Case 3:

Adult Idiopathic Ductopenia Kay Washington, M.D., Ph.D. Pathology, C-3321 MCN Vanderbilt University Medical Center Nashville, TN 37232-2561

Clinical History This 79 year old man living in a nursing home had long-standing chronic liver disease. Viral serologies and anti-mitochondrial and antineutrophil antibodies were negative. ERCP done at an outside institution was reported as normal. Two first degree relatives also had chronic liver disease of unknown etiology. Total bilirubin concentration was 6.6 mg/dL, alkaline phosphatase was 413 IU/L, ALT 78 U/L, and AST 250 U/L. The patient also had diabetes mellitus and chronic obstructive pulmonary disease. He died during hospice care; an autopsy limited to liver and pancreas was performed. Morphologic Findings Grossly the liver was coarsely nodular, firm, and bile stained. The common bile duct was normal, with no evidence of stricture. On microscopic examination, irregular nodules characteristic of biliary cirrhosis are seen on low power. In some but not all portal tracts, no interlobular bile is identified. The portal tracts and fibrous septa contain proliferating bile ductules and a modest chronic inflammatory infiltrate. A few periportal hepatocytes show ballooning degeneration and contain Mallory's hyaline, evidence of chronic cholestasis. Nodular scars suggestive of primary sclerosing cholangitis are not present. Click on each slide thumbnail image for an enlarged view: Slide 7 Adult Idiopathic Ductopenia The liver from this 79 year old man shows a biliary pattern of cirrhosis, with "jigsaw puzzle piece" outlines to the regenerating nodules. The extrahepatic and large intrahepatic ducts were normal. Slide 8 Loss of Interlobular Bile Ducts in Adult Idiopathic Ductopenia No residual bile duct is identified in many of the portal tracts in this case. Nodular scars suggestive of primary sclerosing cholangitis are not present. Proliferating bile ductules are present at the periphery of the portal tracts, but dilated biliary channels suggestive of a ductal plate malformation are not seen. Slide 9 Recurrent Pyogenic Cholangitis Small portal tracts contain a mixed inflammatory infiltrate with numerous neutrophils. Portal edema and fibrosis may also be seen. Slide 10 Hyperplastic Changes in Bile Duct Epithelium In Recurrent Pyogenic Cholangitis Ductal epithelium shows crowding and hyperplastic changes without nuclear pleomorphism or hyperchromasia. Cholangiocarcinoma may complicate recurrent pyogenic cholangitis, and is associated with biliary stones. Diagnosis: Adult Idiopathic Ductopenia The term idiopathic adulthood ductopenia has been used to describe a small group of patients with chronic cholestasis of unknown etiology associated with loss of intrahepatic bile ducts. This disorder usually affects young to middle aged adults and is more common in males .1  Reported cases probably represent a heterogeneous group of related disorders, with some representing late onset of paucity of intrahepatic bile ducts, primary sclerosing cholangitis involving small ducts without large duct involvement, and autoimmune-mediated cholangitis. The criteria generally used for idiopathic adulthood ductopenia are onset of cholestasis in late adolescence or adulthood, ductopenia defined as lack of bile ducts in more than 50% of portal tracts, normal cholangiogram, and no known etiology. The patient with ulcerative colitis, ductopenia or other biopsy features consistent with PSC, but a normal cholangiogram, is considered to have isolated small duct PSC. The frequency of this disorder is low and it probably represents less than 5% of cases of chronic cholestasis in adulthood .2  This case is slightly unusual because of the age of presentation and the possible familial occurrence. Small duct primary sclerosing cholangitis cannot be entirely excluded in this case, although there is no evidence of inflammatory bowel disease. A mild form of idiopathic loss of intrahepatic bile ducts has also been reported in asymptomatic adults with elevated serum liver tests, mainly g glutamyltransferase and alanine aminotransferase concentrations. On biopsy, most portal triads still contained interlobular bile ducts (55 to 78%). Some of the patients were treated with ursodeoxycholic acid with normalization of liver tests. It is not clear if some of these patients represented AMA-negative primary biliary cirrhosis, as most were women and mean age at diagnosis was 41 years .3  The relationship between idiopathic adulthood ductopenia (IAD) and non-syndromic paucity of intrahepatic bile ducts in children remains unclear. Liver changes in IAD are those of chronic cholestasis with loss of interlobular bile ducts, essentially the same changes seen in pediatric patients with the non-syndromic form of paucity of intrahepatic bile ducts. In Alagille's syndrome, the syndromic form of paucity of intrahepatic bile ducts, the liver typically shows less cholestatic changes, and less portal fibrosis and bile ductular proliferation. The gene responsible for many cases of Alagille's syndrome, JAG1 (Jagged1), has been identified ,4,5  and availability of genetic testing may expand our knowledge of the spectrum of abnormalities in this disorder.   References Ludwig J. Idiopathic adulthood ductopenia: an update. Mayo Clin Proc 3:285-91, 1998. Bruguera M, Llach J, Rodes J. Nonsyndromic paucity of intrahepatic bile ducts in infancy and idiopathic ductopenia in adulthood: the same syndrome? Hepatology 15:830-4, 1992. Moreno A, Carreno V, Cano A, Gonzalez C. Idiopathic biliary ductopenia in adults without symptoms of liver disease. N Engl J Med 336:835-8, 1997. Li L, Krantz ID, Genin A, Banta AB , et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16:243-51, 1997. Oda T, Elkahloun AG, Pike BL, Okajima K, et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 16:235-42, 1997.