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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