Pathology of Chronic Viral Hepatitis: Nomenclature

Grade & Stage

Carmen Gonzalez Keelan MD

FCAP FASCP

Consultant, UPR School of Medicine

Chronic hepatitis: term used when there is clinical evidence of

chronicity (hepatic necrosis & inflammation lasting>6 months)

Do you agree?

Yes N

o

Abstain

33% 33%33%

1. Yes

2. No

3. Abstain

Causes of chronic hepatitis

• VHB

• VHC

• Autoimmune

• A1AT

• Wilson

• Drug hepatotoxicity

Which virus is responsible for 40% of acute hepatitis in USA?

HAV

HBV

HCV

HDV

25% 25%25%25%1. HAV

2. HBV

3. HCV

4. HDV

Chronic Liver disease72/100,000

8th cause of death, between diabetes & suicide

• Viral hepatitis C: 57%

• Alcohol: 24%

• NAFLD: 9%

• Viral hepatitis B: 4%

• 44,000 (1.9%) deaths

HCV

• Chronic infection occurs in 85% of patients

• Cirrhosis develops in 20-40% *

• Chronic hepatitis C accounts for 30% of liver transplants in USA

• Annual risk of hepatocellular cancer:

1-4% (genotype 1b)

Occult HCV infection

• Persistent LFT elevation with negative HCV serology

• Positive HCV serology with normal LFT*

Role of the biopsy inChronic liver diseases

• Confirm diagnosis

• Assess prognosis

• Guide treatment

• Goodman, Z J Hepatol 47 598-607, 2007

Biopsy adequacy: 2 cm

• We must educate clinicians to supply adequate samples by obtaining long core or repeating passes

• Right lobe

• Tru cutt or Bard needles

• Thin needles are unsuitable for staging

Chronic Hepatitis Elements of the Pathologic

Report• Etiology

• Grade

• Stage

• Chronic Hepatitis: An Update on Terminology & Reporting Batts & Ludwig AJSP 19 (2): 1409-17, 1995

Grading & Staging Systems in Chronic liver diseases

• Stage: degree of scarring

• Grade: severity of disease process

• Try to predict outcome

• Goodman, Z J Hepatol 47 598-607, 2007

Scoring Systems

• Complex: statistical analysis– Knodell 1981 (0-22) includes fibrosis score– Ishak modified HAI (0-18) with separate

fibrosis score (1-6) 1995

• Evaluation of individual patients:– Scheuer 1991– IASL 1994 – Batts & Ludwig 1995 – Metavir 1996

Grade of Inflammation

• Portal inflammation: dense mononuclear

• Interface activity

• Lobular inflammation

• Parenchymal injury: ballooning, apoptosis & bridging necrosis

Portal inflammationLymphocytes, PC

• T lymphocytes plasma cells & eosinophils

• Lymphoid follicles with GC HCV

Interface Hepatitis: Mononuclears with hepatocyte engulfment in

limiting plate

• Piecemeal / periportal necrosis

• Ballooning degeneration &

Apoptosis of hepatocytes

• Tumor necrosis factor related apoptosis inducing ligand receptors (TRAIL)

Interface hepatitis: Mild: occasional

Moderate <50%Marked > 50:%

Lobular Necro-inflammatory activity

• Variable & spotty necrosis

• Apoptosis, ballooning degeneration

• Zone 3 cholestasis

• Regenerative 2ble liver cell plates & rosettes

Parenchymal injury

• Mild

• Moderate >5 foci /10 HPF

• Marked numerous necroinflammatory foci (bridging necrosis)

Batts-Ludwig: Grade 0-4

Bridging or confluent Necrosis

Which features of chronic viral hepatitis are seen?

• Interface hepatitis

• fatty change,

• ballooning degeneration

• predominantly portal inflammation

• Bridging necrosis

• Cirrhosis Inte

rface

hepa...

fatty c

hange,

ballooning deg...

predominantly

...

Bridgin

g necro

...

Cirrhosis

17% 17% 17%17%17%17%

This biopsy’s interface hepatitis is best graded as Scheuer’s

Grad

e 1

Grad

e 2

Grad

e 3

Grad

e 4

25% 25%25%25%

1. Grade 1

2. Grade 2

3. Grade 3

4. Grade 4

Comparison of simple scoring systems for grading

chronic hepatitis

IASL Batts-Ludwig Metavir

Minimal activity Grade 1 A1

Mild activity Grade 2 A1

Moderate activity Grade 3 A2

Marked activityMarked & bridging necrosis

Grade 4Grade 4

A3A3

Stage: Degree of Fibrosis

• Fibrosis: periportal, may be perivenular

• Early fibrosis

• Incomplete septae

• Complete portoportal septae

• Cirrhotic stage

Fibrosis

• Rounded enlargement of portal tracts / stellate periportal scars with bridging

• Progression to cirrhosis

Fibrosis: Does sample size affect staging accuracy?

Yes N

o

Abstain

33% 33%33%

1. Yes

2. No

3. Abstain

Batts-Ludwig: Stage 0-4

cirrhosis normal

Bridging Portal fibrosis

Comparison of Simple systems for Scoring Fibrosis

Definition IASL Batts-Ludwig Metavir

No fibrosis No fibrosis Stage 0 F 0

Portal expansion

Mild Stage 1 F1

Few septae Moderate Stage 2 F2

Many septae Severe Stage 3 F3

Cirrhosis Cirrhosis Stage 4 F4

Kappa StatisticMeasure of observer variability

• 0 (chance) 1 (perfect)

• Fibrosis: .5-.9 (fair excellent)

• Inflammation: .2-.6 (slight-moderate)

• Cardiac auscultation .19

• Varices endoscopy .38

• Mammograms .47

• Breast cancer grading .43-.74

Consistency & accuracy

• Subspecialty expertise

• > 10 years in academic center

• Improved specimen interpretation despite small biopsy size

• Rousselet, et al Hepatology 2005 41: 257-64

Nomenclature & Scoring• Chronic Hepatitis

• Severity of necroinflammatory activity (grade)

• Extent of Fibrosis (Stage)

• Etiology

• System used in scoring

“Chronic viral hepatitis C/B/D with mild/moderate/marked activity in early fibrosis /incomplete/ portoportal septae/cirrhotic stage”

Additional features to be routinely assessed

• Fat: present in 50% VHC biopsies, genotype 3, NAFLD

• Hemosiderosis

• Neoplasia: Small cell dysplasis

• HIV

Needle biopsies of a 42 y/o ♀ with chronic ↑AST: 240 & ALT: 300

Which Metavir grade & stage is most appropriate?

A1 F1 A2 F2

A3 F3 A2 F?

25% 25%25%25%

1. A1 F1

2. A2 F2

3. A3 F3

4. A2 F?

Is this bridging necrosis?

Yes N

o

50%50%

1. Yes

2. No

Differential Diagnosis

• Acute hepatitis

• Other Chronic hepatitis:– Autoimmune– PSC– PBC– Metabolic disorders: Wilson, Heomchromatosis– Drug reactions

Acute vs Chronic Hepatitisclinical hx

Lobular inflammation

Busy parenchyma

Periportal inflammation

Fibrosis

Autoimmune hepatitisSerology

Duct proliferation in response to hepatocyte loss. This ductular reaction is fibrogenic

Interface hepatitis with ↑ PC

PSC

PBC: non suppurative cholangitis

Metabolic Disorders

• Wilson disease: copper stain

• Hemochromatosis: Iron stain

• A1AT: Diastase treated PAS

Non Alcoholic Fatty Liver Disease (NAFLD)

• 70% chronic hepatitis of unknown cause

• ♀=♂• Obesity• Dyslipeidemia insulinemia with

insulin resistance• Overt type 2 Diabetes AST, ALT, GGT 24%

Drug Reaction

Graft biopsies

Etiology of organ loss

Rejection vs. Recurrence

New disease

Features of chronic viral hepatitis• HBV• Ground glass

hepatocytes

• HCV: • Fatty change• Portal lymphoid

aggregates

Therapeutical Response

• Whether using Metavir, Ishak or Knodell, all HAI scores improve when therapy is truly effective & show statistical differences when compared to placebo

• Goodman 2007

It does not matter which system you use!

• Words provide a picture to the clinician & to the patient so they will have a dynamic picture of the disease

• Remember to name the system being used

Summary

• Pathology of chronic hepatitis

• Role of the biopsy

• Nomenclature

• Grading & staging systems

• Elements of surgical report

• Differential Diagnosis

NAFLD Activity Index

Item Definition Score

Steatosis <5%, <33%, <66% >66% 0-3

Lobular inflammation

None, <2/20X, <4, >4 0-3

Ballooning None, Few, many 0-2

Fibrosis Perisinusoidal /periportalBothBridgingCirrhosis

1A-1C234