Liver and intrahepatic bile ducts - Non tumor
Last revised 25 April 2008
Copyright (c) 2004-2008, PathologyOutlines.com, Inc.
Bold and underlined topics are hypertext links and may open a new window
Table of contents
Primary references, normal anatomy, normal histology, embryology, normal physiology, patterns of hepatic injury, biopsy, diagnostic patterns
Developmental anomalies/cysts: accessory lobe, Alagille’s syndrome, Bloom syndrome, Byler’s disease, Caroli’s disease, choledochal cyst, congenital hepatic fibrosis, Down’s syndrome, extrahepatic biliary atresia, foregut cyst, intrahepatic biliary atresia, multiple hilar cysts, polycystic liver disease, solitary cyst, von Meyenburg complex
Metabolic diseases: general, alpha-1-antitrypsin deficiency, cystic fibrosis, erythropoietic protoporphyria, familial apolipoprotein A-I amyloidosis, galactosemia, Gaucher’s, glycogen storage disease, GM2 gangliosidosis, heme oxygenase-1 deficiency, hemochromatosis, hereditary fructose intolerance, hereditary hepatic coproporphyria, hereditary tyrosinemia, mucopolysaccharidosis, Niemann-Pick, porphyria cutanea tarda, primary hyperoxaluria, Wilson’s disease, Wolman disease, Zellweger syndrome
General concepts: ascites, cirrhosis, cirrhosis-features to report, differential diagnosis of fibrosis, fulminant hepatitis / massive hepatic necrosis, hepatic failure
Hepatitis: general, acute hepatitis-general, prolonged resolving acute hepatitis, chronic hepatitis-general, chronic hepatitis-grading and staging
Hepatitis (non-infectious): alcoholic, autoimmune, drug/toxin induced, granulomatous, neonatal, nonalcoholic steatohepatitis, total parenteral nutrition related
Infectious (non-viral) disorders: Aspergillus, bacterial, Blastomycosis, Candida, Clonorchis sinensis, Coccidiodomycosis, Coxiella, Cryptococcus, dengue fever, Echinococcal cyst, Echovirus, Entamoeba histolytica, Fasciola hepatica, granulomatous, Histoplasma, malakoplakia, microsporidia, Mucor, Mycobacteria, Orientia tsutsugamushi, Penicillium, pyogenic abscess, Reye’s syndrome, Salmonella, Schistosomiasis, visceral larva migrans, visceral leishmaniasis
Viral hepatitis: general, acute viral hepatitis, chronic viral hepatitis, adenovirus, CMV, EBV, hepatitis A, hepatitis B, hepatitis C, Delta agent, hepatitis E, hepatitis G, herpes, HHV6, HIV
Biliary tract disease: cholestasis, acute large duct obstruction, ascending cholangitis, autoimmune cholangitis, cholangitis lenta, chronic large duct obstruction, hyperalimentation, oriental cholangiohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, secondary biliary cirrhosis
Jaundice: physiology, unconjugated hyperbilirubinemia, conjugated hyperbilirubinemia
Vascular disorders: general, arterial disorders, Budd-Chiari, hepatoportal sclerosis, hemorrhagic hereditary telangiectasia, peliosis hepatis, portal hypertension, portal vein obstruction, veno-occlusive disease
Systemic diseases/conditions: amyloidosis, congestive heart failure, Crohn’s disease, diabetes mellitus, hemolytic anemia, myeloproliferative disorders, pregnancy, rheumatoid arthritis, sarcoidosis, sickle cell disease, ulcerative colitis
Transplantation: liver transplant-general, adult to adult liver donor transplantation, hyperacute graft rejection, acute graft rejection, chronic graft rejection, post-bone marrow transplant, acute graft versus host disease, chronic GVHD, posttransplant lymphoproliferative disorder, pseudopeliotic steatosis
Go to Liver and intrahepatic bile ducts - tumor chapter
AJCC Cancer Staging Manual (6th Ed)
American Journal of Surgical Pathology (AJSP), Jan 1999 to Feb 2004
Archives of Pathology and Laboratory Medicine (Archives), Jan 1999 to Apr 2004
Human Pathology, Jan 1999 to Mar 2004
Modern Pathology, Jan 1999 to Mar 2004
Rosai, J: Ackerman’s Surgical Pathology (8th Ed); Mosby-Year Book, Inc., 1996
Sternberg, S: Diagnostic Surgical Pathology (3rd Ed); Lippincott Williams & Wilkins, 1999
USCAP short course: Mod Path 2000;13:679
Loyola University review by Dr. Emilio Orfei
Journal search terms: liver, hepatic
Please refer to these primary references for more detailed discussions and photographs
1200-1600g
Dual blood supply of portal vein (2/3) and hepatic artery (1/3) via porta hepatis (common hepatic bile duct exists in same region)
Blood exits liver via left and right hepatic veins to inferior vena cava
Divided into right and left lobes by Cantlie’s line projecting between gallbladder fossa and vena cava and defined by middle hepatic vein
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
Size of structures varies according to closeness to hepatic hilum
Acini
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
Bile canaliculi
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)
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
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
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
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
Cytology images: normal hepatocytes (Diff-Quik)
Positive stains: CK 8/18, CAM 5.2, HepPat1
EM images: adjacent hepatocytes
Kupffer cells
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
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
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
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
Reticulum
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
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
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
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
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
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
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
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
May appear clinically as hepatic mass
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
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
Impaired secretion of bile salts and phosphatidylcholine causes progressive intrahepatic cholestasis
Micro: enlarged portal tracts with inflammation, ductular proliferation and fibrosis
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
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
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
Case report associated with liver fibrosis, thought due to megakaryocyte derived transforming growth factor beta, Hum Path 1999;30:474
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
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
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
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
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
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