1. PATTERNS OF LIVER INJURY
Wilson M.S. Tsui
Department of Pathology
Tseung Kwan O Hospital

2. INTRODUCTION TO HEPATIC HISTOPATHOLOGY Interpretation
Scan the whole slide on low power
architecture
focal lesions and distribution
Look at everything systematically
hepatocytes & cell plates, sinusoids & lining cells, portal tracts & contents, vasculature, bile ducts, central veins
examine a few lobules in detail
Special stains
very useful to demonstrate changes inapparent on H&E
trichrome/reticulin (2nd choice), orcein (3rd choice)
Clinical correlation
morphological diagnosis to limit the differentials
clinical correlation for definitive and etiological diagnosis

5. INTRODUCTION TO HEPATIC HISTOPATHOLOGY Assessing duration of fibrosis
Stains
Trichrome to detect fibrosis
Orcein to detect elastic formation
Duration
Collapse without fibrosis – days
Fibrosis without elastics – 2 weeks
Fine elastic fibres – 1-2 months
Thick elastic fibres – >6 months
Meaning of “acute” versus “chronic”

7. Collapse in AH

9. Pericellular fibrosis in NASH

11. Elastic fibres in normal PT

12. INTRODUCTION TO HEPATIC HISTOPATHOLOGY PATTERNS OF INJURY
A few sterotyped ways in which the liver responds to a huge number and wide variety of injuries
The changes can be identified morphologically, with different combinations of a finite number of histologic features
Pattern of injury  correlate with histologic, laboratory, and clinical features  definitive diagnosis

13. INTRODUCTION TO HEPATIC HISTOPATHOLOGY COMMON PATTERNS OF INJURY
Necroinflammation – acute, chronic
Steatosis and steatohepatitis
Cholestasis – acute, chronic
Granulomas
Vascular injury
Fibrosis and cirrhosis
Nodule
Specific characteristic features:
specific infections, storage diseases, malformations, neoplasms

14. GRANULOMA
Focal collection of mononuclear phagocytes containing epithelioid cells, with or without giant cells, often but not invariably with a peripheral cuff of lymphocytes
A form of inflammatory reaction to stimulation by specific Ag, circulating Ag-Ab complexes, foreign material
Persistence of phagocytosed material eg TB, ova
Hypersensitivity mechanism eg drugs
5-10% of liver biopsy

15. GRANULOMA Types of no significance
Microgranuloma (Kupffer cell nodules)
Small clusters (<6 cells) of histiocytes/Kupffer cells in sinusoids
Non-specific reaction to necrosis
Some associated with other granulomatous reactions
Lipogranuloma
Loose aggregates of macrophages with identifiable fat droplets
Associated with fatty liver or mineral oil deposits
Bile granuloma
Small clusters of bile-laden and/or foamy histiocytes
Reaction to bile extravasation

16. Kupffer cell granuloma

17. Kupffer cell granuloma or Epithelioid granuloma (PBC)

18. Lipogranuloma

19. Mineral oil

20. GRANULOMA Types of significance
Epithelioid granuloma
Potentially significant process – infection, PBC, sarcoidosis, drugs, metal/foreign particles, neoplasm
Necrotizing granuloma
Infective – TB, fungi, parasites
Suppurative granuloma
Infective – Fungi, cat-scratch disease, chronic granulomatous disease

21. Epithelioid granuloma (sarcoidosis)

22. Necrotizing granuloma (TB)

23. GRANULOMA Types of significance
Foamy macrophage aggregates
Infective in immunocomprised patents – Mycobacterium avium-intracellulare, leprosy, Cryptococcus, Whipple disease
Fibrin-ring granuloma
Highly suggestive of Q fever, also in allopurinol, EBV, CMV, leishmaniasis, toxoplasmosis, giant cell arteritis, SLE and Hodgkin’s disease

24. Histoplasma
Penicillium marneffei

25. Fibrin-ring granuloma (Q fever)

26. Allopurinol

27. GRANULOMA Etiology Infection and Infestation Various material
Mycobacteria eg TB, leprosy
Bacteria eg brucellosis, tularemia
Viruses eg CMV, EBV
Rickettsia eg Q fever
Chylamydia eg psittacosis
Spirochaete eg syphilis
Fungi eg histoplasmosis, cryptococcosis
Parasites eg toxocara, schistosomiasis
Various material
Metal eg beryllium
Foreign particles eg talc, suture

28. GRANULOMA Etiology Drug-induced Neoplasm Miscellaneous diseases
Eg allopurinol, chlorpropamide, phenylbutazone, sulphonamide
Neoplasm
Eg Hodgkin’s disease
Miscellaneous diseases
Sarcoidosis
Liver diseases eg PBC
GI diseases eg Crohn’s disease
Vascular diseases eg Wegener’s granulomatosis
Autoimmune diseases eg RA
Granulomatous disease of childhood
etc

29. GRANULOMA Major causes ~80%
Sarcoidosis ~30%
Drugs ~30%
Infection ~15%
Primary biliary cirrhosis ~10%
Geographic variation
12-15% no obvious cause

30. GRANULOMA Diagnostic approach
Type & distinctive features of granuloma
Acinar distribution
Associated parenchymal changes
Identifiable etiologic agent

31. GRANULOMA Diagnostic approach
Type & distinctive features of granuloma
Epithelioid, necrotizing, suppurative, fibrin-ring
Eosinophils – drug or parasite
Neutrophils – fungi, cat-scratch disease, chronic granulomatous disease
Acinar distribution
Diffuse, often portal/periportal – sarcoidosis
Portal – PBC, schistosomiasis
Parenchyma – drug, TB
Perivenular – lipogranuloma

32. Drug
PBC
Schistosomiasis TB
Lipogranuloma
Sarcoidosis

34. PBC

35. Schistosomiasis

36. Chlorpropamide

37. GRANULOMA Diagnostic approach
Associated parenchymal changes
Hepatitis-like background – infective, drug
Non-specific reactive changes – systemic infection
Confluent necrosis/infarction – fungi
Bile duct destruction – PBC
Bile duct damage – portal-based granulomas like sarcoidosis, Hodgkin’s disease
Fibrosis
Identifiable etiologic agents
Special histochemical and immuno stains, molecular studies
Polarization microscopy

38. Phenylbutazone

39. DRUG-INDUCED GRANULOMAS
1. Kupffer cell granulomas (Histiocytic nodules)
common, but no diagnostic significance
2. Epithelioid granulomas
more distinctive of hypersensitivity reaction
usually discrete, any part of liver
non-caseating,  giant cells
surrounded by mixed inflammatory infiltrate (eosinophils in some cases)
antihypertensives (methyldopa), antibiotics (sulphonamides, isoniazid), antirheumatics (phenylbutazone, aspirin)
3. Fibrin-ring granulomas
allopurinol