The document discusses chronic viral hepatitis and liver biopsy. It provides details on grading liver inflammation and staging liver fibrosis using various scoring systems. Grading assesses necroinflammatory activity, such as interface hepatitis and lobular necrosis. Staging evaluates the extent of fibrosis from none to cirrhosis. Accurately grading and staging on biopsy is important for prognosis and treatment decisions in chronic hepatitis patients.

1. Neil D. Theise, MD Depts. of Pathology and Medicine (Digestive Diseases) Beth Israel Medical Center – Albert Einstein College of Medicine New York City www.neiltheise.com Chronic Viral Hepatitis

2. Neil D. Theise, MD Depts. of Pathology and Medicine (Digestive Diseases) Beth Israel Medical Center – Albert Einstein College of Medicine New York City SLIDESHARE.NET www.neiltheise.com See: “Chronic Viral Hepatitis: A Personal, Practical Guide” Chronic Viral Hepatitis

5. A C U T E

6. A C U T E HAV HEV

7. A C U T E HAV HEV Incidence in Kuwait: 13/100,000 Incidence in Kuwait: 1.4/100,000 RATE OF SPORADIC ENTERICALLY TRANSMITTED VIRAL HEPATITIS IN KUWAIT BETWEEN 1998 AND 2001 AQ Al-Anezi, R Al-Awayesh, F Al-Ali, KM Peltekian Kuwait Health Sciences Centre, Kuwait City, Kuwait & Division of Gastroenterology, Dalhousie University, Halifax, Nova Scotia

8. C H R O N I C

9. C O N S O N A N T S H R O N I C

10. HBV HCV HDV C O N S O N A N T S H R O N I C

11. HBV HCV HDV Prevalence: 4.6% Prevalence of Hepatitis B and C infection in patients admitted at Tertiary Eye Care Centre: A hospital based study. Junejo SA, Khan NA, Lodhi AA. Pak J Med Sci 2009;25(4):597-600. Prevalence: 13% C O N S O N A N T S H R O N I C

12. HBV HCV HDV Prevalence of Hepatitis B and C infection in patients admitted at Tertiary Eye Care Centre: A hospital based study. Junejo SA, Khan NA, Lodhi AA. Pak J Med Sci 2009;25(4):597-600. Prevalence of co-infection: 3.9% C O N S O N A N T S H R O N I C

14. HBV HCV HDV Prevalence: 4% in acute HBV 31% in chronic HBV C O N S O N A N T S H R O N I C Hepatitis delta virus infection in acute hepatitis in Kuwait. Al-Kandari S, Nordenfelt E, Al-Nakib B, Hansson BG, Ljunggren K, Al-Nakib Scand J Infect Dis. 1988;20(1):15-9.

16. Prevalence of HCV Antibody NHANES III Adapted from Alter MJ, et al.,. N Engl J Med. 1999;341:556–562. 0 500,000 1,000,000 1,500,000 2,000,000 Prevalence 6-11 12-19 20-29 30-39 40-49 50-59 60-69 70-79 80+ Age distribution 90s 00s

17. Natural History of Hepatitis C Acute Hepatitis C Chronic Hepatitis 75%- 85 % Cirrhosis 20 % 10-20+ years - Hoofnagle JH, Hepatology. 1997 - Di Bisceglie A, Hepatology, 2000

18. Decompensation, 6% HCC, 4% Death or Tx, 4% Annual rate - Hoofnagle JH, Hepatology. 1997 - Di Bisceglie A, Hepatology, 2000 Natural History of Hepatitis C Cirrhosis, 20 %

19. Liver Fibrosis in Chronic Hepatitis C Intermediate progressors Slow progressors Poynard et al, Hepatology 1999 n=1157 0 1 2 3 4 0 10 20 30 40 50 Years F Metavir Rapid progressors

21. Natural History of Chronic Liver Disease Chronic hepatitis with fibrosis 10-50 years Cirrhosis Normal liver Hepatocellular Carcnoma

25. The Normal Liver Lobule:

27. The Limiting Plate

28. Portal inflammation DEFINES Chronic Hepatitis

31. “ Piecemeal Necrosis” or, better, “ Interface Hepatitis”

35. Chronic Persistent Hepatitis

36. Chronic Active Hepatitis

37. Chronic Lobular Hepatitis

40. Recovery Death/Transplant Chronic Hepatitis CPH CAH CLH

41. Recovery Death/Transplant Chronic Hepatitis CPH CAH CLH Cirrhosis Progression Unlikely

42. Recovery Death/Transplant Chronic Hepatitis CPH CAH CLH Cirrhosis Progression Unlikely

45. Recovery Death/Transplant Chronic Hepatitis CPH CAH CLH Cirrhosis Progression Unlikely

46. Recovery Death/Transplant Chronic Hepatitis STAGING Of Progression GRADING Of Activity

51. Confluent Necrosis

52. Confluent Necrosis

53. Confluent Necrosis

55. Bridging confluent necrosis

56. Confluent necrosis, think about: - HBeAg to Ab conversion - HDV super-infection on HBV - HCV acute exacerbation - HIV co-infection - Autoimmune hepatitis - Drug induced injury, as always

57. LIVER: NEEDLE BIOPSY - Chronic hepatitis, ………. active with……. (stage …/4), compatible with hepatitis C. Comment: A. Interface hepatitis: Absent (0/4). A. Interface hepatitis: Focal, few portal areas (1/4). A. Interface hepatitis: Focal, most portal areas, >5-50% (2/4). A. Interface hepatitis: Continuous around <50% of tracts/septa (3/4). A. Interface hepatitis: Continuous around >50% of tracts/septa (4/4). B. Confluent necrosis: Absent (0/6). B. Confluent necrosis: Focal (1/6). B. Confluent necrosis: Zone 3 necrosis in some areas (2/6). B. Confluent necrosis: Zone 3 necrosis in most areas (3/6). B. Confluent necrosis: Occasional portal-central bridging necrosis (4/6). B. Confluent necrosis: Frequent portal-central bridging necrosis (5/6). B. Confluent necrosis: Panacinar or multiacinar collapse (6/6). C. Lobular necrosis or inflammation: Absent (0/4) C. Lobular necrosis or inflammation: < 1 focus per acinus (1/4) C. Lobular necrosis or inflammation: 2-4 foci per acinus or nodule (2/4). C. Lobular necrosis or inflammation: 5-10 foci per acinus or nodule (3/4). C. Lobular necrosis or inflammation: >10 foci per acinus nodule (4/4). D. Portal inflammation: None (0/4). D. Portal inflammation: Mild, some or all portal tracats (1/4). D. Portal inflammation: Moderate, some or all portal areas (2/4). D. Portal inflammation: Marked, not all portal areas (3/4). D. Portal inflammation: Marked, all portal areas (4/4). E. Staging: No fibrosis (0/4). E. Staging: Fibrous portal enlargement (1/4). E. Staging: Fibrous septa (2/4). E. Staging: Transition to cirrhosis (3/4). E. Staging: Cirrhosis (4/4).

58. 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 occasional portal to portal bridging 3 Fibrous expansion of portal areas with marked bridging portal-portal and/or portal-central 4 Marked bridging (portal-portal and/or portal-central) with occasional nodules (incomplete cirrhosis) 5 Cirrhosis, probable or definite 6 So what do I do…?

59. LIVER: NEEDLE BIOPSY - Chronic hepatitis, ………. active with……. (stage …/4), compatible with hepatitis C. Comment: A. Interface hepatitis: Absent (0/4). A. Interface hepatitis: Focal, few portal areas (1/4). A. Interface hepatitis: Focal, most portal areas, >5-50% (2/4). A. Interface hepatitis: Continuous around <50% of tracts/septa (3/4). A. Interface hepatitis: Continuous around >50% of tracts/septa (4/4). B. Confluent necrosis: Absent (0/6). B. Confluent necrosis: Focal (1/6). B. Confluent necrosis: Zone 3 necrosis in some areas (2/6). B. Confluent necrosis: Zone 3 necrosis in most areas (3/6). B. Confluent necrosis: Occasional portal-central bridging necrosis (4/6). B. Confluent necrosis: Frequent portal-central bridging necrosis (5/6). B. Confluent necrosis: Panacinar or multiacinar collapse (6/6). C. Lobular necrosis or inflammation: Absent (0/4) C. Lobular necrosis or inflammation: < 1 focus per acinus (1/4) C. Lobular necrosis or inflammation: 2-4 foci per acinus or nodule (2/4). C. Lobular necrosis or inflammation: 5-10 foci per acinus or nodule (3/4). C. Lobular necrosis or inflammation: >10 foci per acinus nodule (4/4). D. Portal inflammation: None (0/4). D. Portal inflammation: Mild, some or all portal tracats (1/4). D. Portal inflammation: Moderate, some or all portal areas (2/4). D. Portal inflammation: Marked, not all portal areas (3/4). D. Portal inflammation: Marked, all portal areas (4/4). E. Staging: No fibrosis (0/4). E. Staging: Fibrous portal enlargement (1/4). E. Staging: Fibrous septa (2/4). E. Staging: Transition to cirrhosis (3/4). E. Staging: Cirrhosis (4/4).

60. LIVER: NEEDLE BIOPSY - Chronic hepatitis, ………. active with……. (stage …/4), compatible with hepatitis C. Comment: A. Interface hepatitis: Absent (0/4). A. Interface hepatitis: Focal, few portal areas (1/4). A. Interface hepatitis: Focal, most portal areas, >5-50% (2/4). A. Interface hepatitis: Continuous around <50% of tracts/septa (3/4). A. Interface hepatitis: Continuous around >50% of tracts/septa (4/4). B. Confluent necrosis: Absent (0/6). B. Confluent necrosis: Focal (1/6). B. Confluent necrosis: Zone 3 necrosis in some areas (2/6). B. Confluent necrosis: Zone 3 necrosis in most areas (3/6). B. Confluent necrosis: Occasional portal-central bridging necrosis (4/6). B. Confluent necrosis: Frequent portal-central bridging necrosis (5/6). B. Confluent necrosis: Panacinar or multiacinar collapse (6/6). C. Lobular necrosis or inflammation: Absent (0/4) C. Lobular necrosis or inflammation: < 1 focus per acinus (1/4) C. Lobular necrosis or inflammation: 2-4 foci per acinus or nodule (2/4). C. Lobular necrosis or inflammation: 5-10 foci per acinus or nodule (3/4). C. Lobular necrosis or inflammation: >10 foci per acinus nodule (4/4). D. Portal inflammation: None (0/4). D. Portal inflammation: Mild, some or all portal tracats (1/4). D. Portal inflammation: Moderate, some or all portal areas (2/4). D. Portal inflammation: Marked, not all portal areas (3/4). D. Portal inflammation: Marked, all portal areas (4/4). E. Staging: No fibrosis (0/4). E. Staging: Fibrous portal enlargement (1/4). E. Staging: Fibrous septa (2/4). E. Staging: Transition to cirrhosis (3/4). E. Staging: Cirrhosis (4/4). Mild Moderate Severe

61. STAGING

70. 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 occasional portal to portal bridging 3 Fibrous expansion of portal areas with marked bridging portal-portal and/or portal-central 4 Marked bridging (portal-portal and/or portal-central) with occasional nodules (incomplete cirrhosis) 5 Cirrhosis, probable or definite 6 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 occasional portal to portal bridging 3 Fibrous expansion of portal areas with marked bridging, portal-portal and/or portal-central 4 Marked bridging (portal-portal and/or portal-central) with occasional nodules (incomplete cirrhosis) 5 Cirrhosis, probable or definite 6 Ishak et al. staging scheme

71. 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 occasional portal to portal bridging 3 Fibrous expansion of portal areas with marked bridging portal-portal and/or portal-central 4 Marked bridging (portal-portal and/or portal-central) with occasional nodules (incomplete cirrhosis) 5 Cirrhosis, probable or definite 6 No fibrosis 0 Portal fibrosis 1 Focal Septa 2 Frequent septa 3 Cirrhosis, probable or definite 4 METAVIR staging

72. No fibrosis 0 Portal fibrosis 1 Focal Septa 2 Frequent septa 3 ? Cirrhosis, probable or definite 4 METAVIR staging ?

73. 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 occasional portal to portal bridging 3 Fibrous expansion of portal areas with marked bridging portal-portal and/or portal-central 4 Marked bridging (portal-portal and/or portal-central) with occasional nodules (incomplete cirrhosis) 5 Cirrhosis, probable or definite 6 So what do I do…?

74. No fibrosis 0 Focal portal fibrosis, w or w/o short fibrous septa 1 Widespread portal fibrosis, w or w/o short fibrous septa 2 Focal portal-portal septa 3 Frequent septa (portal-central and/or portal portal) 4 Marked septa with occasional nodules 5 Cirrhosis, probable or definite 6 No fibrosis 0 Portal fibrosis 1 Focal Septa 2 Transition to cirrhosis 3 Cirrhosis, probable or definite 4 Theise modification of Ishak staging ? Ishak et al. staging scheme

75. Stages of Fibrosis 5 6 1 2 focal frequent 1 2 3 4 Portal Fibosis Fibrous Septa Transition to Cirrhosis Cirrhosis 1 4 2 3 focal frequent Metavir Theise ND. Human Pathology 2007 Modified Ishak  Batts-Ludwig 3 4 focal frequent Ishak

76. How much tissue is enough?

77. How much tissue is enough? 1.8 cm? 2.2 cm? 2.5 cm?

78. How much tissue is enough? 1.8 cm? 2.2 cm? 2.5 cm? How much is too little???

79. Case 1A 34 year old woman Hepatitis C positive; biopsy for staging and grading.

80. Case 1A, 4x, H&E

81. Case 1A, 4x, H&E

82. Case 1A, 4x, H&E

83. Case 1A, 4x, Trichrome

84. Case 1A, 4x, Trichrome

85. Case 1A, 10x, Trichrome

86. For example: LIVER: NEEDLE BIOPSY - Chronic hepatitis, mildly active with transition to cirrhosis (modified Ishak stage 3/4), compatible with hepatitis C.

87. For example: LIVER: NEEDLE BIOPSY - Chronic hepatitis, mildly active with transition to cirrhosis (modified Ishak stage 3/4), compatible with hepatitis C. Comment: There is a mild to moderate portal/septal mononuclear infiltrate associated with widespread interface hepatitis and focal lobular hepatitis.

88. For example: LIVER: NEEDLE BIOPSY - Chronic hepatitis, mildly active with transition to cirrhosis (modified Ishak stage 3/4), compatible with hepatitis C. Comment: There is a mild to moderate portal/septal mononuclear infiltrate associated with widespread interface hepatitis and focal lobular hepatitis. There is no confluent necrosis.

89. For example: LIVER: NEEDLE BIOPSY - Chronic hepatitis, moderately active with transition to cirrhosis (modified Ishak stage 3/4), compatible with hepatitis C. Comment: There is a mild to moderate portal/septal mononuclear infiltrate associated with widespread interface hepatitis and focal lobular hepatitis. There is no confluent necrosis. Trichrome and reticulin stains highlight focal fibrous septa, and focal nodularity Indicative of cirrhosis.

90. For example: LIVER: NEEDLE BIOPSY - Chronic hepatitis, moderately active with transition to cirrhosis (modified Ishak stage 3/4), compatible with hepatitis C. Comment: There is a mild to moderate portal/septal mononuclear infiltrate associated with widespread interface hepatitis and focal lobular hepatitis. There is no confluent necrosis. Trichrome and reticulin stains highlight focal fibrous septa, and focal nodularity Indicative of cirrhosis. There is focal steatosis in a pattern typical of that seen with chronic hepatitis C.

91. For example: LIVER: NEEDLE BIOPSY - Chronic hepatitis, moderately active with transition to cirrhosis (modified Ishak stage 3/4), compatible with hepatitis C. Comment: There is a mild to moderate portal/septal mononuclear infiltrate associated with widespread interface hepatitis and focal lobular hepatitis. There is no confluent necrosis. Trichrome and reticulin stains highlight focal fibrous septa, and focal nodularity Indicative of cirrhosis. There is focal steatosis in a pattern typical of that seen with chronic hepatitis C. No significant hemosiderosis or alpha-1-antitrypsin globules are identified (iron, PAS-D stains).

92. For example: LIVER: NEEDLE BIOPSY - Chronic hepatitis, moderately active with transition to cirrhosis (modified Ishak stage 3/4), compatible with hepatitis C. Comment: There is a mild to moderate portal/septal mononuclear infiltrate associated with widespread interface hepatitis and focal lobular hepatitis. There is no confluent necrosis. Trichrome and reticulin stains highlight focal fibrous septa, and focal nodularity Indicative of cirrhosis. There is focal steatosis in a pattern typical of that seen with chronic hepatitis C. No significant hemosiderosis or alpha-1-antitrypsin globules are identified (iron, PAS-D stains).

93. Case 1B 47 year old man Hepatitis C positive; ultrasound guided biopsy of left lobe, for staging and grading.

94. Case 1B, 2x, H&E GLISSON’S CAPSULE

95. Case 1B, 4x, H&E SUBCAPSULAR ZONE

96. Case 1B, 2x, H&E

97. Case 1B, 2x, H&E

98. LIVER: NEEDLE BIOPSY - Chronic hepatitis, mildly active with portal fibrosis (modified Ishak stage 1/4), compatible with hepatitis C.

100. HBV: Ground glass hepatocytes

101. HBV: Ground glass cells (surface antigen inclusions)

102. Immunostain: HBV Surface Antigen

103. HCV: lymphoid aggregates

104. Plasma cells in Autoimmune Hepatitis

105. Mixed Viral Infections

106. HBV + ? = utility of immunostains for HBV core Ag

107. Immunostain for HBcAG: Confirms active viral replication

108. Another example: LIVER: NEEDLE BIOPSY - Chronic hepatitis B, mildly active with transition to cirrhosis (stage 3/4). Comment: … .Ground glass hepatocytes (or immunostains for HBV surface antigen) confirm chronic hepatitis B virus infection. Immunostain for core antigen confirms hepatitis B viral replication….

109. No HBcAg Suspect: HBV DNA neg., Spontaneously resolved or treated infection or sampling or Co-infection with HCV,HDV

111. Diffuse HBcAg Suspect: Immunosuppression, in particular: HBV + HIV!!!

112. HCV + HIV? Increased Activity Decreased Activity Increase rate of progression Decreased rate of progression

113. HCV + HIV? On HAART: In large cohorts, possibly more aggressive, but individual biopsies look the same as HCV alone. Beware: drug toxicity

114. HCV + HIV? Untreated: Often more severe activity. Often more advanced disease.

115. HCV + HIV? Untreated: Often more severe activity. Often more advanced disease. Rare: fibrosing cholestatic hepatitis

116. HCV + HIV? Untreated: Often more severe activity. Often more advanced disease. Rare: fibrosing cholestatic hepatitis Beware: Infiltrating neoplasms, granulomas, HSV, CMV, biliary tract disease, etc.

117. ? Home Work