Arteriohepatic Dysplasia Research Articles

Arteriohepatic dysplasia in infancy and childhood: a longitudinal study of six patients.

Arteriohepatic dysplasia (syndromatic ductular hypoplasia, Alagille syndrome) is a condition of chronic cholestasis dating from infancy accompanied by characteristic facies, pulmonic stenosis, and other somatic abnormalities. The pathologic hallmark of arteriohepatic dysplasia is a paucity or absence of intrahepatic bile ducts, wildely regarded as a congenital deficiency. We present a longitudinal study of six infants and children with arteriohepatic dysplasia, stressing evolution of the characteristic pathology on liver biopsy. All patients were biopsied twice. All five liver biopsies performed during infancy (<6 months old) showed intrahepatic cholestasis and portal inflammation, and two infants had, in addition, giant cell transformation. No infant showed congenital absence of interlobular bile ducts. Three of five infants had normal numbers of interlobular bile ducts (0.5 to 1.0 interlobular bile ducts per triad) and two infants had a paucity of interlobular bile ducts (<0.5 per triad). Three infants showed focal destructive inflammation of interlobular bile ducts. All biopsies performed later in childhood, between 3 and 20 years of age, showed a paucity or absence of interlobular bile ducts. At this time cholestasis and inflammation had largely resolved but some fibrosis persisted. The number of interlobular bile ducts decreased with age in each patient but there was no characteristic age at which interlobular bile ducts disappeared completely. The presence of interlobular bile ducts in infancy followed later in childhood by paucity or absence of interlobular bile ducts, suggests that intrahepatic bile duct deficiency in some patients with arteriohepatic dysplasia is acquired rather than congenital. The mechanism of bile duct disappearance in these patients may have been destructive inflammation of duct epithelium. Histopathologic diagnosis of arteriohepatic dysplasia may be difficult or impossible in infancy since interlobular bile ducts may be present at that time. However, arteriohepatic dysplasia should be considered in the differential diagnosis of all infants with cholestasis and such infants should have careful clinical evaluation for the syndromatic features of arteriohepatic dysplasia. Evaluation of their liver biopsies should include specific morphometric assessment of interlobular bile ducts.

Arteriohepatic dysplasia: Radiologic features of a new syndrome: N. S. Rosenfield, M. J. Kelley, P. S. Jensen, E. Cotlier, A. T. Rosenfield, and C. A. Riely. Am J Roentgenol 135:1217–1223, (December), 1980

Arteriohepatic dysplasia: Radiologic features of a new syndrome: N. S. Rosenfield, M. J. Kelley, P. S. Jensen, E. Cotlier, A. T. Rosenfield, and C. A. Riely. Am J Roentgenol 135:1217–1223, (December), 1980

Congenital heart disease, butterfly vertebrae, and extrahepatic biliary atresia: A variant of arteriohepatic dysplasia?

num, associated malformations tend to be timited to the gut. Multiple atresias, malrotations, gastroschisis, and omphalocele have been reported to occur with increased frequency, but extra-abdominal malformations are unusual. Most postduodenal atresias occur in the small intestine, where a long mesentery suspends the bowel from the posterior abdominal wall. Relatively few occur in the colon, where the mesentery has fused with the posterior wall and the bowel is relatively nonmobile. Observation of these facts followed by experiments in animals suggests that intestinal atresias distant to the duodenum occur as a result of vascular acc ident? The apparent nonfamilial nature of intestinal atresias supports the concept of an accidental etiology. The small family reported here had three affected members in two generations. The existence of a multisystem syndrome was not likely since none had nongastrointestinal malformations. The clustering strongly suggests that genetic factors were involved in the production of these lesions. Louw:' believed that malfixation of the mesentery might predispose to torsion of the intestine. The mesentery was indeed abnormal in the infant managed at this institution. The a'genetic factor might be one which produced abnormally slow fusion of the bowel mesentery with the posterior abdominal wail, in turn producing an unusual ly mobile sigmoid colon. Even in the presence of a redundant mesentery, however, similar accidents sufficient to produce strangulation in closely related individuals would seem unusual. All of the affected individuals in this family were male: two were the offspring of the sister of the third, by different fathers. Although this pattern is strongly suggestive of X-linked recessive inheritance, it is also compatibtc with inheritance of a dominant gene of reduced penetrance, or with polygenic inheritance. It is important that familial cases of disorders thought to occur sporadically be reported. Familial occurrence may in fact be common. None of the reviews of colonic atresia includes pedigrees; detailed family histories arc absent from case histories in the available reports. Even if the lesion is usually accidental, a few families may have a genetic predisposition. More complete studies of famil~ ies in which these lesions occur may provide more data for deriving accurate recurrence risks.

Arteriohepatic Dysplasia

Drs Levin and colleagues1 report five well documented cases of arteriohepatic dysplasia. In addition, they report the results of laboratory tests and physical examination in family members of two of their patients. Their report omits mention of findings related to the eye (posterior embryotoxon and retinal pigmentary changes) or of the additional skeletal findings (decrease in interpedicular distance in the lumbar spine as well as changes in the servical spine and hands) which we have reported to be associated with this syndrome.2,3

Letters to the Editor

The comments of Drs Riely, Rosenfield, and Cotlier are interesting, especially in relation to the abnormal eye findings and additional skeletal anomalies they have reported in cases of arteriohepatic dysplasia.1 Their contention that the syndrome is likely to be of genetic origin receives support from my own observations on two families seen subsequent to submission of our article for publication.2 In one family there were two siblings, a boy aged 5 years 3 months with significant pulmonary arterial stenosis documented at cardiac catheterization, and his younger sister, with clinical evidence of mild peripheral pulmonary stenosis.

Cholestatic jaundice in infancy. The importance of familial and genetic factors in aetiology and prognosis.

One hundred and twenty-four infants admitted to hospitals in Norway between 1955 and 1974 during the first 3 months of life with cholestatic jaundice were studied retrospectively. Sixty-four infants had had extrahepatic atresia of the biliary tree and 60 had had intrahepatic cholestasis. This gives an incidence of about 1:9000 live births for cholestasis. In 4 of the 64 infants with extra-hepatic atresia a bile duct-to-bowel anastomosis had been performed but this was successful in only 2. Sixty of these infants had died by their 2nd birthday. Twenty-six of the infants with intrahepatic cholestasis had died by 1978 and the most common causes of death were cholestasis complicated by infection, bleeding, or hepatoma. The survivors aged between 4 and 23 years were followed up in 1978. In about two-thirds of them aetiological factors--such as alpha-1-antitrypsin deficiency, arteriohepatic dysplasia, cholestasis with lymphoedema--and other familial or genetic factors, or infections were found. Four of the 34 survivors are known to have cirrhosis. Twenty patients had biochemical abnormalities, and 12 had normal liver function tests. Two patients could not be examined. Of the 19 patients with familial or genetic aetiological factors, 4 had cirrhosis, 14 had biochemical abnormalities, and only 5 had normal liver function tests. Of 11 survivors with idiopathic disease or septicaemia, none had cirrhosis and only 4 had abnormal liver function tests.

Syndromatic hepatic ductular hypoplasia (arteriohepatic dysplasia): a clinical and hepatic histologic study of three patients.

Clinical and pathologic features of three patients with chronic intrahepatic cholestasis from birth are described. Each patient exhibited a paucity and hypoplasia of interlobular bile ducts, unusual facies, short stature, a pulmonary ejection systolic murmur, and structural anomalies of vertebrae. This constellation of defects constitutes a distinct syndrome to which the terms arteriohepatic dysplasia and syndromatic hepatic ductular hypoplasia are applied. Clinically, cholestasis was not progressive and, although the SGPT was chronically elevated (122--520 units/liter), features of liver cell failure did not develop. Changes in plasma lipids and lipoproteins and serum bile acids were consistent with chronic cholestasis. Liver biopsies from the three cases revealed pseudoxanthomatous change, increased stainable copper and mild hepatocellular degenerative changes. Electron microscopy of one of the liver biopsies revealed extension of thick bundles of collagen from portal areas into hepatic lobules with obliteration of the space of Mall. With increasing age, portal tracts contained fewer bile ducts. This apparent progression of the lesion was not associated with an inflammatory cell infiltrate, progressive fibrosis, or the development of cirrhosis.

Anterior Segment and Retinal Pigmentary Abnormalities in Arteriohepatic Dysplasia

Arteriohepatic dysplasia (AHD, Alagille's syndrome) is presumed to be one of the six known familial intrahepatic cholestatic syndromes, all of which present with neonatal jaundice or failure to thrive, or both. Accurate early diagnosis of the proper syndrome is important, as arteriohepatic dysplasia has a good prognosis, whereas the other syndromes usually lead to death in infancy or early adulthood. Posterior embryotoxon was found in all five of our patients and may be one of the hallmarks of this syndrome. Axenfeld's anomaly was present in three of five patients, and retinal pigmentary abnormalities were found in four of five patients. Variable abnormalities were found in the cardiovascular system, bones, central nervous system, kidneys, endocrine system, and body habitus. Inheritance may be autosomal dominant as vertical transmission was documented in one family. Liver function improves during the first five years of life so that only the ocular and skeletal signs may be present in adults.

Arteriohepatic Dysplasia: Association of Liver Disease with Pulmonary Arterial Stenosis as Well as Facial and Skeletal Abnormalities

The clinical features and course of five children with the recently described syndrome of arteriohepatic dysplasia are presented. All had bilateral pulmonary arterial stenosis, proven at cardiac catheterization, as well as associated liver disease of varying severity. In one of the fatal cases, a hitherto undescribed anomaly was found--stenosis of the right coronary artery ostium. A viral etiology, eg, the congenital rubella syndrome, was considered most likely, but detailed investigations proved to be negative.

ELEVATED CHOLESTEROL (CH)/PHOSPHOLIPID(PL) MOLAR RATIO IN RED CELL MEMBRANES-AN ACQUIRED DEFECT IN CIRRHOSIS WITH ARTERIOHEPATIC DYSPLASIA

Hemolytic anemia with cholesterol-rich, spur-shaped red cells has been described in adults with severe hepatocellular disease due to alcoholic cirrhosis. The red cell defect(elevated membrane CH content, without changes in PL content)is acquired from serum, and causes an increase in the microviscosity of membrane lipids. A 4½ year old girl with arteriohepatic dysplasia, intrahepatic cholestasis and cirrhosis developed progressive anemia(Hgb=5.8), reticulocytosis(21%), increasing jaundice (41 mgm/dl; 23 direct), and splenomegaly. Serum levels of iron, folate, Vit. B12 and E were normal. Peripheral smear showed fragmented cells and spur cells. Analysis of patient's fresh red cells revealed elevated CH(22.3 γ /108cells; N=14.5), normal PL(33.0γ/108cells; N=31.8), an increased CH/PL molar ratio (1.35; N=0.92), and an increase in microviscosity @ 37°(4.1 poise; N=3.0). Following incubation with the patient's plasma@ 37° for 24 hours, normal cells acquired the spur-shaped morphology with an associated decrease in osmotic fragility and a 25%increase in cholesterol content. Patient's cells incubated with normal plasma acquired morphological feature of spiculated spherocytes, with an increase in osmotic fragility and a 21% decrease in cholesterol content. CONCLUSION: These studies demonstrate that a process identical to spur-cell anemia in adults with alcoholic cirrhosis may accompany cirrhosis in children with intrahepatic cholestasis.