9/3/2009
1
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
Role of Liver Biopsy
Confirm clinical Confirm clinical diagnosisdiagnosis
Grade Grade necroinflammationnecroinflammation
StageStagefibrosisfibrosis
9/3/2009
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
9/3/2009
3
Stages of Fibrosis
Ishak
5 61 2focal frequent
1 2 3 4
PortalFibosis
FibrousSepta
Transitionto Cirrhosis
Cirrhosis
1 42 3focal frequent
Metavir
Theise ND. Human Pathology 2007
Batts-Ludwig (or a modified Ishak)
3 4focal frequent
Confirm clinical Confirm clinical diagnosisdiagnosis
Evaluate possible Evaluate possible concomitant diseases concomitant diseases
Grade Grade necroinflammationnecroinflammation
StageStagefibrosisfibrosis
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
9/3/2009
4
HCV associated steatosisvs.
concomitant fatty liver disease
HCV
AssociatedSteatosis
Concomitant
Fatty Liver Disease(ALD or NAFLD)
Severity Mild Mild, Moderate or Severe
HCV
AssociatedSteatosis
Concomitant
Fatty Liver Disease(ALD or NAFLD)
Severity Mild Mild, Moderate or Severe
Distribution Random Zonal (zone 3, progressing to 1)
HCV
AssociatedSteatosis
Concomitant
Fatty Liver Disease(ALD or NAFLD)
Severity Mild Mild, Moderate or Severe
Distribution Random Zonal (zone 3, progressing to 1)
Steatohepatitis
9/3/2009
5
HCV
AssociatedSteatosis
Concomitant
Fatty Liver Disease(ALD or NAFLD)
Severity Mild Mild, Moderate or Severe
Distribution Random Zonal (zone 3, progressing to 1)
Steatohepatitis Absent Variable
HCV
AssociatedSteatosis
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
HCV
AssociatedSteatosis
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
HCV
AssociatedSteatosis
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
Lipogranulomas +/- +/-
9/3/2009
6
Case 1
44 year old man with HCV and mild ALT/AST elevations
9/3/2009
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…
Liver Biopsy in Viral Hepatitis:beyond grading and staging…
� Other diseases• Fatty liver disease
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.
9/3/2009
8
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 2Grade 4 – zones 1, 2, and 3
9/3/2009
9
HCV
AssociatedIron
Type I
HereditaryHemochromatosis
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
9/3/2009
10
9/3/2009
11
Case 2: Diagnoses
- Chronic hepatitis, mildly active with transition to cirrhosis (modifiedIshak 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 (modifiedIshak 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
9/3/2009
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?
9/3/2009
13
Liver Biopsy in Viral Hepatitis:beyond grading and staging…
� Other diseases• Fatty liver disease• Hemochromatosis• HIV co-infection
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.
9/3/2009
14
HCV + HIV?
On HAART:In large cohorts,
possibly somewhat more aggressive, but individual biopsies look the same
as HCV alone.
Beware: drug toxicity
Role of Liver Biopsy
Confirm clinical Confirm clinical diagnosisdiagnosis
Stage Stage necroinflammationnecroinflammation
Evaluate possible Evaluate possible concomitant diseases concomitant diseases
Assess features ofAssess features ofHCC riskHCC risk
GradeGradefibrosisfibrosis
Liver Biopsy in Viral Hepatitis:beyond grading and staging…
� Other diseases
� HCC risk screening
• Fatty liver disease• Hemochromatosis• HIV co-infection
• Large cell change
9/3/2009
15
Liver Biopsy in Viral Hepatitis:beyond grading and staging…
� Other diseases
� HCC risk screening
• Fatty liver disease• Hemochromatosis• HIV co-infection
• Large cell change
1st: 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
1st: Pre-malignantNext: malignancy-associated, but NOT
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
Now: Sometimes pre-malignant…?Large liver cell change in hepatitis B virus-related liver cirrhosis.
Kim H et al.
Hepatology Sep 2009; 50: 752.
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
9/3/2009
16
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
9/3/2009
17
Case 3
52 year old woman
with HCV and mild LFT elevation.
Mass lesion noted on USG –attempted biopsy of lesion.
9/3/2009
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)
9/3/2009
19
9/3/2009
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.
Role of Liver Biopsy
Confirm clinical Confirm clinical diagnosisdiagnosis
Stage Stage necroinflammationnecroinflammation
Evaluate possible Evaluate possible concomitant diseases concomitant diseases
Assess features ofAssess features ofHCC riskHCC risk
GradeGradefibrosisfibrosis
9/3/2009
21
?