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

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

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”

Collapse in AH

Pericellular fibrosis in NASH

Elastic fibres in normal PT

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

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

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

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

Kupffer cell granuloma

Kupffer cell granuloma or Epithelioid granuloma (PBC)

Lipogranuloma

Mineral oil

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

Epithelioid granuloma (sarcoidosis)

Necrotizing granuloma (TB)

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

Histoplasma Penicillium marneffei

Fibrin-ring granuloma (Q fever)

Allopurinol

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

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

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

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

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

Drug PBC Schistosomiasis TB Lipogranuloma Sarcoidosis

PBC

Schistosomiasis

Chlorpropamide

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

Phenylbutazone

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