ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 14, No. 6 Copyright © 1984, Institute for Clinical Science, Inc.

Arteriohepatic Dysplasia (Alagille’s Syndrome): A Common Cause of Conjugated Hyperbilirubinemia ELLEN KAHN, M.D.* and FREDRIC DAUM, M.D.f *Department of Laboratories and Department of Pediatrics, f Division of Pediatric Gastroenterology, Department of Pediatrics, North Shore University Hospital, Manhasset, NY 11030 Cornell University Medical College, New York, NY 10021 ABSTRACT Syndromatic paucity of interlobular bile ducts is a common cause of conjugated hyperbilirubinemia in children. The clinical presentation is not always obvious. Therefore, the liver biopsy may be a useful diagnostic tool in the definition of this entity. The hepatic and biliary morphology of five children with arteriohepatic dysplasia (Alagille’s syndrome) is described. Prior to diagnosis, four un­ derwent Kasai procedures after intraoperative cholangiograms failed to demonstrate patency of the extrahepatic bile ducts. In three patients, a focal proximal hypoplasia of the common hepatic duct was demonstrated. Hypoplasia of the gallbladder occurred in two patients. Hepatic features of sequential liver biopsies obtained in the five patient^ were divided into early and late changes. From birth to four months of age, the pathology consisted of cholestasis and bile duct destruction. After four months of age, there was persistent cholestasis, paucity of interlobular bile ducts and portal fibrosis. The etiology of arteriohepatic dysplasia is unclear. The main pathoge­ nic mechanisms are discussed. It is felt that the syndromatic duct paucity represents an acquired primary ductal defect resulting from a genetically determined immune response to as yet undefined agent or agents.

Introduction and may not be obvious in the newborn. The liver biopsy has provided the clini­ Paucity of interlobular bile ducts is the cian with perhaps a more objective most common cause of conjugated hy­ means of characterizing this group of syn­ perbilirubinemia.3’6,8 It may present as dromatic children.9,14 an isolated defect (nonsyndromatic In this report, the hepatic morphology paucity of interlobular bile ducts) or may of five patients with arteriohepatic dys­ be associated with other extrahepatic plasia is described. anomalies (structural syndromatic, Ala­ The clinical data are summarized in ta­ gille’s syndrome, arteriohepatic dys­ bles I and II. Prior to the diagnosis of plasia).3 These anomalies are variable arteriohepatic dysplasia, four of five pa-

480 0091-7370/84/1100-0480 $01.20 © Institute for Clinical Science, Inc. ARTERIOHEPATIC DYSPLASIA 481 TABLE I contiguous to interlobular bile ducts, Clinical Data periductal fibrosis, and focal ductal obli­

Hepatic Visualiza ti on teration by cellular fibrous connective Conjugated Excretion of Intrahepatic Porto- Hyperbili- of Radio- B.T. by enter- tissue (figure 2). Large bile ducts are ei­ Patieut rubinemia nuclide Cholangiogram ostomy ther hypoplastic or completely obliter­ ated by cellular fibrous connective tissue #1 3d + #2 3d + (figure 3). Portal spaces are of normal size #3 2m + #4 lm + and there is no ductular proliferation. #5 2m + The late changes consist of persistent cholestasis, a decreased number of inter­ B.T. = Biliary tree * = Not performed d = Days m = Months lobular bile ducts, and a lack of ductular proliferation. Portal fibrosis is present. Hepatocellular and canalicular choles­ tients had undergone Kasai procedures tasis is moderate to severe and centrilob- after intraoperative cholangiograms had ular or diffuse. A paucity of interlobular failed to demonstrate patency of the ex- bile ducts is apparent after four months. trahepatic biliary tree. Most portal spaces do not contain bile ducts (figure 4). Pathology Discussion Microscopic examination of the extra- hepatic biliary tree in three patients re­ Arteriohepatic dysplasia is an auto­ vealed a common bile duct of normal cal­ somal dominant16 or recessive2 disease. ibre and hypoplasia of the proximal he­ It is characterized by a distinctive facies patic duct (150 to 308 microns; normal = and specific extrahepatic anomalies, in­ 900 microns (figure 1). The gallbladder cluding cardiovascular (peripheral pul­ was also hypoplastic in two patients monic stenosis, coarction of the aorta), (table III), hypoplasia being defined as a ocular (prominent Schwalbe’s line, ret­ narrow but patent lumen.112,20 Atresia inal pigmentary changes), and vertebral denotes complete obliteration of the (butterfly vertebrae) changes.3,7,1617 De­ structure.10,19 layed mental and sexual development as Two to five sequential liver biopsies well as growth retardation have also been were obtained between 19 days and 27 described. The disease is nonprogressive months of age (table IV). Detailed micro­ in the majority of the patients and its scopic findings have been recently re­ etiology remains unclear. ported.9 The features of these biopsies Because the diagnosis of arteriohepatic can be divided into early (birth to four dysplasia may not be obvious, patients months) and later stages (older than four months). Early hepatic morphology consists pri­ marily of cholestasis associated with giant TABLE I I cell transformation. A decrease in the Clinical Features of Arteriohepatic Dysplasia number of interlobular bile ducts is not Peripheral Abnormal apparent at this stage, although there is Typical Pulmonic Butterfly Oph thalmol ogi c early duct destruction. This is reflected Patient Facies Stenosis Vertebrae Findings by pyknosis of the ductal epithelium, #1 + + + #2 + + + focal destruction of the basement mem­ #3 + + + + brane, luminal collapse, asymmetrical #4 + + cellular infiltration of the portal spaces #5 + + 482 KAHN AND DAUM

Figure 1. A. Serial sections of the extrahepatic biliary system. Patent common bile duct (c.b.) and cystic duct (c.d.) Hypoplasia of the gallbladder (g.b.) and of the common hepatic duct (h.d.) is apparent, (p.h.) porta hepatis. B. Higher magnification of the bracketed area depicting a hypoplastic 150 micron hepatic duct. Hematoxylin-eosin x 50. ARTERIOHEPATIC DYSPLASIA 483

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Figure 2. Composite of progressive destruction of interlobular bile ducts. A. Portal space with asym­ metrical mononuclear in­ filtration adjacent to an in­ terlobular bile duct. He- matoxylin-eosin X 120. B. Bile duct seen as solid cluster of epithelial cells (arrows). Hematoxylin- eosin X300. C. Higher magnification of figure 2a; obliterated interlobular bile duct (arrow). Hema- toxylin-eosin X300. 484 KAHN AND DAUM T A B L E III of other etiologies. Electron microscopic Hypoplasia of the Extrahepatic Biliary Tree examination was not performed in our patients prior to portoenterostomy. P atients The autosomal dominant or recessive #1 #2 #3 #4 #5 inheritance of arteriohepatic dysplasia implies a possible genetic predisposition Gallbladder NLNL + + * Common Hepatic Duct + * + + * among certain individuals.16 What trig­ Common Bile Duct NL NL NL NL NL gers the destruction of the interlobular bile ducts and whether this process be­ The common hepatic ducts in patients 3 and 4 were gins distally or proximally in the biliary serially sectioned. Patency persists throughout. *Not examined system is unclear. Toxins and infectious NL - Normal agents have been implicated.3,6'11 Our +Hypoplasia present observations seem to suggest that ductal may be subjected to laparotomy and in- destruction begins in the larger and in­ traoperative cholangiography. Intraop­ termediate size bile ducts, while small erative cholangiograms may be indistin­ interlobular bile ducts are affected later guishable from those seen in children in the course of the disease. On purely with extrahepatic biliary atresia. Hypo­ morphologic criteria, the ductal destruc­ plasia of the common hepatic duct, ob­ tion seen in our patients, including the served in three of the infants, most likely basement membrane destruction and accounted for the nonvisualization of the disappearance of ducts without scarring, intrahepatic radicles. Indeed, hypoplasia bears strong resemblance to that seen in of the extrahepatic biliary tree may be primary biliary cirrhosis, an autoimmune common in patients with arteriohepatic process observed in adults. In primary dysplasia. The hepatic morphology of the biliary cirrhosis, there is also a periductal portal spaces seems to be quite charac­ mononuclear response followed by dis­ teristic. Before four months of age, the appearance of intermediate bile ducts portal spaces are not increased in size without subsequent ductal fibrosis.13 and contain a normal number of interlob­ Paucity of interlobular bile ducts has also ular bile ducts with the ratio of interlob­ been described in graft versus host dis­ ular bile ducts to portal spaces being 0.9 ease and in liver transplant,5,18 further to 1.8.3 Bile duct destruction is associ­ supporting an immune etiology for the ated with a mononuclear cell infiltration. duct destruction. Hypoplasia of the ex­ Three main theories have been pro­ trahepatic biliary tree might be inter­ posed to explain paucity of interlobular preted either as a manifestation of “dis­ bile ducts: failure of development, use” or perhaps, inasmuch as it was atrophy, and ductal destruction. The present early in the course, a less severe consensus is that arteriohepatic dysplasia involvement by the same basic patho­ is not a developmental anomaly but genic process. rather an acquired disease.4,918 The ac­ tual destruction of interlobular bile ducts in the early stage with eventual disap­ T A B L E IV pearance of these structures mitigates Nature of Material and Time of Liver Biopsies against a developmental anomaly. Some15 have proposed a primary hepatocellular Pt. 1 P t. 2 P t.3 Pt. 4 Pt. 1 defect resulting in atrophy and subse­ 5W J.4M 27M 19D 7W 3M 8M 17M 3M 7M 6W 3M 5M J.J.W 7M 27M WB + + + + + + + + quent ductal paucity. This is based on NB + + + + + + + ultrastructural signs of hepatocellular Autopsy + bile retention not associated with biliary Pt. = Patient W = Week M - Months canalicular changes seen with cholestasis D = Days WB = Wedge biopsy NB = Needle biopsy ARTERIOHEPATIC DYSPLASIA 485

Figure 3. Large bile duct obliterated by fibrous connective tissue. Remnants of cuboidal epithelium are indicated by arrows. Hematoxylin-eosin X500.

' * v

Figure 4. Portal space without interlobular bile ducts. Hematoxylin-eosin X 50 486 KAHN AND DAUM

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