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

?