04TheiseChronicHepatitisAndTheProblemDiagnosis · 9/3/2009 1 Liver Biopsies in Viral Hepatitis: Beyond Grading and Staging Neil Theise, MD. Depts of Pathology and Medicine (Digestive

9/3/2009

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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



Grade Grade necroinflammationnecroinflammation

StageStagefibrosisfibrosis

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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

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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


Evaluate possible Evaluate possible concomitant diseases concomitant diseases

Grade Grade necroinflammationnecroinflammation

StageStagefibrosisfibrosis


Liver Biopsy in Viral Hepatitis:beyond grading and staging…

� Other diseases• Fatty liver disease • Hemochromatosis• HIV co-infection


� Other diseases• Fatty liver disease • Hemochromatosis• HIV co-infection

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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



Distribution Random Zonal (zone 3, progressing to 1)

HCV

AssociatedSteatosis

Concomitant




Steatohepatitis

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HCV

AssociatedSteatosis

Concomitant




Steatohepatitis Absent Variable

HCV

AssociatedSteatosis

Concomitant





Steatofibrosis

HCV

AssociatedSteatosis

Concomitant





Steatofibrosis Absent Variable

HCV

AssociatedSteatosis

Concomitant





Steatofibrosis Absent Variable

Lipogranulomas +/- +/-

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Case 1

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

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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


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• 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


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.

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� 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

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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

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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

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• NAFLD • HCV: the virus itself…? but also treatment

related…?




• 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?

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� Other diseases• Fatty liver disease• Hemochromatosis• HIV co-infection

HCV + HIV?

Untreated HIV:Often more severe activity.

Often more advanced disease.

HCV + HIV?



Rare: fibrosing cholestatic hepatitis

HCV + HIV?



Rare: fibrosing cholestatic hepatitis

Beware: Infiltrating neoplasms, granulomas, HSV, CMV, biliary tract disease, etc.

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HCV + HIV?

On HAART:In large cohorts,

possibly somewhat more aggressive, but individual biopsies look the same

as HCV alone.

Beware: drug toxicity



Stage Stage necroinflammationnecroinflammation


Assess features ofAssess features ofHCC riskHCC risk

GradeGradefibrosisfibrosis


� Other diseases

� HCC risk screening

• Fatty liver disease• Hemochromatosis• HIV co-infection

• Large cell change

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� Other diseases




1st: Pre-malignant


� Other diseases




1st: Pre-malignantNext: malignancy-associated, but NOT

pre-malignant.


� Other diseases




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



• Large cell change• Small cell change

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� Other diseases



• Large cell change• Small cell change

Generally thought to be directly pre-malignant.


� Other diseases



• Large cell change• Small cell change• Iron free foci

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Case 3

52 year old woman

with HCV and mild LFT elevation.

Mass lesion noted on USG –attempted biopsy of lesion.

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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)

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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.



Stage Stage necroinflammationnecroinflammation


Assess features ofAssess features ofHCC riskHCC risk

GradeGradefibrosisfibrosis

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Documents

04TheiseChronicHepatitisAndTheProblemDiagnosis · 9/3/2009 1 Liver Biopsies in Viral Hepatitis: Beyond Grading and Staging Neil Theise, MD. Depts of Pathology and Medicine (Digestive