Bile duct, vein, artery),  Inflammation (Type, intensity, relation with normal structures),  Fibrosis, edema,  Bile duct changes (inflammation, proliferation, necrosis, cholestasis, loss),  Arterial / venous changes (inflammation, thrombosis)
  25. 25. Medium & High power :  Lobule : Inflammation (type, intensity, location/zonality), Necrosis (type, intensity, location/zonality), Status of cell plates (regeneration, atrophy),  Status of sinusoids (dilated, congested)  Other changes : Amyloid deposition, Fibrosis,
  26. 26. Medium & High power :  Central vein :  Size, shape (round / compressed),  Inflammation,  Fibrosis
  27. 27. Degeneration :  Ballooning  Feathery,  Fatty (Steatosis),
  28. 28. • Hydropic change / Oncosis): increased cell volume with pale staining granular cytoplasm • seen in damage from toxic, ischemic or immunological insult, e.g. Ac Hep., Alc. Hep.
  29. 29. •.swollen hepatocytes with thread-like reticular yellowish brown cytoplasm • seen in Cholestasis
  30. 30. HYALINE DEGENERATION – Mallory's hyaline represents aggregates of intermediate filaments- alcoholic hepatitis , non alcoholic steatohepatitis , HCC, ICC, Wilson Ds,
  31. 31. Type of deposition Acinar distribution Possible complications  Macrovesicular- alcohol, obesity, DM, TPN, PEM  Microvesicular- AFLP, Reyes, Tn, jamiakan vomiting sickness  Mixed  Focal
  32. 32. Type of fat Acinar distribution Possible complications  Periportal- TPN, AIDS, Kwashiorkar  Centrilobular- Alc, obesity, DM  Diffuse
  33. 33. Type of fat Acinar distribution Possible complications  Steatohepatitis  Portal fibrosis  Cirrhosis
  34. 34.  Alcoholic liver disease (ALD),  Obesity,  diabetes mellitus,  Kwashiorkor,  Drugs,  Ethanol,  Methotrexate  Chr. HCV,  Metabolic diseases
  35. 35.  Acute fatty liver of pregnancy  Reye’s syndrome  Drugs  Tetracyclins,  Valproate toxicity  Salicylates,  TPN  Cholesterol storage diseases  Toxic shock syndrome
  36. 36. Apoptosis :  Acidophil / Councilman bodies •hepatocyte shrinkage, • increased eosinophilia •and nuclear pyknosis •Acute Viral hepatitis, AIH
  37. 37. Necrosis :  Spotty / Focal,  Confluent / Bridging  Submassive,  Massive,  Zonal,
  38. 38. Zones Causes Zone 1 • Eclampsia, • HAV, • Infectious mononucleosis, • Phosphorous poisoning Zone 2 • Yellow fever Zone 3 • Shock, • CCF, CCL4 • Chloroform poisoning
  39. 39. Liver Cell Necrosis 1. Focal necrosis- Non specific reaction to disease elsewhere in body, spotty-same lesion with Gap in liver cell plates- Liver cell dropout & inflammatory reaction.- acute hepatitis 2. Haphazardly distributed areas of necrosis- Disseminated herpes virus, micobacteria. 3. Tumor Necrosis- Reticulin pattern 4. Bridging necrosis- Bridging of THV to PT- acute viral hepatitis (No elastic fibers) 5. Piecemeal Necrosis: Destruction of liver cells at an interface between portal tract & parenchyma with lymphoplasmacytic infiltrate- chronic hepatitis
  40. 40. Diffuse confluent necrosis: With inflammation : Viral hep, Drug induced hep Without : Shock, LVF
  41. 41. Inflammation : Hepatitis, Interface hepatitis,  Lymphocytic (Classic),  Biliary (Lympho + Poly)
  42. 42. Hemosiderin Golden brown refractile, PB positive  In hepatocytes – genetic hemochomatosis  In kupffer cells – hemolytic anemia ,viral hepatitis , Parenteral iron , blood transfusion , impaired release of iron – chronic infl , malignancy Lipofuscin – granular, near cytoplasmic membrane Bile:- Homogeneously stained- green/yellow or orange, bile plugs in small ductuels, hall staining Hemozoin pigment:- Malarial pigment in kupffer cells, finely granular, dark brown or black.
  43. 43. Hemosiderin- golden brown, PB + Lipofuschin- Yellow brown DJ pigment- Dark brown & black Bile pigment
  44. 44. Regeneration :- Disorganization of structure Mitoses, Multinucleation, Thickening of hepatocyte cords,
  45. 45. Fibrosis :- Bridging Cirrhosis
  46. 46. Non neoplastic lesions :  Infections : Hepatitis,  Cirrhosis,  Cholestatic liver dis,  Metabolic disorders,  Liver transplant,  Granuloma  Liver in systemic condn , Tumours & D/Ds :  Focal nodular hyperplasia,  Hepatocellular Adenoma,  Hepatoblastoma  Hepatocellular carcinoma,  Bile duct adenoma  Cholangiocarcinoma
  47. 47. Acute, Chronic, Autoimmune, Steatohepatitis
  48. 48. INFECTIVE :  Viral,  Bacterial,  Parasitic,  Fungal, DRUG INDUCED, AUTOIMMUNE
  49. 49. EBV- mild hepatitis during the acute phase; CMV - particularly in the newborn or immunosuppressed patient yellow fever- which has been a major and serious cause of hepatitis in tropical countries. Infrequently, in children and immunosuppressed patients, the liver is affected in the course of rubella, adenovirus, herpesvirus, or enterovirus infections. Hepatotropic viruses cause overlapping patterns of disease. Each hepatotropic virus and the disease conditions it causes will be introduced before a general discussion of hepatitis.
  50. 50. Ballooning degeneration (Hydropic change) Acidophil / Councilman bodies Interface hepatitis
  51. 51. Focal necrosis (Spotty necrosis) with collapse & mild lymphocytic infiltran Same (focal collapse) area on Reticulin stain
  52. 52. Lobular disarray, Portal tract infiltrate of lymphocytes & plasma cells with some neutrophils & eosinophils, Lobular infiltration of mixed infiltrate, ‘Ceroid macrophages’, Cholestasis (Cholestatic hepatitis), Ductular reaction,
  53. 53. Severe necrotizing hepatitis, with  ‘Confluent necrosis’, (usually centrilobular)  Bridging necrosis
  54. 54. Cause Histological Findings Other Features HAV Mild portal + lobular PL infiltrate, Cholestasis Serological markers, Self limiting HBV Prominent centrilobular bollooning degeneration Serological markers HCV Prominent portal lymphoid follicles, Bile duct damage Rarely acute, Serological markers CMV / HSV / EBV Confluent necrosis with minimal infiltrate, Typical viral inclusions Drugs Mixed infiltrate, Prominent eosinophils, Granulomas, Mixed steatosis History of hepatotoxic drug ingestion, Resolves after discontinuation AIH Abundant plasma cells, periportal areas of collapse, bridging necrosis Serum markers for Ab, ed  Globulins
  55. 55. Non neoplastic lesions :  Infections : Hepatitis,  Cirrhosis,  Cholestatic liver dis,  Metabolic disorders,  Liver transplant,  Liver in systemic condn , Tumours & D/Ds :  Focal nodular hyperplasia,  Hepatocellular Adenoma,  Hepatoblastoma  Hepatocellular carcinoma,  Bile duct adenoma  Cholangiocarcinoma
  56. 56. Acute, Chronic, Autoimmune, Steatohepatitis
  57. 57. INFECTIVE :  Viral,  Bacterial,  Parasitic,  Fungal, DRUG INDUCED, AUTOIMMUNE
  58. 58. Ballooning degeneration (Hydropic change) Acidophil / Councilman bodies Interface hepatitis
  59. 59. Focal necrosis (Spotty necrosis) with collapse & mild lymphocytic infiltran Same (focal collapse) area on Reticulin stain
  60. 60. Lobular disarray, Portal tract infiltrate of lymphocytes & plasma cells with some neutrophils & eosinophils, Lobular infiltration of mixed infiltrate, ‘Ceroid macrophages’, Cholestasis (Cholestatic hepatitis), Ductular reaction,
  61. 61. Severe necrotizing hepatitis, with  ‘Confluent necrosis’, (usually centrilobular)  Bridging necrosis
  62. 62. Cause Histological Findings Other Features HAV Mild portal + lobular PL infiltrate, Cholestasis Serological markers, Self limiting HBV Prominent centrilobular bollooning degeneration Serological markers HCV Prominent portal lymphoid follicles, Bile duct damage Rarely acute, Serological markers CMV / HSV / EBV Confluent necrosis with minimal infiltrate, Typical viral inclusions Drugs Mixed infiltrate, Prominent eosinophils, Granulomas, Mixed steatosis History of hepatotoxic drug ingestion, Resolves after discontinuation AIH Abundant plasma cells, periportal areas of collapse, bridging necrosis Serum markers for Ab, ed  Globulins
  63. 63. • Chronic hepatitis •HBV •HCV•HBV+HDV •AIH •Wilson’s Disease•PBC •PSC •A1AT •Hemochromatosis •Drugs •Cryptogenic •NASH •ALD
  64. 64. Hepatocellular necrosis (spotty/confluent) Portal / periportal inflammation Fibrosis Cirrhosis
  65. 65. Type Special Features HBV Ground glass hepatocytes HCV Portal lymphoid aggregates, Steatosis, Bile duct injury AIH Plasma cell portal infiltrate, Severe damage with rossettes & giant cell formn Drugs Any possible change
  66. 66. GRADE INFLAMMATION NECROSIS 0 None None 1 Portal or lobular None 2 Mild interface Focal 3 Moderate interface Confluent 4 Severe interface Bridging
  67. 67. STAGE FIBROSIS 0 No firosis 1 Enlarged portal tracts 2 Periportal / P-P septa 3 Bridging fibrosis 4 Cirrhosis
  68. 68. • Usually +nt as chr hepatitis, predominantly affecting females, viral serological markers must be negative, • IgG and Gamma globulin levels are raised (> 1.5 times), • High titre of ANA, AsmAb and Anti-LKM, Anti- mitochondrial Ab absent, • Correct diagnosis is imp. because pt. may benefit from immunosuppressive therapy, • High necro-inflammatory pathology, bridging confluent necrosis, marked interface hepatitis, hepatic liver cell rossettes, • Plasma cells, usually in clusters – prominent feature, • Lymphoid aggregates and follicles – may +nt (< HCV
  69. 69. Steatosis, Mallory bodies Neutrophilic infiltrate (Satellitosis) Perivenular/ pericellular fibrosis Alcoholic cirrhosis
  70. 70. Disruption of architecture, Regenerating nodules, Bridging fibrous septae
  71. 71. Establish diagnosis Possible aetiology To detect HCC
  72. 72. GROSS : Fragmented, Rounded, smooth MICRO (Retic stain): Thick cell plates, Condensed reticulin fibres surrounding nodules
  73. 73. Congenital Hepatic Fibrosis Parenchyma does not show e/o destruction or regeneration Disease Diffuse Involvement Septa Nodule Cirrhosis + + + Nodular regenerative Hyperplasia + - + Focal Nodular Hyperplasia - + +
  74. 74. Primary Sclerosing Cholangitis Primary Biliary cirrhosis, Sec. Biliary Cirrhosis
  75. 75. • CANALICULAR – dilated bile canaliculi bet hepatocytes • CYTOPLASM OF HEPATOCYTES & KUPFFER CELLS • DUCTULAR CHOLESTASIS – sepsis , ductal plate malformation • Acute – canalicular (perivenular ) •Chronic – periportal hepatocytes
  76. 76. Four stages : Florid duct lesion, Ductular proliferation, Scarring , Cirrhosis,
  77. 77. • AI dis with unknown etiology selectively affecting the small IHBD, • Initial lesions may be called ‘chronic non-suppurative destructive cholangitis’, • Middle aged women (peak 40-60 yrs), • Presents with intense pruritus d/t cholestatic jaundice, ass with antimitochondrial Ab (95%), granulomas (40-70%), • Progressive destruction of intrahepatic biliary tree by lymphoplasmacellular infiltrate, • Biopsy needle may fail to sample duct lesions owing to their focal distribution, •
  78. 78. Causes –  Cholelithiasis, Stricture  Malignancies of BT, ca of head of pancrease Histology –  Coarse fibrous septae divides the liver into irregular jigsaw pattern pseudolobules  FS contais small & large bile ducts with inspissated bile Extensive ductular proliferation  Hepatocytes showe xtensive feathery deg, with bile lakes,  PMN infiltrate around bile ducts
  79. 79. EHBA Cystic fibrosis Choledochal cyst
  80. 80. Aetiology Histological Features Extrahepatic biliary atresia Proliferation of bile ductules in portal tracts; portal fibrosis; ductular cholestasis Neonatal hepatitis Portal & lobular mononuclear cell inflammation; Giant cells; acidophil bodies
  81. 81. • Variety of disorders causing conjugated hyperbilirubinemia are called Neonatal hepatitis. • Infants present with jaundice, dark urine acholic stools n hepatomegaly • Biopsy critical role in distinguish between above two conditions,
  82. 82.  Primary • Hemochromatosi ss  Secondary
  83. 83.  Wilson’s disease,  Indian childhood cirrhosis
  84. 84. In alpha1-antitrypsin (AAT) deficiency, alpha1-antitrypsin accumulates in the cytoplasm of hepatocytes. Due to an inherited metabolic defect, the protein is not secreted and thus accumulates in hepatocytes. This is apparent as eosinophilic globular material in the cytoplasm of hepatocytes in a PAS-with-diastase-stained section.
  85. 85. Focal nodular hyperplasia, Adenoma, HCC,  Typical,  Fibrolamellar, Hepatoblastoma, Cholangiocarcinoma
  86. 86. Liver Cell Adenoma : – More or less normal reticulin pattern is detected throughout which is rarely seen even in well differentiated HCC. – Absence of fibrous tracts & bile ducts – differentiate from focal nodular hyperplasia – Absence of large amount of oedematous mesenchyme- from hamartoma
  87. 87. Hepatocellular Carcinoma
  88. 88.  Hepatocellular Carcinoma: – Trabecular Misshapen upto many cells thick, sinusoidal stroma – Deficiency of reticulinIn low grade Ca Differentiate from adenoma or dysplastic nodule. – Quality of stroma separating cords of tumour cells in HCC Empty or blood containing vessels where as in bile duct carcinoma Fibrous connective tissue. – Sinusoidal pattern and / or bile production  HCC – Glandular pattern and/or mucous secretion  CHOLANGIO CARCINOMA
  89. 89. Liver, hepatocellular carcinoma - Medium power This biopsy specimen shows irregular trabeculae or cords of malignant hepatocytes with enlarged nuclei that contain nucleoli, consistent with a well-differentiated hepatocellular carcinoma.
  90. 90. Liver, cholangiocarcinoma - Low power Malignant glands are noted within dense, fibrotic tissue (desmoplastic response) in this case of cholangiocarcinoma of the liver. Normal hepatic parenchyma is present in the upper right of the image.
  91. 91. Portal Tracts Points to be noted: 1. Adequacy of biopsy- At least 3 portal tracts 2. Contains hepatic artery, bile duct (of same size in the center), portal vein branch. 3. Number of bile ducts equal hepatic artery branches-look for ductopenia & ductal proliferation. 4. Inflammation 5. Limiting plate
  92. 92. INFLAMMATION CONFINED TO PORTAL TRACT  Canalicular cholestasis, spotty necrosis, stain for elastic fibers :Acute hepatitis – P,L,E,N – hepatitis A – L,P – hepatitis B, D, C – N,L – hepatitis E  Partial or complete loss of small & medium sized bile ducts ,lymphocytes , neutrophils ,granulomas  Chronic biliary tract disease  Wilsons disease –biochemical , clinical  PAS positive globulesAAT deficiency  Dense , more homogeneous , total or near total involvement of portal tractLymphoma – NHL
  93. 93. A Liver-Biopsy Specimen from a 32-Year-Old Man Presumed to Have Acute Hepatitis. The specimen shows a portal mononuclear infiltrate with prominent plasma cells (arrow in Panel A) and lobular inflammation with apoptotic hepatocytes (arrow in Panel B), findings consistent with the presence of autoimmune hepatitis (hematoxylin and eosin, ¬100). A B
  94. 94. Inflammation Confined To Portal Tract Portal Inflammation, lesions of bile duct in portal tract, periportal injury (piecemeal necrosis- destruction of limiting plates), degeneration & necrosis of hepatocytes, fibrosis (periportal or bridging)  Chronic Hepatitis 1. Grading Degree of activity 2. Staging Degree of fibrosis
  95. 95. Portal tract showing stellate "maple leaf" pattern of chronic active hepatitis with extensive piecemeal necrosis and loss of limiting plates
  96. 96. Margin of portal tract showing inflammation (predominantly lymphocytes) and piecemeal necrosis
  97. 97. Hepatic Artery  Systemic arterial diseases- SLE, giant cell arteritis  Systemic HTN- Thickened & hyaline  Amyloidosis- Thickening of arterial wall, congo red with polarized microscope Infarct- arteritis, aneurysm, thrombosis, embolism
  98. 98. Loss of bile ducts (ratio of BD HA <1)  Fibrous obliteration of ducts , dense portal fibrosis with little inflammation PRIMARY SCLEROSING CHOLANGITIS  Four Stages showing- 1. Florid duct lesion , portal hepatitis, 2. ductular proliferation & periportal hepatitis, 3. scarring, bridging necrosis ; septal fibrosis 4. cirrhosis (granulomatous cholangitis ,chronic inflammation of portal tract )  PRIMARY BILIARY CIRRHOSIS  Idiopathic  GVHD  Sarcoidosis  Rejection of liver graft
  99. 99. Liver, primary sclerosing cholangitis - High power Concentric periductular fibrosis around bile ducts, leading eventually to destruction and stricture of affected bile ducts, is seen in primary sclerosing cholangitis. In between the areas of stricture, bile ducts become ectatic and inflamed. The liver in primary sclerosing cholangitis eventually becomes cirrhotic.
  100. 100. Liver, primary biliary cirrhosis - Low power In this biopsy specimen of liver from a patient with primary biliary cirrhosis, the portal areas contain a chronic inflammatory infiltrate, consisting of lymphocytes, macrophages, plasma cells, and eosinophils.
  101. 101. Liver, primary biliary cirrhosis - Medium power At higher magnification, it is apparent that the chronic inflammation in the portal areas is associated with bile duct destruction by the inflammatory infiltrate. These are the hallmarks of the florid duct lesions in primary biliary cirrhosis.
  102. 102. Liver, primary biliary cirrhosis - Low power As liver damage progresses in patients with primary biliary cirrhosis, fibrous bridges form between portal areas. The end stage of the process is the development of biliary cirrhosis.
  103. 103. Bile Duct Proliferation – – Ductular proliferation – chronic liver disease (new duct formation ) – Elongation & tortuosity of preexisting interlobular ducts – obstruction to large bile ducts
  104. 104. PORTAL VEIN  Thrombosis – disorders of coagulation , cirrhosis , liver transplantation , invasion by HCC septic thrombi  Non cirrhotic portal fibrosis – portal vein branches are thickened , narrowed  Pipe stem fibrosis – schistosoma granuloma around parasitic ova
  105. 105. HEPATIC VEINS  Veno occlusive diseases – terminal hepatic venule , & intercalated veins occluded by fibrous tissue  Obstrution to large veins – ( budd chiari syndrome ) – perivenular sinusoids are dilated , hemorrhages & necrosis in zone3
  106. 106. SINUSOIDS  Dilatation & congestion – – CCF – Oral contraceptives – Venous outflow obstruction , tumor , granuloma – Sickle cell disease – Sickled RBCS  Neutrophilic infiltration – sepsis  Lymphocytes – mononucleosis , TSS  Fibrin thrombi – DIC , ( PTAH)  Peliosis – blood filled spaces , incomplete endothelial lining  Neoplasia – mets , leukemia , systemic mastocytosis  Parasites – malaria , microfilaria  Obliteration of sinusoids- GSD type 1
  107. 107. KUPFFER CELLS  Hypertrophy- 1. Malaria- Hemozoin pigment, in acute malaria-parasites, RBCs, iron 2. Leishmaniasis- LD bodies  Swollen foamy & DPAS positive neimann pick  Enlarged, moderate DPAS positive- Gauchers diseases
  108. 108. Aetiology Favoured Site Special Features Sarcoidosis Portal/Periportal Clustering, Hyalinization, Inclusion in giant cells Tuberculosis None Necrosis PBC Portal Near damaged bile duct, acinar granuloma uncommon Drugs None Eosinophills, Other lesions often presents (Hepatitis, fat, cholestasis) Mineral Oil Portal, perrivenous Oil Vacuoles Cue fever None Fibrin-ring granuloma HEPATIC GRANULOMA
  109. 109. CAUSES OF CHRONIC HEPATITIS Agent Morphologic Clues Hepatitis B Ground-glass hepatocytes Hepatitis C Fat Bile duct injury Portal Lymphoid aggregates Talc (IV drug abuse) Autoimmune Hepatitis Severe hepatocellular injury; Rosettes, giant cell transformation, many plasma cells Drugs None
  110. 110. Liver, chronic viral hepatitis (hepatitis C virus) - Low power This image of liver is from a patient with chronic hepatitis C virus infection. Portal inflammatory infiltrates in chronic hepatitis C viral infections frequently contain lymphoid aggregates or lymphoid follicles. Steatosis is also present in HCV infections, in contrast to HBV infection.
  111. 111. Grading Activity In Chronic Hepatitis Grade Piecemeal Necrosis Parenchymal Injury a Activity Mild Found only after diligent search >5 per 10 X field Both are Mild Moderate Majority of portal areas have atleast some, but most have <50% of circumference 5-20 per 10 X field Either is moderat e Marked >50% of circumference of the majority of the portal areas >20 per 10 X field Either is marked. a--> Apoptotic bodies, ballooned cells, inflamatory cell aggregates.
  112. 112. Liver, chronic viral hepatitis (hepatitis B virus) - Medium power In this image of liver from a patient with chronic hepatitis due to hepatitis B virus, a chronic inflammatory infiltrate is seen that is limited to the portal area. It does not extend into the adjacent lobule.
  113. 113. Liver, chronic viral hepatitis (hepatitis B virus) - Medium power This image is from another patient who has chronic viral hepatitis. In this patient, there is a chronic inflammatory infiltrate in the portal areas of the liver that extends beyond the portal area into the adjacent lobule, where it encircles hepatocytes, many of which are undergoing degeneration and necrosis. This is the morphologic correlate of progressive active liver damage that is present in some patients with chronic viral hepatitis.
  114. 114. Change Score No Fibrosis 0 Fibrous expansion of some portal areas, with or without short fibrous septa 1 Fibrous expansion of most portal areas, with or without short fibrous septa 2 Fibrous expansion of most portal areas, with occassional portal to portal (P-P) bridging 3 Fibrous expansion of portal areas, with marked bridging ( portal-portal (P-P) as well as portal- central (P-C)) 4 Marked bridging (P-P and/or P-C) with occassional nodules (incomplete cirrhosis) 5 Cirrhosis, probable or definite 6 Histological Activity Index Staging
  115. 115. CIRRHOSIS  Establish diagnosis  Assess cause as far as possible  To detect HCC Microscopic clues  1. Fragmented biopsy, fragments have rounded edges 2. Alteration in the spatial relationship between portal vessels & central veins 3. Cell plates- > one cell in thickness , compressed sinusoids are invisible 4. Complete loss of acinar structure 5. Reticulin stain – irregular pattern ,thin strips of connective tissue investing margins of fragments 6. Liver cell dysplasia
  116. 116. Differential Diagnosis Of Cirrhosis  Budd chiari – portal tracts remain largely uninvolved  SBC – fibrosis is portal in distribution  AAT deficiency – PAS , immunostain  Wilsons disease , PBC – Cu stain  Biliary cirrhosis – absence of bile ducts  Hemochromatosis – iron stain  Post necrotic – immunostain for hepatitis B Sag
  117. 117. Liver-Biopsy Specimens from a 45-Year-Old Woman with Chronic Hepatitis C Virus Infection, in Whom There Was No Clinical Suspicion of Cirrhosis. Panel B shows a dense portal infiltrate with the formation of lymphoid aggregates (hematoxylin and eosin, ¬66). Panel A shows bridging fibrosis with architectural distortion and early cirrhosis (Masson trichrome, ¬10). A B
  118. 118. Congenital Hepatic Fibrosis Parenchyma does not show e/o destruction or regeneration Disease Diffuse Involvement Septa Nodule Cirrhosis + + + Nodular regenerative Hyperplasia + - + Focal Nodular Hyperplasia - + + D/D OF CIRRHOSIS
  119. 119. Liver Biopsy In Transplantation  Graft rejection- Hyper acute- hemorrhagic infarct Cellular rejection – acute ,triad of portal inflammation , bile duct & hepatocyte damage , endotheliitis Ductopenic ( chronic rejection ) – - progressive loss of bile ducts - obliterative arteriopathy of small & med sized vessels l/d widespresd ischemic damage to hepatocytes
  120. 120. Liver in GVHD Acute - 10-50 days after BMT - Donar Lym attack hepatocytes & bile duct epithelial cells causes injury & necrosis - Inflammation in PT & lobules Chronic- >100 days after - severe PT inflammation - BD destruction - Fibrosis
  121. 121. Graft Dysfunction  Infections –CMV (intranuclear & cytoplasmic inclusions ), EBV ( portal tract & sinusoids – atypical lymphocytes & immunoblasts )  Vascular thrombosis  Drug toxicity - cyclosporine A ( cholestasis) , azathioprin – (sinusoidal congestion& zone3 necrosis )  Recurrent viral hepatitis & PBC  Post transplant lymphoproliferative disease
  122. 122. Liver, transplant rejection - Medium power Rejection of this transplanted liver is manifest in this image as an inflammatory portal infiltrate with bile ductular destruction. The morphologic evidence of bile ductular damage includes a disordered appearance of bile duct epithelial cells, lack of a visible bile duct lumen, and inflammatory cell infiltrates in the bile duct walls.
  123. 123. Liver, transplant rejection - Medium power Endothelialitis of the central vein is present in this image of the transplanted liver undergoing rejection. This is manifest as an inflammatory infiltrate surrounding and infiltrating the central vein wall.
  124. 124.  Assessement of viral serologies  Microbial culture  Review of drug therapy  Radiological demonstration of patency of biliary tree & vessels
  125. 125. Rejection Rec. HBV Rec. HCV Bile Duct Obstruction Cholestasis Yes Portal inflammation Mixed Yes L, P Yes Yes Neutrophils Yes Bile Duct Damage Yes Yes Endotheliitis Yes Zone-3 necrosis If chronic Sinusoidal infla. ++ Acidophilic Bodies + ++
  126. 126. Childhood Liver Diseases • Is acinar structure normal for age ?,see for fibrosis ,nodularity,cirrhosis early in evaluation • Are cholestasis & giant cells present ? – cholestasis – in portal tract-biliary tract obstruction , portal tract & parenchyma- hepatitis • Hepatitis – giant multinucleated hepatocytes , liver cell degeneration , mononuclear cell infiltration in acini & portal tract • Are interlobular ducts normal -
  127. 127. Proliferation of bile ducts Paucity of bile ducts Malformation of bile ducts  Does specimen contain iron or Cu – neonatal hemochromatosis , ICC ( Cu toxicity) , Wilson's disease  Study by DPAS – AAT deficiency  Are storage cells present – metabolic diseases
  128. 128. Metabolic Diseases  Hepatocytes – glycogenosis , AAT def  Macrophages – Gauchers disease  Both –Niemann pick , cholesterol ester storage PAS stain – Electron microscopy – Frozen – biochemical & histochemical studies
  129. 129.  Type 1 GSD – swollen pale staining hepatocytes , centrally placed nuclei , mallory bodies , uniform mosaic pattern  AAT defi – periportal hepatocytes show PAS positive DR globules  Gauchers – enlarged kupffer cells & portal macrophages,  Neimann pick – hepatocytes & macrophages are swollen ,foamy
  130. 130. Aetiology Histological Features Extrahepatic biliary atresia Proferation of bile ductules in portal tracts; portal fibrosis; ductular cholestasis Paucity of intrahepatic bile ducts Loss of intelobular bile ducts (bile duct; hepatic artery ratio <1) Neonatal hepatitis Lobular disaaray , cholestasis,Portal & acinar mononuclear cell inflammation; acidphil bodies, giant cells , EMH Metabolic disorders Fat; fibrosis or cirrhosis; storage product in liver cells or Kupffer cells Proliferation of bile ductules, portal Liver Biopsy interpretation in Neonatal Cholestasis
  131. 131. CHOLESTASIS A— • CANALICULAR – dilated bile canaliculi bet hepatocytes • CYTOPLASM OF HEPATOCYTES & KUPFFER CELLS • DUCTULAR CHOLESTASIS – sepsis , ductal plate malformation B- Acute – canalicular (perivenular ) Chronic – periportal hepatocytes
  132. 132. Intrahepatic Extrahepatic Causes Pure cholestasis-D-J- S,Rotor S Gallstones,Ca Head pancreas,Inflammatory,stricture s,Tumors of bile duct. Acquired cholestasis-Viral hepatitisAlcohlic Hep,Drug induce,PBC,PSC, Degree Mild More marked Biopsy HPE findings Dilated bile canaliculi,bile plugs,feathery,degene ration of hepatocytes,proliferati on of bile ductules initially followed by destruction and periportal fibrosis Dilated bile ducts,rupture->Bile Lakes->toxic to HEP->Focal necrosis,ascending cholangitis proliferation of bile ductules
  133. 133. Biopsy In AIDS  Abnormal LFTs  AFB & silver stains- mycobacteria & fungus  Gram stains or warthin starry stain  Portion of biopsy should be sent for culture  Opportunistic infection & infestations:  Histiocytes-striated appearance  Mycobacterium avium intracellular  Mycobacterium Tuberculosis AIDS Cholangoipathy  Lymphomas Nodular masses or portal tract infiltration
  134. 134. Pregnancy, Amyloidosis
  135. 135. • Ac Fatty liver of pregnancy (Microvesic), IH Cholestasis, • Eclampia :- Fibrin deposits in periportal sinusoids with haemorrhages in space of Disse, • Amyloidosis :- in hep art branches, along sinusoids in space of Disse, Light chains of Kappa type
  136. 136. Fibrotest- Actitest The Fibrotest-Actitest™ is a six-parameter scoring system that allows quantification of liver fibrosis and inflammation. This test has been validated by several studies in hepatitis B and C viruses and alcoholic liver disease, with a high correlation between the liver biopsy. Six parameters evaluated are total bilirubin, GGT, alpha-2 macroglobulin, haptoglobin, , and ALT, apolipoprotein-A1.
  137. 137.  Fibroscan(Transient Elastography)  Transient elastography is an ultrasound-based, non- invasive method, which measures the liver stiffness by means of a FibroScan® device (EchoSens, Paris, France).  By using an ultrasound transducer probe mounted on the axis of a vibrator, the transmission of low- frequency vibrations from the right intercostal space creates an elastic shear wave that propagates into the liver. A pulse-echo ultrasound acquisition is then used to detect the velocity of wave propagation.  This velocity is proportional to the tissue stiffness, with faster wave progression occurring through stiffer material. Measurement of liver stiffness is then performed and measured in kPa.  The stiffer the liver, the more severe the hepatic fibrosis (scarring).

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