Date post: | 12-Jan-2016 |
Category: |
Documents |
Upload: | dorothy-mckinney |
View: | 214 times |
Download: | 0 times |
Evaluation of Liver Histology in Clinical
Trials for Chronic Viral Hepatitis
Zachary Goodman, M.D., Ph.D.Chief, Hepatic PathologyArmed Forces Institute of Pathology
Viral Replication
Chronic Viral HepatitisPresumed Pathogenesis
Immune Response
Tissue Damage
Scarring
HCC
Cirrhosis Death
Histologic Evaluation
Hepatitis• Acute
• Chronic
• Hepatocellular Injury– Apoptosis– Focal “necrosis”
• Inflammation– Parenchymal– Portal– Periportal
• Repair and Regeneration– +/- Scarring
Chronic HepatitisHistologic Grading & Staging for
Therapeutic Trials
• Goal– To assess whether there is
improvement in a cohort of patients treated with a new therapy in comparison to a control cohort
Chronic HepatitisHistologic Grading & Staging for
Therapeutic Trials• Methods
– Semiquantitative numerical scoring
– Ranked assessment
– Single pathologist
– Paired biopsies from each patient
– Blinded as to treatment arm and order
Histology Activity Index(Knodell Score)
Periportal Injury 0-4
Confluent Necrosis 0-6
Parenchymal Injury 0-4
Portal Inflammation 0-4
Grade (Inflammation) 0-18
Stage (Fibrosis) 0-4
Mild = 1 Moderate = 3(< 50% circ.)
Marked = 4(> 50% circ.)
Periportal Injury(Interface hepatitis,
Piecemeal necrosis)
Mild = 1(<5 per 10X field)
Moderate = 3(5-20 per 10X field)
Marked = 4(>20 per 10X field)
Parenchymal Injury
Mild = 1 Moderate = 3 Marked = 4
Portal Inflammation
Histology Activity Index(Knodell Score)
Periportal Injury 0-4
Confluent Necrosis 0-6
Parenchymal Injury 0-4
Portal Inflammation 0-4
Grade (Inflammation) 0-18
Stage (Fibrosis) 0-4
None = 0 Portal Fibrosis = 1
Bridging Fibrosis = 3 Cirrhosis = 4
Fibrosis Scoring MethodsKnodell Metavir Ishak
None 0 0 0
Portal fibrosis (some) 1 1 1
Portal fibrosis (most) 1 1 2
Bridging (few) 3 2 3
Bridging (many) 3 3 4
Incomplete cirrhosis 4 4 5
Established cirrhosis 4 4 6
Chronic Viral HepatitisHistologic Evaluation
Grade (Activity, HAI score)– Correlates with ALT– Improves with successful therapy
Stage (Fibrosis)– Changes slowly– May improve with successful
therapy
Paired biopsies from each patient– Blinded as to treatment arm and
order Inflammation (same, better, worse) Fibrosis (same, better, worse)
Chronic Viral HepatitisRanked Assessment
Chronic HepatitisHistologic Grading & Staging for
Therapeutic Trials•Primary Endpoint
– Proportion of patients with 2 point improvement in HAI inflammation with no worsening of fibrosis score
•Other (Exploratory) Endpoints
– Ranked assessment
– Mean change in HAI
– Other scoring systems