Liver Pathology 1 & 2 Lecture PDF

LIVER PATHOLOGY 1 & 2 DR N Moagi DEPARTMENT OF ANATOMICAL PATHOLOGY INKOSI ALBERT LUTHULI CENTRAL HOSPITAL / UNIVERSITY OF KWAZULU-NATAL NORMAL ADULT LIVER  Weighs 1400 to 1600 g  Dual blood supply  Portal vein providing 60% to 70%  Hepatic artery supplying the 30% – 40%  Porta hepatis...

LIVER PATHOLOGY 1 & 2 DR N Moagi DEPARTMENT OF ANATOMICAL PATHOLOGY INKOSI ALBERT LUTHULI CENTRAL HOSPITAL / UNIVERSITY OF KWAZULU-NATAL NORMAL ADULT LIVER  Weighs 1400 to 1600 g  Dual blood supply  Portal vein providing 60% to 70%  Hepatic artery supplying the 30% – 40%  Porta hepatis  Portal veins  Hepatic arteries  Bile ducts travel in parallel within portal tracts LOBULE MODEL  1- to 2-mm hexagonal lobules  Central veins  Terminal tributaries of the hepatic vein at the centre  Portal tracts are located at the periphery Further subdivided into six triangular acini ACINAR MODEL On the basis of blood flow ZONE 3 - Centrilobular Hepatocytes next to central vein Farthest from blood supply ZONE 1 - Periportal Hepatocytes near portal tract Closest to the blood supply Metabolic activities highest at the centre Zone 3 lowest at the Zone 1 1. Viral Hepatitis 2. Autoimmune hepatitis 3. Drug induced hepatitis 4. Alcoholic liver disease 5. Cirrhosis 6. Portal hypertension LIVER PATHOLOGY 1 Viral hepatitis  Hepatotropic viruses o Hepatitis A, B, C, D, and E  Non-hepatotropic viruses o EBV, CMV, HSV, Adenovirus, and Yellow fever virus Hepatitis A Self-limited disease NO chronic hepatitis or a carrier state Modes of transmission Faeco-oral transmission Consumption of raw or steamed shellfish (oysters, mussels, clams) Contaminated water Hepatitis A Small, non-enveloped, positive single strand RNA (ssRNA) picornavirus Genus Hepatovirus Receptor - HAVCR-1 (also known as TIM-1) Glycoprotein serving as receptors for several other viruses Hepatocellular injury by cytotoxic T-lymphocytes and NK cells No cytopathic features EM - icosahedral capsid - 27 nm in diameter Hepatitis A Incubation period - 2 to 6 weeks Non-specific symptoms Fatigue Loss of appetite, jaundice Laboratory diagnosis IgM - Onset of symptoms up to 3 to 6 months IgG - During recovery, lifelong immunity against re-infection Faecal – 6-12 weeks Hepatitis A Extrahepatic manifestations Rash Arthralgia Immune complex mediated complications LCV, glomerulonephritis and cryoglobulinemia Uncommon complications Prolonged cholestasis Relapse of disease within 6 months Hepatitis B Varied clinical outcomes Modes of transmission Parenteral Blood transfusion Sharing of needles and syringes for intravenous drug use Unprotected sex Child birth Hepatitis B Genus Hepadnaviridae Outer surface envelope - Viral proteins & Host-derived lipids Core Nucleocapsid proteins Viral polymerase Viral DNA Double-stranded circular DNA molecule with several open reading frames Hepatitis B Viral DNA encodes the following proteins: Hepatitis B surface antigen (HBsAg) Large, Middle, Small envelope glycoproteins Hepatitis B core antigen (HBcAg) Nucleocapsid protein Assembly of hepatitis Be antigen (HBeAg) HBV polymerase (Pol) DNA polymerase and reverse transcriptase activities Hepatitis B Entry into host cells Large HBsAg binds NTCP (sodium taurocholate co-transporting polypeptide) Bile salt transporter Genome enters the nucleus Plus-strand is synthesized to form covalently closed circular DNA (ccc DNA) HBV replication occurs through reverse transcription Hepatitis B Cytopathic changes in infected cells Hepatocellular injury by CD8+ cytotoxic T cells on infected cells CD4+ and CD8+ interferon (IFN)-γ–producing cells are associated with resolution of acute infection Hepatitis B MAJOR CLINICAL PRESENTATIONS ACUTE HEPATITIS followed by recovery and clearance of the virus ACUTE HEPATIC FAILURE with massive liver necrosis CHRONIC HEPATITIS with or without progression to cirrhosis “Healthy” CARRIER STATE – asymptomatic Special microscopic features “Ground-glass” appearance. Swollen ER filled with HBsAg Positive Hepatitis B surface Hepatitis B Incubation period 4 to 26 weeks Non-specific symptoms – Anorexia, Fever, RUQ pain, Jaundice Serology HBsAg – Early & Persists in cases that progress to chronicity Anti-HBs antibody resolution of acute disease Persist for life, conferring immunity Not produced in cases that progress to chronic liver disease Substituted by IgM anti-HBc antibody is delayed appearance Hepatitis B Serology HBeAg, HBV DNA, and HBV DNA polymerase Active viral replication, together with HBsAg HBeAg Mutated strains may show active replication without HBeAg and express HBcAg Anti-HBe antibody Acute infection has peaked and is on the wane Not produced or appears only late in the disease course in chronic infection Hepatitis B Extrahepatic manifestations Immune complex–mediated phenomena – Glomerulonephritis; PAN OUTCOMES Recover within 3 months Acute liver failure (Acute on chronic) - 0.1% to 0.5% of patients Chronic hepatitis - 5% to 10% of infected individuals, approximately 90% in infants Risk of HCC Vaccination - Protective anti-HBs antibody response in 95% of infants, children, and adolescents. Hepatitis C Varied clinical outcomes >80% end up with chronic liver disease Modes of transmission Parenteral Blood transfusion Sharing of needles and syringes for intravenous drug use Unprotected sex Child birth Hepatitis C Genus Flaviviridae Small, enveloped, single-stranded RNA virus with one open reading frame Encodes single polyprotein that is processed into functional proteins Two envelope proteins - E1 and E2 Five core proteins - P7, NS2, NS3/4a (protease), NS5A (replication complex), NS5B (RNA polymerase) Special morphological features Portal tract dense lymphoid aggregates Lymphoid follicles Steatosis Genotype 3 infection Bile duct injury Mimics biliary disease Hepatitis C Incubation period 4 to 26 weeks (Mean – 9 weeks) Non-specific symptoms Anorexia, Fever, RUQ pain, Jaundice Laboratory diagnosis HCV RNA - 1-4 weeks, increased transaminases Anti-HCV antibodies - 3 to 6 weeks after infection May be negative in immunocompromised patients Hepatitis C OUTCOMES Spontaneous clearance of the virus after 4 to 6 months - Rare Chronic hepatitis in 80-90% of infected individuals, approximately 90% in infants 20% patients get Cirrhosis Risk of developing HCC Factors associated with progression Older age, Male gender, Alcohol, Immunosuppressive drugs, Hepatitis B/HIV co- infection, Diseases associated with insulin resistance Hepatitis D Dependent on HBV 5% of HBV-infected individuals co-infected with HDV Parenteral transmission 35-nm, double-shelled, Circular single-stranded RNA virus External coat antigen surrounding an internal polypeptide assembly Delta antigen (HDAg) - Only protein produced Replication – RNA-directed RNA synthesis by host RNA polymerase Cytopathic effects and enhanced cytotoxic host responses Hepatitis D Infection arises in two settings Co-infection - Exposure to serum containing HBV and HDV Increased risk of progression to cirrhosis and HCC Superinfection - Chronic HBV carrier with new inoculum of HDV 2 PHASES OF SUPER INFECTION ACUTE PHASE CHRONIC PHASE Active HDV replication Decreased HDV replication Suppression of HBV Increased HBV replication High transaminase levels Fluctuating transaminase levels Hepatitis D Serology HDV RNA- acute symptomatic disease IgM anti-HDV antibody- most reliable indicator, Appears late and short-lived Superinfection Persist for months or longer HBsAg is present in serum Vaccination for HBV also prevents HDV infection Hepatitis E Self-limited acute hepatitis Resolution in 2 to 4 weeks Young to middle-aged adults Mortality rate approaching 20% among pregnant women Chronic HEV infection in Immunosuppression Zoonotic disease with animal reservoirs Spread by ingestion of contaminated water and foods Hepatitis E Genus Hepevirus Unenveloped, positive- single stranded RNA virus 7.3 kb in length and contains four open reading frames Encode multiple proteins Viral protease Viral RNA polymerase No cytopathic features Hepatic damage from the host response to cells infected with virus Hepatitis E Serology IgM anti-HEV- transaminitis Persistent IgG anti-HEV antibodies- during recovery Faecal HEV RNA and HEV virions - PCR in stool Also in serum CLINICOPATHOLOGIC SYNDROMES OF VIRAL HEPATITIS 1. Acute asymptomatic infection with recovery 2. Acute symptomatic hepatitis, anicteric or icteric, with recovery 3. Acute liver failure with massive to submassive hepatic necrosis 4. Chronic hepatitis, with or without progression to cirrhosis Acute asymptomatic infection with recovery Minimally elevated serum transaminases Presence antibodies after recovery HAV and HBV infection can be subclinical Presence of anti-HAV or anti-HBV antibodies. Acute symptomatic hepatitis, anicteric or icteric, with recovery Four phases Incubation period – different for each of the viruses Symptomatic pre-icteric phase Symptomatic icteric phase Convalescence Acute liver failure with massive to submassive hepatic necrosis 10% of cases of acute hepatic failure HAV and HEV are the most common causes worldwide HBV is more common in Asia and the Mediterranean  Chronic hepatitis, with or without progression to cirrhosis Evidence of continuing or relapsing hepatic disease for more than 6 months. Symptoms Fatigue, Malaise, Loss of appetite, Jaundice Biochemical/Serologic Persistent elevation of serum transaminases, Prolonged prothrombin time, Mild ALP elevation Hyperglobulinemia, Hyperbilirubinemia Immune complex disease Chronic HBV and HCV infection Vasculitis Glomerulonephritis Cryoglobulinemia Carrier state An individual who harbors and can transmit an organism, but has no symptoms. Two separate scenarios Individuals who harbour the virus but have no liver disease Individuals who harbour the virus and have asymptomatic non-progressive liver damage Hepatitis B “Healthy carrier” state HBsAg and anti-HBe presence Negative HBeAg Normal aminotransferases, low or undetectable serum HBV DNA Lack of significant inflammation or liver injury on biopsy  Hepatitis Viruses Virus HAV HBV HCV HDV HEV Type of viral Circular defective SsRNA Partial dsDNA SsRNA SsRNA genome ssRNA Parenteral Sexually Parenteral Transmission Feco-oral Parenteral Feco-oral transmitted Intranasal cocaine Vertical Incubation 2-6 weeks 2-26 weeks 4-26 weeks 2-26 weeks 4-5 weeks period Acute liver Asia NIL Pregnant females failure 10% co-infection Chronic liver Immunocompromised NIL 5-10% >80% 90-100% disease hosts superinfection HBsAg HCV antibody – IgM IgM Diagnosis IgM HBcAg ELISA IgG IgG HBV DNA HCV RNA HDV RNA HEV RNA Acute viral hepatitis Portal tracts Scanty portal and lobular inflammation Lymphocytes, plasma cells, eosinophils Hepatocyte Ballooning degeneration Cholestasis Necrosis or apoptosis Types of necrosis Confluent necrosis - Necrosis of groups of hepatocytes Pan-lobular or panacinar necrosis Bridging necrosis Pigmented macrophage aggregates Chronic viral hepatitis Dense portal tract inflammation Lymphocytic, or lymphoplasmacytic Portal tract fibrosis Portal and periportal fibrosis porto-portal bridging fibrosis Interface activity Variable lobular inflammation Inflammatory activity (grade) and fibrosis (stage) AUTOIMMUNE HEPATITIS Chronic, progressive hepatitis associated with genetic predisposition, autoantibodies, and therapeutic response to immunosuppression Female predominance (78%) Proposed triggers Viral infections Drugs/toxin - Minocycline, nitrofurantoin, and α-methyl dopa AUTOIMMUNE HEPATITIS MORPHOLOGY Interface hepatitis Plasma cell clusters CD8+ cytotoxic T cells Lobular inflammation Emperipolesis Regenerative changes Rosettes Fibrosis Burnout cirrhosis Cirrhosis limited by inflammation AUTOIMMUNE HEPATITIS Diagnostic features Autoantibodies May be negative (seronegative hepatitis) Also present in steatohepatitis and viral hepatitis Type 1 - More common ANA and ASMA Soluble liver antigen(SLA)/Liver pancreas antigen AMA (typical in PBC) Type 2 - More common in children Anti-liver-kidney microsome-1 (LKM-1) Serum IgG elevation AUTOIMMUNE HEPATITIS Asymptomatic – transaminitis Acute liver failure – Fatigues, Anorexia, Nausea, Abdominal pain Overlap syndrome - Associated with PBC, PSC-paediatrics Associated autoimmune disease - T2DM, Thyroiditis, Celiac sprue DRUG OR TOXIN-INDUCED LIVER INJURY Injury is mediated by reactive metabolites generated in the liver Cytochrome p-450 mediated More active in the central zone of the lobule Necrosis of perivenular hepatocytes Cytochrome P450 inducers SCRAP GP – Sulfonamides/smoking, Carbamazepine, Rifampicin, Alcohol, Phenytoin, Griseofulvin, Phenobarbital Exacerbate the toxicity of other drugs MECHANISMS DRUG OR TOXIN-INDUCED LIVER INJURY IDIOSYNCRATIC (unpredictable) DOSE-DEPENDENT (predictable) Most common form Acetaminophen Most common cause Occur after 1 to 3 months of exposure Hypersensitivity response to the drug or its metabolite N-Acetyl-benzoquinone immine (NAPQI) Produced by the cytochrome p-450 system Pericentral zone 3 hepatocytes affected Genetic susceptibility Variants of N-Acetyltransferase (NAT2) Inducers associated with Decreased enzymatic activity acetaminophen Slow metabolism of isoniazid Alcohol, Codeine, organic solvents, and toxins in mushrooms PATTERN OF INJURY MORPHOLOGY CAUSATIVE AGENTS Contraceptive Anabolic steroids Cholestasis Hepatocellular cholestasis Antibiotic ART Hepatocellular cholestasis Antibiotics Cholestatic hepatitis Necroinflammatory activity Phenothiazine Bile duct destruction Statins Spotty necrosis Methyldopa, phenytoin Hepatocellular necrosis Massive necrosis Acetaminophen, halothane Chronic hepatitis Isoniazid Macro/microvesicular steatosis Alcohol, steroid, methotrexate, TPN Valproate, tetracycline, aspirin (Reyes), Fatty liver disease Microvesicular steatosis ART Steatohepatitis with Mallory denk bodies Alcohol, amlodipine, Irinocten Alcohol, methotrexate, Enalapril, Vit-A Fibrosis/Cirrhosis Periportal and pericellular fibrosis or retinoids Non-necrotising granuloma Sulfonamides, amiodarone, isoniazid Granulomatous inflammation Fibrin ring granuloma Allopurinol Sinusoidal obstruction syndrome with central vein Chemo, bush tea obliteration Vascular lesions Budd-Chiari syndrome Oral contraceptives Peliosis hepatis – blood filled cavities not lined by Anabolic steroids, Tamoxifen endothelial cells HCA Oral contraceptive, anabolic steroids HCC Alcohol, Thorotrast Neoplasms Cholangiocarcinoma Thorotrast Angiosarcoma Thorotrast, vinyl chloride DRUG OR TOXIN-INDUCED LIVER INJURY Biochemical findings HEPATOCELLULAR INJURY ALT ≥5 times the upper limit of normal ALT/ALP ratio >5 CHOLESTASIS ALP ≥2 times the upper limit of normal ALT/ALP ratio M - Oestrogen-dependent responses of the liver to gut-derived endotoxin (lipopolysaccharide [LPS]) 2. Ethnic and genetic difference ALDH*2 - very low enzyme activity → Inability to oxidize acetaldehyde 3. Comorbidities Iron overload, NASH, HBV/HCV viral hepatitis ALCOHOLIC LIVER DISEASE Excessive alcohol intake (Changes in lipid metabolism related to altered redox potential) Steatosis Factors contributing to steatosis Reduced nicotinamide adenine dinucleotide (NADH) Altered redox balance effects Lipogenesis Suppression of fatty acid oxidation Increased expression of enzymes that carry out fatty acid synthesis Impaired lipoprotein assembly and secretion Peripheral catabolism of fat Dysfunction of mitochondria microtubules and cellular membranes Oxidative stress ALCOHOLIC LIVER DISEASE Contributory factors underlying hepatocyte injury and alcoholic hepatitis Acetaldehyde - Lipid peroxidation, Acetaldehyde-protein adduct formation CYP2E1 induction - Metabolises alcohol to produce ROS – Cell damage Methionine metabolism Decreases glutathione levels - Sensitises liver to oxidative injury Homocysteine production - Endoplasmic reticulum stress response Induction of cytochrome P-450 enzymes Converts drugs to toxic metabolites Increased uptake of bacterial endotoxin from the gut leading to inflammation Normal liver, gross Hepatic steatosis (FATTY LIVER) Enlarged (4 to 6 kg), soft, yellow, and greasy liver  HEPATIC STEATOSIS (FATTY LIVER) Reversible Microvesicular (small droplets) Macrovesicular (large droplets) Macrovesicular steatosis is the predominant form in alcoholic liver disease Alcoholic foamy degeneration Chronic heavy alcohol use Associated ER and mitochondrial damage  Alcoholic hepatitis - Steatohepatitis Ballooned hepatocytes Mallory hyaline/Denk bodies Non-specific NASH, Wilson disease, Chronic biliary tract diseases. Inflammation Neutrophils predominant Necrosis Pericellular/Perivenular fibrosis Zone 3 - “chicken wire” Phlebosclerosis - Vascular derangements related to perivenular Fibrosis, fibrous obliteration Interrelationships among hepatic steatosis, alcoholic hepatitis, and alcoholic cirrhosis Laennec cirrhosis - micronodular cirrhosis seen in ALH  Cirrhosis Causes of cirrhosis Alcohol abuse, viral hepatitis, and NASH Biliary disease, iron overload Pathogenesis Hepatic stellate cell - principal cell type involved in scar deposition Normal function - Lipid storage, Vitamin A storage Activation by Inflammatory cytokines (TNF-α), ROS Conversion into myofibroblast by PDGFR-β, Cytokines (TGF-β, IL-17) and Chemokines ECM deposition in Space of Disse Sinusoidal capillarisation and loss of sinusoidal endothelial cell fenestration Hepatocyte loss with collapse of reticulin framework, deposition of collagen Vascular compromise  Cirrhosis THREE MAIN MORPHOLOGIC CHARACTERISTICS Bridging fibrous delicate bands or broad scars Portal-Portal / Portal-Central venule Parenchymal nodules - cycles of hepatocyte regeneration and scarring Micronodular – up to 3mm (alcoholic liver disease) Macronodular - >3mm (Hepatitis B_ A greater risk of hepatocellular carcinoma Disruption of the architecture of the entire liver Thick bands of collagen separate rounded cirrhotic nodules  Complications of Cirrhosis Liver failure Portal hypertension Hepatocellular carcinoma Portal hypertension Increased resistance to portal blood flow Causes Obstruction at the prehepatic, intrahepatic, or post-hepatic level If portal hypertension develops within days to weeks Obstruction is predominantly intrahepatic and the major clinical consequence is ascites Pressure within portal venous system is 7 mmHg  CAUSES OF PORTAL HYPERTENSION Obstructive thrombosis of portal vein PREHEPATIC CAUSES Structural abnormalities of the portal vein before it ramifies in the liver Cirrhosis Nodular regenerative hyperplasia PBC Schistosomiasis INTRAHEPATIC CAUSES Fatty liver disease Diffuse, fibrosing granulomatous disease (e.g., sarcoid) Infiltrative malignancy, primary or metastatic Focal malignancy with invasion into portal vein - Hepatocellular carcinoma Amyloidosis Severe right-sided heart failure POST-HEPATIC CAUSES Constrictive pericarditis Hepatic vein outflow obstruction  Portal hypertension RESISTANCE TO PORTAL FLOW AT THE LEVEL OF SINUSOIDS Contraction of vascular smooth muscle cells and myofibroblasts Scarring and parenchymal nodules Sinusoidal endothelial cells alterations Decrease in (NO) production, Increased release of endothelin-1, angiotensinogen, and eicosanoids Sinusoidal remodelling Arterial and portal system anastomoses in portal tracts Metabolic exchange between sinusoidal blood and hepatocytes INCREASE IN PORTAL FLOW CAUSED BY HYPERDYNAMIC CIRCULATION Arterial vasodilation, primarily in the splanchnic circulation - Prostacyclin, NO and TNF Increased venous efflux into the portal venous  Portal hypertension The four major consequences of portal hypertension Hepatic encephalopathy Ascites Porto-systemic venous shunts - Sites of the porto-systemic anastomoses Haemorrhoids - Superior haemorroidal veins with middle and inferior haemorroidal veins Oesophageal varices - Left gastric vein and azygous minor vein Retroperitoneum Caput medusae – Hallmark of portal hypertension Falciform ligament of the liver - Portal vein and the superficial veins of the anterior abdominal wall Congestive splenomegaly 1. Bacterial liver abscess 2. Amoebic liver abscess 3. Hydatid disease 4. Ascariasis 5. TB in the liver 6. Schistosomiasis 7. Sarcoidosis LIVER PATHOLOGY 2 THE LIVER ABSCESS Most common cause Pyogenic - representing a complication of a bacterial infection elsewhere Other common causes Echinococcal and amoebic infections Less common causes Other protozoal and helminthic organisms THE LIVER ABSCESS Routes of infection Portal vein - Appendicitis, diverticulitis, colitis Arterial supply Ascending infection in the biliary tract Ascending cholangitis - severe acute inflammatory response within the intrahepatic biliary tree Direct invasion of the liver from a nearby source Trauma - Penetrating injury PYOGENIC LIVER ABSCESS Causative agents that infect the liver directly Staphylococcus aureus in toxic shock syndrome Salmonella typhi in typhoid fever Bartonella henselae in cat scratch disease Causative agents that infect the liver when outflow is compromised Reflects the gut flora - Escherichia coli, Klebsiella, Proteus, Pseudomonas, PYOGENIC LIVER ABSCESS Macroscopically Solitary or multiple Bacteraemic spread through the arterial or portal system → multiple small abscesses More common on the right lobe Microscopic to >3cm PYOGENIC LIVER ABSCESS Central suppurative inflammation Granulation tissue formation Surrounding fibrosis Adjacent liver parenchyma Ductular reaction Hepatocellular cholestasis Ductular or cholangiolar cholestasis COMPLICATIONS Empyema or a lung abscess Peritonitis or localized peritoneal abscesses AMOEBIC LIVER ABSCESS Causative agent Entamoeba histolytica Amoeboma Clusters of amoeba trophozoite AMOEBIC LIVER ABSCESS Trophozoites Resemble macrophages 10 - 60 microns Round to oval Surrounded by a halo Retraction artefact or parasite toxins Abundant eosinophilic vacuolated cytoplasm May contain ingested red blood cells - Erythrophagocytosis Small, round nucleus Highlighted by PAS HYDATID CYST Caused by larval form of Echinococcus granulosus Characteristic calcifications in the cyst walls – seen on radiology Found in the liver in about two thirds of cases Other sites – thoracic cavity, bone Complications Similar to pyogenic abscesses Rupture of this cyst has severe clinical consequences Systemic spread - shock from massive immune response  HYDATID CYST Cyst wall Uni or multilocular Outer, opaque layer Inner tan –white layer Contents Opalescent fluid Hydatid sand - Degenerating scolices Hydatid cyst Outer non-nucleated, laminated eosinophilic wall Inner, nucleated, germinative layer Brood capsules Central vesicles containing daughter cysts Minute projections of the germinative layer Surrounded by granulation tissue, fibrosis, giant cells, mononuclear inflammation and eosinophils ASCARIASIS Causative agent - Ascaris lumbricoides Direct faecal-oral transmission Larvae can also form hepatic abscesses Worms commonly enter the common bile duct Obstructive jaundice Ascending cholangitis ASCARIASIS Diffuse eosinophil infiltrates Mammillated and decorticated eggs Mammillated Characteristic Small protrusions from the exterior Decorticated Absence of outer mammillated layer Infections that cause granulomatous inflammation in the liver BACTERIAL INFECTIONS Treponema pallidum in secondary or tertiary syphilis - Syphilitic gummas MYCOBACTERIAL INFECTIONS FUNGAL INFECTION Medically important Yeasts - Histoplasmosis capsulatum, Blastomyces dermatitidis and Coccidioides immitis Fungi showing hyphae – Aspergillus PARASITIC INFECTIONS Schistosomiasis – S.Mansoni, S. Japonicum Malaria, cryptosporidiosis, liver flukes, Strongyloidis stercoralis MYCOBACTERIAL INFECTIONS Causative organisms MTB, MOTT Morphology Central granular caseous necrosis Epithelioid histiocytes with multinucleate giant cell formation Lymphocytic cuff Non-necrotising granulomas – No central caseation Acid-fast stain – Ziehl-Neelsen, Fite-Farraco SCHISTOSOMIASIS Also known as bilharzia 5 different species: 3 major and 2 minor 3 major species include: Schistosoma mansoni; S. japonicum; S. haematobium 2 minor species include: S. mekongi; S. intercalatum Complications Granulomatous pulmonary arteritis with intimal hyperplasia Progressive arterial obstruction and cor-pulmonale in the lung Mesangioproliferative or membranous glomerulopathy SCHISTOSOMIASIS The pathology of schistosomiasis is caused by host inflammatory reactions to different stages of the parasite Early stage - Acute schistosomiasis Severe febrile illness that peaks about 2 months after infection Helper T-cell response - Th1 dominant Chronic schistosomiasis Helper T-cell response - Th2 dominant  SCHISTOSOMIASIS Pinhead-sized granulomas Darkened liver Heme-derived pigments from the schistosome gut Late S. Mansoni or S. Japonicum infections Pipe-stem fibrosis Fibrous tracts resemble the stem of a clay pipe PYOGENIC LIVER ABSCESS Schistosome egg containing miracidia Surrounding granulomas Mansoni - Subterminal/Lateral spines; Japonicum - Ill-defined Eosinophils sub-terminal knob, Haematobium - large terminal spine Most deaths are due to hepatic cirrhosis OTHER GRANULOMATOUS DISEASES IN THE LIVER SARCOIDOSIS Systemic granulomatous disease of unknown cause Involves many tissues and organs Aetiology unknown Immunologic abnormalities suggesting a cell-mediated immune response to an unidentified antigen Intra-alveolar and interstitial accumulation of CD4+ T cells in the lung Increased levels of T cell–derived Th1 cytokines Increased levels of several cytokines in the local environment Impaired dendritic cell function SARCOIDOSIS Portal tract granulomas Well-formed non-necrotizing granulomas Aggregates of tightly clustered epithelioid macrophages, often with giant cells Central necrosis is unusual Characteristic features Found within giant cells in approximately 60% of the granulomas Schaumann bodies Laminated concretions composed of calcium and proteins Asteroid bodies Stellate inclusions Not pathognomonic SARCOIDOSIS Other sites Lung – common finding Lymph nodes Spleen Bone marrow Skin – Presents as erythema nodosum Eyes – Sicca syndrome and Mikulicz syndrome Skeletal muscle