Proliferation to Paucity: Evolution of Bile Duct Abnormalities in a Case of Alagille Syndrome

Alagille syndrome is an autosomal dominant disorder characterized by abnormalities in multiple organ systems, including the liver, and is caused by mutations in JAG1. Chronic cholestasis secondary to paucity of interlobular bile ducts is traditionally both a clinical and a pathologic hallmark of this disease at diagnosis. We describe the biliary changes on serial liver biopsies in a patient who presented with jaundice and extrahepatic stigmata of Alagille syndrome. Her initial specimens at 6 and 10 months of age demonstrated interlobular bile duct proliferation and cholestasis, suggestive of distal biliary obstruction. A specimen at 2 years of age showed near-total absence of interlobular bile ducts, with the classic histologic appearance of bile duct paucity. We present this case to underscore the potential pitfalls in interpreting cholestatic liver morphology in the absence of clinical information. The progression of bile duct abnormalities is discussed in the context of the role postulated for JAG1 in postnatal liver growth and development.     

Clinical and pathological characteristics of Alagille syndrome in Chinese children

Background  Alagille syndrome (AS) is regarded as the most common cause of chronic cholestasis in childhood associated with specific phenotypic features in western countries. This study was undertaken to investigate the significance of AS in Chinese children with chronic cholestasis and to describe its clinical and histological features. Methods  From October 2004 to January 2007, 157 children who presented with conjugated jaundice from less than 3 months of age were admitted to a tertiary hospital in Shanghai. Investigations of the heart, spine, eyes and kidneys were conducted in 13 children who experienced prolonged cholestasis beyond 1 year of age after exclusion of biliary atresia and familial progressive intrahepatic cholestasis type 1 or 2. In patients with interlobular bile duct paucity, AS was diagnosed if 3 or more of the following 5 major features were present: cardiac murmur, posterior embryotoxon, butterfly-like vertebrae, renal abnormalities and characteristic faces. In patients without interlobular bile duct paucity or who did not receive liver biopsy, 4 or more features were required for the diagnosis. Results  Of the 13 children, 6 were diagnosed with AS at ages ranging from 1 year and 7 months to 3 years and 11 months. Jaundice was noticed in early infancy and then pruritus developed in all the 6 patients, of whom 5 presented with acholic stool and 4 had been misdiagnosed as having presumed biliary atresia by hepatobiliary scintigraphy or laparoscopic cholangiography. Biochemical examinations demonstrated increased concentration of total bile acid and hyperlipidemia. Interlobular bile duct paucity was demonstrated histologically in 5 patients who received liver biopsy. Vertebral abnormalities, heart murmur, characteristic faces and failure to thrive were found in all the 6 patients. Two patients had evidence of renal involvement. Micropenis, empty scrotum, and gall stone were seen in 1 patient. Conclusion  AS is also an important cause of prolonged cholestasis in Chinese children. It is difficult to differentiate AS from biliary atresia. Liver biopsy and spine X-ray may be helpful in the early detection of AS.     

Liver transplantation in Ellis-van Creveld syndrome: a case report

This case represents a rare association of Ellis-van Creveld (EvC) syndrome, a chondroectodermal disorder, with congenital paucity of bile ducts. Sequential liver biopsies during the patient's childhood demonstrated progressive fibrosis that can occur in other chondrodysplastic malformations. However, this EvC case is the first report to demonstrate paucity of intra-hepatic bile ducts progressing to cirrhosis and subsequently requiring transplant.     

The Fetal Liver in Pizz Alpha-1-Antitrypsin Deficiency: a Report of Five Cases

The lack of information on the state of fetal liver in PiZZ alpha-1-antitrypsin (AAT) deficiency and a single case report claiming a hypoplasia of interlobular bile ducts in a 20-week PiZZ fetus, instigated this histologic study of the liver in five PiZZ fetuses, 17-20 weeks of gestation and five age-matched controls. We found no difference between the percentage of portal tracts with identifiable bile ducts in the PiZZ (median 22.2%, range 21%-23%) and in the control (median 21.4%, range 20%-24%) on hematoxylin- and eosin-stained sections. Immunostaining with AE1, a monoclonal antibody to cyto-keratins restricted to normal bile ducts, doubled the number of recognizable ducts in both PiZZ and control livers. In four PiZZ livers, but in none of the controls, granular deposits of AAT could be detected by specific immunoperoxidase staining. We conclude that an apparent paucity of interlobular bile ducts is normal in the 20-week fetal liver, and our data may be taken as reference for future study dealing with similar material. Except for the cytoplasmic deposition of granules immunoreactive to AAT antiserum, there was no evidence of any developmental anomaly, in particular of the bile duct system in these five PiZZ fetal livers.     

Unconjugated, Glycine-conjugated, Taurine-conjugated Bile Acid Nonsulfates and Sulfates in Urine of Young Infants with Cholestasis

ABSTRACT. A direct assay system for conjugated bile acids using an enzymatic procedure and high-performance liquid chromatography was used for the analysis of urinary bile acid profiles in young infants with intrahepatic cholestasis (idiopathic neonatal hepatitis syndrome) or extra-hepatic biliary atresia. The major urinary bile acids were cholate and chenodeoxycholate conjugates, but a small amount of deoxycholate and 3β-hydroxy-5-cholenate conjugates were detected. Although there was no significant difference in total bile acid excretion between patients with intrahepatic cholestasis and extrahepatic biliary atresia, mean ratios of cholate to chenodeoxycholate and sulfated to total urinary bile acids were different between the two groups examined (5.63±2.83 vs. 2.50±1.25, p <0.05, 15.8±9.9 vs. 34.5±9.9%, p < 0.005). The proportion of taurine-conjugated chenodeoxycholate in the sulfate fraction to the total bile acid was lower in intrahepatic cholestasis, compared with that in biliary atresia (7.7±7.5 vs. 22.7±7.8 %, p < 0.005). The greater ratio of cholate to chenodeoxycholate and the reduced excretion of sulfated urinary bile acids in intrahepatic cholestasis was due to decreased taurine-conjugated chenodeoxycholate sulfate excretion.     

Beckwith-Wiedemann Syndrome with Unusual Hepatic and Pancreatic Features: A Case Expanding the Phenotype

We describe an infant with Beckwith-Wiedemann syndrome (BWS) who had hepatic and pancreatic findings not previously described in BWS. These were biliary dysgenesis and enlargement and cystic dysplasia of the pancreas. The biliary dysgenesis was characterized by proliferation of abnormally shaped ducts in the portal tracts. Massive enlargement and cystic dysplasia of the pancreas was associated with ductular proliferation, virtual absence of normal exocrine tissue, and an increase in endocrine tissue.     

Neonatal cholestasis can be the first symptom of McCune–Albright syndrome: A case report

BACKGROUNDMcCune–Albright syndrome (MAS) is caused by postzygotic somatic mutations of the GNAS gene. It is characterized by the clinical triad of fibrous dysplasia, café-au-lait skin spots, and endocrinological dysfunction. Myriad complications in MAS, including hepatobiliary manifestations, are also reported.CASE SUMMARYThis is a case of a 4-year-old boy who presented with MAS with neonatal cholestasis. He was suspected to have Alagille syndrome due to neonatal cholestasis with intrahepatic bile duct paucity in liver biopsy, peripheral pulmonary artery stenosis, and renal tubular dysfunction. By the age of 2 years, his cholestatic liver injury gradually improved, but he had repeated left femoral fractures. He did not exhibit endocrinological abnormality or café-au-lait skin spots. However, MAS was suspected due to fibrous dysplasia at the age of 4 years. No mutation was identified in the GNAS gene in the DNA isolated from the peripheral blood, but an activating point mutation (c.601C>T, p.Arg201Cys) was observed in the DNA extracted from the affected bone tissue and that extracted from the formalin-fixed paraffin-embedded liver tissue, which was obtained at the age of 1 mo.CONCLUSIONMAS should be considered as a differential diagnosis for transient cholestasis in infancy.     

Improvement of hepatopulmonary syndrome after transjugular intrahepatic portasystemic shunting: case report and review of literature

The hepatopulmonary syndrome has been described in as many as 5-29% of patients with liver disease. Patients with this syndrome may suffer from chronic hypoxemia, and mortality rates of liver patients with this syndrome are as high as 41%. Early diagnosis of such patients is essential. Currently, liver transplantation is the only effective therapy for such patients, and reversal of this syndrome is seen in up to 80% of patients post-transplant. Transjugular intrahepatic portasystemic shunting (TIPS) as a therapeutic maneuver for this syndrome has been described in five patients to date with mixed results. Reduction in portal hypertension with consequent redistribution of blood flow and altered synthesis of vasodilatory chemicals have been postulated to help resolve this disease. In this report, we describe an 11-yr-old female with biliary atresia and hepatopulmonary syndrome. Her disease was complicated with recurrent variceal bleeding. TIPS achieved a therapeutic response of both her bleeding and respiratory complications.     

Paucity of intrahepatic bile ducts,solitary kidney and atrophic pancreas with diabetes mellitus: Atypical Alagille syndrome?

Abstract A child with the tentative diagnosis of Alagille syndrome is reported. Additional renal abnormalities are unilateral kidney agenesis and a kidney with subcortical cysts with decreased function. At the age of 5 years, insulin-dependent diabetes mellitus developed, with the pancreas being atrophic and negative pancreatic islet cell antibodies.Conclusion This observation extends the picture of Alagille syndrome and suggests an overlap with renal-hepatic-pancreatic dysplasia (Iyemark syndrome).     

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??Abstract?? Objective??To evaluate the value of biochemical markers in the diagnosis of biliary atresia ??BA?? and neonatal intrahepatic cholestasis caused by citrin deficiency ??NICCD??. Methods??Totally 77 infants in hospital with infantile hepatitis syndrome ??IHS?? were enrolled from December 1?? 2008 to March 31?? 2009. Totally 27 patients were diagnosed as having BA and 11 with NICCD. Biochemical markers were compared between groups including alanine transaminase ALT?? aspartate transaminase AST ?? alkaline phosphatase ALP?? γ-glutamyl transpeptidase γ-GT?? total bilirubin TB?? direct bilirubin DB?? total bile acid TBA?? total cholesterol TC??to compute ALT/AST??ALP/γ-GT and glucose GLU?? lactic acid LAC?? total protein TP?? albumin ALB in the NICCD group. The data were analyzed by T test and ROC curve with SPSS10.0. Results??γ-GT was significantly elevated in the infants with BA when compared to non-BA group ??P = 0.003???? cut-off point was 332.5U/L. ALP/γ-GT was significantly lower in the patients with BA??and cut-off point was 1.93. The infants with NICCD had significantly different biochemical markers including GLU?? LAC?? TP?? ALB?? ALT/AST and γ-GT. Conclusion??Biochemical markers could be considered as complementary diagnosis of BA and NICCD for differentiating infants with IHS.     

Development and Transformation of the Ductal Plate in the Developing Human Liver

The livers of 15 embryos and fetuses measuring from 0.5 cm to 21 cm in crown-rump length were examined. The liver of the smallest embryo showed a sheet of hepatocytes without any ductal plates or intrahepatic bile ducts. Transformation of the hepatocytes of a hilar ductal plate was first observed in a 1.8-cm embryo. A 10.0-cm fetus had ductal plates virtually throughout the liver. Focal transformation of the flattened cells of the ductal plates into tubules composed of columnar or cuboidal ductal cells was observed. Mature interlobular ducts were observed predominantly in the hilum whereas scattered primitive interlobular ducts were scattered throughout the parenchyma. The transformation of hepatocytes into interlobular ducis thus seemed to occur in two stages: in the first, the hepatocytes of the ductal plate became flattened and developed increased cytokeratin; in the second, these flattened cells became focally cuboidal or columnar, lost their carcinoembryonic antigen, became strongly positive for epithelial membrane antigen, and formed tubules and primitive interlobular bile ducts.     

Mesenchymal Hamartoma of the Liver: Report of 30 Cases and Review of the literature

Thirty cases of mesenchymal hamartoma of the liver are presented and compared with 42 previously published cases. The patients, 69% male, range in age from newborn to 10 years (average age 15 months, median age 10 months). Except for occasional cases in which the lesion is an incidental finding at autopsy, most present with progressive abdominal enlargement over a period of days to months. Physical and radiologic examinations are nonspecific except for the demonstration of a mass within or attached to the liver. The masses are large, averaging 1311 g, and frequently contain cysts filled with clear fluid or gelatinous material. Histologic examination shows a mixture of loose mesenchymal tissue, bile ducts, connective tissue, and hepatocytes along with cysts formed either from degenerative areas of mesenchyme or from dilated bile ducts and lympathics. Treatment is partial or total excision of the lesion. Mortality (7-17%) is related to intraoperative or postoperative complications. Recurrence or malignant transformation has not been noted.     

Ectopic drainage of the common bile duct into the lesser curvature of the gastric antrum in a newborn with pyloric atresia,annular pancreas and congenital short bowel syndrome

We report a newborn with bilious vomiting and the rare combination of pyloric atresia, annular pancreas and ectopic drainage of the common bile duct into the lesser curvature of the gastric antrum. Radiologic, sonographic and percutaneous transhepatic transcholecystic cholangiographic (PTTC) findings, with surgical correlation, are presented.     

Bile Acid Abnormalities and the Diagnosis of Cerebro-Hepato-Renal Syndrome (Zellweger Syndrome)

ABSTRACT. The Zellweger or cerebro-hepato-renal syndrome (CHRS) is a congenital disorder characterized by cerebral dysfunction, craniofacial dysmorphic features, transient cholestasis and renal cysts. Patients fail to thrive, and usually die in their first year of life. In some cases, a definite diagnosis on purely clinical signs might not be possible. Several biochemical abnormalities have been observed in these patients and some of them have been tested as diagnostic markers. The aim of this study is to evaluate bile acid metabolites as biochemical markers of the CHRS. From a study of 20 CHRS patients, we conclude that screening for the presence of coprostanic acids and the C-29 dicarboxylic bile acid in serum or urine is a reliable method for detection of CHRS and confirmation of the diagnosis.     

先天性胆总管囊肿致肝脏病损的临床分析及转归

为了对儿童先天胆总管囊肿（ＣＢＤ）导致肝脏病损的有关临床因素及其转归进行分析， 对收治的３７例先天性胆总管囊肿患儿按肝脏病理改变的程度分成三组：肝硬变组１５例，肝硬变前期组２０例及正常肝细胞组２例。结果，肝硬变组年龄明显小于肝硬变前期组，前者平均年龄１７．３７个月，后者为７０．２５个月（Ｐ＜０．００１）。肝硬变组患儿均有持续性贡疽史，肝硬变前期组有持续性黄疸史的仅３例，肝硬变组囊肿直径平均值为７．８ｃｍ，肝硬变前期组囊肿直径平均值为４．７ｃｍ（Ｐ＜０．０５）。肝硬变组９例获术后长期随访，８例恢复满意。结论：①ＣＢＤ患儿出现症状越早，肝硬变机会越大。　②胆道梗阻是ＣＢＤ导致肝脏病损的主要原因。　③ＣＢＤＩ型患儿囊肿越大，对胆流动力学影响越大，　对肝脏的影响也越大。　④对已出现严重肝硬变的ＣＢＤ患儿仍应持积极态度，胆道梗阻解除后肝硬变仍有逆转的可能。     

Studies on the Enterohepatic Circulation of Bile Acids in Infancy and Childhood

To elucidate the enterohepatic circulation of bile acids in hepatobiliary disorders, the present author measured the fasting cholic acid levels in serum and followed up the changes of the levels after MCT milk administration. The subjects were 17 cases of neonatal hepatitis, 24 cases of congenital biliary atresia (CBA), 19 cases of other hepatobiliary disorders and 117 normal children. The serum cholic acid levels in the neonatal period were significantly high, which suggested a physiological cholestasis in neonates which gradually decreased with age. The mean level in CBA was rather higher than that in neonatal hepatitis but showed overlap of the levels. The patterns of changes of serum cholic acid levels in MCT milk test were classified into 6 types which were respectively characteristic of each disorders according to varied disturbance of the enterohepatic circulation of bile acids. This MCT milk test may be useful in making a differential diagnosis of various hepatobiliary disorders, especially neonatal hepatitis and CBA.     

Cell cultures of bile duct epithelium and the pathogenesis of biliary atresia

The pathogenesis of biliary atresia is unknown. The authors describe a technique for culturing extrahepatic bile duct epithelial cells of human and bovine origin in monolayer cell cultures. Light-, electron microscopy and immunohistological studies prove the epithelial nature of the cultured cells.Inoculation of the cells with reovirus 3 showed no destruction; adenovirus 6, herpes simplex and polio virus 1 and 2 destroyed the cells within 24 h.The cells produce a growth factor maintaining the integrity of the cells, even in the absence of serum.     

Evaluation of risk for atherosclerosis in Alagille syndrome and progressive familial intrahepatic cholestasis: two congenital cholestatic diseases with different lipoprotein metabolisms

OBJECTIVES: To evaluate the risk for atherosclerosis in Alagille syndrome (AGS) and progressive familial intrahepatic cholestasis (PFIC) on the basis of lipoprotein metabolism and by ultrasonography. STUDY DESIGN: Five patients with AGS and 5 with PFIC, ages 3 to 4 years, were enrolled. Intimal-medial thickness and wall stiffness of the common carotid artery were examined by ultrasonography. Serum levels of lipids and lipoproteins were determined. Further, the chemical composition of LDL and its ability to transform macrophages into foam cells were determined. RESULTS: Intimal-medial thickness and wall stiffness were increased in patients with PFIC but not in patients with AGS. Total cholesterol, LDL cholesterol, HDL cholesterol, and lipoprotein X were remarkably increased in patients with AGS, whereas in patients with PFIC, an increase in triglyceride and a decrease in HDL cholesterol were the prominent findings. However, despite the normal LDL cholesterol level, oxidized LDL level was strikingly high in patients with PFIC. LDLs from patients with PFIC had high TG contents and exhibited high abilities to transform macrophages into foam cells. CONCLUSIONS: These findings suggest that patients with PFIC are at high risk for cardiovascular disorders involving atherosclerosis.