Prolonged Cholestasis Research Articles

Alagille综合征的临床特征

目的：探讨Alagille综合征的临床特征、诊断及治疗。方法：回顾性分析1例Alagille综合征患儿的临床表现及实验室检查，并结合文献进行讨论。结果：患儿为5岁女孩，因皮肤瘙痒、肝功能异常5年住院。既往经抗感染及保肝治疗，皮肤瘙痒及肝功能改善不明显。体检可见前额突出及尖下颌，胸骨左缘第II肋间可闻及3/6级收缩期杂音，眼科检查见双眼角膜后胚胎环。结论：Alagille综合征是引起婴儿慢性胆汁淤积的重要原因，对婴儿期起病的慢性胆汁淤积性肝病患儿，如合并存在面容异常及心脏杂音，应考虑Alagille综合征的可能。 Objectives: To elucidate the clinical features, diagnosis and treatment of Allagille syndrome. Methods: Clinical data including history, physical examination and laboratory findings were collected from a child who was diagnosed with Alagille Syndrome. The clinical data were discussed with related literatures. Results: A five-year girl presented with persistent liver dysfunction and pruritus for about five years, which couldn’t be relieved by antiinfective and liver-protecting therapy. Physical examination showed cardiac murmur in the second and third left intercostals spaces. Characteristic face malformations manifested as prominent forehead and small mandible. Funduscopy examination showed posterior embryotoxon. Conclusions: Alagille syndrome is an important cause of chronic cholestasis. When examining child with prolonged cholestasis, face malformations and heart murmur, Alagille syndrome should be included in the differentiate diagnosis.

Acute hepatitis C infection with prolonged intrahepatic cholestasis and remarkable progression of fibrosis mimicking fibrosing cholestatic hepatitis

Acute hepatitis C infection with prolonged intrahepatic cholestasis and remarkable progression of fibrosis mimicking fibrosing cholestatic hepatitis

The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice

Many regulatory pathways are involved in liver regeneration after partial hepatectomy (PH) to initiate growth, protect liver cells, and sustain functions of the remnant liver. Bile acids (BAs), whose levels rise in the blood early after PH, stimulate both hepatocyte proliferation and protection, in part through their binding to the nuclear farnesoid X receptor (FXR). However, the effect of the BA receptor, TGR5 (G-protein-coupled BA receptor 1) after PH remains to be studied. Liver histology, hepatocyte proliferation, BA concentrations (plasma, bile, liver, urine, and feces), bile flow and composition, and cytokine production were studied in wild-type (WT) and TGR5 KO (knockout) mice before and after PH. BA composition (plasma, bile, liver, urine, and feces) was more hydrophobic in TGR5 KO than in WT mice. After PH, severe hepatocyte necrosis, prolonged cholestasis, exacerbated inflammatory response, and delayed regeneration were observed in TGR5 KO mice. Although hepatocyte adaptive response to post-PH BA overload was similar in WT and TGR5 KO mice, kidney and biliary adaptive responses were strongly impaired in TGR5 KO mice. Cholestyramine treatment, as well as Kupffer cell depletion, significantly improved the post-PH TGR5 KO mice phenotype. After bile duct ligation or upon a cholic acid-enriched diet, TGR5 KO mice exhibited more severe liver injury than WT as well as impaired BA elimination in urine. TGR5 is crucial for liver protection against BA overload after PH, primarily through the control of bile hydrophobicity and cytokine secretion. In the absence of TGR5, intrahepatic stasis of abnormally hydrophobic bile and excessive inflammation, in association with impaired bile flow adaptation and deficient urinary BA efflux, lead to BA overload-induced liver injury and delayed regeneration.

Hepatitis A in Children- Clinical Course, Complications and Laboratory Profile

To study the course and complications of hepatitis A in children. Seventy eight children diagnosed as acute viral hepatitis A by IgM antiHAV were prospectively studied for involvement of other systems and complications. The mean age of children was 7.85 ± 3.4y. Jaundice was present in all the patients as this was the inclusion criteria. Fever was present in 82.1%, hepatomegaly in 98.7% and splenomegaly in 39.7%. More than 5 fold rise in Aspartate transaminase (AST) and Alaninetransaminase (ALT), were seen in 62 cases (79.5%) and 55 cases (70.5%) respectively. Coagulopathy (Prothrombin time INR > 1.5) was observed in 12 cases (15.4%) and abnormal APTT in 10 cases (12.8%). Thrombocytopenia was observed in 5.1% of children and 8.9% had more than 2 hematological abnormalities. Ascites was noted in 35 cases (44.9%), gallbladder wall thickening in 32 cases (41%) and pleural effusion in 11 cases (14.1%). Acute renal failure, acute glomerulonephritis and acute pancreatitis were present in 1 case (1.3%) each. Raised CK-MB values more than 3 times the normal was noted in 5 cases (6.4%). On follow up, most of the children recovered completely by 2mo and prolonged cholestasis was observed in 2 of them. In the present study mortality was 1.3% and it was attributable to fulminant hepatic failure. Eventhough hepatitis A infection is a self-limiting disease, extrahepatic manifestations and mortality are not uncommon. All cases should be followed up till complete recovery and only a strong index of suspicion will enable us to recognize the complications.

Mitochondrial genome depletion in human liver cells abolishes bile acid-induced apoptosis: Role of the Akt/mTOR survival pathway and Bcl-2 family proteins

Acute accumulation of bile acids in hepatocytes may cause cell death. However, during long-term exposure due to prolonged cholestasis, hepatocytes may develop a certain degree of chemoresistance to these compounds. Because mitochondrial adaptation to persistent oxidative stress may be involved in this process, here we have investigated the effects of complete mitochondrial genome depletion on the response to bile acid-induced hepatocellular injury. A subline (Rho) of human hepatoma SK-Hep-1 cells totally depleted of mitochondrial DNA (mtDNA) was obtained, and bile acid-induced concentration-dependent activation of apoptosis/necrosis and survival signaling pathways was studied. In the absence of changes in intracellular ATP content, Rho cells were highly resistant to bile acid-induced apoptosis and partially resistant to bile acid-induced necrosis. In Rho cells, both basal and bile acid-induced generation of reactive oxygen species (ROS), such as hydrogen peroxide and superoxide anion, was decreased. Bile acid-induced proapoptotic signals were also decreased, as evidenced by a reduction in the expression ratios Bax-α/Bcl-2, Bcl-xS/Bcl-2, and Bcl-xS/Bcl-xL. This was mainly due to a downregulation of Bax-α and Bcl-xS. Moreover, in these cells the Akt/mTOR pathway was constitutively activated in a ROS-independent manner and remained similarly activated in the presence of bile acid treatment. In contrast, ERK1/2 activation was constitutively reduced and was not activated by incubation with bile acids. In conclusion, these results suggest that impaired mitochondrial function associated with mtDNA alterations, which may occur in liver cells during prolonged cholestasis, may activate mechanisms of cell survival accounting for an enhanced resistance of hepatocytes to bile acid-induced apoptosis.

Lipoprotein X: clinical implications

In this issue of the journal, Stepien et al. describe a case of serum lipoprotein X (Lp-X) in a patient with cholestasis and severe hyperlipidaemia. This abnormal lipoprotein is rich in phospholipid and unesterified cholesterol. The main protein component is albumin within the core and apolipoprotein C upon the surface. Unlike low-density lipoprotein (LDL), Lp-X does not contain apolipoprotein B nor is it removed by the LDL receptor, but Lp-X is cleared by the reticuloendothelial system and the kidneys. Lp-X is about 50 nm in diameter and its major component bile acid is lithocholic. Early studies reported the presence of Lp-X in the serum of patients with cholestasis. The failure of Lp-X to exert feedback inhibition on cholesterol synthesis may contribute to the mechanism of hypercholesterolaemia in obstructive jaundice. However, the presence of serum Lp-X does not facilitate the distinction between intrahepatic and extrahepatic cholestasis. Bile lipoprotein is a precursor of Lp-X and in cholestasis this refluxes into the plasma pool and binds to albumin to form Lp-X. Serum Lp-X usually disappears soon after the cholestasis is relieved. The ratio of plasma bile salts to albumin is important for the integrity of Lp-X and it is catabolized by the action of phospholipase which helps convert lecithin into lysolecithin. In graft versus host disease involving the liver and with cholestasis plasma Lp-X can result in severe hypercholesterolaemia, xanthelasma and cholesteroloma. Lp-X can also be found in cholestasis of pregnancy and primary biliary cirrhosis (PBC). The case presented by Stepien et al. confirms these earlier observations of raised serum Lp-X in cholestasis. Increased serum cholesterol concentrations occur in PBC and this is largely due to the presence of Lp-X, although it is debatable whether this confers increased cardiovascular risk. Indeed, Lp-X may not be atherogenic and data suggest it may have antioxidant LDL activity. Additionally, Lp-X is not significantly taken up by macrophages but is taken up by hepatocytes. Sometimes severe and prolonged cholestasis can result in very high serum Lp-X concentrations resulting in severe hypercholesterolaemia and tendon xanthomata. Complete regression of these xanthomata has been described by treatment with apheresis, which the authors stated should be considered possible first-choice treatment for patients with massive Lp-X accumulation due to cholestasis. Statin therapy may be ineffective in lowering Lp-X. Lecithin-cholesterol acyltransferase (LCAT) is an enzyme responsible for cholesterol esterification in plasma. Lp-X is found in LCAT deficiency which is characterized by low concentrations of high-density lipoprotein (HDL) as well as anaemia, corneal opacities, proteinuria and chronic kidney disease. The Lp-X found in LCAT deficiency may contribute to the renal disease observed in this condition by stimulating monocyte renal infiltration. Proteoglycans have an important role in regulating the uptake of Lp-X into kidney mesangial cells and this mechanism is independent of the scavenger receptor. Guerin et al. reported that in LCAT deficiency the presence of Lp-X is correlated with a progressive change in renal function. In addition to cholestasis and LCAT deficiency, Lp-X may also be found in the plasma after intravenous infusion of Intralipid emulsion such as occurs with total parenteral nutrition. Intralipid administration can elicit an increase in serum total cholesterol (mainly unesterified), phospholipid and LDL. The Lp-X associated with Intralipid infusion seems to occur when phospholipid clearance is exceeded, resulting in phospholipid accumulation with unesterified cholesterol. Pseudohyponatraemia has also been described in some patients with severe hypercholesterolaemia secondary to raised Lp-X. Thus the presence of Lp-X should be considered in pseudohyponatraemia associated with cholestasis. Sivakumar et al. described not only pseudohyponatraemia, but also pseudohypokalaemia and pseudohypochloridaemia in the presence of high concentrations of Lp-X. Various researchers have also found assay bias for serum LDL-cholesterol in the presence of Lp-X. This is an important practical point when it comes to interpreting LDL cholesterol results in severely cholestatic serum samples. Lp-X possesses strong aggregatory properties and can bind to alkaline phosphatase (ALP) producing a Lp-X-ALP complex. This complex may be found in cholestasis; typically that evoked by hepatic malignancy. The Lp-X-ALP complex is also associated with the presence of high-molecular mass ALP and the liver isoenzyme of ALP. Brocklehurst et al. described a stationary band of ALP using starch gel electrophoresis of serum samples from patients with biliary obstruction which was thought to be due to ALP binding to Lp-X. The strong aggregating ability of Lp-X may be important as it can bind and remove free cholesterol from the circulation. There are various assays available for measuring serum Lp-X. Agarose gel electrophoresis utilizes the cathodal

Evaluation of adults with acute viral hepatitis a and review of the literature.

In developing countries HAV infection is very common in the first years of life and it is often asymptomatic. However especially in regions of intermediate endemicity, exposure to the virus may delay and outbreaks of hepatitis A may be encountered in adults. The aim of this study is to evaluate the clinical and laboratory findings and risk factors of adults with acute viral hepatitis A. In present study we evaluated 203 patient with acute viral hepatitis A, who were admitted to four different hospitals of three cities of Turkey between January 2000-December 2011, retrospectively. The diagnosis of acute viral hepatitis A was performed by laboratory findings and clinically. In a total of 203 patients, 120 (59.1%) patients were male and 83 (40.9%) were female. Mean age of cases with acute viral hepatitis A was 24.7 +11.8 years (ranged 15 to 82 years old). Acute viral hepatitis A were seen in patient who were 15-20 years and 21-30 years old, commonly. Jaundice (74%), fatigue (68%), nausea- vomiting (56%) and dark urine (48%) were the most common symptoms in cases. Prolonged cholestasis (6.8%) was the most common atypical manifestation. Prolonged jaundice was more frequent in the cases with positive HBsAg (P < 0.001). Acute viral hepatitis A can cause atypical presentations such as prolonged cholestasis, acute kidney injury and fulminant hepatitis. Some precautions such as routine vaccination program, improvement of hygiene conditions and informing people about it, should be taken for reducing of acute viral hepatitis A infection incidence.

Computed tomography findings for predicting severe acute hepatitis with prolonged cholestasis

To evaluate the significance of computed tomography (CT) findings in relation to liver chemistry and the clinical course of acute hepatitis. Four hundred and twelve patients with acute hepatitis who underwent enhanced CT scanning were enrolled retrospectively. Imaging findings were analyzed for the following variables: gallbladder wall thickness (GWT), arterial heterogeneity, periportal tracking, number and maximum size of lymph nodes, presence of ascites, and size of spleen. The serum levels of alanine aminotransferase, alkaline phosphatase, bilirubin, albumin, and prothrombin time were measured on the day of admission and CT scan, and laboratory data were evaluated every 2-4 d for all subjects during hospitalization. The mean age of patients was 34.4 years, and the most common cause of hepatitis was hepatitis A virus (77.4%). The mean GWT was 5.2 mm. The number of patients who had findings of arterial heterogeneity, periportal tracking, lymph node enlargement > 7 mm, and ascites was 294 (80.1%), 348 (84.7%), 346 (84.5%), and 56 (13.6%), respectively. On multivariate logistic regression, male gender [odds ratio (OR) = 2.569, 95%CI: 1.477-4.469, P = 0.001], toxic hepatitis (OR = 3.531, 95%CI: 1.444-8.635, P = 0.006), level of albumin (OR = 2.154, 95%CI: 1.279-3.629, P = 0.004), and GWT (OR = 1.061, 95%CI: 1.015-1.110, P = 0.009) were independent predictive factors for severe hepatitis. The level of bilirubin (OR = 1.628, 95%CI: 1.331-1.991, P < 0.001) and GWT (OR = 1.172, 95%CI: 1.024-1.342, P = 0.021) were independent factors for prolonged cholestasis in multivariate analysis. In patients with acute hepatitis, GWT on CT scan was an independent predictor of severe hepatitis and prolonged cholestasis.

Atypical manifestations of viral hepatitis A and E

Acute viral hepatitis A and E (HAV/HEV) are usually self-limiting illnesses. However, they can have atypical presentations which lead to increased morbidity and mortality. We studied 81 patients from all age groups admitted with these infections at our centre over a 1 year period. Acute liver failure, prolonged cholestasis, ascites and haemolysis are common atypical manifestations of acute viral HAV and HEV. Relapsing hepatitis, ascites and double peak jaundice were seen more often in the paediatric age group.

Prognostic value of biochemical liver parameters in neonatal sepsis‐associated cholestasis

The aim of the study was to evaluate the significance of total bilirubin, aspartate transaminase (AST), alanine transaminase and gamma-glutamyltransferase (GGT) for predicting outcome in sepsis-associated cholestasis. A retrospective cohort review of the hospital records was performed in 181 neonates admitted to the Neonatal Care Unit. A comparison was performed between subjects with low and high liver values based on cut-off values from ROC analysis. We defined poor prognosis to be when a subject had prolonged cholestasis of more than 3.5 months, developed severe sepsis, septic shock or had a fatal outcome. The majority of the subjects were male (56%), preterm (56%) and had early onset sepsis (73%). The poor prognosis group had lower initial values of GGT compared with the good prognosis group (P = 0.003). Serum GGT (cut-off value of 85.5 U/L) and AST (cut-off value of 51 U/L) showed significant correlation with the outcome following multivariate analysis. The odds ratio (OR) of low GGT and high AST were OR 4.3 (95% CI:1.6 to 11.8) and OR 2.9 (95% CI:1.1 to 8), respectively, for poor prognosis. In subjects with normal AST values, those with low GGT value had relative risk of 2.52 (95% CI:1.4 to 3.5) for poorer prognosis compared with those with normal or high GGT. Serum GGT and AST values can be used to predict the prognosis of patients with sepsis-associated cholestasis.

Does chronic hepatitis B infection affect the clinical course of acute hepatitis A?

The impact of chronic hepatitis B on the clinical outcome of acute hepatitis A remains controversial. The aim of present study was to evaluate the clinical characteristics of acute hepatitis A in cases with underlying chronic hepatitis B compared to cases of acute hepatitis A alone. Data on 758 patients with acute hepatitis A admitted at two university-affiliated hospitals were reviewed. Patients were classified into three groups: group A, patients with both acute hepatitis A and underlying chronic hepatitis B (n = 27); group B, patients infected by acute hepatitis A alone whose sexes and ages were matched with patients in group A (n = 54); and group C, patients with acute hepatitis A alone (n = 731). None of the demographic features of group A were significantly different from those of group B or C, except for the proportion of males and body weight, which differed from group C. When comparing to group B, clinical symptoms were more frequent, and higher total bilirubin and lower albumin levels were observed in group A. When comparing to group C, the albumin levels were lower in group A. There were no differences in the duration of hospital stay, occurrence of acute kidney injury, acute liver failure, prolonged cholestasis, or relapsing hepatitis. This study revealed that clinical symptoms and laboratory findings were less favorable for patients with acute hepatitis A and chronic hepatitis B compared to those with acute hepatitis A alone. However, there were no differences in fatal outcomes or serious complications.

A tribute to Keiko Kobayashi and her work on citrin deficiency

Article history: Received 3 January 2012 Accepted 3 January 2012 Available online 10 January 2012 risky investigations in infants with neonatal cholestasis, provision of appropriate dietary management and genetic counseling, and long term health surveillance [5]. In many centers in Asia and elsewhere, NICCD is a condition to be excluded early in infants with prolonged cholestasis and this had led to a change in pediatric practice. The awareness that biochemical changesmay be absent inNICCD led to the need to develop a cost effective technique formolecular diagnosis Associate Professor Keiko Kobayashi from Kagoshima University, together with Professor Takeyori Saheki, was the pioneer in the field of research on citrin deficiency. Since hermedical graduation and subsequent obtainment of her PhD at Tokushima University, Japan, Associate Professor Kobayashi had been involved in the field of biochemistry and molecular genetics—her early interest had been in the study of the molecular mechanism on the heterogeneous distribution of argininosuccinate synthetase in the liver of type II citrullinemia in 1986 [1]. This led to further research in the 1990s culminating in the characterization of the gene involved in citrin deficiency [2]. Together with Professor Saheki and their collaborators, they identified two phenotypes of citrin deficiency: citrullinemia type II (CTLN2) andneonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) anddelineated the involvement of the aspartate–glutamate carrier for urea synthesis and maintenance of the urea cycle [3]. She and her teamhadworked on all aspects of citrin deficiency, ranging from the basic sciences to epidemiology aspects aswell as the clinical and molecular heterogeneity of the condition [4–6], development of mouse models [7] as well as formulating the treatment options for citrin deficiency [8]. Associate Professor Kobayashi and her team faced a number of challenges. First, there was a perception that citrin deficiency was found mostly in Japanese and East Asians only. However, as a result of research of this condition on a global basis, citrin deficiency is now recognized as a pan-ethnic disorder [9]. Secondly, as the biochemical changes of NICCD often normalized by 6 months of age, molecular diagnosis was the main option available for a definitive diagnosis. She received numerous requests from many developing countries, particularly from Asia who sought her help in making the molecular diagnosis of this condition. Despite many limitations, she always managed to answer her email correspondence promptly with her offers to help out. As prolonged cholestasis is a common condition in Asian infants, many babies were subjected to liver biopsy and laparotomy to exclude biliary atresia. As a result of the availability of genetic testing of the SLC25A13, this led to the earlier diagnosis of

Drug rash with eosinophilia and systemic symptoms syndrome following cholestatic hepatitis A: a case report

Hepatitis A virus (HAV) infections occur predominantly in children, and are usually self-limiting. However, 75-95% of the infections in adults are symptomatic (mostly with jaundice), with the illness symptoms usually persisting for a few weeks. Atypical manifestations include relapsing hepatitis, prolonged cholestasis, and complications involving renal injury. Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a severe, drug-induced hypersensitivity reaction characterized by skin rash, fever, lymph-node enlargement, and internal organ involvement. We describe a 22-year-old male who presented with acute kidney injury and was diagnosed with prolonged cholestatic hepatitis A. The patient also developed DRESS syndrome due to antibiotic and/or antiviral treatment. To our knowledge, this is the first report of histopathologically confirmed DRESS syndrome due to antibiotic and/or antiviral treatment following HAV infection with cholestatic features and renal injury.

Prolonged cholestasis following hepatitis a virus infection: Revisiting the role of steroids

Prolonged cholestasis following hepatitis a virus infection: Revisiting the role of steroids

Expression and function of renal and hepatic organic anion transporters in extrahepatic cholestasis

Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct. The absorption, distribution and elimination of drugs are impaired during this pathology. Prolonged cholestasis may alter both liver and kidney function. Lactam antibiotics, diuretics, non-steroidal anti-inflammatory drugs, several antiviral drugs as well as endogenous compounds are classified as organic anions. The hepatic and renal organic anion transport pathways play a key role in the pharmacokinetics of these compounds. It has been demonstrated that acute extrahepatic cholestasis is associated with increased renal elimination of organic anions. The present work describes the molecular mechanisms involved in the regulation of the expression and function of the renal and hepatic organic anion transporters in extrahepatic cholestasis, such as multidrug resistance-associated protein 2, organic anion transporting polypeptide 1, organic anion transporter 3, bilitranslocase, bromosulfophthalein/bilirubin binding protein, organic anion transporter 1 and sodium dependent bile salt transporter. The modulation in the expression of renal organic anion transporters constitutes a compensatory mechanism to overcome the hepatic dysfunction in the elimination of organic anions.

Síndrome colestásico neonatal prolongado secundario a panhipopituitarismo. Informe de un caso y revisión de la literatura

Prolonged neonatal cholestasis syndrome has several etiologies, some of them are endocrinological; one of these includes hypopituitarism which is infrequent and whose incidence is unknown. Although isolated cases have been reported worldwide, there are no reports in Mexico. We present the case of a 28 day-old male who was admitted to our service with cholestasis and hypoglycemia. A hypophyseal hormone deficiency was documented. Hormone replacement therapy was started, which resulted in remission of symptomatology. Physiopathology of hypopituitarism cholestasis is unclear. However, it is believed that the deficit of growth hormone may alter liver function decreasing biliary salt synthesis and altering the biliary duct structure. The importance of this case stems from the fact that this etiology should be intentionally

A Case of Sustained Cholestasis Caused by Acute A Viral Hepatitis in Dubin-Johnson Syndrome

Dubin-Johnson syndrome is a rare clinical entity. It shows intermittent symptoms such as chronic or intermittent jaundice, abdominal pain, weakness, nausea, vomiting, anorexia and diarrhea. Symptoms are precipitated or aggravated by pregnancy, alcoholism, surgical procedures and intercurrent disease. Chronic idiopathic jaundice is typical of Dubin-Johnson syndrome and its prognosis is good. We describe a case of prolonged cholestasis for more than 10 months caused by acute A viral hepatitis in a patient with Dubin-Johnson syndrome. It is a first report of cholestasis complicated by acute A viral hepatitis in a patient with Dubin-Johnson syndrome.

Bile duct duplication as a cause of distal bowel gas in neonatal duodenal obstruction

Purpose The aim of this study is to investigate the clinical characteristics of cases of duodenal atresia (DA) which present with bowel gas distal to a typical double-bubble sign through an anomalous bile duct conduit. Methods Medical records of 57 neonates with duodenal obstruction (atresia or stenosis), presenting with a double-bubble sign and treated at our institute from 1978 to 2010, were retrospectively reviewed. Results Thirteen (23%) of 57 neonates presented with bowel gas distal to the double-bubble sign. Passage of gas through the duodenal stenosis may have occurred in 3 cases, whereas in 9 cases, gas may have bypassed the atresia through an anomalous bifurcated bile duct termination and through the pancreatic duct from the accessory to the main pancreatic duct in one case. A preoperative upper gastrointestinal series was performed in 9 cases, and an anomalous bifurcated bile duct conduit was demonstrated in 5 cases. Severe and prolonged cholestasis necessitating evaluation for biliary atresia was found in 2 patients with anomalous bile duct anatomy. Conclusions Neonatal DA presenting with distal bowel gas via an anomalous bifurcated bile duct conduit is more common than initially thought and occurs more frequently than duodenal stenosis. These patients might be at risk for cholestasis, possibly owing to duodeno-biliary reflux through the ampulla.

A new Caucasian case of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD): A clinical, molecular, and functional study

Citrin is the liver-specific isoform of the mitochondrial aspartate/glutamate carrier (AGC2). AGC2 deficiency is an autosomal recessive disorder with two age related phenotypes: neonatal intrahepatic cholestasis (NICCD, OMIM#605814) and adult-onset type II citrullinemia (CTLN2, OMIM#603471). NICCD arises within the first few weeks of life resulting in prolonged cholestasis and metabolic abnormalities including aminoacidemia and galactosuria. Usually symptoms disappear within the first year of life, thus making a diagnosis difficult after this time. In this study we report a new Caucasian case of NICCD, a seven week old Romanian boy with prolonged jaundice. Sequencing of the AGC2 gene showed a novel homozygous missense double-nucleotide (doublet) mutation, which produces the change of the glycine at position 437 into glutamate. Functional studies, carried out on the recombinant mutant protein, for the first time demonstrated, that NICCD is caused by a reduced transport activity of AGC2. The presence of AGC2 deficiency in other ethnic groups besides Asian population suggests further consideration for NICCD diagnosis of any neonate with an unexplained cholestasis; a prompt diagnosis is crucial to resolve the metabolic decompensation with an appropriate dietary treatment.

Incidence and Risk Factors for the Development of Prolonged Severe Intrahepatic Cholestasis After Pediatric Living-Donor Liver Transplantation

The aim of this study is to evaluate the incidence, etiology, and risk facrors for prolonged severe intrahepatic cholestasis (PSIC) after 129 pediatric living-donor liver transplantations (LDLT). The incidence of PSIC was 25.6% (n = 33). Twenty-eight (84.8%) versus 5 (15.2%) children experienced early versus late PSIC, respectively. Among these 33 children with PSIC, 8 (24.2%) received a donor liver with mild to moderate fatty change, 4 (12.1%) with low graft–body weight ratios, and 4 (12.1%) with ABO incompatibility. The predominant etiologies were acute rejection (n = 15; 45.5%), chronic rejection (n = 6; 18.2%), virus (n = 3; 9.1%), vascular complications (n = 4; 12.1%), and initial graft dysfunction (n = 10; 30.3%). ABO incompatibility (P = .032; odds ratio [OR] 3.25), chronic rejection (P = .012; OR 4.76), and vascular complications (P = .046; OR 1.82) were significant variables associated with PSIC. Donor selection with ABO compatibility as well as early detection and management of chronic rejection and vascular complications may be important to prevet PSIC in LDLT.