1. Pathology of Chronic Viral Hepatitis: Nomenclature Grade & Stage Carmen Gonzalez Keelan MD FCAP FASCP Consultant, UPR School of Medicine

2. Chronic hepatitis: term used when there is clinical evidence of chronicity (hepatic necrosis & inflammation lasting>6 months) Do you agree? 1.Yes 2.No 3.Abstain

3. Causes of chronic hepatitis VHB VHC Autoimmune A1AT Wilson Drug hepatotoxicity

4. Which virus is responsible for 40% of acute hepatitis in USA? 1.HAV 2.HBV 3.HCV 4.HDV

5. Chronic Liver disease 72/100,000 8 th cause of death, between diabetes & suicide Viral hepatitis C: 57% Alcohol: 24% NAFLD: 9% Viral hepatitis B: 4% 44,000 (1.9%) deaths

6. 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)

7. Occult HCV infection Persistent LFT elevation with negative HCV serology Positive HCV serology with normal LFT*

8. Role of the biopsy in Chronic liver diseases Confirm diagnosis Assess prognosis Guide treatment Goodman, Z J Hepatol 47 598-607, 2007

9. 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

10. 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

11. 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

12. 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

13. Grade of Inflammation Portal inflammation: dense mononuclear Interface activity Lobular inflammation Parenchymal injury: ballooning, apoptosis & bridging necrosis

14. Portal inflammation Lymphocytes, PC T lymphocytes plasma cells & eosinophils Lymphoid follicles with GC  HCV

15. 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)

16. Interface hepatitis: Mild: occasional Moderate <50% Marked > 50:%

17. Lobular Necro-inflammatory activity Variable & spotty necrosis Apoptosis, ballooning degeneration Zone 3 cholestasis Regenerative 2ble liver cell plates & rosettes

18. Parenchymal injury Mild Moderate >5 foci /10 HPF Marked numerous necroinflammatory foci (bridging necrosis)

19. Batts-Ludwig: Grade 0-4

20. Bridging or confluent Necrosis

21. Which features of chronic viral hepatitis are seen? Interface hepatitis fatty change, ballooning degeneration predominantly portal inflammation Bridging necrosis Cirrhosis

22. This biopsy’s interface hepatitis is best graded as Scheuer’s 1.Grade 1 2.Grade 2 3.Grade 3 4.Grade 4

23. Comparison of simple scoring systems for grading chronic hepatitis IASLBatts-LudwigMetavir Minimal activityGrade 1A1 Mild activityGrade 2A1 Moderate activityGrade 3A2 Marked activity Marked & bridging necrosis Grade 4 A3

24. Stage: Degree of Fibrosis Fibrosis: periportal, may be perivenular Early fibrosis Incomplete septae Complete portoportal septae Cirrhotic stage

25. Fibrosis Rounded enlargement of portal tracts / stellate periportal scars with bridging Progression to cirrhosis

26. Fibrosis: Does sample size affect staging accuracy? 1.Yes 2.No 3.Abstain

27. Batts-Ludwig: Stage 0-4

28. cirrhosisnormal BridgingPortal fibrosis

29. Comparison of Simple systems for Scoring Fibrosis DefinitionIASLBatts-LudwigMetavir No fibrosis Stage 0F 0 Portal expansion MildStage 1F1 Few septaeModerateStage 2F2 Many septaeSevereStage 3F3 Cirrhosis Stage 4F4

30. Kappa Statistic Measure 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

31. Consistency & accuracy Subspecialty expertise > 10 years in academic center Improved specimen interpretation despite small biopsy size Rousselet, et al Hepatology 2005 41: 257-64

32. 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”

33. Additional features to be routinely assessed Fat: present in 50% VHC biopsies, genotype 3, NAFLD Hemosiderosis Neoplasia: Small cell dysplasis HIV

34. Needle biopsies of a 42 y/o ♀ with chronic ↑AST: 240 & ALT: 300 Which Metavir grade & stage is most appropriate? 1.A1 F1 2.A2 F2 3.A3 F3 4.A2 F?

35. Is this bridging necrosis? 1.Yes 2.No

36. Differential Diagnosis Acute hepatitis Other Chronic hepatitis: –Autoimmune –PSC –PBC –Metabolic disorders: Wilson, Heomchromatosis –Drug reactions

37. Acute vs Chronic Hepatitis clinical hx Lobular inflammation Busy parenchyma Periportal inflammation Fibrosis

38. Autoimmune hepatitis Serology Duct proliferation in response to hepatocyte loss. This ductular reaction is fibrogenic Interface hepatitis with ↑ PC

39. PSC

40. PBC: non suppurative cholangitis

41. Metabolic Disorders Wilson disease: copper stain Hemochromatosis: Iron stain A1AT: Diastase treated PAS

42. 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%

43. Drug Reaction

44. Graft biopsies Etiology of organ loss Rejection vs. Recurrence New disease

45. Features of chronic viral hepatitis HBV Ground glass hepatocytes HCV: Fatty change Portal lymphoid aggregates

46. 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

47. 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

48. Summary Pathology of chronic hepatitis Role of the biopsy Nomenclature Grading & staging systems Elements of surgical report Differential Diagnosis

49. NAFLD Activity Index ItemDefinitionScore Steatosis 66%0-3 Lobular inflammation None, 40-3 BallooningNone, Few, many0-2 FibrosisPerisinusoidal /periportal Both Bridging Cirrhosis 1A-1C 2 3 4