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Liver Biopsies in Viral Hepatitis:
Beyond Grading and Staging
Neil Theise, MD.Depts of Pathology and Medicine (Digestive Diseases)
Beth Israel Medical Center – Albert Einstein College of MedicineNew York City
for further reference:
Liver biopsy assessment in chronic viral hepatitis:
a personal, practical approach
www.neiltheise.com
Role of Liver Biopsy
Confirm clinical Confirm clinical diagnosisdiagnosis
Confirm clinical Confirm clinical diagnosisdiagnosis
Grade Grade necroinflammationnecroinflammation
Grade Grade necroinflammationnecroinflammation
StageStagefibrosisfibrosisStageStage
fibrosisfibrosis
Confirm clinical Confirm clinical diagnosisdiagnosis
Confirm clinical Confirm clinical diagnosisdiagnosis
Evaluate possible Evaluate possible concomitant diseases concomitant diseases
Evaluate possible Evaluate possible concomitant diseases concomitant diseases
Grade Grade necroinflammationnecroinflammation
Grade Grade necroinflammationnecroinflammation
StageStagefibrosisfibrosisStageStage
fibrosisfibrosis
Role of Liver Biopsy
Liver Biopsy in Viral Hepatitis:beyond grading and staging…
Other diseases• Fatty liver disease • Hemochromatosis• HIV co-infection
Liver Biopsy in Viral Hepatitis:beyond grading and staging…
Other diseases• Fatty liver disease • Hemochromatosis• HIV co-infection
HCV associated steatosisvs.
concomitant fatty liver disease
HCVAssociatedSteatosis
ConcomitantFatty Liver Disease
(ALD or NAFLD)
Severity Mild Mild, Moderate or Severe
HCVAssociatedSteatosis
ConcomitantFatty Liver Disease
(ALD or NAFLD)
Severity Mild Mild, Moderate or Severe
Distribution Random Zonal (zone 3, progressing to 1)
HCVAssociatedSteatosis
ConcomitantFatty Liver Disease
(ALD or NAFLD)
Severity Mild Mild, Moderate or Severe
Distribution Random Zonal (zone 3, progressing to 1)
Steatohepatitis
HCVAssociatedSteatosis
ConcomitantFatty Liver Disease
(ALD or NAFLD)
Severity Mild Mild, Moderate or Severe
Distribution Random Zonal (zone 3, progressing to 1)
Steatohepatitis Absent Variable
HCVAssociatedSteatosis
ConcomitantFatty Liver Disease
(ALD or NAFLD)
Severity Mild Mild, Moderate or Severe
Distribution Random Zonal (zone 3, progressing to 1)
Steatohepatitis Absent Variable
Steatofibrosis
HCVAssociatedSteatosis
ConcomitantFatty 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
HCVAssociatedSteatosis
ConcomitantFatty 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
Lipogranulomas +/- +/-
Case 1
44 year old man with HCV and mild ALT/AST elevations
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…
BUT!!!
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 in some patients.
Liver Biopsy in Viral Hepatitis:beyond grading and staging…
Other diseases• Fatty liver disease • Hemochromatosis• HIV co-infection
HCV associated ironvs.
other 2ndary causes vs.
Hereditary Hemochromatosis (type 1: HFE mutated)
HCVAssociated
Iron
Type IHereditary
Hemochromatosis
Severity
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
HCVAssociated
Iron
Type IHereditary
Hemochromatosis
Severity Grade 1/4 to 2/4
Grade 1/4 to 4/4
Example: Type 1 HH
• 46 y.o. man with mild ALT/AST elevations• Irish-Scottish descent • Ferritin 1700 gm/ L• Iron saturation 89%• dry weight iron 18,528 gm/ g• Hepatic iron index 4.2 mol/ gm/ yr• HCV negative• 1 drink/ day
Case 2
56 year old man referred for HCV and mild liver test elevation
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
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?
Liver Biopsy in Viral Hepatitis:beyond grading and staging…
Other diseases
HCC risk screening
• Fatty liver disease • Hemochromatosis• HIV co-infection
• Large cell change• Small cell change• Iron free foci
HCV + HIV?
On HAART: In large cohorts,
possibly more aggressive, but individual biopsies look the same
as HCV alone.
Beware: drug toxicity
HCV + HIV?
Untreated:Often more severe activity.
Often more advanced disease.
HCV + HIV?
Untreated:Often more severe activity.
Often more advanced disease.
Rare: fibrosing cholestatic hepatitis
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.
Role of Liver Biopsy
Confirm clinical Confirm clinical diagnosisdiagnosis
Confirm clinical Confirm clinical diagnosisdiagnosis
Stage Stage necroinflammationnecroinflammation
Stage Stage necroinflammationnecroinflammation
Evaluate possible Evaluate possible concomitant diseases concomitant diseases
Evaluate possible Evaluate possible concomitant diseases concomitant diseases
Assess features ofAssess features of
HCC riskHCC risk
Assess features ofAssess features of
HCC riskHCC risk
GradeGradefibrosisfibrosisGradeGrade
fibrosisfibrosis
Liver Biopsy in Viral Hepatitis:beyond grading and staging…
Other diseases
HCC risk screening
• Fatty liver disease • Hemochromatosis• HIV co-infection
• Large cell change
Liver Biopsy in Viral Hepatitis:beyond grading and staging…
Other diseases
HCC risk screening
• Fatty liver disease • Hemochromatosis• HIV co-infection
• Large cell change
Probably malignancy associated,NOT directly pre-malignant
Liver Biopsy in Viral Hepatitis:beyond grading and staging…
Other diseases
HCC risk screening
• Fatty liver disease • Hemochromatosis• HIV co-infection
• Large cell change• Small cell change
Liver Biopsy in Viral Hepatitis:beyond grading and staging…
Other diseases
HCC risk screening
• Fatty liver disease • Hemochromatosis• HIV co-infection
• Large cell change• Small cell change
Generally thought to be directly pre-malignant.
Liver Biopsy in Viral Hepatitis:beyond grading and staging…
Other diseases
HCC risk screening
• Fatty liver disease • Hemochromatosis• HIV co-infection
• Large cell change• Small cell change• Iron free foci
Case 3
52 year old woman
with HCV and mild LFT elevation.
Mass lesion noted on USG – attempted biopsy of lesion.
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)
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.
Role of Liver Biopsy
Confirm clinical Confirm clinical diagnosisdiagnosis
Confirm clinical Confirm clinical diagnosisdiagnosis
Stage Stage necroinflammationnecroinflammation
Stage Stage necroinflammationnecroinflammation
Evaluate possible Evaluate possible concomitant diseases concomitant diseases
Evaluate possible Evaluate possible concomitant diseases concomitant diseases
Assess features ofAssess features of
HCC riskHCC risk
Assess features ofAssess features of
HCC riskHCC risk
GradeGradefibrosisfibrosisGradeGrade
fibrosisfibrosis
?