Role of Liver Biopsy. Role of Liver Biopsy 9/3/2009. Liver Biopsies in Viral Hepatitis: Beyond Grading and Staging

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1 Liver Biopsies in Viral Hepatitis: Beyond Grading and Staging for further reference: Liver biopsy assessment in chronic viral hepatitis: a personal, practical approach Neil Theise, MD. Depts of Pathology and Medicine (Digestive Diseases) Beth Israel Medical Center Albert Einstein College of Medicine New York City Confirm clinical diagnosis Confirm clinical diagnosis Stage fibrosis Grade necroinflammation Role of Liver Biopsy Role of Liver Biopsy 1

2 Severe activity: Confluent necrosis Severe activity: Confluent necrosis Severe activity: Confluent necrosis Confluent necrosis, think about: In HBV: - HBeAg to Ab conversion - HDV super-infection on HBV In HCV: - HCV acute exacerbation - Immunocompromise (undx d HIV) - Concomitant autoimmune hepatitis Always: - Drug/toxin mediated injury 2

3 Stages of Fibrosis Batts-Ludwig (or a modified Ishak) Ishak Metavir focal frequent 3 4 focal frequent focal frequent Confirm clinical diagnosis Stage fibrosis Role of Liver Biopsy Grade necroinflammation Evaluate possible concomitant diseases Portal Fibosis Fibrous Septa Transition to Cirrhosis Cirrhosis Theise ND. Human Pathology 2007 Other diseases Other diseases 3

4 HCV associated steatosis vs. concomitant fatty liver disease HCV Associated Steatosis Concomitant Fatty Liver Disease (ALD or NAFLD) Severity Mild Mild, Moderate or Severe HCV Associated Steatosis Concomitant Fatty Liver Disease (ALD or NAFLD) HCV Associated Steatosis Concomitant Fatty Liver Disease (ALD or NAFLD) Severity Mild Mild, Moderate or Severe Distribution Random Zonal (zone 3, progressing to 1) Severity Mild Mild, Moderate or Severe Distribution Random Zonal (zone 3, progressing to 1) Steatohepatitis 4

5 HCV Associated Steatosis Concomitant Fatty Liver Disease (ALD or NAFLD) HCV Associated Steatosis Concomitant Fatty Liver Disease (ALD or NAFLD) Severity Mild Mild, Moderate or Severe Distribution Random Zonal (zone 3, progressing to 1) Steatohepatitis Absent Variable Severity Mild Mild, Moderate or Severe Distribution Random Zonal (zone 3, progressing to 1) Steatohepatitis Absent Variable Steatofibrosis HCV Associated Steatosis Concomitant Fatty Liver Disease (ALD or NAFLD) HCV Associated Steatosis Concomitant Fatty Liver Disease (ALD or NAFLD) Severity Mild Mild, Moderate or Severe Distribution Random Zonal (zone 3, progressing to 1) Steatohepatitis Absent Variable Steatofibrosis Absent Variable Severity Mild Mild, Moderate or Severe Distribution Random Zonal (zone 3, progressing to 1) Steatohepatitis Absent Variable Steatofibrosis Absent Variable Lipogranulomas +/- +/- 5

6 Case 1 44 year old man with HCV and mild ALT/AST elevations 6

7 Case 1: Diagnoses Fibrous septum formation with mixed features of: - chronic hepatitis C (mildly active) - fatty liver disease (? alcoholic vs. non-alcoholic) Case 1: Diagnoses Fibrous septum formation with mixed features of: - chronic hepatitis C (mildly active) - fatty liver disease (? alcoholic vs. non-alcoholic) Comment: The amount of steatosis in the specimen is significantly more than is usually seen with hepatitis C alone, implying possible concomitant fatty liver disease Other diseases BUT!!! Sites and mechanisms of insulin resistance in nonobese, nondiabetic patients with chronic hepatitis C. Vanni et al. Hepatology Sep 2009; 50: 697. Case 1: Diagnoses Fibrous septum formation with mixed features of: - chronic hepatitis C (mildly active) - fatty liver disease (? alcoholic vs. non-alcoholic) Comment: The amount of steatosis in the specimen is significantly more than is usually seen with hepatitis C alone, implying possible concomitant fatty liver disease; however, it must be kept in mind that hepatitis C itself may lead to insulin resistance in some patients and thus may also be a direct cause of non-alcoholic fatty liver disease. 7

8 Other diseases HCV associated iron vs. other 2 ndary causes vs. Hereditary Hemochromatosis (type 1: HFE mutated) Severity HCV Associated Iron Type I Hereditary Hemochromatosis Grading of iron Grade 1 zone 1, some periportal areas Grade 2 zone 1, all periportal areas Grade 3 zones 1 and 2 Grade 4 zones 1, 2, and 3 8

9 HCV Associated Iron Type I Hereditary Hemochromatosis Severity Grade 1/4 to 2/4 Grade 1/4 to 4/4 Case 2 56 year old man referred for HCV and mild liver test elevation 9

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11 Case 2: Diagnoses - Chronic hepatitis, mildly active with transition to cirrhosis (modified Ishak stage 3/4), compatible with hepatitis C. - Hemosiderosis, grade 1/4,? Hereditary vs. secondary hemochromatosis Case 2: Diagnoses - Chronic hepatitis, mildly active with transition to cirrhosis (modified Ishak stage 3/4), compatible with hepatitis C. - Hemosiderosis, grade 1/4,? Hereditary vs. secondary hemochromatosis Comment: Prussian blue stain highlights increased hepatocyte iron stores in some, but not all periportal regions. This relatively small amount does not exclude a diagnosis of hereditary hemochromatosis due to the variable penetrance of that disease. Genetic testing may be helpful. Secondary iron overload Cirrhosis (non-biliary) Alcoholic liver disease NAFLD HCV 11

12 Secondary iron overload Cirrhosis (non-biliary) Alcoholic liver disease NAFLD HCV: the virus itself? but also treatment related? Secondary iron overload Cirrhosis (non-biliary) Alcoholic liver disease NAFLD HCV: the virus itself? but also treatment related? Increased Hepatic Iron Deposition Resulting From Treatment of Chronic Hepatitis C With Ribavirin Fiel MI et al. Am J Clin Path 2000 Jan;113(1):35-9. HCV and iron Increased degree of inflammation Increased degree of fibrosis More fibrosis at younger age, especially if homozygous HCV and iron Increased degree of inflammation Increased degree of fibrosis More fibrosis at younger age, especially if homozygous >> Pre-Tx phlebotomy? 12

13 Other diseases HCV + HIV? Untreated HIV: Often more severe activity. Often more advanced disease. HCV + HIV? Untreated HIV: Often more severe activity. Often more advanced disease. Rare: fibrosing cholestatic hepatitis HCV + HIV? Untreated HIV: Often more severe activity. Often more advanced disease. Rare: fibrosing cholestatic hepatitis Beware: Infiltrating neoplasms, granulomas, HSV, CMV, biliary tract disease, etc. 13

14 HCV + HIV? On HAART: In large cohorts, possibly somewhat more aggressive, but individual biopsies look the same as HCV alone. Beware: drug toxicity Confirm clinical diagnosis Evaluate possible concomitant diseases Grade fibrosis Role of Liver Biopsy Stage necroinflammation Assess features of HCC risk Other diseases HCC risk screening Large cell change 14

15 Other diseases HCC risk screening Large cell change 1 st : Pre-malignant Other diseases HCC risk screening Large cell change 1 st : Pre-malignant Next: malignancy-associated, but NOT pre-malignant. Other diseases HCC risk screening Large cell change Now: Sometimes pre-malignant? Large liver cell change in hepatitis B virus-related liver cirrhosis. Kim H et al. Hepatology Sep 2009; 50: 752. Other diseases HCC risk screening Large cell change Small cell change 15

16 9/3/2009 Other diseases HCC risk screening Large cell change Small cell change Other diseases HCC risk screening Large cell change Small cell change Iron free foci Generally thought to be directly pre-malignant. 16

17 Case 3 52 year old woman with HCV and mild LFT elevation. Mass lesion noted on USG attempted biopsy of lesion. 17

18 Case 3: Diagnoses - Chronic hepatitis, mildly active with marked portal fibrosis (modified Ishak stage 1/4), compatible with hepatitis C. - Large cell change. - Small cell change. - Lipogranuloma. Case 4 61 year old Chinese woman with HBV (low serum HBV DNA) 18

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20 Case 4: Diagnoses - Chronic hepatitis, mildly active with cirrhosis (modified Ishak stage 4/4) and possible features of regression, compatible with hepatitis B. - Hemosiderosis, grade 3/4 to 4/4,? Cirrhosis-associated vs. hereditary. - Large cell change. - Small cell change. - Iron free foci. Confirm clinical diagnosis Evaluate possible concomitant diseases Grade fibrosis Role of Liver Biopsy Stage necroinflammation Assess features of HCC risk 20

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