Liver and intrahepatic bile ducts

Right lobe is divided into anterior and posterior segments by right hepatic vein; left lobe is divided into medial and lateral segments by left hepatic vein

Intrahepatic biliary tree: classified into intrahepatic large bile ducts (grossly visible with fibrous ductal wall and peribiliary glands) and small bile ducts

Regional lymph nodes: hilar, hepatoduodenal ligament, caval

Gross images: liver in situ, external surface, cut surface #1, #2

Normal histology

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Size of structures varies according to closeness to hepatic hilum

Acini

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Hemodynamic model of hepatic microanatomy that explains centrilobular necrosis; a concept, not an identifiable microscopic structure; triangular (spherical) area; base is terminal twigs of hepatic artery and portal vein

Diagram of acini

Bile canaliculi

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Drain bile from hepatocytes to portal space; 1-2 micron wide areas between neighboring hepatocytes, formed by grooves in plasma membranes and separated from vascular space by tight junctions; intracellular actin and myosin filaments surrounding the canaliculi propel secreted biliary fluid along canaliculi into canals of Hering, the terminal tributaries of the bile duct system (low cuboidal epithelium), to interlobular bile ducts (more robust cuboidal epithelium); connected to bile ducts by cholangioles (bile ductules), usually not visible unless distended by bile; highlighted by CEA which stains biliary glycoprotein I in canalicular membrane (cross reacting substance)

EM images: bile canaliculi

Bile ducts (intrahepatic)

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Develop from primitive hepatocytes of periportal limiting plate

Micro: cuboidal cells with mildly basophilic cytoplasm and single nuclei

Micro images: normal bile ducts

Positive stains: CK7, CK 8/18, CK 19

Bile ductules

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Also called ductular cells, cholangioles

Converge from hepatic lobule onto portal tract and connect bile canaliculi to the interlobular bile ducts

Represent the most proximal portion of the bile drainage pathway with a cholangiocyte lining

Usually not seen in normal liver

Proliferate in pathologic conditions, and can differentiate into hepatocytes to repopulate a destroyed liver

Micro: small ovoid cells lying singly at periphery of portal tract or as strings within the lobule; not accompanied by artery

Positive stains: CK7, CK8, CK18, CK19, HLA-DR

Central veins

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Also called terminal hepatic venules (NOT terminal hepatic vein); smallest component of venous outflow tract, merge to form hepatic veins, then empty into inferior vena cava

Hepatocytes

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Polygonal cells 25-30 microns, arranged in three dimensional plates that radiate away from central vein towards portal tracts; one cell thick at age 5 years or more, two cells thick in children ages 0-5 years; are lined by sinusoids on two sides in which blood flows from portal space to central vein; also have biliary and lateral surfaces (for attachment to adjacent hepatocytes); cells are uniform with abundant granular and eosinophilic cytoplasm with scattered fat vacuoles, glycogen and lipofuscin (prominent in centrilobular hepatocytes, increases with age); have central round to oval nuclei, but nuclei may be pleomorphic and multiple (all mononuclear at birth, 10% binuclear at 8 years, 15% at 15 years, 25% in adults); hepatocytes are continuously renewed with proliferation near portal space and death near central vein at 50-300 days; mitotic figures are rare

Positive stains: CK 8/18, CAM 5.2, HepPat1

EM images: adjacent hepatocytes

Kupffer cells

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Attached to endothelium in space of Disse

Phagocytic cells that are part of reticuloendothelial system; triangular or star shaped with bean-shaped nuclei and clear to granular cytoplasm

Proliferate and enlarge in response to hepatocyte damage

Degrade hemoglobin to unconjugated bilirubin

Contain ceroid pigment, PAS+ diastase resistant granules that represent degraded cellular debris

Micro images: PAS diastase

Positive stains: macrophage markers (lysozyme, CD68)

Limiting plate

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Encircling ring around portal tracts formed by lamina propria of hepatocytes immediately abutting the portal tract; disrupted by inflammation with hepatocellular death (piecemeal necrosis)

Lobules

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Traditional model of hepatic microanatomy; 1-2 mm hexagonal area with a central terminal hepatic venule (also called central vein) and 3-6 portal tracts at periphery; centrilobular zone surrounds central vein and periportal zone adjoins portal tract; zone 1 is closest to vascular supply/portal tract, zone 3 is closest to central vein, is called centrilobular area, is furthest from arterial blood and most prone to vascular insults

Micro images: lobule with central vein, portal vein dye injection highlights lobule and blood flow towards not visible central vein, lobular zones

Portal triad / portal tract

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Contains intrahepatic bile ducts, branches of hepatic artery and branches of portal vein; 70-80% of arteries are normally accompanied by bile ducts; normally contains small numbers of lymphocytes and macrophages and occasional mast cells and eosinophils; no neutrophils or plasma cells normally; row of hepatocytes around portal tract is ductal plate (limiting plate), contains stem cells responsible for bile duct growth and development; bile ducts are lined by cuboidal epithelium; portal tracts are more fibrotic in subcapsular zone

Micro images: #2, #3

Reticulum

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Collagen fibers in space of Disse, stain black with silver impregnation, produced by Ito cells; forms supporting framework of hepatocytes; if present, even necrotic liver can regenerate; if damaged, liver heals with fibrosis and possibly cirrhosis

Micro images: reticulin stain

Sinusoids

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Interposed between hepatic plates, carry arterial/venous blood to terminal hepatic vein, lined by fenestrated and discontinuous endothelial cells and Kupffer cells, which demarcate an extrasinusoidal space of Disse into which hepatocyte microvilli protrude; endothelial cells lack a basement membrane and the endothelial markers of larger vessels

Micro images: sinusoids, endothelial cells of sinusoid (PAS diastase)

Negative stains: von Willebrand Factor, CD34, Ulex europaeus

Stellate cells

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Also called Ito cells

Fat-containing hepatic stellate cells of mesenchymal origin in space of Disse

Not normally seen on routine H&E sections

Activated after injury and transformed into myofibroblasts with liver fibrosis and inflammation

Store and metabolize Vitamin A; may become laden with fat in hypervitaminosis A

Micro images: fat stain

Positive stains: smooth muscle actin, desmin

EM images: space of Disse with hepatocyte villi

Embryology

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Hepatic diverticulum buds from ventral foregut at end of third week, grows into primitive septum transversum

Liver forms from endodermal cells of diverticulum and mesenchyme

Blood supply primarily from umbilical vein; also portal vein and hepatic artery

Placenta clears wastes in bile and absorbs nutrients, and umbilical vein blood bypasses liver via ductus venosus

Bile duct system not complete until after birth; derived from endoderm (large ducts) and embryonic ductal plate (smaller intrahepatic ducts)

Hematopoietic cells are present in embryonic/fetal liver but absent at term

Normal physiology

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Bile: promotes dietary fat absorption via detergent action of bile salts; eliminates waste products (bilirubin, excess cholesterol, xenobiotics that are insufficiently water soluble to be excreted into urine)

Bile acids: carboxylate steroid molecules, derived from cholesterol, that promote bile flow and secretion of phospholipid and cholesterol; primary bile acids are cholic acid and chenodeoxycholic acid, secreted as tuarine and glycine conjugates

Bile acid circulation: all bile acids are reabsorbed via sodium-bile acid cotransporter in apical membrane of ileal enterocytes, and transported back to liver; enterohepatic circulation of bile acids maintains a large endogenous pool of bile acids for digestive and excretory purposes

Jaundice: also called icterus; discoloration of skin and sclera due to disruption of bile formation by either retention of pigmented bilirubin or block in bilirubin secretion (cholestasis)

Bilirubin: end product of heme degradation; 200 mg produced daily from old red blood cells broken down via monocyte phagocytic system in spleen, liver, marrow; also from turnover of P450 cytochromes and premature destruction of marrow red blood cells (with ineffective erthyropoiesis)

Red blood cells are broken down and produce hemoglobin

Globin proteins are removed, leaving heme molecule

Heme is converted to biliverdin via heme oxygenase

Biliverdin is converted to bilirubin via biliverdin reductase

Bilirubin is bound to serum albumin since it is insoluble in blood at physiologic pH; the % unbound increases in severe hemolytic disease or if protein-binding drugs displace bilirubin

Hepatocytes take in bilirubin at sinusoidal membrane, conjugate it with glucuronic acid using bilirubin uridine diphosphate-glucuronosyltransferase (UGT) in endoplasmic reticulum, then bilirubin is excreted into bile

Bacteria have beta glucuronidases which deconjugate and degrade bilirubin to colorless urobilinogens, excreted in feces

20% of urobilinogens are reabsorbed in ileum/colon, returned to liver, re-excreted into bile

Patterns of hepatic injury

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Acidophil body: type of focal necrosis in which dead hepatocyte is identifiable as shrunken, eosinophilic round body with variable nucleus, usually not accompanied by inflammation; also called Councilman body, single cell death, apoptotic cell; signifies nonspecific hepatocellular injury

Ballooning (feathery) degeneration: swelling of hepatocytes with increased and pale cytoplasm, nonspecific; leads to lytic necrosis and replacement by inflammatory cells

Bile ductules (see also above): proliferate in pathologic conditions, and can differentiate into hepatocytes to repopulate a destroyed liver

Bridging necrosis: necrotic cells spans adjacent lobules in portal-portal, portal-central or central-central pattern

Centrilobular necrosis: necrotic hepatocytes around terminal hepatic venule, usually due to ischemia, drugs or toxins; common finding at autopsy, because it is associated with circulatory failure or shock which is common before all deaths

Gross images: centrilobular necrosis

Micro images: centrilobular necrosis #1, #2, coagulative necrosis

Giant cell transformation: hepatocyte with 6 or more nuclei

Glycogen nuclei: homogenous clearing of hepatocyte nuclei, usually with enlargement, usually periportal; seen in most biopsies in a few nuclei; abundant in hyperglycemia, glycogen storage disease, Wilson’s disease, nonalcoholic steatohepatitis

Ground glass cells: eosinophilic granular cytoplasm, due to drug reaction (proliferation of endoplasmic reticulum diffusely throughout cell), oncocytic change (proliferation of mitochondria), hepatitis B infection (granules are surface antigen, focal)

Interface hepatitis: inflammatory cells between inflamed portal tracts and periportal parenchyma

Interlobular bile duct: bile duct of medium sized portal tract that is centrally located in tract and accompanies similarly sized arteriole

Large cell change: also called large cell dysplasia; atypical hepatocytes with nuclear and cytoplasmic enlargement, nuclear pleomorphism with hyperchromasia, multinucleation but normal nuclear to cytoplasmic ratio; often periseptal; don’t deform surrounding architecture; may be associated with prolonged cholestasis; appears to NOT be a premalignant condition

Mallory’s hyaline: also called Mallory bodies; irregular, rope-like, sharply defined, intracytoplasmic eosinophilic deposits of cytokeratin, may assume C-shape around nucleus, often in ballooning cells, surrounded by neutrophils in alcoholic liver disease; associated with alcoholic and nonalcoholic steatohepatitis, various cholestatic conditions, Wilson’s disease

Micro images: Mallory’s hyaline #1, #2, anti-ubiquitin

Positive stains: CK8, ubiquitin

Microvesicular steatosis: multiple tiny intracytoplasmic fat droplets that do not displace the nucleus; may be so small that they simulate ballooning degeneration; associated with alcoholic liver disease, acute fatty liver of pregnancy, outdated tetracycline, valproic acid, Reye’s syndrome, nucleoside analog therapy for HIV (Archives 1999;123:189)

Virtual slides: microvesicular steatosis

Macrovesicular steatosis: single large intracytoplasmic fat droplet that displaces nucleus; associated with alcoholic liver disease, obesity, diabetes, nonalcoholic steatohepatitis, drug reactions, cystic fibrosis

Gross images: fatty change

Virtual slides: macrovesicular steatosis

Necrosis: may be bridging (joins structures such as portal tracts), confluent (clusters of adjacent hepatocytes), focal (individual hepatocytes, usually apoptosis), massive (all hepatocytes in biopsy), piecemeal (below) or zonal (specific region such as centrilobular)

Micro images: focal necrosis, multifocal necrosis (PAS stain), necrotic hepatocytes

Necrosis, piecemeal: necrosis of hepatocytes at limiting plate; either necrosis of cells or irregularity of limiting plate caused by loss of hepatocytes and replacement with inflammatory cells or fibrosis; usually minimal lobular inflammation is present

Passive congestion: common finding at autopsy, because associated with circulatory failure which is common before all deaths; also called nutmeg liver; due to right sided cardiac decompensation; liver large, tense, cyanotic around edges with congestion of centrilobular sinusoids; over time, get centrilobular necrosis

Gross images: chronic passive congestion #1, #2, after right heart failure

Micro: congestion around central vein

Small cell change: also called small cell dysplasia; small hepatocytes with increased nuclear density; may have basophilic cytoplasm, but no significant nuclear atypia or enlargement; usually present in clusters; found in regeneration, atrophy, premalignant or malignant conditions

Submassive necrosis: prominent necrosis involving centrilobular zones or entire lobules in most of liver: associated with hepatic failure; bile ductular proliferation prominent in necrotic zones in late stages; no significant collagen or elastic fiber deposition; collapse of reticulin network in necrotic zones

Micro images (Mod Path subscribers): within regenerative stage of acute hepatitis

Biopsy

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Core biopsies are 1-3 cm by 1-2 mm, representing only .002% of total liver mass

Adequacy important; difficult to diagnosis chronic hepatitis with less than 4 identifiable portal tracts

Recommended to routinely obtain levels, trichrome stain (highlights type I collagen), possibly reticulin stain (highlights type III collagen framework) and iron stain (to assess iron overload)

“Clinical history is necessary to render an interpretation rather than a description of the biopsy” - Rosai

Difficult to differentiate well differentiated hepatocellular carcinoma from benign lesions, or poorly differentiated hepatocellular carcinoma as hepatic origin on small biopsy

Features to examine: adequate of biopsy, site of biopsy (is it from liver?), architecture on low power; portal tracts, lobules, central veins; assess inflammation (degree, type), necrosis, fibrosis, tumor cells

portal tracts: presence of vein, artery and bile duct

inflammation: type, severity, relationship to bile duct or other structures

bile duct changes: inflammation, proliferation or loss, necrosis, cholestasis, atypia

vascular changes: inflammation, thrombosis, thickening

lobular changes: inflammation, necrosis, sinusoids, cell plates, inclusions, amyloid, fibrosis

central veins: size and shape, inflammation and fibrosis

Final diagnosis should include clinical data, as histologic features are usually insufficient for a nonneoplastic diagnosis

Diagnostic patterns-differential diagnosis

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Adopted from Sternberg, S: Diagnostic Surgical Pathology (3rd Ed); Lippincott Williams & Wilkins, 1999

Lobular lymphocytic infiltrate: acute viral hepatitis (A, B, C, delta virus, CMV, EBV), autoimmune hepatitis, extramedullary hematopoiesis (not actually lymphocytes), leukemia, lymphoma, mastocytosis, primary biliary cirrhosis

Lobular neutrophilic infiltrate: alcoholic hepatitis, post-surgical, viral hepatitis, sepsis

Portal lymphoplasmacytic infiltrate with minimal lobular inflammation or degeneration/necrosis: resolving acute hepatitis, autoimmune hepatitis, chronic bile duct obstruction, graft versus host disease, leukemia/lymphoma, area adjacent to granuloma or neoplasm, primary biliary cirrhosis, primary sclerosing cholangitis, graft rejection, hepatitis B or C, Wilson’s disease, steatohepatitis

Variable involvement of portal tracts suggests primary biliary cirrhosis, hepatitis C, steatohepatitis; extensive piecemeal necrosis suggests autoimmune hepatitis; lack of eosinophils or plasma cells makes hepatitis C or Wilson’s disease less likely; exclusive lymphocytic infiltrate favors hepatitis C; bile duct loss and bile ductular proliferation favor primary biliary cirrhosis or primary sclerosing cholangitis; granulomas favor primary biliary cirrhosis

Portal neutrophilic infiltrate with minimal lobular inflammation or degeneration/necrosis: ascending cholangitis, acute biliary tract obstruction, hyperalimentation, medication reaction, viral hepatitis

Portal eosinophilic infiltrate: autoimmune hepatitis, extramedullary hematopoiesis, drug reaction, parasites, primary biliary cirrhosis, primary sclerosing cholangitis, rejection

Hepatocellular necrosis with minimal inflammation: ischemia, fulminant hepatitis, drug/toxin reaction, trauma, acute hepatitis in immunocompromised, hepatic venous outflow obstruction, epithelioid hemangioendothelioma

Congestion/hemorrhage: venous outflow disease, Budd-Chiari syndrome, congestive heart failure, angiosarcoma or epithelioid hemangioendothelioma, nodular regenerative hyperplasia, peliosis hepatis

Pigments: bile (green-brown, usually in bile ducts or bile canaliculi, usually centrilobular), iron (gold-brown, usually periportal but centrilobular with congestive liver disease, in hepatocytes in primary hemochromatosis, in Kupffer cells secondary to hemolysis, iron overload or hepatocyte necrosis; highlighted with Prussian blue stain), lipofuscin (brown, in centrilobular hepatocytes, highlighted with Fite stain), gold (brown-black in Kupffer cells in arthritis patients), thorium dioxide / Thorotrast (gray-blue in Kupffer cells)

Micro images: lipofuscin, bile

Inclusions: adenovirus, alpha-1-antichymotrypsin, alpha-1-antitrypsin deficiency, amylopectin, CMV, glycogen nuclei, herpes, Mallory’s hyaline, macrovesicular steatosis, microvesicular steatosis

Fatty change with no/mild necrosis: alcoholic steatohepatitis, fatty liver of pregnancy, biopsy associated, hepatocellular adenoma or carcinoma, drug/toxin reaction, metabolic disease (features defined by specific disease), nonalcoholic steatohepatitis, nonspecific, Wilson’s disease

Nearly normal biopsy: hepatoportal sclerosis, drug/toxin reaction, missed lesion, nodular regenerative hyperplasia, metabolic diseases

Loss of bile ducts: mild to moderate if less than 0.9 bile ducts per portal tract; severe if less than 0.6 bile ducts per portal tract; causes include chronic biliary tract obstruction, primary biliary cirrhosis, primary sclerosing cholangitis, paucity in neonates, idiopathic adult ductopenia, drug reaction (Augmentin), ischemia, chronic graft versus host disease, chronic graft rejection

Loss of central veins: sampling error, cirrhosis, hepatocellular adenoma or carcinoma, nodular regenerative hyperplasia (central veins present but difficult to see)

Loss of hepatocytes: massive hepatic necrosis / fulminant hepatitis

Loss of portal tracts: sampling error, cirrhosis, hepatocellular adenoma or carcinoma

Loss of portal veins but portal tracts present: hepatoportal sclerosis

Loss of sinusoids: metabolic storage diseases, cirrhosis

Developmental anomalies/cysts

Accessory lobe

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May appear clinically as hepatic mass

Alagille’s syndrome

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Also called arteriohepatic dysplasia

Autosomal dominant, due to mutations in Jagged1 gene on #20p, which encodes a ligand for Notch1 and plays a role in epithelial-mesenchymal interactions

Normal liver, but no portal tract bile ducts (progressive loss, may occasionally regrow)

Characteristic facies, vertebral arch anomalies, supravalvular pulmonic stenosis

May survive into adulthood, but increased risk of hepatic failure and hepatocellular carcinoma

Bloom syndrome

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Rare, autosomal recessive, with normally proportioned but markedly small body size, characteristic facies, photosensitive facial skin lesion, immunodeficiency, marked predisposition to variety of cancers.

Case report of pronounced sclerosing hyaline necrosis of liver with Mallory bodies, Archives 1999;123:346

Micro images: diffuse sclerosing around central vein with Mallory bodies, CAM 5.2, anti-ubiquitin, diffuse bridging and periportal fibrosis

Byler’s disease

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Impaired secretion of bile salts and phosphatidylcholine causes progressive intrahepatic cholestasis

Micro: enlarged portal tracts with inflammation, ductular proliferation and fibrosis

Caroli’s disease

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Also called communicating cavernous biliary ectasia

Autosomal recessive disorder, mildly associated with autosomal dominant and autosomal recessive polycystic kidney disease

Due to arrest of remodeling of ductal plate of larger intrahepatic bile ducts

Larger ducts of intrahepatic biliary tree are segmentally dilated and may contain inspissated bile

Usually associated with congenital hepatic fibrosis; often associated with intrahepatic cholelithiasis, cholangitis, liver abscess and portal hypertension

7-14% develop dysplasia and cholangiocarcinoma

Often gallstones, ulcer, hyperplasia

Poor prognosis, with death due to sepsis or liver failure

Caroli’s syndrome: Caroli’s disease plus congenital hepatic fibrosis

Gross: 1-4 cm cysts separated by normal bile ducts

Micro: dilated ducts lined by cuboidal or columnar epithelium with fibrotic duct wall

Micro images: dilated portal bile ducts #1, #2, #3 (trichrome stain), #4 with inspissated bile, #5 with congenital hepatic fibrosis

DD: primary sclerosing cholangitis

Choledochal cyst

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Classically presents with pain, right upper quadrant mass and jaundice, particularly in children

Cholangitis symptoms may predominate in adults

Usually women

14% develop adenocarcinoma with increasing age

Gross: often huge cysts

Micro: thick fibrous wall, often inflamed; discontinuous columnar epithelium; variable squamous metaplasia

Congenital hepatic fibrosis

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Progressive lesion associated with autosomal recessive infantile polycystic kidney disease, mildly associated with autosomal dominant polycystic kidney disease

Often diagnosed in adolescents with portal hypertension

May be due to ductal plate malformation of intralobular bile ducts

Complications: portal hypertension, cholangitis

Gross: entire liver affected by microscopic cysts; rarely macroscopic hepatic cysts

Micro: anastomosing biliary channels in irregular, bland fibrous stroma, continuous with biliary tree, hepatocyte nodules with central veins and normal architecture; marked proliferation of bile ductules; angulated bile ducts often with inspissated bile in fibrotic portal tracts with portal-portal bridging fibrosis; no inflammation, no regenerative nodules

Micro images: portal fibrosis with dilated biliary channels #1, #2

Down’s syndrome

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Case report associated with liver fibrosis, thought due to megakaryocyte derived transforming growth factor beta, Hum Path 1999;30:474

Extrahepatic biliary atresia

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Most common cause of pathologic infant jaundice; common reason for pediatric liver transplantation

Definition: total or partial loss of permeable bile ducts between porta hepatis and duodenum

Typically presents with symptoms at 1-2 months of age

Stenotic or atretic portions of extrahepatic biliary tree cause chronic extrahepatic large duct obstruction

May have infectious or autoimmune etiology

Histologically resembles choledochal cyst or other causes of large duct obstruction

Note: since biopsies have 7% false-positive rate, radiographic studies are mandatory

Treatment: hepatoportenterotomy (Kasai procedure), liver transplant; to assess likelihood of success of surgical correction, surgeon may biopsy porta hepatis, pathologist indicates size and number of bile ducts present; also indicates amount of fibrosis and inflammation

Gross images: with cirrhosis

Micro: lobular cholestasis, portal neutrophilic infiltrate, bile ductular proliferation (peaks at 200 days), with elongated and angulated ductules and occasional bile plugs; variable vacuoles and lymphocytes; late-fibrosis or cirrhosis; may have focal giant cell transformation (periportal, not extensive), ductopenia (occurs rapidly at 400 days) and focal extramedullary hematopoiesis

Micro images: bile plugs, bile ductular proliferation and fibrosis

Positive stains: CD56 (biliary epithelium stains strongly in >65% of portal tracts)

Molecular: 10% have mutations in Jagged 1 gene (associated with Alagille’s syndrome)

References: AJSP 2003;27:1454 (CD56)

DD: alpha-1-antitrypsin deficiency, congenital cytomegalovirus infection, neonatal hepatitis

Foregut cyst

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Rare, < 100 cases reported

Intrahepatic ileal and duodenal duplications and ciliated foregut cysts have been described

4 cm or smaller, have smooth muscle bundles in cyst wall

Slightly more common in men, and in medial segment of left hepatic lobe

Resemble bronchiolar epithelium

Case reports: ciliated foregut cyst with squamous cell carcinoma, Archives 1999;123:1115

Gross: solitary, rarely multilocular, 1-4 cm

Micro: ciliated pseudostratified columnar epithelium with goblet cells, subepithelial connective tissue, 1-3 smooth muscle layers, outer fibrous capsule

Micro images: ciliated foregut cyst with squamous metaplasia, dysplasia and carcinoma

References: AJSP 1999;23:671, Hum Path 2000;31:241

Intrahepatic biliary atresia

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Also called paucity of intrahepatic bile ducts in neonates

Occurs in syndromic form (Alagille’s syndrome) or nonsyndromic form

In nonsyndromic form, bile duct loss is present from birth; may actually represent cystic fibrosis, alpha-1-antitrypsin deficiency, trihydroxycoprostanic acidemia; bile duct recovery depends on etiology

Micro: loss of interlobular bile ducts (0.5 ducts/portal tract vs. normal 0.9-1.8 ducts/portal tract; count only bile ducts accompanying hepatic arterioles in center of portal tracts, keratin staining may be helpful); usually minimal ductular proliferation; no/minimal fibrosis, no/minimal inflammation

Multiple hilar cysts

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Arise from peribiliary glands surrounding extrahepatic and large intrahepatic bile ducts in hilum

Cysts are incidental finding in 20% of autopsies

May compress adjacent bile duct; also associated with cirrhosis and portal vein thrombosis

Gross: up to 2 cm, unilocular with clear serous fluid, if multiple may make liver appear spongy

Micro: lined by columnar to cuboidal epithelium with mild chronic inflammatory infiltrate, fibrosis, fibrous obliteration of small veins; occasional hyperplasia

Polycystic liver disease

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Autosomal dominant, associated with autosomal dominant (but not autosomal recessive) polycystic kidney disease (71-93%) and defect in ADPKD1 gene on #16

Cysts don’t communication with biliary tree

80% occur in females

Associated with abdominal tenderness, pain with stooping; may present during pregnancy

Cysts more common with increased age (75% at age 70+ vs. <5% in teenagers)

1-7% risk of adenocarcinoma if coexisting Caroli’s disease; otherwise extremely rare

Complications: infection, cholangiocarcinoma, squamous cell carcinoma

Gross: multiple variably sized unilocular cysts, liver rarely is massively enlarged

Gross images: polycystic liver disease

Micro: multiple diffuse cystic lesions resembling solitary cysts, lined by cuboidal to flat biliary epithelium, containing straw colored fluid; 40% have identifiable von Meyenburg complexes; don’t contain pigmented material

Micro images: cystic lesions with von Meyenburg complexes, cyst wall epithelium

Solitary cyst

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Also called unilocular, simple or congenital cyst

Not associated with cysts in other organs

80% occur in women

Usually incidental finding; may be due to von Meyenburg complexes that separate from biliary tree and dilate

20x more common than cystadenomas; present in 14% of autopsies if looked for

Complications are torsion, hemorrhage, rupture, compression of adjacent biliary tree; rarely carcinoma arises in these cysts

Treatment: excision, sclerotherapy, cyst fenestration

Gross: single, unilocular cyst, usually subcapsular or in falciform ligament; 2-40 cm with flat glistening lining; variable amounts of clear amber fluid (may contain blood, bile, mucus, pus); usually separate from biliary tree

Micro: lined by biliary-type epithelium (flat/cuboidal), occasionally ciliated (called foregut cyst) or squamous lined (epidermoid cyst); epithelium rests on thin collagenous wall without spindle-cell stroma

Degenerative changes include epithelial desquamation, multiloculation, calcification

von Meyenburg complex

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Also called bile duct hamartoma or microhamartoma

Incidental finding in 6% of adults and 1% of children at autopsy; found in 1% of all liver needle biopsies

No clinical significance, although may resemble liver metastases to surgeons

Associated with autosomal dominant polycystic hepatorenal disease, other ductal plate malformations such as congenital hepatic fibrosis and Caroli’s disease

Due to incomplete involution of embryonic bile duct remnants; a type of ductal plate malformation

Rarely associated with neoplastic transformation to hyperplasia, adenoma and cholangiocarcinoma, AJSP 2000;24:1131, Archives 2000;124:1704

Gross: single or multiple (20% have 4+ nodules) well circumscribed nodules, subcapsular, gray-white, occasionally green; often less than 5 mm

Micro: periportal small clusters of modestly dilated bile ducts, often angulated, in fibrous stroma; may contain intraluminal bile; epithelial cells are bland; usually no/minimal inflammatory infiltrate, no atypia

Micro images: periportal cluster of dilated bile ducts, dilated bile ducts in fibrous stroma (figure 3)

Positive stains: mucin (variable)

Metabolic diseases

Metabolic diseases-general

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Diagnosis may require special stains, electron microscopy, biochemical examination

Due to congenital inborn errors of metabolism or acquired

Alpha-1-antitrypsin deficiency

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Common cause of neonatal cholestasis

Autosomal recessive disease, causing low serum levels of alpha-1-antitrypsin (AAT), and leading to emphysema (80%) and liver disease

AAT is a small, 394 amino acid, plasma glycoprotein, synthesized predominantly by hepatocytes, encoded by a gene on #14

AAT is a protease inhibitor (Pi), which inhibits neutrophilic elastase released at sites of inflammation; also inhibits trypsin

Although there are 75 AAT forms, PiMM (normal phenotype) is present in 90% of population

PiZZ: 1 per 7,000; have 10-15% of normal AAT levels, are at high risk for clinical disease; accumulate AAT variant Z in endoplasmic reticulum and have slowdown in degradation pathway, but only 10% get clinical disease

PiZZ hepatic syndromes range from neonatal hepatitis (10%), biliary atresia (intra- or extrahepatic), fibrosis, childhood cirrhosis; 2% develop hepatocellular carcinoma, not always associated with cirrhosis

PiMZ: intermediate plasma levels of AAT (expression of alleles is autosomal codominant)

Pi-null: rare variant with no detectable serum AAT

Pi-S: low serum AAT but no disease

AAT deficiency variants: secretory protein does not move from endoplasmic reticulum to Golgi; for PiZ, is due to single AA substitution, causing abnormal folding, blocking its movement along the remainder of the secretory pathway

Diagnosis: serum protein electrophoresis; liver biopsy to determine extent of histologic damage

Treatment: liver transplantation, avoid cigarette smoking (which causes earlier and more severe emphysema)

Micro: round to oval cytoplasmic eosinophilic globular inclusions in periportal hepatocytes; rare Mallory bodies and fatty change; also hepatocellular degeneration, giant cell formation, cholestasis and cholangitis, portal fibrosis and cirrhosis

Micro images: PAS+ hyaline globules

Positive stains: AAT immunostains; inclusions are strongly PAS+ and diastase resistant

EM: granular material in dilated endoplasmic reticulum

DD: AAT that is present in damaged and regenerating hepatocytes (usually diffuse granules, not periportal, no globules, PAS negative), AAT+ globules present in alcoholic hepatitis

Cystic fibrosis

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Most common lethal genetic disease in US of whites - affects 1 per 2000-4500 newborns

1 in 20 in US are carriers; most common mutation is #708 of protein that regulates chloride ion transport on chromosome #7 (seen in 70% with disease)

Mutations cause reduced chloride ion in secretions, thicker respiratory secretions, upper respiratory infections, late pancreatic insufficiency; also cause defective cilia and infertility, meconium ileus (5-10%), intussusception

May present as neonatal cholestasis, although most patients have no clinical evidence of liver disease

Treatment: liver transplantation (if end stage liver disease)

Gross: emphysema, bronchiectasis, abscess, fibrosis

Gross images: lung

Micro: macrovesicular steatosis, focal biliary cirrhosis (focal findings of inspissated granular eosinophilic material within portal bile ductules, chronic inflammatory infiltrate in portal tract, bile duct proliferation), cirrhosis (10% by age 25)

EM: filamentous material in bile ducts

Erythropoietic protoporphyria

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Micro: deep brown colored bile in canaliculi, bile ducts and Kupffer cells with red “Maltese cross” under polarized light

EM: star-burst crystalline array

Familial apolipoprotein A-I amyloidosis

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Apo A-I is major protein constituent of plasma high density lipoprotein; is synthesized in liver and intestine

Are at least 4 different amyloidogenic Apo A-I mutations

Treatment: liver transplant slows disease progression

Case reports of 2 sisters with liver transplants, Mod Path 2001;14:577

Micro: often striking liver parenchymal involvement by large patches of amyloid replacing hepatic lobules, separating hepatic cords, accentuation around central veins, involving portal triads, hilar soft tissue; no involvement of hilar nerve branches or vagus nerve

Micro images (Mod Path subscribers): extensive amyloid deposition, Congo red

Positive stains: Congo red

Galactosemia

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Micro: hepatocellular degeneration with focal fatty change, particularly in regenerative nodules; pseudorosettes, cholestasis, fibrosis, cirrhosis

EM: cholestasis, lipid droplets, increased endoplasmic reticulum, abnormal mitochondria

Gaucher disease

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Preferable to “Gaucher’s disease”

Etiology: lysosomal storage disease caused by an autosomal recessive mutation in the β-glucocerebrosidase gene (also called glucosylceramidase and β-glucosidase); defective enzyme leads to accumulation of glucocerebroside substrate in cells of the mononuclear phagocyte system, including histiocytes in the spleen, lymph nodes, bone marrow, GI and GU tracts; Kupffer cells in liver; osteoclasts in bone; microglia in CNS; and alveolar macrophages in lungs (Arch Pathol Lab Med 2008;132:851)

Epidemiology: highest risk are Ashkenazi Jews - 1 in 15 are carriers

Clinical: three subtypes; all may have hepatosplenomegaly, hypersplenism, osteoporosis, yellow-brown skin, anemia; types II or III may have seizures and dementia.

Type I - non-neuropathic, may be mild

Type II (acute infantile neuropathic Gaucher disease) - affects infants within a few months of birth, usually fatal within 2 years

Type III - chronic neurological variant, with onset anytime between birth and adulthood, presents with slowly progressing neurological decline

Diagnosis: measure glucocerebrosidase activity in peripheral blood leukocytes; <15% of mean normal activity is diagnostic; note: enzyme activity in carriers (heterozygotes) is generally half-normal, but may overlap with healthy controls; molecular analysis, particular in Ashkenazi patients, may also be helpful.

Case reports: 51 year old man with chronic liver disease (Case of the Week #164)

Treatment: enzyme replacement therapy with imiglucerase (Cerezyme), a recombinant version of β-glucocerebrosidase, for patients with Types I or III (Curr Opin Pediatr 2007;19:628).

Micro: enlarged Kupffer cells and portal macrophages with “crinkled paper” cytoplasm

Micro images: #1; #2; PAS; Iron

EM: intralysosomal tubular inclusions; angulated lysosomes

EM images: thick section; EM

Differential diagnosis:

Niemann-Pick disease: foamy and vacuolated cytoplasm, due to sphinomyelin accumulation

Pompe disease: primarily affects skeletal and cardiac muscle

Gaucher-like cells: seen in CML, AML and CLL

References: eMedicine, Wikipedia

Glycogen storage disease

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Type I

Micro: mosaic pattern due to enlarged hepatocytes compressing sinusoids; fatty change, hyperglycogenated nuclei

EM: increased cytoplasmic glycogen, lipid droplets, glycogenated nuclei

Type Ia

Also called von Gierke disease

Rare; due to absence of glucose-6-phosphatase, which is required for gluconeogenesis and glycogenolysis

Symptoms: hypoglycemia and marked hepatomegaly in first year of life; later-short stature, chronic lactic acidosis, focal segmental glomerulosclerosis, hepatic adenomas, iron deficiency

Treatment: liver transplant

Case report of 28 year old woman with multiple hepatic adenomas, Archives 2003;127:e402

Gross: enlarged, pale liver; may have variable sized tumor nodules

Gross images: pale bulging surface, adenomas

Micro: large hepatocytes with prominent cell membrane and glycogenated nuclei; PAS+ accumulated glycogen; rarely contain Mallory’s hyaline and steatosis in hepatic adenomas

Micro images: adenomas with reticulin and trichrome stains, adenomas with steatosis and Mallory’s hyaline

Type II

Micro: increased hepatocellular glycogen

EM: intralysosomal glycogen

Type III

Micro: mosaic pattern due to enlarged hepatocytes compressing sinusoids; fatty change, hyperglycogenated nuclei

EM: increased cytoplasmic glycogen, lipid droplets, glycogenated nuclei

Type IV

Also called amylopectinosis, Andersen disease

Rare, autosomal recessive, caused by deficiency of glycogen branching enzyme on 3p14

Classic form: progressive hepatic fibrosis through age 18 months causing hepatosplenomegaly, failure to thrive, death by 5 years

Rare nonprogressive form: no cirrhosis, live to adulthood

Neuromuscular form: severe hypotonia at birth causing death or myopathy in late childhood or nervous system dysfunction as adults

Case report of 10 month old male with massive hepatomegaly, Archives 2002;126:630

Diagnosis: amylopectin-like material in tissue; deficiency of branching enzyme activity

Treatment: liver transplantation

Micro: basophilic intracytoplasmic inclusions, PAS+, diastase partially resistant

Micro images: H&E (inclusions), PAS, colloidal iron, EM

EM: filamentous nonbranching cytoplasmic aggregates

DD: Lafora disease (similar inclusions but not coarsely clumped, older age with epilepsy, myoclonus, dementia)

GM2 gangliosidosis

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Micro: normal

EM: “zebra bodies” - membrane-bound laminated inclusions

Heme oxygenase-1 deficiency

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Enzyme degrades heme into biliverdin, carbon monoxide and free iron; also is anti-oxidant

Case report of 6 year old boy with growth retardation, anemia, other laboratory abnormalities, Hum Path 2002;33:125

Biochemistry diagram

Micro: amyloid present in liver and adrenal glands, mesangioproliferative glomerular changes in kidney, fatty streaks and fibrous plaques in aorta

Hemochromatosis

General

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Excessive accumulation of iron, usually deposited in liver, pancreas and heart

Either primary or secondary

Normal iron pool is 2-6 gm with 0.5 g in liver and 98% of that in hepatocytes

Primary hemochromatosis

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Autosomal recessive disorder of excessive iron storage; may exceed 50g in liver (normal 2-6 g)

Most common single-gene disorder in whites

80% males, because menstruation and pregnancy delay iron accumulation in women

1/220 of Northern European ancestry are homozygous for mutation; 1/11 are heterozygous; thus disease is very common

Pathophysiology: due to mutation on transferrin receptor binding protein HFE (formerly called HLA-H) on 6p, close to HLA gene, and in linkage disequilibrium with HLA-A3

Common mutation (83% of primary cases) is cysteine to tyrosine at amino acid 282 (C282Y), which inactivates the protein and causes excess iron absorption of 3-4 mg/day vs. 1-2 mg/day normal; normal HFE down regulates transferrin; loss of HFE causes up regulation of transferrin; other mutation is H63D (3-7% of cases) and compound heterozygotes (1-4%)

Excessive iron cannot be eliminated, and is directly toxic, due to lipid peroxidation, stimulation of collagen, interactions of iron with DNA

Mutation causes net iron accumulation of 0.5 to 1.0 g iron/year, although penetrance is less than 100%

Symptoms: after accumulation of 20 g of iron; usually age 40+; primarily micronodular cirrhosis (100%), diabetes mellitus (deposition in pancreas) and skin pigmentation (65%); also hemosiderin deposition in myocardium, pituitary, adrenal, thyroid, parathyroid gland, joints, skin; eventually cirrhosis and pancreatic fibrosis; high risk for hepatocellular carcinoma (200x, 20% risk)

Diagnosis: screen for percent transferrin saturation (serum iron divided by total iron binding capacity); if repeatedly elevated, check serum ferritin; if elevated, do DNA testing for C282Y mutation; also screen family members of affected individuals

Hepatic iron index: micrograms iron per gram dry weight of liver / (55.846 x patient’s age)

Interpretation: >1.9 in non-cirrhotic liver is strongly suggestive of hereditary hemochromatosis, although only 93% sensitive; test is less specific in cirrhotic livers (some suggest raising cut-off to 4.2 in these patients); sampling variation can occur

Diagnostic algorithm

Treatment: phlebotomy 1-2/week until serum ferritin is below 20-50 micrograms/L, then 3-6 times/year; with early treatment, life expectancy is normal

Gross: dark brown liver

Gross images: dark brown liver, pancreas, lymph nodes

Micro: liver - iron within hepatocytes, initially heavy periportal parenchymal iron deposition with sparing of Kupffer cells; iron distribution is pericanalicular, particularly in less involved areas; hepatocytes otherwise normal; no inflammation, no fibrosis

Micro images: late stage-iron in hepatocytes and Kupffer cells #1, #2, #3, within bile ducts, Prussian blue iron stain, in patient with cirrhosis #1, #2

pancreas - intensely pigmented, diffuse interstitial fibrosis

heart - enlarged with hemosiderin within myocardial fibers

joints - acute synovitis, calcium pyrophosphate deposition (pseudogout)

skin - hemosiderin in dermal macrophages and fibroblasts, also increased melanin production; causes slate-gray skin

testes - small, atrophic testis, due to hypothalamic-pituitary derangement; minimal pigment deposition

Positive stains: Prussian blue (iron stain)

Secondary hemochromatosis

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Due to transfusions (secondary to hemodialysis, aplastic anemia, sickle cell anemia, myelodysplasia, leukemia), ineffective erythropoiesis with increased erythroid activity (secondary to beta thallasemia, sideroblastic anemia, pyruvate kinase deficiency), increased oral intake of iron or iron dextran injections, congenital atransferrinemia, chronic liver disease (alcoholism, porphyria cutanea tarda)

Note: transfusions alone are usually not sufficient to cause systemic hemosiderosis

Bantu siderosis: due to alcohol fermented in iron utensils in sub-Saharan Africa

Micro: iron is mainly in Kupffer cells, not hepatocytes, at least initially, and is primarily centrilobular; eventually iron is present in hepatocytes, which are otherwise normal

Neonatal hemochromatosis

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Autosomal recessive, but probably unrelated to adult-type hemochromatosis, although similar histologic patterns

Liver failure soon after birth due to excess iron in liver; also iron deposition in pancreas, thyroid, kidney, GI tract

DD: massive necrosis (also has excess hepatic iron)

Hereditary fructose intolerance

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Micro: hepatocellular degeneration with focal fatty change, particularly in regenerative nodules; pseudorosettes, cholestasis, fibrosis, cirrhosis

EM: lucent partially membrane bound areas of cytoplasm (“fructose holes”), concentric arrays of endoplasmic reticulum and glycogen

Hereditary hepatic coproporphyria

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Case report of 35 year old woman with rapidly progressive liver cirrhosis, Archives 2002;126:751

Hereditary tyrosinemia

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Type I

Autosomal recessive disease caused by deficiency of fumarylacetoacetate hydrolase, the last enzyme in the catabolic pathway of tyrosine; high prevalence in eastern Quebec

May be severe, affecting liver, kidneys, nervous system, but also clinically heterogeneous, with no correlation between genotype and phenotype

Acute form causes hepatic failure in newborns and death by age 1 without treatment

Chronic form is milder, with chronic liver disease, renal tubular dysfunction, hypophosphatemia with rickets and increased risk for hepatocellular carcinoma

80% of patients have reversion of mutant alleles in hepatocytes, associated with better prognosis (no dysplasia, no carcinoma)

Treatment: 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione (NTBC) reduces accumulation of toxic metabolites

Micro: hepatocellular degeneration with focal fatty change, particularly in regenerative nodules; pseudorosettes, cholestasis, fibrosis, cirrhosis

EM: cholestasis, lipid droplets, increased endoplasmic reticulum, abnormal mitochondria

References: Hum Path 2003;34:1313 (mutation reversion)

Mucopolysaccharidosis

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Hurler’s disease: mucopolysaccharidosis type 1

Micro: no abnormalities

Positive stains: colloidal iron stains mucosubstances in Kupffer cells and hepatocytes

EM: lysosomes in all cells contain flocculent material

Niemann-Pick disease

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Micro: foamy Kupffer cells and hepatocytes

EM: intralysosomal myelin-like inclusions

Porphyria cutanea tarda

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Micro: needle-shaped inclusions within hepatocytes

EM: needle-shaped inclusions within hepatocytes

Primary hyperoxaluria

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Case report of 39 year old woman with recurrent nephrolithiasis, Archives 2002;126:1250

Autosomal recessive, either type 1 (defect/absence of alanine-glyoxalate aminotransferase on 2q37.3; patients have variable clinical presentation from end stage renal disease to occasional kidney stones) or type 2 (absence of glyoxylate reductase activity at #9)

Pathophysiology: oxalate is a metabolic end product normally excreted by kidneys; type 1 or 2 disease causes increased oxalate synthesis and excretion, eventually deposition of insoluble calcium oxalate in kidney, bones, heart, arteries; in liver, deposited in portal areas and arterial media

Treatment: increase urine volume, pyridoxine, high phosphate diet

Micro: crystals are birefringent

Micro images: crystals in portal areas

DD of hyperoxaluria: increased Vitamin C, methoxyflurane, ethylene glycol, xylitol, chronic inflammatory bowel disease, small bowel resection, external biliary drainage

Wilson’s disease

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Also called hepatolenticular degeneration

Autosomal recessive disorder affecting 1/30,000 people, causing accumulation of toxic levels of copper in tissues/organs, usually liver, brain, eye

Normal copper physiology: total body copper is 50-150g; 40% of ingested copper is absorbed in stomach and duodenum and transported to liver loosely bound to albumin; free copper dissociates and is transferred to hepatocytes, where it is incorporated into an alpha2 globulin to form ceruloplasmin, and resecreted into plasma; 99% of plasma copper is bound to ceruloplasmin

Senescent ceruloplasmin is endocytosed by the liver, degraded within lysosomes and excreted into bile, which is the primary route for copper elimination

The gene for Wilson’s disease is ATP7B on #13q, which encodes a transmembrane copper-transporting ATPase located on the hepatocyte canalicular membrane, which assists with copper excretion into bile; most affected patients are compound heterozygotes with different mutations of ATP7B on each allele that cause defective biliary excretion of copper; copper accumulates within the liver, exceeding the capacity for ceruloplasmin binding and causing liver injury

By age 5 years, nonceruloplasmin-bound copper causes acute or chronic liver disease, hemolytic anemia, deposition in putamen with frank psychosis or Parkinsonian symptoms, deposition in cornea, kidneys, bones, joints, parathyroid gland; also increased urinary excretion of copper (which is normally minimal)

Diagnosis: serum ceruloplasmin < 20 mg/dl, increased liver copper using rhodanine stain, urinary copper excretion > 50 micrograms/24 hours; biochemical determination from liver biopsy (can use formalin-fixed tissue, > 250 micrograms/g dry weight); serum copper levels are not helpful

Treatment: long-term copper chelation therapy with D-penicillamine; liver transplantation

Micro: liver - fatty change with vacuolated nucleus (due to glycogen or water), focal hepatocyte necrosis; an acute or chronic hepatitis may be present and mimic acute or chronic viral hepatitis; chronic hepatitis may have Mallory bodies; cirrhosis develops late; usually no/minimal eosinophils or plasma cells

Note: copper deposition is focal and may not be present on needle biopsies

Fulminant hepatitis: liver collapse with abundant lipofuscin due to degraded membrane fragments; remaining liver shows low-grade disease with fibrosis

brain - injury to putamen in basal ganglia

eye - Kayser-Fleischer rings (green to brown deposits of copper in Descemet’s membrane in limbus of cornea)

EM: microvesicular steatosis, glycogen nuclei, copper deposits, mitochondrial enlargement with increased matrical body size, increased matrix density, crystalline inclusions, swollen cristae that are separated due to flocculent material in cyst-like dilations

DD: copper accumulation also present in primary biliary cirrhosis, other cholestatic states

Wolman disease

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Micro: foamy Kupffer cells and hepatocytes

EM: lipid droplets in hepatocytes and Kupffer cells; cholesterol clefts in Kupffer cells

Zellweger syndrome

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Micro: nonspecific changes of hepatocyte degeneration

EM: no peroxisomes

General concepts

Ascites

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Excess fluid in peritoneal cavity; usually detectable when 500 ml; usually serous, < 3 g/dl of protein

Presence of neutrophils suggests secondary infection, red blood cells suggests disseminated intraabdominal cancer, hydrothorax suggests long standing process with seepage through transdiaphragmatic lymphatics

Causes: sinusoidal hypertension drives fluid into space of Disse, normally removed by hepatic lymphatics; ascites is promoted by hypoalbuminemia; cirrhosis, portal hypertension

Cirrhosis-general

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Defined as diffuse nodulation of liver, due to fibrous bands subdividing liver into regenerative nodules

All three features must be present: congenital hepatic fibrosis lacks regenerative nodules, focal nodular hyperplasia lacks diffuse nodulation, nodular regenerative hyperplasia lacks fibrous bands

Fibrosis is usually considered irreversible (regression rare in schistosomiasis, hemochromatosis) and alters patterns of blood flow and hepatocyte perfusion; initially around portal tracts, central vein or within space of Disse; later subdivides liver into nodules of regenerating hepatocytes surrounded by scar tissue (cirrhosis)

Nodules tend to increase in size over time

Represents the final common pathway of causes listed below; difficult to determine cause once present

Causes: alcoholic liver disease (60%), viral hepatitis (10%), biliary disease (5%), primary hemochromatosis (5%), idiopathic (5%), rare causes are Wilson’s disease, alpha-1-antitrypsin deficiency, galactosemia or tyrosinosis in children, cancer, drugs, syphilis, severe cardiac disease (cardiac cirrhosis), jejunoileal bypass, extensive small bowel resection

Idiopathic cases are often nonalcoholic steatohepatitis (33%), autoimmune liver disease (22%), alcoholic liver disease (14%), Hum Path 2002;33:1098

Pathogenesis: normally interstitial collagen types I and III is present in portal tracts, around central veins and occasionally in space of Disse; reticulin along hepatocytes is composed of type IV collagen; in cirrhosis, type I and III collagen are deposited in lobule, creating septal tracts; new vascular channels form, but blood is shunted around the parenchyma; get loss of fenestrations in sinusoidal endothelial cells, sinusoidal space resembles a capillary more than a channel for exchange of solutes between hepatocytes and plasma; Ito cells (hepatic stellate cells with myofibroblastic features) produce excess collagen in cirrhosis; normally store vitamin A, but are activated during development of cirrhosis, lose their retinyl ester stores and transform into myofibroblast-like cells;

Collagen synthesis and deposition are due to chronic inflammation (TNF-alpha, TGF-beta, IL-1); cytokines from Kupffer cells, endothelial cells, bile duct cells and hepatocytes; also disruption of extracellular matrix and toxins

Ito cells also constrict sinusoidal vascular channels

Bile channels are obliterated due to disruption of interface between parenchyma and portal tracts, causing jaundice

Symptoms: none; also anorexia, weight loss, weakness, osteoporosis; late - frank debilitation, portal hypertension, hepatic failure (with new stress)

Hepatopulmonary syndrome: due to imbalances of pulmonary blood flow, causes further stress

Death due to progressive liver failure, portal hypertension complications, hepatocellular carcinoma

Regression: controversial topic; proponents argue that it may occur if therapy halts progression; suggested by delicate perforated septa (incomplete fibrous septa whose residual components form linear, usually curved structure), isolated thick collagen fibers (not visibly attached to portal structure, hepatic vein or septum), delicate periportal fibrous spikes (collagenous extensions from portal tracts without visible connection to other portal tracts or hepatic veins), portal tract remnants (artery/duct pairs, unaccompanied arteries, or unaccompanied ducts, usually with absent portal vein, usually have less portal tract collagen than normal), hepatic vein remnants with prolapsed hepatocytes within the lumen, hepatocytes within portal tracts or splitting septa (clusters/cords of hepatocytes 2 or more cells in thickness within portal tracts or wedged between layers of fibrous septa), minute regenerative nodules (small clusters of hepatocytes less than 10 cells in diameter mixed with ductules), aberrant parenchymal veins (veins within 5 hepatocyte diameters of portal tracts), Archives 2000;124:1599

Gross images: macronodular cirrhosis #1, #2; micronodular cirrhosis #1, #2, #3, #4, #5, #6; post necrotic cirrhosis, cardiac cirrhosis

Micro: disruption in architecture of entire liver (loss of normal central-portal relationships) with bridging fibrous septa (delicate bands, broad scars) and rounded parenchymal nodules of regenerating hepatocytes without central veins; also abnormal vasculature due to parenchymal damage and scarring

Hard to diagnose cases: fragmented specimens with rounded edges containing connective tissue (use Trichrome or reticulin stains to visualize), no normal portal tracts, irregular central veins, two cell thick plates, large cell change is suggestive

Micro images: regenerative nodules #1, #2 with fatty change, cardiac sclerosis / cirrhosis, bridging fibrosis #1 (portal-portal), #2 (central-central), #3 (portal-central), macronodular cirrhosis

Regression images (according to some): #1, #2, #3, #4, #5, #6, #7, #8, #9, #10, diagram of creation and resorption of septa, diagram of natural history of cirrhosis

Biopsy: cannot distinguish cirrhosis from bridging fibrosis due to small sample size, although reticulin stain may confirm regenerative nodules based on cell plates 3+ cells thick; absence of regenerative activity or presence of normal portal tracts and central veins argues against diagnosis of cirrhosis; don’t call definite cirrhosis unless at least one complete regenerative nodule can be identified; cirrhotic liver biopsy often has multiple small fragments of hepatocytes with smooth rounded contour due to leaving fibrous tissue behind

Positive stains: reticulin stain and collagen stains may highlight disordered lobular features, cirrhotic fibrosis is strongly positive for vitronectin (Hum Path 2001;32:1356)

DD: localized subcapsular or parenchymal scars, wedge biopsies (subcapsular connective tissue is more prominent and extends into portal tracts within 1 cm of capsule), normal portal tract containing large artery and large duct with “normal” fibrous tissue, nodular regenerative hyperplasia

Alcoholic cirrhosis

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Larger nodules are associated with periodic alcohol abstinence, causing more regeneration of hepatocytes

Micro: micronodular cirrhosis, Mallory bodies, fatty change; also perivenular and pericellular fibrosis (highlighted with Trichrome stain) with partial/complete obliteration of central vein (identify as central vein due to lack of arterioles); more prominent bridging from central zone to central zone and central zone to portal zone than in other causes of cirrhosis; usually few inflammatory cells unless superimposed viral or alcoholic hepatitis

Micro images (Mod Path subscribers): alcoholic cirrhosis

DD: non-alcoholic steatohepatitis

Biliary tract disease related

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Caused by primary biliary cirrhosis, primary or secondary sclerosing cholangitis, idiopathic inflammatory bowel disease, duct obstruction

Laboratory: elevated serum alkaline phosphatase

Micro: jig saw pattern of cirrhosis due to portal to portal bridging fibrosis; no rounded cirrhotic nodules; minimal distortion of central veins until late; may have cholangiole proliferation, portal tract inflammation with pericholangiole neutrophils, disruption of terminal plate by mononuclear cells and piecemeal necrosis

Positive stains: copper (due to chronic cholestasis)

DD: chronic hepatitis

Hepatitis C

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Micro: rounded nodules; lymphoid aggregates

Micro images (Mod Path subscribers): Hepatitis C with cirrhosis

Incomplete septal cirrhosis

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Portal hypertension with normal liver function

Hepatic nodules separated by extremely thin bands of collagen difficult to recognize on needle biopsy

May have disorganized cell plates / zones resembling nodular regenerative hyperplasia

Good prognosis if portal hypertension is controlled

Micro images: incomplete septal cirrhosis

Cirrhosis - features to report

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Certain, probable or possible cirrhosis

Micronodular (2 mm or less with delicate fibrous bands, due to alcoholic liver disease or chronic biliary obstruction), macronodular (3 mm or more with wide fibrous bands, variable nodules) or mixed

Grade activity as with chronic hepatitis

Developing or fully established

Etiology of cirrhosis (often cannot be determined; granulomas suggest primary biliary cirrhosis; Mallory’s hyaline, fatty change or neutrophils suggest alcoholic liver disease)

Differential diagnosis of fibrosis

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Alcoholic liver disease: see below

Amyloidosis: see below

Budd-Chiari syndrome: see below

Cirrhosis: see above

Congestive heart failure: see below

Congenital hepatic fibrosis: see above

Congenital syphilis: pericellular fibrosis

Chronic veno-occlusive disease: see below

Cystic fibrosis: see above

Focal nodular hyperplasia: see Liver-Tumor page

Hepatoportal sclerosis: see below

Metabolic diseases: various

Tumors: various

Fulminant hepatitis / massive hepatic necrosis

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Uncommon (<1%) complication of acute viral hepatitis

Progresses from onset of symptoms to hepatic encephalopathy in 2-3 weeks in previously healthy patient

Orderly regeneration due to massive destruction of confluent lobules

Liver can regenerate after massive necrosis if connective tissue framework is intact

Regeneration: portal ductules increase in size and number and become dilated; individual hepatocytes with clear cytoplasm appear from ductules; ductules are transformed into hepatocytes and form round cell clusters, which organize into trabeculae with fibrosis; lobular architecture is established; normal at 14 months, Mod Path 2000;13:152

Causes: viruses (Hepatitis B, C), drugs (acetaminophen, halothane, rifampin, isoniazid, carbon tetrachloride), ischemia, hepatic vein obstruction, tumor, Wilson’s disease, hyperthermia, acute fatty liver of pregnancy

Subfulminant hepatitis: less rapid, up to 3 months to hepatic encephalopathy

Treatment: liver transplant, auxiliary partial orthotopic liver transplant; mortality without liver transplant is 25-90%

Case reports-causes: phenytoin and trimethoprim-sulfamethoxasole (Archives 2000;124:1800), concentrated acetic acid (Archives 2000;124:127), troglitazone (Hum Path 2000;31:250)

Gross images: post phenytoin-trim-sulfa: necrosis at autopsy

Micro: massive necrosis of hepatocytes in all zones (possible periportal sparing) with reticulin collapse, often with minimal inflammatory reaction; may be bile duct proliferation, lymphocytic infiltration of central veins; biopsies may have minimal findings due to variability of disease

Micro images: hepatocyte necrosis, chronic inflammatory infiltrate and bile duct proliferation, post acetic acid periportal fibrosis

Micro images (Mod Path subscribers): regeneration after transplant - days 0-7, day 29, 2-3 months, 6-14 months

Hepatic failure

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Usually due to progressive liver damage

No hepatic failure until loss of 80% of functional capacity or increased demands on liver (GI bleed, systemic infection, electrolyte disturbance, surgery, heart failure)

70-95% mortality

Causes: chronic liver disease is most common; causes without overt hepatocellular necrosis are Reye’s syndrome, tetracycline toxicity, acute fatty liver of pregnancy

Symptoms: jaundice, hypoalbuminemia, elevated serum ammonia, fetor hepaticus (musty body odor due to mercaptans from GI bacteria and methionine), palmar erythema, spider angiomas, hypogonadism (men), gynecomastia (in men due to impaired estrogen metabolism and increased serum estrogen)

Complications: multiple organ failure (respiratory failure with pneumonia and sepsis; renal failure, coagulopathy due to reduction in functional Vitamin K dependent coagulation Factors II, VII, IX, X

Treatment: support until hepatocellular regeneration restores adequate hepatic function, or liver transplantation

Hepatic encephalopathy: altered consciousness, rigidity, hyperreflexia, asterixis (nonrhythmic, rapid extension-flexion movements of head and extremities), associated with elevated serum ammonia

Hepatorenal syndrome: acute renal failure in patients with only severe liver disease; kidney function improves with improving hepatic function; due to decreased renal perfusion through unknown mechanism; patients have reduced urine output, elevated serum BUN; 80-95% mortality; borderline renal insufficiency (Creatinine of 2-3 mg/dl) may persist for months

Hepatitis

Hepatitis-general

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Definition: hepatocyte injury plus acute or chronic inflammatory cells

T cells commonly attack viable hepatocytes

Scavenger macrophages engulf dead hepatocytes within hours

Granulomatous reaction due to foreign bodies, organisms, drugs

Regeneration occurs in all but most fulminant diseases; see mitotic activity, thickening of hepatocyte cords, disorganization of parenchymal structure; prominent bile duct profiles within portal tracts suggests bile duct epithelial proliferation

DD: mild chronic hepatitis vs. early biliary disease (normal periportal hepatocytes without necrosis, swelling or rosette formation, mononuclear cells don’t encircle hepatocytes, fibrosis doesn’t form leaf-like extensions into nodule; also positive for antimitochondrial antibody, other antibodies)

Acute hepatitis-general

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Acute: active hepatocellular damage and necrosis, usually with a lobular inflammatory response, less than 6 months duration

Micro: typically more spotty hepatocyte inflammation than chronic hepatitis; diffuse sinusoidal and portal mononuclear inflammation, swollen hepatocytes, apoptotic hepatocytes; usually not biopsied

Micro images: expansion of portal tracts by lymphocytes, apoptotic hepatocytes

Prolonged resolving acute hepatitis

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Micro: focal microgranulomas prominent within sinusoids near central veins and scattered within hepatic parenchyma; Kupffer cells may contain PAS+ iron or lipochrome; residual centrilobular necrosis and inflammation; minimal portal tract inflammation and fibrosis

DD: mild chronic hepatitis

Chronic hepatitis-general

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Chronic hepatitis with piecemeal (periportal) necrosis: also called interface hepatitis; formerly called chronic active hepatitis; patients with liver disease 6 months or more and portal-based inflammation, fibrosis, disruption of terminal plate and piecemeal necrosis; also periportal hepatocyte rosettes due to regeneration; may have ballooned hepatocytes and peripheral apoptotic bodies; collagen deposition occurs in periportal zone forming septa that extend into lobule in holly-leaf pattern; no prominent ductular proliferation except in severe lesions

Chronic hepatitis without piecemeal necrosis: formerly called chronic persistent hepatitis or chronic lobular hepatitis (if focal hepatocyte apoptosis)

Chronic hepatitis - grading / staging

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Diagnosis should include etiology and grading/staging based on most severe degree of portal or lobular injury (Scheuer)

Sample diagnosis: Chronic hepatitis B with mild piecemeal necrosis (grade 2) and periportal fibrosis (stage 2)

References: J Hepatol 1991;13:372

Grade: degree of inflammation, piecemeal or bridging necrosis

Grade 0: no / minimal inflammation

Grade 1: portal inflammation or lobular inflammation without necrosis

Grade 2: mild periportal inflammation and piecemeal necrosis or focal hepatocellular necrosis

Grade 3: moderate periportal inflammation and piecemeal necrosis or severe focal cell damage

Grade 4: severe periportal inflammation and piecemeal necrosis or bridging necrosis

Stage: degree of fibrosis

Stage 0: no fibrosis

Stage 1: enlarged fibrotic portal tracts

Stage 2: periportal fibrosis or portal to portal septa, without architectural distortion

Stage 3: bridging fibrosis with architectural distortion, no obvious cirrhosis

Stage 4: cirrhosis (probable or definite)

Hepatitis-noninfectious

Alcoholic hepatitis and alcoholic liver disease

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U.S. has 10 million alcoholics, 200,000 alcohol related deaths/year, 25% of hospitalized patients have problems related to alcohol abuse

Alcohol is largest single cause of liver failure in US; damage affected by duration and quantity of consumption and patient’s genetic makeup

8 beers/day causes reversible fatty liver; 16 beers/day for 10 years is associated with severe injury

Alcohol related liver disease consists of hepatic steatosis (50%), alcoholic hepatitis (20%) and cirrhosis (10%); 20% have other liver pathology, including Hepatitis C infection

Alcoholic cirrhosis: only 10% of alcoholics develop cirrhosis; may develop without steatosis or alcoholic hepatitis; resembles cirrhosis from other causes

Women are more susceptible to hepatic injury than men

Pathophysiology: alcohol consumption causes shunting of normal substrates away from catabolism and toward lipid biosynthesis due to (a) excess NADH generation from alcohol dehydrogenase and acetaldehyde dehydrogenase, (b) impaired assembly/secretion of lipoproteins and (c) increased peripheral fat catabolism; P450 induction causes other drugs to be transformed to toxic metabolites; free radicals, from microsomal oxidation of alcohol, damage proteins and membranes

Alcohol directly affects microtubular and mitochondrial function, also induces immunologic attack on hepatic neoantigens

Acetaldehyde (alcohol metabolite) causes lipid peroxidation and acetaldehyde-protein adduct formation

Collagen deposition by perisinusoidal hepatic stellate (Ito) cells is due to Kupffer cell activation (release of TNF-alpha, IL1/6, TGF-beta), platelet-activating factor, influx of neutrophils into parenchyma

Alcohol also causes derangements of vascular perfusion

Symptoms of alcoholic hepatitis: acute onset, usually after heavy drinking; variable symptoms ranging from none to acute hepatic failure; may have acute cholestatic syndrome; 10% risk of death with each bout of hepatitis, cirrhosis in 1/3 within a few years with repeated bouts; hepatitis may persist and progress even with abstinence

5 year survival: 90% in abstainers without jaundice, ascites or hematemesis vs. 50% if continue to drink

Death due to hepatic coma, GI bleed, infection, hepatorenal syndrome after bout of alcoholic hepatitis, hepatocellular carcinoma (3%); sudden death may be due to abnormality in heart conduction system, Archives 2001;125:21

Gross: initially liver is 4-6 kg, yellow, greasy, easily fractured; later liver becomes red with bile-stained areas; may contain visible nodules and fibrosis

Micro: early - hepatocyte swelling and necrosis, macrovesicular fatty change due to triglyceride in centrilobular area, Mallory’s hyaline with surrounding neutrophils; also portal lymphocytes (40%, even without hepatitis B/C) and macrophages; reversible macrovesicular steatosis occurs after moderate alcohol intake, fibrosis may develop late around central veins and extend into parenchyma (sclerosing hyaline necrosis, highlighted with trichrome stain); may have marked cholestatic features or giant mitochondria that appear as globular eosinophilic hyaline inclusions larger than hepatocyte nuclei

Micro images: acute alcoholic hepatitis, macro and microsteatosis, Mallory bodies, CAM5.2, ubiquitin, EM, centrilobular fibrosis, fat stain (osmium tetraoxide)

Fibrosis: initially sinusoidal and perivenular; periportal fibrosis may predominate with repeated bouts of heavy alcohol intake

Alcoholic cirrhosis: final and irreversible form of alcoholic liver disease; initially cirrhotic liver is yellow, fatty, enlarged (> 2 kg); eventually becomes brown, shrunken, nonfatty, < 1 kg; initial fibrous septa are delicate, regenerative micronodules; nodules then become larger and have hobnail appearance on hepatic surface, and bands of fibrous tissue become wider.

Laennec cirrhosis: broad expanses of tough, pale scar tissue due to ischemic necrosis and fibrous obliteration of nodules; also bile stasis; Mallory’s hyaline rare

EM: giant mitochondria

DD alcoholic hepatitis: jejunoileal bypass, drug reactions, nonalcoholic steatohepatitis, megamitochondria (resemble Mallory’s hyaline but coarsely granular and more regular in contour, and trichrome stains them red)

References: Hum Path 2002;33:1170

Autoimmune hepatitis

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Formerly called lupoid hepatitis

Indolent or severe

70% women, usually ages 20-45 years

A diagnosis of exclusion

Associated with HLA-B8 or HLA-DRw3

60% have other autoimmune disorders (rheumatoid arthritis, thyroiditis, Sjogren’s syndrome, ulcerative colitis)

Symptoms: amenorrhea, arthralgias, symptoms of chronic hepatitis

Laboratory: viral markers negative, elevated IgG, high ALT and AST (300-500 mg/dl); elevated anti-nuclear antibody, anti-smooth muscle antibody, anti liver-kidney-microsomal antibody, anti-mitochondrial antibody

Antinuclear antibody: 80% have ANA > 1:80, but ANAs also present in 60% with primary biliary cirrhosis, 50% with alcohol related liver disease, 40% with hepatitis B

Anti-smooth muscle actin antibody: 50% sensitive, not specific, often occurs with antinuclear antibodies; directed against F-act, part of hepatocyte cytoskeleton, usually > 1:80 vs. low titers in normals; indirect fluorescence shows uniform staining of rat stomach muscularis propria, muscularis mucosa and walls of blood vessels but faint staining of glomerular mesangial zones; cable-like staining of Hep 2 cells

Anti-liver-kidney-microsomal antibody: 25% sensitive, usually younger patients; antibodies to LKMA and CK 8/18; rat distal tubules are negative, but hepatocytes and proximal convoluted tubules are positive; if positive, anti-mitochondrial antibodies are negative; confirm LKMA with Western blot; LKMA is cytochrome P450 component for LKMA-1; LKMA-2 in patients taking ticrynafen (off market), LKMA-3 in patients with delta hepatitis

Anti-mitochondrial antibody: 15%, may be part of overlap syndrome with primary biliary cirrhosis

Type 1: anti-smooth muscle antibody and antinuclear antibody positive; typically teenager girls or ages 45-70 years; 10% have other autoimmune disorders such as arthralgias and thyroid disease

Type 2: anti-liver-kidney-microsomal antibody positive; more common in children; adult cases may represent chronic hepatitis C; often presents with acute or fulminant hepatitis; 17% have other autoimmune disorders

Type 3: 25% have only antisoluble liver protein antibody; negative for ANA and anti-liver-kidney-microsomal antibody; 75% have anti-smooth muscle antibody or anti-liver membrane antibody; usually women, mean age 37 years; usually no systemic autoimmune manifestations

Treatment: steroids (dramatic response); failure to respond suggests diagnosis is wrong

Gross images: macronodular cirrhosis

Micro: dense uniform portal infiltrate with abundance of plasma cells, central vein to portal tract bridging necrosis, extensive piecemeal necrosis, central necrosis with plasma cells, variable eosinophils

DD: hepatitis A, chronic hepatitis C (less severe and more focal interface hepatitis), primary biliary cirrhosis, primary sclerosing cholangitis, drug/toxin reaction

Drug / toxin induced hepatitis

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Occurs through hepatic conversion of drug/toxin to active toxin or via immune mechanisms (drug or metabolite acts as hapten)

Either predictable (intrinsic) or unpredictable (idiopathic); either hepatocellular (cytotoxic) or cholestatic

Predictable: dose related, affects virtually everyone (acetaminophen, tetracycline, anti-neoplastic agents, Amanita phalloides toxin, carbon tetrachloride, alcohol); either direct effect of drug or via interference with a metabolic pathway

Unpredictable: depends on host’s propensity to metabolize a drug/toxin or mount an immune response; not dose related; either hypersensitivity related or toxic metabolite related

Micro: mixed macro- and microvesicular steatosis; may have eosinophils if allergic, lymphocytes if immune-mediated, neutrophils with phenothiazines; epithelioid granulomas with phenylbutazone, sulfonamides, sulfonylureas; centrilobular necrosis with carbon tetrachloride, acetaminophen; periportal necrosis with yellow phosphorus; microvesicular steatosis with intravenous tetracycline, cholestasis with anabolic steroids and oral contraceptives, cholestatic hepatitis with phenothiazines

Acetaminophen

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Discrete centrilobular coagulative necrosis

Micro: extensive hepatocyte necrosis

Amiodarone

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Dose related liver toxicity if > 200 mg daily

Micro: alcohol-like changes with periportal Mallory bodies and late periportal fibrosis

Micro images: hydropic swelling, inflammation, acidophil bodies, cytoplasmic cholestasis, periportal Mallory bodies

EM images: Mallory bodies, giant mitochondria, myelin figures

Carbon tetrachloride

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Micro: centrilobular necrosis

Chlorpromazine

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Slow metabolizers have cholestasis and jaundice 1-5 weeks after treatment

Good prognosis

Micro: cytoplasmic and canalicular cholestasis, portal inflammation with eosinophils; minimal necrosis

Cresol

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Case history of 42 year old man with ingestion as suicide attempt, Archives 2003;127:364

Micro images: focal hepatocyte dropout and regeneration

Halothane

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Rare, fatal immune-mediated hepatitis

Gross: soft friable liver due to massive necrosis

Isoniazid

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Hepatocellular inflammation

Methotrexate

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Related to duration of therapy

Micro: steatosis, ballooning degeneration and necrosis, cholestasis, portal inflammation, progressive fibrosis, cirrhosis.

Micro images: advanced lesion with ballooning degeneration and necrosis, cholestasis, early fibrosis

Oral contraceptives

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Micro: pure canalicular cholestasis with normal portal tracts

Phenothiazines

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Micro: neutrophils, cholestatic hepatitis

Phenylbutazone

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Micro: epithelioid granulomas

Phenytoin (Dilantin)

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Micro: multiple histiocytic granulomas; also cholestasis, multifocal necrosis, lymphocyte beading in sinusoids (similar to infectious mononucleosis)

Micro images: cytoplasmic cholestasis and lymphocyte beading in sinusoids, histiocytic granuloma

Ramipril

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An inhibitor of angiotensin-converting enzyme

Case reports of hepatitis in 3 men ages 51-59 years, Archives 2003;127:1493

May cause prolonged cholestatic hepatitis and biliary cirrhosis; other ACE inhibitors may rarely cause cholestasis

Micro: cholestasis, duct necrosis, extravasation of bile, ductular proliferation, portal inflammation

Micro images: necrotic bile ducts

Sulfa drugs

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Micro: granulomas, often epithelioid

Micro images: granuloma

Terbinafine

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Anti-fungal drug for treating onychomycosis and chronic subcutaneous mycosis

May cause persistent cholestasis (even after drug withdrawal), liver failure and death

Histologic changes resemble acute cellular rejection, Hum Path 2003;34:187

Micro: marked centrilobular cholestasis, severe bile duct damage

Tetracycline

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Micro: microvesicular steatosis

Micro images: microvesicular steatosis

Granulomatous hepatitis - noninfectious

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See also granulomatous hepatitis - infectious, below

Chronic granulomatous disease of childhood: necrotizing poorly formed granulomas with lipofuscin in histiocytes

Crohn’s disease: see below

Drug/toxin induced hepatitis: see above

Foreign material: periportal talc or other material from intravenous drug abusers, periportal silicone in dialysis patients, amyloid

Idiopathic: numerous non-caseating granulomas, usually lobular; may precede sarcoidosis; a diagnosis of exclusion; good prognosis if remain in idiopathic group after workup; some may require corticosteroids

Lipogranulomas: usually centrilobular, contain lipid, variable steatosis in adjacent liver; may be a response to endogenous and dietary lipid; no additional evaluation required

Malignancy: epithelioid granulomas occur in Hodgkin’s lymphoma and other malignancies, but do not imply metastatic spread

Primary biliary cirrhosis: see below

Sarcoidosis: see below

Neonatal hepatitis

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Neonatal cholestasis usually due to prolonged conjugated hyperbilirubinemia; affects 1/2500 live births; due to extrahepatic biliary atresia and neonatal hepatitis disorders (non-infectious and infectious)

Some use terms neonatal hepatitis and giant cell hepatitis in neonates interchangeably

Causes: idiopathic (50%), bile duct obstruction (20%), neonatal infection (CMV, congenital rubella, Coxsackievirus, echovirus, Hepatitis B, herpes simplex, rubella, sepsis, syphilis, Toxoplasmosis, urinary tract infection, varicella), toxins (drugs, intravenous nutrition), metabolic disease (alpha-1-antitrypsin disease [15%], cystic fibrosis, defective bile acid synthesis disorders, galactosemia, Gaucher’s disease, Neimann-Pick disease, tyrosinemia), other genetic disorders (Alagille’s syndrome, Down’s syndrome, trisomy 17/18, Turner’s syndrome, Zellweger’s syndrome), other (Indian childhood cirrhosis, myeloproliferative disorder, shock/hypoperfusion)

Death in a few months or evolution to cirrhosis in 30% in some studies

May be associated with mitochondrial DNA depletion

Symptoms: jaundice, dark urine, light or acholic stools, hepatomegaly; may have hypoprothrombinemia

Case reports: newborn boy with lactic acidosis, hepatomegaly, hypoglycemia, icterus, muscle hypotonia and abnormal mitochondria (Hum Path 2002;33:247)

Micro: lobular disarray (evident at low power) with mildly inflamed portal tracts and giant cell transformation of hepatocytes (particularly around central vein), focal hepatocyte necrosis, prominent hepatocellular and canalicular cholestasis, extramedullary hematopoiesis, reactive changes in Kupffer cells; no portal fibrosis, no/patchy ductular proliferation

Note: in neonates, giant cell transformation is a nonspecific response to any hepatocyte injury

Micro images: lobular disarray with giant cells, hepatocyte necrosis, lymphocytes

Negative stains: CD56

DD: metabolic or cholestatic liver disease also shows giant cells

Nonalcoholic steatohepatitis (NASH)

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Occurs in children and adults; associated with obesity (affected 20% of markedly obese patients in an autopsy study), diabetes, drugs/toxins (see drugs/toxins above, amiodarone, glucocorticoids, methotrexate, nifedipine, perhexiline maleate, synthetic estrogens, tamoxifen) or idiopathic

Resembles alcoholic liver disease clinically and histologically, but by definition, alcohol is not a possible etiologic factor

Due to complex metabolic derangements and necroinflammatory lesions causing hepatocellular fat accumulation, hepatocyte injury, inflammation and perisinusoidal fibrosis that may progress to cirrhosis

May be mediated by Kupffer cells, Mod Path 2002;15:699

Often positive antinuclear antibodies in obese patients

15-20% progress to cirrhosis; presence of hepatocyte injury (ballooning degeneration or Mallory bodies) is associated with fibrosis (Hum Path 2004;35:196), fibrosis is associated with hepatic stellate cell activation (alpha smooth muscle actin+, Hum Path 2000;31:822)

Micro: micro- and macrovesicular steatosis, mild lobular plasma cell and lymphocyte infiltrate with variable involvement of portal tracts, ballooning degeneration of hepatocytes with Mallory’s hyaline, intra-acinar perisinusoidal fibrosis; lesions usually centrilobular; glycogenated nuclei with diabetes, lipogranulomas, no neutrophils

Note: diagnosis requires both evidence of hepatocyte injury and steatosis

Micro images: morbid obesity: figure F

Micro images (Mod Path subscribers): severe NASH, primary biliary cirrhosis, alpha-1-antitrypsin deficiency, hepatitis C

References: Mod Path 2003;16:86

Total parenteral nutrition (TPN) related liver disease

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TPN provides support for prematurity, malabsorption, loss of bowel, severe inflammatory bowel disease, necrotizing enterocolitis, congenital gastrointestinal disorders

Complications: steatosis and steatohepatitis, usually in adults; cholestasis, primarily in infants; biliary sludge and cholelithiasis in infants and adults

Liver damage and clinical outcome are more related to underlying disease than to details of TPN

Laboratory: infants have elevated serum alkaline phosphatase, serum bilirubin, ALT, AST

Treatment: begin oral intake (even minimal) as soon as possible, monitor liver function tests, provide balanced TPN, don’t overfeed

Micro:

Infants: early - steatosis, canalicular and centroacinar cholestasis, macrophage aggregates; later (3 months) - portal fibrosis; 4 months - variable changes of triaditis, macrophages with lipofuscin, portal fibrosis, marked portal ductular proliferation, micronodular cirrhosis

Adults: usually periportal steatosis, rarely progresses to fibrosis and cirrhosis

Infectious (non-viral) disorders

Aspergillus

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Micro: hemorrhagic infarction, vasoinvasive fungi have straight septate hyphal forms with acute angle branching

Micro images: hyphal forms with acute angle branching

Bacterial infections

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Either cholestasis of sepsis, bacterial infection of liver or ascending cholangitis

Cholestasis of sepsis

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Usually gram negative sepsis

Diagnosis of exclusion

Micro: canalicular cholestasis, neutrophils in sinusoids, variable cholangiolar cholestasis

Micro images: ductular cholestasis

DD: cholestatic drug reaction, early biliary obstruction (portal involvement), postoperative cholestasis, familial cholestatic syndromes

Bacterial infection of liver

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Various bacterial species, including atypical mycobacteria (smaller epithelioid granulomas), Bartonella henselae (vascular proliferation simulates Kaposi’s sarcoma or peliosis), Brucella (poorly formed sinusoidal granulomas), Listeria (poorly formed sinusoidal granulomas), Mycobacteria tuberculosis (giant cell granulomas with variable necrosis), congenital Syphilis (pericellular fibrosis), Salmonella typhi (typhoid fever), Staphylococcus aureus (toxic shock syndrome)

Blastomycosis

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Immunocompromised patients

Micro images: image1

Candida albicans

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Often causes abscesses

Micro: yeast forms and pseudohyphae, although may be sparse within an abscess

Positive stains: GMS

Clonorchis sinensis

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Liver fluke infection, associated with cholangiocarcinoma

Coccidiodomycosis

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Immunocompromised patients

Micro images: large spherules

Coxiella burnetii

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Rickettsia that causes Q fever, affecting respiratory tract and liver

Micro: granulomas have central vacuole surrounded by hyaline ring (may not be present in every section); portal and lobular lymphohistiocytic infiltrate, hepatocellular necrosis, steatosis

DD (central vacuole): CMV, staphylococcus, allopurinol toxicity, Hodgkin’s lymphoma, toxoplasmosis

Cryptococcus

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Immunocompromised patients

Micro images: round organisms with distinct “capsule”

Dengue fever

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Case report associated with splenic rupture, hepatitis and death, Hum Path 1999;30:1106

Micro: splenic hematomas, liver necrosis, hepatitis with apoptotic hepatocytes

Echinococcal cyst

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Most common cause of hepatic cysts worldwide, particularly in Middle East, Greece, Australia, North Africa, parts of South America

In US, usually in immigrants from above areas

Due to dog tapeworm in larval or cystic stage: E. granulosis (causes cystic hydatid disease), less commonly E. multilocularis (alveolar hydatid disease), or E. vogeli (polycystic hydatid disease)

Definitive hosts are dogs, wolves, cats or other carnivores

Intermediate or cystic stage usually affects sheep, hogs or cows, rarely man or other mammals

Laboratory: serum assays for E. granulosis are 90% sensitive with occasional false positives; high sensitivity and specificity for E. multilocularis; frequent eosinophilia if cyst is viable

Sites: 60-70% in liver, also brain, lung, other sites; frequently communicates with biliary tract

Echinococcus granulosis

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Most common species of infection

Cyst enlarges 1-5 cm per year; becomes symptomatic at 10 cm

Cysts may be infectious or sterile, superficial or deep

Life cycle: protoscolices (future heads of adult tapeworm) develop within brood capsules; when brood capsules detach, are called daughter cysts

Treatment: PAIR - Puncture of cysts percutaneously, Aspiration of fluid, Introduction of protoscolicidal agent, Reaspiration) plus antiparasitic drugs to minimize risk of anaphylaxis

Gross: 75% solitary; unilocular cyst, white, fluid filled

Gross images: hydatid cyst with fluid and daughter cysts,

Micro: 3 layers in cyst wall - (a) innermost (germinal layer) is 10-25 microns, contains nuclei, gives rise to brood capsules attached by short stalk in infectious (fertile) cysts; often with daughter cysts; also protoscolices (attached or separated) with double row of refractile, birefringent, acid-fast hooklets 22-40 microns and 4 round suckers that comprise “hydatid sand”; daughter cysts may merge and provide internal septation; (b) laminated membrane beneath germinal layer is 1 mm thick, avascular, eosinophilic, refractile and chitinous; strongly PAS+, GMS+; (c) outer layer is dense fibrovascular tissue with chronic inflammatory cells, variable calcification develops after 5+ years

Micro images: daughter cysts with germinal layer and scolices

Echinococcus multilocularis

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Less common, slower growing than E. granulosis

Restricted to Northern hemisphere

More tissue invasive than E. granulosis and may simulate malignancy or cirrhosis

Treatment: radical surgery

Gross: alveolar structure with numerous irregular cysts 1-20 mm, appear infiltrative into adjacent liver, may have necrosis, calcification

Micro: thin laminated layer, only 10% have brood capsules and protoscolices; usually no/minimal germinal layer

Echovirus

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Case report of fatal echovirus 6 sepsis in newborn with massive hepatic necrosis, anasarca, adrenal hemorrhagic necrosis, severe encephalomalacia, renal medullary hemorrhage, hemorrhagic pneumonia, Mod Path 2001;14:85

Type 11 is most frequent cause of serious neonatal morbidity and mortality

Gross/micro images (Mod Path subscribers): massive hepatic necrosis (figures A/D)

Entamoeba histolytica abscess

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Also called amebic abscess

Common in developing world

Complication of 3-9% of amebiasis cases

Trophozoites: 10-60 microns with small, single, round nucleus with distinctive karyosome; thick, beaded nuclear membrane; bubbly cytoplasm with ingested red blood cells

Complications: bacterial superinfection, extension or perforation into other structures; death in less than 1% of cases

Diagnosis: serology is 90% sensitive

Treatment: metronidazole, surgery only if complications

Gross: well circumscribed, firm cavities, usually right sided near liver dome; initially yellow, later odorless, orange-brown, pasty, necrotic material resembles anchovy sauce

Micro: shaggy necrotic fibrinous zone, granulation tissue, no/rare neutrophils (not actually an “abscess”), peripheral trophozoites up to 60 microns with small eccentric nucleus and cytoplasmic vacuoles that may contain red blood cells; resemble histiocytes; adjacent liver has fibrosis, chronic inflammation and reactive hepatocytes

Micro images: clusters of trophozoites

Cytology: use saline wet mounts and stained material; 50% positive if material obtained from periphery; very rarely if from center of cyst

Positive stains: PAS, iron hematoxylin, Diff-Quik

DD: macrophages (bean-shaped nuclei, fine chromatin, delicate nuclear membrane, small nucleoli)

Fasciola hepatica (liver fluke)

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Occurs where population consumes watercress or other freshwater plants containing metacercariae

Usually produces lesions in liver, rarely gallbladder and stomach

Parasite penetrates hepatic capsule, migrates into bile ducts causing necrosis, scarring and eosinophilic granulomas

Diagnosis: operculated eggs in stool, duodenal or biliary drainage; immunodiagnostic testing

Gross: solitary or multiple surface yellow nodules, 5-20 mm, resembling metastases; cut sections show tracks ending at subcapsular cavities filled with necrotic material

Micro: dilated intrahepatic bile ducts contain adult flukes, necrotic debris, eosinophils with Charcot-Leyden crystals, histiocytes, eosinophilic granulomas; also dystrophic calcification; rarely eggs

Granulomatous hepatitis - infectious

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See also granulomatous hepatitis - noninfectious above

Bacterial infection: Brucella, Listeria have poorly formed sinusoidal granulomas

Fungal infection: Histoplasma, Aspergillus and Candida cause necrosis and abscesses, usually no granulomas

Mycobacteria (see below)

Rickettsiae infection: Q fever (Coxiella) has doughnut-hole granulomas with hyaline ring

Viral infection: CMV and EBV infections

Histoplasma capsulatum

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Immunocompetent or immunocompromised patients

More common in Ohio River valley

Micro: necrotizing or hyalinized granulomas

Positive stains: silver stains (GMS)

Malakoplakia

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Rare in liver; more common in bladder, but described in numerous locations

Usually associated with Klebsiella and Escherichia coli infection, but also other bacteria, often in association with underlying systemic disease

Three phases: histiocytes (also called Von Hanseman histiocytes after co-discoverer) and plasma cells early; then granulomatous phase with numerous Michaelis-Gutmann calcospherites; late fibroblasts and collagen with histiocytes and only rare Michaelis-Gutmann bodies

Apparently due to defective macrophages that phagocytose bacteria but cannot digest them, causing enlarged phagolysosomes which accumulate crystals, leading to laminated Michaelis-Gutmann inclusions

Case report of 19 year old man with small bowel ileus after Klebsiella pneumonia sepsis, Archives 2002;126:372

Micro: aggregates of histiocytes containing small, round to oval, targetoid structures (Michaelis-Gutmann bodies)

Micro images: H&E and stains, EM

Positive stains: PAS-diastase resistant, calcium, colloidal iron, CD68 (Michaelis-Gutmann bodies are within histiocytes)

Microsporidia

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Case report of disseminated microsporidiosis due to Encephalitozoon cuniculi III at autopsy in a 33 year old Italian woman with AIDS, with spores found in necrotic lesions of liver, kidney, adrenal gland, ovary, brain, heart, spleen, lung, lymph nodes, Mod Path 2002;15:577

Micro: large necrotic lesions with rings of macrophages, fibrosis and occasional lymphocytes and granulocytes; 2 micron oval, pink, slightly refractile bodies present in necrotic areas and surrounding cells; focally associated with granulomatous reactions, occasionally found in hepatic sinusoidal cells

Micro images (Mod Path subscribers): fibrosis surrounding necrotic areas, red stained spores within macrophage-like cells, indirect immunofluorescence

Positive stains: Kinyoun acid-fast, Giemsa, modified Trichrome

EM (adrenal gland): spore containing polar tube arranged in single row with six coils

Mucor

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Micro: often hemorrhagic infarction by vasoinvasive fungi with irregular nonseptate hyphae with right angle branching; may only see hyphal fragments

Positive stains: PAS

Mycobacteria

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Granulomas usually lobular, organisms identified with acid-fast stain

M. leprae

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Liver granulomas present in lepromatous leprosy

May cause relapse

Micro: large histiocytes (“lepra cells”) with clear cytoplasm containing weakly acid-fast bacilli

Micro images: large histiocytes with clear cytoplasm #1, #2 with Fite acid-fast stain

M. mucogenicum

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Member of M. fortuitum-chelonae complex; formerly classified as M. chelonae-like

Water contaminant in hospitals

Rapid growing, rarely present in human infections

Case report of 51 year old man with rapidly progressive granulomatous hepatitis, Archives 2002;126:73

Culture: smooth, nonpigmented, tan-white, undulating edges, rapid-growing colonies

Images: liver-gross, granulomatous inflammation and necrosis, gross culture morphology

M. tuberculosis

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Caseating granulomas

Micro images: early non-caseating granuloma

Atypical mycobacteria

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Includes mycobacterium avium-intracellulare complex

Non-caseating granulomas

Micro images: non-caseating granuloma of M. avium intracellulare #1, #2 with acid-fast stain

Orientia tsutsugamushi

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Formerly called Rickettsia tsutsugamushi

Rickettsiael agent of scrub typhus, a chigger-borne zoonosis highly prevalent and life-threatening in tropical Asia and islands of western Pacific Ocean

Present within liver and spleen macrophages and cardiac muscle cells; also endothelial cells of heart, lung, brain, kidney, pancreas, skin Transmitted to humans via larval mite (chigger) during feeding

Micro images (Mod Path subscribers): immunostained organisms in hepatic and splenic macrophages

EM images (Mod Path subscribers): organism in cardiac myocytes

References: Mod Path 2001;14:752

Penicillium marneffei

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Opportunistic fungus, endemic in Southeast Asia, particularly HIV+ patients in northern Thailand

Causes deep-seated infections, focal or disseminated, with fever, generalized lymphadenopathy, hepatosplenomegaly, mucosal ulcers, skin lesions

Granulomatous response may reflect more intact cell mediated immune function, Archives 2004;128:191

Diagnosis: liver biopsy

Micro: hepatic lesions either diffuse, granulomatous or mixed; diffuse pattern contains widespread macrophages containing fungi, but minimal other inflammatory cells; granulomatous pattern contains multiple granulomas; within macrophages, fungi is round-oval, yeastlike, measuring 2-7 microns, with central septum and no budding forms; outside of cells, it is up to 15 microns long

Micro images: GMS, H&E, PAS

Pyogenic abscess

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Uncommon, associated with immunodeficiency

Usually older patients due to bacteria in biliary tract (30-70%), HIV+ patients with tuberculosis; also other local or systemic infections

40% have no known source of infection

Bacteria detected by aspiration and culture in 85-100% of cases; usually E. coli (35-45%), but often anaerobes or polymicrobial

Yersinia enterocolitica is associated with iron overload (hemochromatosis)

Treatment: drainage, antibiotics; treat source of infection if known

Mortality dependant on abscess size (30-90% if large), number of abscesses, severity of underlying illness, patient age

Gross: single or multiple cavities, usually in right lobe, filled with foul-smelling, creamy yellow, necrotic material; may have fibrous capsule

Gross images: small abscesses associated with pylephlebitis

Micro: necrotic material with numerous neutrophils; adjacent hepatocytes appear reactive

Reye’s syndrome

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First described in 1963 by Reye and colleagues

Encephalopathy and fatty degeneration of liver in children due to mitochondrial dysfunction after febrile viral-like illness treated with aspirin

Disease has almost disappeared in children as aspirin use has declined for viral-like illnesses

Current cases are more common in adults; in children are associated with inborn errors of urea cycle or fatty acid metabolism

Changes similar to Jamaican vomiting sickness and valproic acid toxicity

Micro: diffuse, panlobular, microvesicular fatty change, no necrosis, no inflammation

Positive stains: fat stains

EM: enlarged, pleomorphic mitochondria with expanded matrix and fewer mitochondrial dense bodies

Salmonella typhi

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Produces typhoid nodules (granulomas)

Micro: necrosis with histiocytes; bacteria present within some neutrophils

Micro images: necrosis with histiocytes

Schistosomiasis

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Flat worms (trematodes) with species S. haematobium, S. intercalatum, S. japonicum, S. mansoni, S. mekongi

All but S. haematobium parasitize intestinal venules and may spread to liver

Infect millions in Asia, Africa and South America; rare in US

Infectious cycle: fresh water snails release cercarial form into water; cercarie are mobile and penetrate human skin or mucosa, enter circulation, pass through lungs and lodge in hepatic branches of portal vein; mature into adults, copulate and migrate to colonic and rectal submucosa where female releases ova that enter colonic lumen, are defecated, and infect other snails; ova may also enter portal circulation and cause periportal fibrosis; rarely adult S. mansoni worms are identified in hepatic branches of portal vein (10-16 mm)

Gross: pipe stem fibrosis of cut surface; no cirrhosis unless coexisting hepatitis B

Micro: portal eosinophilic infiltrate with granulomas containing ova with characteristic lateral spine; dense periportal fibrosis

Micro images: eggs in intestinal mucosa, dense periportal fibrosis

Visceral larva migrans

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Due to Toxocara canis, Toxocara catis (dog and cat worms) or Capillaria hepatica

Lesions in liver, lung and other viscera with extreme chronic eosinophilia

Toxocara larva are 400 x 15-20 microns

All ages, male and female

Associated with inadequate sewage and presence of dogs and cats

60% asymptomatic; also fever, abdominal pain

Serial sections, immunostains or serology may be required for diagnosis

Gross: 74% have visible lesion, 80% multiple, often in subcapsular right lobe, 3-10 mm, gray-white

Micro: multiple palisading granulomas with central necrosis surrounding by eosinophils, chronic inflammatory cells and neutrophils, granulomas often periportal; Charcot-Leyden crystals (44%); parasites present on H&E in only 25%

Positive stains: Toxocaris antibody staining of macrophages, Biebrich scarlet stain (for eosinophils)

References: AJSP 2001;25:1316

Visceral leishmaniasis

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Cases due to Leishmania infantum are endemic in Southern France, associated with HIV, Hum Path 2000;31:75

Fever, hepatosplenomegaly, pancytopenia are common; often fatal when associated with HIV

Diagnosis: amastigotes (Leishmania donovani [L-D] bodies) in bone marrow smears or biopsies (skin, GI, liver, duodenum)

Micro: rounded bodies 2-3 microns within macrophages and sinusoidal endothelial cells

Micro images: small rounded bodies within macrophages

Viral hepatitis

General

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Infections differ if host is immunocompromised

Hepatotrophic viruses are A, B, C, delta agent, E, G

May be self-limiting (hepatitis A), cause chronic liver disease and cirrhosis (hepatitis B and C), cause massive necrosis and acute liver failure (rare with hepatitis C)

Viruses that infect liver and other organs: adenovirus, Crimean/Congo hemorrhagic fever (Russia, Africa, Pakistan, Iraq, Dubai), Ebola (Africa), enteroviruses, Junin hemorrhagic fever (Argentina), Lassa fever (Nigeria), Machupo hemorrhagic fever (Bolivia), Marburg virus (Uganda green monkeys), measles (rubeola), Rift valley fever (Africa), rubella, yellow fever

Carrier state: virus present, but either no clinically apparent disease or chronic hepatitis; best characterized for hepatitis B; present in 90% infected early in life or at childbirth versus 1-10% of adult infections with hepatitis B; associated with impaired immunity

Acute viral hepatitis

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Phases: incubation, symptomatic preicteric, symptomatic icteric, convalescence

Peak infectivity is at end of incubation period and early symptomatic period

Preicteric phase: constitutional symptoms, malaise, fatigue, loss of appetite; serum-sickness like syndrome in 10% (fever, rash, arthralgias due to circulating immune complexes), enlarged and tender liver, elevated serum aminotransferases

Icteric phase: may have abatement of severe symptoms (high fever, shaking chills, headache, right upper quadrant pain), jaundice due to conjugated hyperbilirubinemia (dark urine, light stools, pruritis), increased prothrombin time

Icteric phase common in acute phase of hepatitis A, 50% of hepatitis B, unusual in hepatitis C

Gross images: acute hepatitis #1, #2

Micro: irregular hepatic plates due to variability in hepatocyte size and inflammatory cells; hepatocyte necrosis, portal and lobular lymphocytic inflammation and regenerative activity; hepatocyte death via apoptosis, ballooning degeneration or cytolysis (collapse of reticulin network where cells have disappeared with appearance of lymphocytes or macrophages); infiltrate is usually lymphocytes, most prominent in lobules, then spills over into periportal hepatocytes (interface hepatitis, more sinusoidal in hepatitis C, CMV, EBV); in resolving phase, portal lymphocytes and plasma cells are present with minimal lobular inflammation; Kupffer cells contain hemosiderin and lipofuscin; hepatocytes are present in irregularly thickened plates with occasional rosettes and multinucleation

Micro images: trichrome stain documents collapse of liver parenchyma

Report: degree of hepatocellular damage, presence of regenerative activity, describe inflammatory and stromal response

Stains: reticulin shows lobular disarray and areas of dropout; hepatitis viral stains not useful for identifying virus in acute period because infected hepatocytes are destroyed as soon as they express surface viral antigens; however, may be helpful for acute hepatitis D

Chronic viral hepatitis

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Difficult to diagnosis from biopsies with less than 4 identifiable portal tracts

Biopsy performed to confirm diagnosis and assess inflammatory grade and fibrotic stage of disease

Diagnosis requires symptomatic, serologic or biochemical evidence of continuing or relapsing hepatic disease of 6 months or more, with histologically documented necrosis and inflammation

Etiology (hepatitis C > hepatitis B) is the most important predictive factor for chronic hepatitis; clinical features are not predictive

Terms chronic active hepatitis and chronic persistent hepatitis, based on presence (“active”) or absence (“persistent”) of piecemeal necrosis, are no longer used

Symptoms: spider angiomas, palmar erythema, mild hepatosplenomegaly, hepatic tenderness, increased prothrombin time and partial thromboplastin time, vasculitis due to immune complex deposition (HBV, HCV), glomerulonephritis, cryoglobulinemia (35% of HCV)

Micro: predominantly lymphocytic portal infiltrate with less lobular involvement than acute hepatitis; may have piecemeal necrosis and fibrosis

DD (non viral causes): Wilson’s disease, alpha-1-antitrypsin deficiency, alcoholism, drug reaction (isoniazid, methyldopa, methotrexate), autoimmune hepatitis, sclerosing cholangitis, resolving acute hepatitis

Adenovirus hepatitis

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Associated with immunocompromise and transplant recipients; may have fulminant hepatic failure

Case report of 21 year old man with allogeneic bone marrow transplant and death due to adenovirus, Archives 2003;127:e246

Micro: may have random areas of bland coagulative necrosis, nuclear inclusions are either large and basophilic or bubbly and vesicular, with smudgy nuclei and chromatin margination

Micro images: H&E, adenovirus stain

Positive stains: adenovirus

Cytomegalovirus hepatitis (CMV)

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Affects immunocompetent and immunocompromised

Usually acute self-limited disease resembling infectious mononucleosis

May be associated with massive hepatic necrosis

Associated with viral-associated hemophagocytic syndrome, with prominent erythrophagocytosis by sinusoidal Kupffer cells and portal histiocytes (DD: sinus histiocytosis with massive lymphadenopathy [nodular, portal areas uninvolved])

Micro: predominantly sinusoidal infiltrate of atypical lymphocytes with minimal necrosis; variable mitotic figures and small epithelioid granulomas; immunocompromised patients have enlarged endothelial cells, bile duct epithelium or hepatocytes with large, eosinophilic to amphophilic nuclear inclusions surrounded by a clear halo, and cytoplasmic inclusions consisting of basophilic dots (inclusions are viral particles); microabscesses composed of neutrophils are present instead of lymphocytes

CMV stains not helpful for diagnosis

Micro images: intranuclear and cytoplasmic inclusions #1, #2 in neonatal hepatitis

DD: EBV, hepatitis C, diphenylhydantoin drug reaction

Epstein Barr virus hepatitis (EBV)

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Affects immunocompetent and immunocompromised

Usually acute self-limited disease resembling infectious mononucleosis; rarely causes hepatic failure and death in patients with immunodeficiency syndromes

Laboratory: elevated transaminase levels (80%), high EBV serum viral load, elevated bilirubin in only 7%

Infiltrating CD8+ T cells, but not hepatocytes, are infected with EBV, Hum Path 2001;32:757

Micro: predominantly sinusoidal infiltrate of atypical T lymphocytes with minimal necrosis; variable mitotic figures and small epithelioid granulomas; may cause polymorphic B cell hyperplasia or lymphoma in immunocompromised; no bile duct injury or venulitis

Associated with viral-associated hemophagocytic syndrome, with prominent erythrophagocytosis by sinusoidal Kupffer cells and portal histiocytes

Micro images: prominent inflammation without hepatocyte necrosis, hepatocyte regeneration with binucleated figures and mitotic activity

Positive stains: EBV antigen, EBV encoded RNA (EBER)

DD: CMV, hepatitis C, diphenylhydantoin drug reaction, sinus histiocytosis with massive lymphadenopathy [nodular, portal areas uninvolved]

Hepatitis A virus (HAV)

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Fecal-oral transmission via contaminated food or water; associated with overcrowding or poor sanitation; usually children (asymptomatic or symptomatic without jaundice); in adults, infection more severe with malaise and jaundice for 7-10 days

Rarely causes massive hepatic necrosis and acute liver failure; fatal in < 0.5% of cases

May cause acute cholestatic hepatitis with bile ductular proliferation, neutrophils around ducts, cholestasis, hepatocyte ballooning, pseudo-glands around bile plugs

Does not produce chronic disease or carrier state in immunocompetent patients

Causes 50% of hepatitis cases in US; effective vaccine available

Virology: due to Picornavirus, 27 nm virion with single stranded RNA

Drawing of virion

Laboratory: serum IgM anti-HAV is more reliable than immunostains

Micro: periportal inflammation and necrosis, ballooning degeneration, apoptosis; cholestasis and increased portal and periportal plasma cells are relatively specific for hepatitis A; acidophil bodies or cytolysis are present (collapse of reticulin network where cells have disappeared with appearance of macrophage aggregates); bridging necrosis if severe hepatitis; also interface hepatitis (inflammatory infiltrate spills over into adjacent parenchyma to cause necrosis of periportal hepatocytes); relative sparing of centrilobular hepatocytes

Micro images: portal and periportal inflammation with some ballooning degeneration, lobular inflammation, confluent necrosis (PAS), acidophil bodies and hydropic degeneration, with marked cholestasis

DD: chronic hepatitis with moderate/severe activity (fibrosis present)

Hepatitis B virus (HBV)

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Usually subclinical disease, but may lead to fulminant hepatic failure, chronic liver disease and cirrhosis

Lifetime risk for hepatocellular carcinoma is 40% for men and 15% for women

Spread by acutely infected patients or chronic viral carriers through intimate / sexual contact, intravenous drug abuse, contaminated blood or infected instruments, maternal to infant via delivery

Causes 40% of hepatitis cases in US

Virology: due to Hepadnavirus; intact virus is known as Dane particle; has 28 nm central nucleocapsid core enclosed by outer surface envelope; core contains DNA genome with DNA polymerase, hepatitis B core antigen and hepatitis B e antigen; viral envelope contains hepatitis B surface antigen

Drawing of virion

Hepatitis B surface antigen (HBsAg): carries no particularly useful clinical information, but is first serum marker of active infection

Hepatitis B core antigen (HBcAg): indicates active replication of virus, patient is infective; present in hepatocyte nuclei

Carrier: antigenemia > 6 months, normal ALT and AST, no symptoms; occurs in 10%

Immunostains may be helpful for chronic disease

Fibrosing cholestatic hepatitis: unusual presentation of Hepatitis B virus in liver allograph recipients

Gross images: atrophic liver due to fulminant hepatitis

Micro: acute - ground glass hepatocytes (finely granular eosinophilic cytoplasm consisting of spherules and tubules of HBsAg) with central ballooning degeneration

Micro images: piecemeal necrosis , ballooning degeneration and acidophil body, lobular disarray, acidophil bodies #1, #2, #3, submassive necrosis, ground glass hepatocytes in asymptomatic carrier, moderate portal inflammation, portal inflammation with minimal interface hepatitis, portal fibrosis with minimal inflammation (trichrome), severe with marked portal inflammation #1, #2 with piecemeal necrosis, immunostain for surface antigen, immunostains for core antigen (in nuclei)

Positive stains: immunostains for HBsAg or HBcAg or orcein stain (highlights HBsAg)

Hepatitis C virus (HCV)

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0.2% incidence in US, 170 million people infected worldwide

90% of non-A, non-B hepatitis cases, 75-95% of transfusion associated hepatitis cases are due to Hepatitis C

Causes: 35% IV drug abuse, 15% household contact or heterosexual exposure, 5% blood transfusion, 45% unknown

50-80% develop chronic liver disease, 20% of these develop cirrhosis; high risk for hepatocellular carcinoma, particularly with alcoholic cirrhosis (57% at 10 years); acute liver failure is rare

CD34+ sinusoidal endothelial cells are a risk factor for hepatocellular carcinoma in HCV associated chronic liver disease, Hum Path 2001;32:1363

In HIV+ patients, cirrhosis more common if CD4 < 200 cells/microL, Hum Path 2000;31:69

Virion: a flavivirus, enveloped RNA virus

Complications: deterioration of liver status with cirrhosis in 20% and improvement in 10% with chronic hepatitis C; also hepatocellular carcinoma

Treatment: long term interferon alpha causes regression of cirrhosis in 5-10%, Hum Path 2004;35:107

Interferon used in combination with ribavirin; orthotopic liver transplantation

10% have stainable iron; some hepatologists use iron content and location in patient management; occasionally may be due to mutation in gene for hereditary hemochromatosis, Archives 2000;124:1632

Poor prognostic factors: necroinflammatory activity is associated with fibrosis progression (Hum Path 2001;32:904), also alcohol consumption, advanced age at the time of infection, and immunocompromise

Post liver transplant: recurrence of Hepatitis C (as opposed to reinfection, which is almost universal) associated with more single cell hepatocyte necrosis (acidophil bodies), bile duct damage, lymphoid aggregates, cholestasis, fibrous septum, viral load (HCV RNA) > 1.25 million viral equivalents/ml; recurrence may resemble cellular rejection; serial biopsies may be necessary; Hum Path 2002;33:277, Archives 2000;124:1623, Mod Path 2002;15:897; HCV RNA levels are highest at time of active hepatocellular destruction (Mod Path 1999;12:1043)

Case reports: with diffuse large B cell lymphoma (AJSP 1999;23:1124), with hepatocellular carcinoma and diffuse large B cell lymphoma (Archives 2000;124:1532)

Micro: predominantly sinusoidal lymphocytic infiltrate, often with lymphoid follicles that surround damaged bile ducts, often involvement of portal tracts; Mallory’s hyaline, mild and focal macrovesicular steatosis, minimal necrosis; usually no/minimal plasma cells or eosinophils; may have irregular acidophil bodies

Lymphoid aggregates are specific for hepatitis C, but only 50% sensitive

Micro images: macronodular cirrhosis, necrosis, inflammation, steatosis, portal lymphocytosis, bile duct involvement, portal-portal fibrosis, immunostain

Recurrence post transplant: acidophil bodies, lymphoid aggregate, fibrous septum, cellular rejection

Micro images (Mod Path subscribers): Hepatitis C with cirrhosis, post-transplant at 1 week, post-transplant at 6 weeks with apoptotic bodies

References: Mod Path 2000;13:679 (post-transplant)

Hepatitis delta agent (Hepatitis D)

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Only occurs with hepatitis B virus because delta agent is a defective RNA virus that requires hepatitis B infection for its own replication

May cause any clinical syndromes or histologic patterns of hepatitis B

May also cause an acute hepatitis with atypical biphasic pattern or a chronic hepatitis that progresses rapidly to cirrhosis in 15% of patients

Consider delta virus infection if (a) recurrent acute hepatitis or (b) sudden fulminant hepatitis in chronic hepatitis B carrier

Diagnosis: serology

Micro: typical histology of hepatitis B infection; may also show morule cell (multivesicular change due to vacuoles in infected hepatocytes) and more pronounced necrosis and inflammatory activity

Micro images: lobular and portal inflammation with fatty macrovacuoles, acidophil bodies, immunostains for HBV surface antigen, immunostain for HDV antigen (nuclear localization)

Hepatitis E virus

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Rare in United States; initial outbreak in 1978 in Kashmir Valley with 52,000 cases and 1500 deaths

Fecal-oral transmission similar to Hepatitis A, often through contaminated water

Associated with poor outcome in pregnant women (up to 22% fatality rate due to disseminated intravascular coagulation and fulminant hepatitis)

May cause acute cholestatic hepatitis with bile ductular proliferation, neutrophils around ducts, cholestasis, hepatocyte ballooning, pseudo-glands around bile plugs

Due to Calicivirus

Drawing of virion

Micro: resembles Hepatitis A with canalicular cholestasis, dense portal and periportal inflammation

Hepatitis G virus

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Also called GBV-C virus

RNA virus that, like HCV, is member of Flaviviridae family

Accounts for 10% of non A-E hepatitis

Identified in 1.5% of blood donors with normal ALT

Spreads via transfusion, IV drug use, multiple sexual partners

10% have coexisting HBV, 20% have coexisting HCV

May be “passenger” virus; does not appear to be significant cause of hepatitis by itself or to alter clinical outcome of patients with HBV or HCV

Herpes simplex virus hepatitis

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Uncommon complication of adult HSV1 or HSV2 infection

Usually pregnant women (mean 31 weeks) or immunocompromised patients

Rapid downhill course, usually fatal (81% in adults) due to massive hepatic necrosis

Often not diagnosed until autopsy due to nonspecific clinical features

Laboratory: sudden, marked elevation of ALT or AST, fever, leukopenia

Case report of low birth weight newborn with disseminated infection, Archives 2000;124:469

Micro: may have random areas of bland coagulative necrosis with minimal inflammatory response; hepatocytes may have multinucleated forms; at edge of necrotic areas, cells contain intranuclear eosinophilic inclusion surrounded by clear halo with peripheral chromatin margination (Cowdry type A inclusion), with ground-glass nuclei

Gross/micro images: necrotic foci, multinucleation, inclusions, neonatal infection, necrosis with inclusions

HHV6 (human herpes virus 6)

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Infection in infancy causes exanthem subitum (HHV-6B), a mild infection; rarely leads to hepatitis, meningoencephalitis or febrile convulsions

Case history of 8 month old boy with fulminant hepatic failure due to HHV-6 infection, Hum Path 2001;32:887

Micro: panlobular microvesicular steatosis in glycogen-depleted hepatocytes resembling Reye’s syndrome, eosinophilic central hepatocytes, with some nuclear disappearance; minimal inflammation, no changes in portal areas

HIV (human immunodeficiency virus)

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Often infections with atypical mycobacteria (often without granulomas at autopsy), Bartonella henselae (bacillary angiomatosis), CMV, Coccidiodes, Cryptococcus, Cryptosporidium (may affect biliary tree), Histoplasma, Pneumocystis

Also higher incidence of lymphoma, Kaposi’s sarcoma, peliosis hepatis

High incidence of serologic infection with hepatitis B, although usually no significant liver disease

Micro: usually no lymphocytes in portal tract due to leukopenia; canalicular cholestasis, polarizable material in portal tracts of intravenous drug abusers

Children may have bile duct damage and endothelialitis, with portal and lobular infiltrate, resembling graft versus host disease

Biliary tract disease

Cholestasis

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Bile stagnation due to hepatocellular dysfunction, intra- or extrahepatic biliary obstruction

Other causes: pregnancy, benign familial recurrent cholestasis, medications, postoperative, sepsis, amiodarone (Archives 1999;123:251)

Symptoms: pruritis (due to bile acid deposition in skin), skin xanthomas (due to hyperlipidemia); may cause deficiencies of fat soluble vitamins A, D, E, K

Laboratory: elevated serum alkaline phosphatase (present in bile duct epithelium and hepatocyte canalicular membrane), elevated serum bilirubin

Micro: bile pigment within hepatic parenchyma (green-brown bile plugs), also within Kupffer cells, foamy degeneration of hepatocytes, bile duct proliferation (proliferation of epithelial cells and looping/reduplication of ducts), concretions, periportal neutrophils; late - bile lakes, portal tract fibrosis

Micro images: ballooning degeneration with neutrophil satellitosis, Mallory bodies and bile plugs, canalicular cholestasis, ductular cholestasis

EM images: hepatocyte with cytoplasmic lysosomal lamellar phospholipid inclusions and phagosomes

Acute large duct obstruction

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Usually due to gallstones in common bile duct; also bile plugs or surgical ligation

Without treatment, may progress to portal fibrosis and biliary cirrhosis with loss of bile ducts

Note: cholestasis and ductular proliferation are non-specific changes

Gross images: stone obstructing intrahepatic bile duct

Micro: early - centrilobular canalicular cholestasis with edema of portal tracts, proliferation of small bile ductules without lumina at periphery of portal tract and neutrophils outside of the ducts, bile stasis in hepatocytes and canaliculi; late - bile accumulation within ducts and ductules and possibly bile lakes (very specific); feathery degeneration of hepatocytes adjacent to areas of cholestasis, foamy and bile-containing Kupffer cells; lobule is not affected since injury occurs via portal tracts

DD: sepsis (neutrophils present within lobules as well as portal areas), drug reaction, treated liver transplant rejection, hyperalimentation toxicity

Ascending cholangitis

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Biliary tract infection (E. coli, enterococci) with obstruction

Micro: neutrophils within lumina of interlobular bile ducts; large ducts may be destroyed and replaced by scar or atretic ducts

Autoimmune cholangitis

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Newly described, may be variant of antimitochondrial negative primary biliary cirrhosis

More common in women

Presents with pruritis, associated with arthralgias, sicca syndrome, Raynaud's phenomenon

Laboratory: positive antinuclear antibody, negative antimitochondrial antibody

Micro: ductopenia with bile duct damage similar to primary biliary cirrhosis, mild chronic active hepatitis-like portal changes, bile ductular proliferation; variable granulomas

Cholangitis lenta

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Also called bile ductular cholestasis

Common cause of jaundice after persistent fever or sepsis

Micro: dilated, peripherally located ductules that contain inspissated bile; neutrophilic infiltrate

DD: large duct obstruction (dilated ducts are in center of triads, not peripheral)

Chronic large duct obstruction

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Causes: impacted stones, recurrent passed stones, biliary fibrosis, primary sclerosing cholangitis

Micro: diffuse bile ductular proliferation with more fibrosis than acute cases, primarily chronic inflammatory infiltrate, onion skin cuffing of fibroblasts around large bile ducts, variable cholestasis, variable Mallory’s hyaline in periportal hepatocytes, usually no edema, minimal neutrophils, minimal interlobular bile ducts

Micro images: bile ductular proliferation

DD: hepatitis C, primary sclerosing cholangitis, primary biliary cirrhosis

Hyperalimentation

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Simulates biliary obstruction

Micro: portal edema, bile ductular proliferation, variable cholestasis, centrilobular ballooning of hepatocytes, fatty change, PAS+ material in Kupffer cells

Oriental cholangiohepatitis

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Also called recurrent pyogenic cholangitis

Endemic in Southeast Asia, usually young adults

Symptoms: recurrent attacks of sepsis, usually E. coli, with associated abdominal pain, fever, and jaundice

Xray: dilation of extrahepatic bile ducts with relatively mild/no dilation of intrahepatic ducts, localized dilatation of the lobar or segmental bile ducts, increased periportal echogenicity, segmental hepatic atrophy, and gallstones; localized intrahepatic segmental ductal stenosis may be present, especially in the lateral segment of the left lobe or posterior segment of the right hepatic lobe

Micro: proliferation of bile ducts and inflammatory cells along the periportal spaces and hepatic parenchyma; hepatic and intraductal abscesses

Primary biliary cirrhosis

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Chronic, progressive, often fatal cholestatic liver disease with destruction of small, intrahepatic bile ducts, portal inflammation and scarring leading to cirrhosis and liver failure

Possibly autoimmune; associated with Sjogren’s syndrome, scleroderma, thyroiditis, rheumatoid arthritis, Raynaud’s phenomenon, membranous glomerulonephritis, systemic lupus erythematosus, celiac disease

Involves most proximal portion of biliary tree, the small bile ducts and canals of Hering; larger bile ducts affected only irregularly, Hum Path 2002;33:983

85% women, usually ages 40-60

Symptoms: insidious onset of pruritis, malaise, dark urine, light stools, hepatomegaly, xanthomas, xanthelasma

Laboratory: elevated serum alkaline phosphatase and cholesterol, IgM antimitochondrial autoantibodies in 95%, elevated conjugated bilirubin (late)

Note: if negative antimitochondrial antibody (occurs in 5%), must have a cholangiogram to rule out primary sclerosing cholangitis

Note: M2 form of anti-mitochondrial antibody, present in 90%, is against E2 subunit of pyruvate dehydrogenase complex–dihydrolipoamide acetyltransferase on inner face of inner mitochondrial membrane, causes hypocomplementemia and formation of immune complexes

Antimitochondrial antibodies are most important diagnostic marker; has coarse granular cytoplasmic staining of distal renal tubules and parietal cells (rodent stomach/kidney blocks) with indirect immunofluorescence

Note: anti-liver-kidney-microsomal antibody does NOT stain distal renal tubules

NOMA - natural occurring mitochondrial Ab; found in close contacts of PBC patients, even lab techs processing sera from these patients; are antibodies to M2 and M9, but different epitopes; significance uncertain, raises question of infectious etiology

Death due to liver failure, hemorrhage of varices, infection

Treatment: liver transplant

Gross: liver eventually turns green; capsule initially smooth, then granular, then micronodular

Micro: dense lymphocytic infiltrate in portal tracts with granulomatous destruction and loss of medium sized interlobular bile ducts, focal and variable within the liver; florid duct lesions (see below); may involve sinusoids early; periportal Mallory’s hyaline late, usually minimal neutrophils, variable portal eosinophils; resembles graft versus host disease and graft rejection; ductules derived from periportal hepatocytes are still present; prominent Ito cells with fat vacuoles

Florid duct lesion: interlobular bile ducts (those that course alongside the hepatic artery) are destroyed by poorly formed portal epithelioid granulomas, lymphocytes, plasma cells and macrophages; obstruction to bile flow causes progressive hepatic damage (periportal granulomas are relatively specific)

Upstream portal tracts have bile ductular proliferation, inflammation and necrosis of hepatic parenchyma; eventually causes portal tract scarring and bridging fibrosis

Staging: 1-florid duct lesion; portal inflammation with damage to septal or interlobular bile ducts but without expansion of portal tracts or piecemeal necrosis; 2-expansion of portal tracts with piecemeal necrosis and ductular proliferation, but no bridging; 3-decreased inflammation but fibrous septum formation with bridging necrosis or fibrosis; 4-cirrhosis

Micro images: chronic inflammatory infiltrate and loss of bile ducts #1, #2, #3, epithelial damage with granuloma #1, #2 with lymphocytic inflammation, AMA immunofluorescence

Micro images (Mod Path subscribers): lymphocytic infiltrate with loss of interlobular bile duct

Positive stains: copper (indicates chronic cholestatic condition)

DD: secondary biliary sclerosis, Hepatitis C

Primary sclerosing cholangitis

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65% men, usually under 45 years

Possibly autoimmune, 50-70% also have inflammatory bowel disease (particularly ulcerative colitis, although only 4% with ulcerative colitis have primary sclerosing cholangitis)

Secondary sclerosing cholangitis: due to stones, prior surgery

Symptoms: fatigue, pruritis, jaundice, right upper quadrant pain / tenderness

Increased risk for cholangiocarcinoma

End stage disease is associated with hyperplasia of glands of extrahepatic bile ducts, with low incidence of dysplasia and adenocarcinoma, AJSP 2003;27:349

Laboratory: elevated alkaline phosphatase, IgM, IgG; variable bilirubin; 2/3 are p-ANCA positive (also positive in ulcerative colitis without PSC); negative antimitochondrial antibody

Xray: beading of barium column in cholangiogram due to irregular strictures and dilations of affected bile ducts

Treatment: liver transplant since no effective medical therapy (associated with autoimmune liver disease in 42% and recurrence in 33%)

Gross: periductal portal tract fibrosis, segmental stenosis of extrahepatic and intrahepatic bile ducts

Gross images: liver with white fibrous cords

Micro: fibrosing cholangitis of intra- and extrahepatic bile ducts (large and small) with lymphocytic infiltration; progressive atrophy of bile duct epithelium and obliteration of the lumen, diffuse bile ductular proliferation; “onion skin” fibrosis around affected ducts, which later disappear, leaving cord-like fibrous scar; remaining ducts are ectatic and inflamed, often elongated; variable portal eosinophils; cirrhotic nodules, when present, have “jigsaw” pattern due to portal to portal nature of fibrosis; also sclerosis and prominent lymphoid aggregates in gallbladder

Post-transplant recurrences exhibit bile duct structuring and nonspecific autoimmune hepatitis with variable fibrosis

Micro images: portal tract fibrosis, bile duct with marked periductal sclerosis #1, #2, #3, #4

Micro images (Mod Path subscribers): interlobular bile duct with periductal and concentric fibrosis, scar at site of missing bile duct, presence of copper (Orcein stain) shows chronic cholestasis

Staging: 1-inflammation without expansion of portal tracts or piecemeal necrosis, 2-piecemeal necrosis or fibrosis without bridging, 3-bridging necrosis or fibrosis, 4-cirrhosis

DD: primary biliary cirrhosis (florid duct lesions, not fibrous-obliterative lesions), chronic viral hepatitis (more prominent lymphocytic infiltrate and less periportal copper deposition), cholangiocarcinoma (may have similar radiologic findings)

References: Hum Path 2003;34:1127 (transplants)

Secondary biliary cirrhosis

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Extrahepatic bile duct obstruction due to biliary atresia, choledochal cysts, cystic fibrosis, Alagille’s syndrome, gallstones, post-surgical stricture, carcinoma of pancreatic head or biliary tree

Symptoms and laboratory: same as primary biliary cirrhosis, but no antimitochondrial antibodies

Secondary inflammation causes periportal fibrosis, scarring and nodule formation

Gross: yellow-green, icteric discoloration of tissues and fluids; hard, granular liver

Micro: fibrosis divides liver into jigsaw-like pattern; septa contain large and small bile ducts with inspissated pigment; extensive proliferation of bile ductules and edema, particularly at interface of septa and parenchyma; may have bile lakes, extensive feathery degeneration

Jaundice

Physiology

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Definition: total bilirubin > 2.0 mg/dl (normal is 0.3 to 1.2 mg/dl)

Conjugated bilirubin (produced by normal liver) is water soluble, nontoxic, loosely bound to albumin; can be excreted in urine

Unconjugated bilirubin and bilirubin glucuronides are insoluble in water and tightly complexed to albumin; cannot be excreted in urine despite high levels due to insolubility; may diffuse into tissues and produce toxic brain injury

Hemolytic disease of newborn (erythroblastosis fetalis) causes severe neurologic damage (kernicterus) due to accumulation of unconjugated bilirubin

Causes of jaundice: excessive production of bilirubin that overwhelms liver’s conjugating capacity, reduced hepatocyte uptake of bilirubin, other causes of impaired conjugation, decreased hepatocyte excretion of bilirubin, impaired bile flow (intra- or extrahepatic)

Unconjugated hyperbilirubinemia

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Due to excessive production, reduced hepatic intake or impaired conjugation

Excessive production: hemolytic anemia, internal hemorrhage with blood resorption, ineffective hematopoiesis

Reduced hepatic uptake: Gilbert syndrome (some cases), drug interference with membrane carrier system

Impaired conjugation: physiologic jaundice of newborn (decreased UGT activity, decreased excretion, because hepatic function does not fully mature until 2 weeks old), breast milk jaundice, genetic deficiency of UGT (Crigler-Najjar syndrome types I & II), Gilbert syndrome (some cases), diffuse hepatocellular disease (hepatitis, cirrhosis)

Crigler-Najjar syndrome type I: autosomal recessive, no UGT activity, fatal in neonates due to kernicterus

Crigler-Najjar syndrome type II: autosomal dominant, decreased UGT activity, mild kernicterus; yellow skin

Gilbert syndrome: may be autosomal dominant, UGT activity is 30% of normal due to mutations in promoter region, asymptomatic, affects 6% of US population, detected during periods of stress (illness, strenuous exercise, fasting)

Conjugated hyperbilirubinemia

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Due to decreased hepatic excretion or deficiency of canalicular membrane transporters (Dubin-Johnson syndrome, Rotor syndrome)

Dubin-Johnson syndrome: autosomal recessive, impaired excretion due to canalicular membrane-carrier defect, have darkly pigmented cytoplasmic globules in liver, asymptomatic; normal liver function tests; electron microscopy shows coarse granules in lysosomes which appear to be polymers of adrenaline metabolites

Micro images: brown-black pigment within hepatocytes

Rotor syndrome: rare, autosomal recessive, cause unknown, asymptomatic, liver is not pigmented

Vascular disorders

General

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Due to obstruction to inflow (hepatic artery or portal vein) or outflow (central veins, major hepatic veins, inferior vena cava, congestive heart failure) or severe hypotension

Normal liver is resistant to ischemia due to dual inflow and possibly also collaterals

Obstruction of outflow causes central passive congestion, leading to hepatocellular atrophy and centrilobular fibrosis that may obliterate central vein lumina

Causes of outflow obstruction: radiotherapy, alkylating agents, Comfrey tea

Arterial disorders

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Due to emboli, neoplasia, polyarteritis nodosa, sepsis

May cause local infarct of Zahn (sharply demarcated, anemic, pale tan or hemorrhagic area due to portal blood), although retrograde arterial flow through accessory vessels and portal supply may sustain liver parenchyma

In transplanted liver, hepatic artery thrombosis causes loss of organ, since there is no portal supply

Gross images: infarct

Micro: ischemia causes centrilobular or random necrosis; may have coagulative necrosis or ballooning degeneration with hepatocyte dropout

Budd-Chiari syndrome

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Also called hepatic vein thrombosis

Common form of venous outflow obstruction

Either acute thrombotic occlusion (usually fatal) or subacute and chronic occlusive syndromes with hepatomegaly, weight gain, ascites, abdominal pain

Associated with contraceptive steroids, myeloproliferative disorders; also paroxysmal nocturnal hemoglobinuria, pregnancy, postpartum state, intra-abdominal cancer (hepatocellular carcinoma) with inferior vena cava occlusion, idiopathic (30%)

High mortality for acute disease

Survival: high mortality for acute thrombotic occlusion, 5 year survival of 50% for chronic form

Treatment: portosystemic venous shunt (causes reverse flow through portal vein), angiography (to dilate obstruction)

Gross: swollen liver with red-purple, tense capsule

Gross images: normal hepatic veins, occluded hepatic veins

Micro: severe centrilobular congestion/necrosis, progressing to centrilobular fibrosis

Hepatoportal sclerosis