[Biliary atresia and congenital cholestatic syndromes : Characteristics before, after and during transition]. / Gallengangatresie und angeborene Cholestasesyndrome : Besonderheiten vor, nach und während der Transition.

BACKGROUND: A growing number of patients with biliary atresia and congenital cholestatic syndromes are reaching adulthood. These patients often have a number of typical medical features, including specific characteristics of liver transplantation medicine. OBJECTIVE: What are the special features in the care of adults suffering from liver diseases with manifestation in childhood and adolescence, both before and after liver transplantation (LTX). How does the progression of individual diseases differ depending on age at manifestation? What are specific aspects following pediatric LTX? PATIENTS AND METHODS: Evaluation and discussion of existing guidelines and recommendations of the individual disciplines and professional societies as well as the current literature. Joint discussion of the recommendations between disciplines (gastroenterology, pediatric gastroenterology, surgery). Inclusion of center-specific experiences with transition from existing transition outpatient departments and training. RESULTS: The recommendations are presented specifically for each disease. Special features in individual diseases after LTX are also discussed. Diagnosis-independent general treatment concepts for cholestasis and chronic liver disease are presented. CONCLUSION: Patients with biliary atresia and congenital cholestatic syndromes have a life-long chronic liver disease with and without LTX and require specific medical care. The patients benefit from the pooling of expertise in the individual disciplines.

Liver Donation and Transplantation in Poland: Numbers, Indicators, and Trends.

We aim to provide a panorama of liver donation and transplantation in Poland, where each year around 300 liver transplantations from deceased donors and 20 liver fragment transplantations from living donors are performed. This means about 9 transplantations per population of 1 million. Each year, the number of deceased donors reaches more than 500. In more than 50% of cases, livers are used. The law allows liver procurement from living donors. Until the end of 2013, liver fragments were recovered from 236 living donors and transplanted mainly to pediatric recipients (n = 232). A living-donor registry was created to monitor and assess the health condition of donors. The range of the national waiting list and allocation is nationwide. It is managed with the use of the Web tool www.rejestry.net. There are 2 modes of recipient referral: "urgent" and "elective." Allocation is either patient oriented and center oriented. Disease groups, which comprise the most frequent indications for transplantation in adults, include the cirrhosis group (48%), in which the highest number of procedures was performed for patients with hepatitis C virus (24%); alcohol-induced cirrhosis (14%); alcohol-induced hepatitis (8%), and hepatitis B virus cirrhosis (7%). Among pediatric recipients, the most frequent indications were congenital cholestatic diseases, which made up 38% of all transplantation indications. The results of liver transplantations are collected in the national transplant register. The 1-year graft and recipient survival with deceased donor transplantation are 81% and 84% and with living donor transplantation 86% and 89%. The 5-year graft and recipient survival in deceased donor transplantation are 69% and 73%, and in living donor transplantation are 80% and 83%.

Common misdiagnoses of biliary atresia.

OBJECTIVES: Discrimination of biliary atresia (BA) from other causes of neonatal cholestasis (NC) is challenging. We aimed to analyze the clinicopathological findings in cholestatic infants who were provisionally diagnosed with BA and then excluded by intraoperative cholangiography compared with those with a definitive diagnosis of BA and to shed light on common misdiagnoses of BA. METHODS: We retrospectively analyzed the data of infants diagnosed preoperatively with BA and referred to surgery between the years 2009 and 2013. On the basis of intraoperative cholangiography results, infants were divided into those with a definitive diagnosis of BA and those misdiagnosed with BA. RESULTS: Out of 147 infants, there was a misdiagnosis of BA in 10 (6.8%) infants. Alanine transaminase was significantly higher in the non-BA group, whereas other clinical and laboratory findings were comparable in both groups. Hepatomegaly and abnormal gallbladder in ultrasound, and ductular proliferation and advanced grades of portal fibrosis in liver biopsy were significantly higher in infants with BA. However, giant cells were more common in the non-BA infants. Nonetheless, the frequency of clay stool, hepatomegaly, abnormal gallbladder, ductular proliferation, and advanced portal fibrosis was remarkable (100, 70, 40, 70, and 50%, respectively) in the misdiagnosed infants. The misdiagnoses were idiopathic neonatal hepatitis, progressive familial intrahepatic cholestasis type 3, cytomegalovirus hepatitis, Alagille syndrome, and a cholangitic form of congenital hepatic fibrosis. CONCLUSION: A meticulous preoperative workup should be performed to exclude other causes of NC even if signs of BA are present, especially if features such as giant cells in histopathology are present. This involves completing the NC workup in parallel involving all common causes of NC rather than performing them in series to avoid loss of valuable time and efforts.

Efficacy of the seven feature, fifteen point histological scoring system and CD56 in interpretation of liver biopsies in persistent neonatal cholestasis: a five-year study.

CONTEXT: Neonatal cholestasis (NC) lasting more than 2 weeks affects one in 2500 live births. Extrahepatic biliary atresia (EHBA) and idiopathic neonatal hepatitis account for about 70% of all cases of NC. Differentiating these two conditions is important as patient management is very different for both the conditions. AIMS: To assess the usefulness of the seven-feature, 15-point histological scoring system in the interpretation of liver biopsy in NC and usefulness of immunostaining with CD56 (N-CAM) in EHBA. SETTINGS AND DESIGN: Retrospective study of 5 years' duration at a pediatric referral institute, where the case load of NC is high and definitive surgery for EHBA is undertaken after histological confirmation. MATERIALS AND METHODS: The study is of a 5-year duration conducted between June 2007 and May 2012. A total of 210 cases of NC were clinically diagnosed during this period. All the slides were reviewed with reference to a seven-feature, 15-point histological scoring system assessing its usefulness in the interpretation of liver biopsy in NC and utility of the immunohistochemical marker CD56 was also assessed as an aid in the characterization of bile ductular proliferation in EHBA. STATISTICAL ANALYSIS: Statistical analysis was performed and sensitivity and specificity of the histological scoring system for EHBA was analyzed. RESULTS: Of the 210 liver biopsies reviewed using the scoring system, 122 cases were diagnosed as EHBA and 88 cases were diagnosed as other causes of NC. The overall sensitivity of this scoring system was 95.5%, specificity was 93.1% and diagnostic accuracy was 94.6%. CONCLUSIONS: The seven-feature, 15-point histological scoring system has good diagnostic accuracy in the interpretation of liver histology in NC as advanced histopathological findings even at younger age require immediate surgery. CD-56 is a useful marker in the assessment of bile ductular proliferation in EHBA.

Evaluation of ultrastructural changes by electron microscopy in neonatal cholestasis.

BACKGROUND: Biliary atresia (BA) and idiopathic neonatal hepatitis (NH) account for 50-70% of all cases with neonatal cholestasis. The treatment of the former is early surgical intervention, while the latter requires non-surgical supportive care. Failure to differentiate the two conditions may result in avoidable surgery in NH, which may significantly increase morbidity. The lack of differentiating clinical features, biochemical markers and other specific investigations to distinguish the two is still a major problem. AIM: This study was thus initiated to evaluate electron microscopic changes in the liver in patients with NH and BA, to correlate these with changes on light microscopy and look for specific differentiating features between the two. METHODS: Ten patients with neonatal cholestasis whose liver specimens were available for electron microscopic analysis were included in the study. There were 6 patients with BA and 4 patients with NH. RESULTS: Among the biochemical parameters, serum alkaline phosphatase and gamma glutamyl transpeptidase were significantly higher in BA than in patients with NH. On light microscopy, giant cell transformation was seen in 75% patients with NH and 33.3% of patients with BA. Even in BA, intracellular cholestasis was more prominent than ductular cholestasis (100% vs. 50%). Ductular proliferation was seen in 50% of NH patients and all patients of BA. Electron microscopy revealed prominent endoplasmic changes in all patients with NH and to a milder degree in BA. Changes in mitochondria and glycogen content were similar in both groups. CONCLUSION: Ultrastructural changes in neonatal cholestasis seen through electron microscopy are largely non-specific and do not differentiate BA from NH.

Congenital cholestatic syndromes: what happens when children grow up?

Although advances in the management of children with congenital cholestasis have enabled many to survive into adulthood with their native livers, even the most common of these conditions remains rare in adult hepatology practice. Among four congenital cholestatic syndromes (biliary atresia, Alagille syndrome, Caroli disease and congenital hepatic fibrosis, and progressive familial intrahepatic cholestasis), the published data on outcomes of the syndromes into adulthood suggest that a spectrum of severity of liver disease can be expected, from cirrhosis (almost universal in adults with biliary atresia who have not required liver transplantation) to mild and subclinical (eg, in the previously undiagnosed affected parent of an infant with Alagille syndrome). Complications associated with portal hypertension and nutritional deficiencies are common, and other associated features of the cholestatic syndrome may require appropriate attention, such as congenital heart disease in Alagille syndrome. Indications for liver transplantation include synthetic failure, progressive encephalopathy, intractable pruritus, recurrent biliary sepsis and recurrent complications of portal hypertension. Improved understanding of biliary physiology will hopefully translate into improved therapy for children and adults with cholestasis.

The course of neonatal cholestasis in congenital combined pituitary hormone deficiency.

BACKGROUND: Neonatal cholestatic hepatitis is frequently associated with congenital combined pituitary hormone deficiency (CCPHD). Data on the course of this hepatopathy are scarce. AIM: We retrospectively analyzed the data of all CCPHD infants with cholestasis who presented at the University Children's Hospital, Tuebingen. RESULTS: All infants (n = 9; 2 females) presented with early and prolonged jaundice, failure to thrive and recurrent hypoglycemia. All males had micropenis and 3/7 cryptorchidism. Median age at diagnosis was 1.4 months. Cholestasis began at a median age of 13 days (range 5-31) and resolved at 88 days (54-174). Maximum direct bilirubin level was 6.9 mg/dl (2.4-11.6). Peaks of ALP (median 721 U/l), ALT (148 U/l) and AST (195 U/l) occurred 2-4 weeks later, while GGT levels were elevated in only two infants (167 U/l). Functional liver parameters were always normal. Liver biopsies (n = 4) showed canalicular cholestasis and mild portal eosinophilic infiltration. TEBIDA radioisotope excretion into the intestinal tract was blocked. Substitution with Lthyroxine, hydrocortisone and growth hormone seemed to accelerate the cure from cholestasis. Liver function at follow-up (median 4 yr) stayed normal. CONCLUSION: Cholestasis in CCPHD follows the course described here, frequently with normal GGT levels.

Neonatal cholestasis.

Neonatal cholestasis must always be considered in a newborn who is jaundiced for more than 14-21 days and a measurement of the serum total and conjugated bilirubin in these infants is mandatory. Conjugated hyperbilirubinaemia, dark urine and pale stools are pathognomic of the neonatal hepatitis syndrome which should be investigated urgently. The neonatal hepatitis syndrome has many causes and should be investigated using a structured protocol. The most important condition in the differential diagnosis is biliary atresia and affected infants require a Kasai portoenterostomy performed by an experienced surgeon, ideally before the infant is 60 days old. A modified evaluation schedule should be used for preterm infants who have required neonatal intensive care. Genetic causes of the neonatal hepatitis syndrome are increasingly recognized and early diagnosis facilitates genetic counselling and, in some situations, specific treatment. The management of cholestasis is largely supportive, consisting of aggressive nutritional support with particular attention to fat-soluble vitamin status. The use of ursodeoxycholic acid is associated with improvement in biochemical measures of cholestasis and may improve the natural history of cholestasis in some circumstances. Outcome is dependent on aetiology. In idiopathic neonatal hepatitis more than 90% make a complete biochemical and d clinical recovery.

Neonatal cholestasis and infantile Gaucher disease: a case report.

AIM: To report on clinical complications of liver disease occurring during Gaucher disease. METHODS: A case of Gaucher disease was revealed by neonatal cholestasis and early onset of portal hypertension. RESULTS: At 7 d of age, a newborn was admitted for cholestasis associated with hepatosplenomegaly and thrombocytopenia. At that time, bone marrow aspirate and liver biopsy did not reveal any engorged cells. The clinical course was marked by early progressive portal hypertension, and the patient died of uncontrollable upper gastrointestinal bleeding. The histological results of the postmortem showed that Gaucher cells were present in the liver, spleen and bone marrow. The diagnosis was confirmed by enzymatic studies. CONCLUSION: Isolated neonatal cholestasis could be the first sign of Gaucher disease. Gaucher disease should always be considered in such circumstances, even if, initially, the bone marrow aspirate and liver biopsy do not reveal any engorged cells.

Advances in familial and congenital cholestatic diseases. Clinical and diagnostic implications.

Recent progress in liver cell biology and molecular genetics revealed that a number of familial and congenital cholestatic disorders are caused by mutations in genes coding for hepatobiliary-transporter or for signalling proteins involved in morphogenesis. The status of the field is reviewed in the light of its impact on current diagnostic and clinical practice. The heterogeneous progressive familial intrahepatic cholestasis can now be separated into different genetic diseases. FIC1-defective progressive familial intrahepatic cholestasis (previously Byler disease) is determined by mutations in the FIC1 gene, coding for P-type ATPases of unknown physiological function, while a second form (bile salt export pump defective progressive familial intrahepatic cholestatis) is caused by a defective function of the canalicular bile salt export pump. Furthermore, a group of progressive familial intrahepatic cholestasis patients with high serum gamma glutamyltranspeptidase have mutations in the gene (PGY3) coding for the MDR3 protein, a canalicular ATP-dependent phopshatidylcholine translocator. Recurrent intrahepatic cholestasis (previously benign recurrent cholestasis), is also linked to specific mutations in the FIC1 gene. Finally, in Alagille syndrome, mutations in the JAG1 gene cause deficiency Jagged 1, a ligand for Notch 1, a receptor determining cell fate during early embryogenesis. Diagnosis of Alagille syndrome, a condition that should be suspected in all patients with unexplained cholestasis, will thus be confirmed by genetic analysis for mutations of JAG1. In children with cholestasis and low serum bile acid levels, an inborn error of bile acid synthesis should be excluded by urinary bile acid analysis by means of fast atom bombardment-ionization mass-spectrometry. In contrast, in children with cholestasis and high serum bile acid concentrations, a high serum gamma glutamyltranspeptidase value would indicate MDR3 deficiency, which should be excluded through biliary phospholipid determination and genetic analysis of PGY3 gene. Finally, in those children with cholestasis, high serum bile acids and low gamma glutamyltranspeptidase activity, analysis of mutation in FIC1 and bile salt export pump genes may lead to the diagnosis of progressive familial intrahepatic cholestasis either from bile salt export pump or FIC1 deficiency.

MR cholangiography in the evaluation of neonatal cholestasis.

PURPOSE: To evaluate the usefulness of magnetic resonance (MR) cholangiography in excluding biliary atresia as the cause of neonatal cholestasis. MATERIALS AND METHODS: MR cholangiography was performed on 10 control and 16 jaundiced neonates and infants aged 3 days to 5 months. Diagnosis of biliary atresia (n = 6) was confirmed with surgery and liver biopsy, with or without surgical cholangiography. Diagnosis of neonatal hepatitis (n = 9) was confirmed with clinical follow-up until jaundice resolved. In one infant, paucity of intrahepatic ducts was diagnosed at liver biopsy. MR cholangiography was performed with respiratory-triggered, heavily T2-weighted turbo spin-echo and optional inversion-recovery turbo spin-echo sequences. Diagnosis of biliary atresia was based on nonvisualization of either the common bile duct or common hepatic duct. Cholescintigraphy with technetium 99m disofenin was performed in all 16 jaundiced patients. RESULTS: In the 10 controls, the nine patients with neonatal hepatitis, and the one infant with paucity of intrahepatic ducts, MR cholangiography clearly depicted the gallbladder and common hepatic and common bile ducts. MR cholangiography was 100% accurate in excluding biliary atresia as the cause of neonatal cholestasis, while 99mTc disofenin cholescintigraphic findings were false-positive in four of 10 patients with nonobstructive cholestasis. CONCLUSION: MR cholangiography can be used to depict the major biliary structures of neonates and small infants and to exclude biliary atresia as the cause of neonatal cholestasis by allowing visualization of the biliary tract.

[Early diagnosis of neonatal cholestatic jaundice]. / Diagnostic précoce des ictères cholestatiques chez le nouveau-né.

Neonatal cholestasis should be considered in every baby in whom jaundice persists after day 10. Biliary atresia is the main cause of neonatal cholestasis and its prognosis is highly dependent on the early age at which surgery is performed. Finding the cause of cholestasis before day 30 is therefore crucial. This relies, in most instances, on simple clinical, biochemical, radiological and ophthalmologic criteria, the most important of which is a careful study of the degree and duration of stool discoloration.

Neonatal cholestasis and focal medullary dysplasia of the kidneys in a case of microcephalic osteodysplastic primordial dwarfism.

We report on a male infant who presented with intrauterine growth retardation, severe postnatal failure to thrive, microcephaly, facial dysmorphism, and skeletal dysplasia. The clinical and radiological findings are consistent with former descriptions of microcephalic osteodysplastic primordial dwarfism (MOPD) type I/III. In addition to previously published features, multiple fractures of the long bones, severe neonatal cholestasis, and histological dysplasia of the kidneys were found. The boy died at the age of 8 months. The new finding of focal renal medullary dysplasia further supports the hypothesis of a basic defect in tissue differentiation in the pathogenesis of this rare condition.

Imaging of neonatal cholestasis.

In the neonate with cholestasis, clinical features and standard tests of liver function frequently cannot distinguish between diseases of the hepatocyte and those of the biliary tree. Therefore, a multidisciplinary approach to diagnosis is required. A priority in investigation is the identification of patients requiring surgery. A correct diagnosis regarding the need for surgery can be made in the majority of cases after synthesis of information obtained from abdominal sonography, hepatobiliary scintigraphy, and liver biopsy. Intraoperative cholangiography is performed routinely to precisely delineate the anatomy of the intrahepatic and extrahepatic bile ducts.