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Familial glucocorticoid deficiency is caused by variants in the MC2R and MRAP genes. We report an Iranian patient with congenital glucocorticoid deficiency and cholestasis due to pathogenic variants in the MC2R gene. This is the first documented case of a patient with conditions. Clinical evaluations and lab assessments were conducted on a six‐month‐old male infant. Next‐generation sequencing identified the genetic causes of the disease, and Sanger sequencing confirmed the variants through segregation analysis. The clinical presentation included prolonged jaundice, progressive skin hyperpigmentation, seizures, fever, and a large umbilical hernia. Two variants in the MC2R gene, c.560delT and c.676G > C, were detected and classified as pathogenic and likely pathogenic, respectively. The cooccurrence of cholestasis and glucocorticoid deficiency illustrates the clinical heterogeneity caused by MC2R variants. The prevalence of c.560delT and c.676G > C between Iranian populations suggests these variants may be common. The high frequency of c.560delT could be attributed to a founder effect. [ABSTRACT FROM AUTHOR]

Objective: Early diagnosis of biliary atresia (BA) and the timing of Kasai hepatic portoenterostomy are associated with improved survival rates of the native liver. Acholic stool is a major and earliest sign of BA. We evaluated the awareness and recognition of medical students and primary health care professionals (PHCPs) about neonatal cholestasis and acholic stool as a marker of BA. Materials and Methods: The knowledge of students and PHCP about prolonged jaundice and acholic stool was evaluated through a questionnaire. In the first step, 5 questions evaluating the knowledge of prolonged jaundice were asked. The sixth question was “Have you ever seen acholic stool before?” Following this question, stool color cards with 9 colors were shown, and participants were asked “Which of the following stool pictures would you define as acholic?” Results: A total 724 students and 88 PHCPs were included in the study. In both groups, about half of the participants could not answer the first 4questions related to prolonged jaundice and cholestasis correctly. Twenty-four percent of the students and 11.4% of PHCP answered correctly to all of the stool colors. The rate of correct answers to acholic stool colors were approximately 43.9%-87.6% and 23.9%-86.4% for students and PHCP, respectively. Whitish acholic stool colors were better known than mild yellowish pale stool colors. The percentages of recognition were less than about 50% for these stool colors. Conclusion: This study showed that recognition and awareness of prolonged jaundice are low, and acholic stool is not well known. This may lead to delay in diagnosis. Considering the international success of stool color cards, using stool color cards will improve the outcomes of biliary atresia in our country as well. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study is to reveal the diagnostic yield of the progressive familial intrahepatic cholestasis (PFIC) gene panel that we have used in the diagnosis of this patient group, which accounts for approximately 10% of cholestatic liver disease, and to report the clinical findings of our patients with the detected variants. Methods: In this study, we retrospectively evaluated the results of molecular genetic analysis of pediatric patients whose PFIC gene panel contained the ATP8B1, ABCB11, and ABCB4 genes. Results: In 10 patients, 12 different variants were detected that could explain the PFIC clinical picture. Three of these variants were considered novel variants. Conclusions: Our study demonstrates the usefulness of the NGS panel in diagnosing pediatric patients with PFIC findings. This diagnostic method also contributed to the variant spectrum of PFIC-related genes. [ABSTRACT FROM AUTHOR]

Portal biliopathy (PB) refers to biliary obstruction caused by cavernous transformation of the portal vein (CTPV). CTPV occurs most frequently in patients with liver cirrhosis or malignancy. Less common causes include congenital malformations and neonatal umbilical vein cannulation. We present a case of portal biliopathy in a 28-year-old man with CTPV secondary to umbilical vein catheterization in neonatal age. The case illustrates portal biliopathy as a late complication of neonatal invasive procedures and highlights the importance of a multimodality imaging approach to achieve a prompt diagnosis.

Introduction: For many years, congenital panhypopituitarism has been recognized to cause infantile cholestasis. However, the isolated cortisol deficiency as a cause of cholestasis and liver failure was rarely reported. Case description: A 32-days old male infant presented to the hepatology clinic with infantile cholestasis. His initial workup revealed alanine transaminase (ALT) level of 138 U/L, aspartate transaminase level of 76 U/L, total bilirubin (T.Bil) of 103 mmol/L, direct bilirubin of (D.Bil) 83 mmol/L, gamma-glutamyl transpeptidase (GGT) level of 28 U/L with normal prothrombin time (PT) of 13 seconds. One week later, the patient developed severe bronchiolitis necessitating mechanical ventilation associated with acute liver failure and worsening cholestasis. His ALT increased to 303.5 U/L and direct bilirubin increased to 204 mmol/L with prolongation of PT to 18.9 seconds reflecting derangement in synthetic liver functions. There was associated hypoglycemia, hyponatremia and high normal potassium level with a picture of adrenal insufficiency. Hormonal workup and genetic testing revealed isolated cortisol deficiency with a novel homozygous mutation c.763_764delAT (p. Met255ValfsX17) in Melanocortin 2 receptor gene (MC2R) and the patient was diagnosed as familial primary glucocorticoid deficiency. The patient was maintained on cortisol replacement therapy with the resolution of cholestasis and normalization of liver functions. Conclusions: Patients presenting with infantile cholestasis associated with documented hypoglycemia should alert pediatricians about the possibility of familial glucocorticoid deficiency and prompt investigation of adrenal function should be considered. Cortisol replacement therapy leads to the resolution of cholestasis. [ABSTRACT FROM AUTHOR]

Background: Infants with cholestasis are at risk of fat‐soluble vitamin deficiency. The present study amied to review practice relating to the assessment, deficiency and supplementation of fat‐soluble vitamins in infants with cholestasis. Methods: The medical records of all newly diagnosed infants with cholestasis (conjugated bilirubin >17 mmol L–1/>20% total bilirubin) at King's College Hospital between 2017 and 2019 were reviewed. Data extracted included bilirubin, serum vitamin concentrations (A, D, E), international normalised ratio and evidence of supplementation at initial assessment, as well as at 3 and 6 months. Rates of vitamin assessment, deficiency and supplementation were compared using chi‐squared or Fisher's exact test. Results: In total, 136 infants (87 male) with idiopathic neonatal cholestasis (n = 62), biliary atresia (n = 40) and other aetiology (n = 34) were included. Assessment of serum vitamins (A, D, E) was low (33.3%–52.2%) and deficiency was initially high for vitamin D (60.6%) and vitamin E (70.9%). Supplementation prevalence at initial assessment was high (A, E, K), but dropped significantly at 3 and 6 months for vitamin E (p = 0.003) and vitamin K (p = 0.001), whereas vitamin D supplementation was consistently low throughout (25%–33.3%). Infants with biliary atresia were more likely to have vitamins assessed (3 months), be deficient initially (D, E) and supplemented (E, K) throughout. Supplementation continued in up to 80% of infants despite cholestasis resolving. Conclusions: Supplementation was generally high and continued in many despite cholestasis resolving. Deficiency of vitamin D and vitamin E was high at initial assessment, although lower at follow‐up. Actual prevalence of deficiency of all vitamins is unknown because monitoring was not consistently performed. Key points: The present study shows the importance of fat‐soluble vitamin supplementation in infants with cholestasis. Supplementation of fat‐soluble vitamins was generally high, except for vitamin D. Supplementation continued in many infants despite cholestasis resolving. On presentation, 61% were deficient in vitamin D and 71% were deficient in vitamin E. Actual deficiency prevalence is not known because vitamins were assessed in less than 52% of cases. [ABSTRACT FROM AUTHOR]

Alagille syndrome (ALGS) is an autosomal dominant multisystem disorder with cholestasis as a defining clinical feature. We sought to characterize hepatic outcomes in a molecularly defined cohort of children with ALGS‐related cholestasis. Two hundred and ninety‐three participants with ALGS with native liver were enrolled. Participants entered the study at different ages and data were collected retrospectively prior to enrollment, and prospectively during the study course. Genetic analysis in 206 revealed JAGGED1 mutations in 91% and NOTCH2 mutations in 4%. Growth was impaired with mean height and weight z‐scores of <−1.0 at all ages. Regression analysis revealed that every 10 mg/dL increase in total bilirubin was associated with a decrease in height z‐score by 0.10 (P = 0.03) and weight z‐score by 0.15 (P = 0.007). Total bilirubin was higher for younger participants (P = 0.03) with a median of 6.9 mg/dL for those less than 1 year old compared with a median of 1.3 mg/dL for participants 13 years or older. The median gamma glutamyl transferase also dropped from 612 to 268 in the same age groups. After adjusting for age, there was substantial within‐individual variation of alanine aminotransferase. By 20 years of age, 40% of participants had developed definite portal hypertension. Estimated liver transplant–free survival at the age of 18.5 years was 24%. Conclusions: This is the largest multicenter natural history study of cholestasis in ALGS, demonstrating a previously underappreciated burden of liver disease with early profound cholestasis, a second wave of portal hypertension later in childhood, and less than 25% of patients reaching young adulthood with their native liver. These findings will promote optimization of ALGS management and development of clinically relevant endpoints for future therapeutic trials. [ABSTRACT FROM AUTHOR]

Multidrug-resistant P-glycoprotein 3 (MDR3) is a phospholipid translocator encoded by the ABCB4 gene located on chromosome 7. MDR3 mediates the translocation of phosphatidylcholine across the canalicular membrane of the hepatocyte into bile. Severe MDR3 deficiency typically occurs during childhood with progressive cholestasis evolving to cirrhosis and liver failure, requiring liver transplantation. In this article, we report 2 pediatric cases of severe MDR3 deficiency with paucity of interlobular bile ducts. Both underwent living donor liver transplantation at our center for decompensated liver disease and portal hypertension. We diagnosed severe MDR3 deficiency in both the cases with negative MDR3 immunostaining in the explanted liver. Genetic studies revealed homozygous deletion single base pair deletion in exon 24 of the ABCB4 gene in the second child. The patients are on regular follow-up after liver transplant and are doing well. Our report highlights that cholangiopathy in MDR3 deficiency can lead to ductopenia in pediatric livers. [ABSTRACT FROM AUTHOR]

Kawasaki disease is a systemic vasculitis that develops during childhood, especially in those younger than 5 years. Gastrointestinal involvement does not belong to the classic diagnostic criteria. We reported here, a 9‐year old girl who presented with febrile cholestasis, and developed a medium right coronary artery aneurysm despite intravenous immunoglobulin administration on the 9th day of fever. Hepatobiliary ultrasonographic evaluation revealed normal findings. Seroimmunologic markers of cholestasis were negative. Her clinical feature was ameliorated shortly after a second dose of intravenous immunoglobulin administration. We consider that a high index of suspicion of Kawasaki disease could prevent delayed diagnosis and complications. [ABSTRACT FROM AUTHOR]

Aim: Children with ultra-short bowel syndrome (USBS) have not been extensively studied to date because the condition is rare. The aim of the study was to assess the nutritional status of children with USBS receiving home parenteral nutrition, using citrulline serum concentration and cholestasis.Methods: We studied 17 patients with USBS, with a median age of 6.6 years and median duration of parenteral nutrition of 6.6 years. The study was carried out at The Children's Memorial Health Institute, Warsaw, from January 2014 to January 2015.Results: The median standard deviation score (SDS) was -1.2 for body mass according to chronological age, -1.72 according to height and -0.59 according to height for age. Patients requiring seven days per week parenteral nutrition had a citrulline concentration below 10 μmol/L. Decreased bone-mineral density was observed in 87% of the patients. Low values of 25-hydroxyvitamin D were found in 53% of the children. None of the patients had elevated conjugated bilirubin levels above 34.2 μmol/L.Conclusion: Children with USBS were growth deficient according to their chronological age, with frequent abnormal bone mineralisation and vitamin D deficiency. Children requiring parenteral nutrition seven days a week had citrulline concentrations below 10 μmol/L. Cholestasis was not seen. [ABSTRACT FROM AUTHOR]

When encountered in children, xanthomas are most commonly associated with a group of disorders known as familial hyperlipidemias. Aside from cosmetic concerns, these xanthomas are typically asymptomatic, but when generalized pruritus is a prominent associated symptom, clinicians should consider a different set of diagnoses that includes cholestasis of the liver. In this article we present two illustrative cases of children with cholestatic disease, pruritus, and xanthomas and discuss other disorders that may include this triad. [ABSTRACT FROM AUTHOR]

The treatment of biliary stenosis after pediatric LDLT is challenging. We describe an innovative technique of peripheral IHCJ for the treatment of patients with complex biliary stenosis after pediatric LDLT in whom percutaneous treatment failed. During surgery, the percutaneous biliary drainage is removed and a flexible metal stylet is introduced trough the tract. Subsequently, the most superficial aspect of the biliary tree is recognized by palpation of the stylet's round tip in the liver surface. The liver parenchyma is then transected until the bile duct is reached. A side-to-side anastomosis to the previous Roux-en-Y limb is performed over a silicone stent. Among 328 pediatric liver transplants performed between 1988 and 2015, 26 patients developed biliary stenosis. From nine patients requiring surgery, three patients who had received left lateral grafts from living-related donors due to biliary atresia were successfully treated with IHCJ. After a mean of 45.6 months, all patients are alive with normal liver morphological and function tests. The presented technique was a feasible and safe surgical option to treat selected pediatric recipients with complex biliary stenosis in whom percutaneous procedures or rehepaticojejunostomy were not possible, allowing complete resolution of cholestasis and thus avoiding liver retransplantation. [ABSTRACT FROM AUTHOR]

Background Biliary atresia (BA) is a congenital, progressive, fibro-obliterative disease of the extrahepatic biliary tree and the most common cause of end-stage liver disease in children. BA is characterized by extensive intrahepatic proliferating ductular reactions that may contribute to biliary fibrosis. Lineage tracing during experimental cholestasis indicates that cells within ductular reactions derive from PROM1-expressing hepatic progenitor cells. Given the role of Notch signaling in normal biliary development, we hypothesize that activated Notch signaling promotes the formation of ductular reactions in BA. Methods Liver samples collected from BA infants at Kasai portoenterostomy and age-matched controls, as well as from wild-type and Prom1 knockout mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced experimental cholestasis were analyzed histologically using immunofluorescence and by quantitative polymerase chain reaction. Results Increased expression of genes encoding Notch ligand JAG1 and its receptor NOTCH2 was observed in BA livers compared with control by quantitative polymerase chain reaction analyses. Livers of DDC-treated mice, which exhibit cytokeratin-19–positive ductular reactions typical of BA livers, demonstrated significant increases in the expression level of the gene encoding Notch2 , as well as downstream Notch target gene Hes1 compared with control. Prom1 knockout mice exhibit diminished ductular reactions and decreased levels of Jag1 and Hes1 compared with littermate controls. Conclusions Human BA and cholestasis induced by DDC are associated with Notch signaling activation. Null mutation of Prom1 is associated with decreased ductular reactions and decreased Notch signaling activation during DDC treatment. These data are consistent with Notch signaling promoting ductular reactions of Prom1 expressing progenitor cells in BA. [ABSTRACT FROM AUTHOR]

Purpose: The goal of this study was the early diagnosis of ABCB11 spectrum liver disorders, especially those focused on benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis. Methods: Fifty patients presenting neonatal cholestasis were evaluated to identify underlying etiologies. Genetic analysis was performed on patients suspected to have syndromic diseases or ABCB11 spectrum liver disorders. Two families with proven ABCB11 spectrum liver disorders were subjected to genetic analyses to confirm the diagnosis and were provided genetic counseling. Whole exome sequencing and Sanger sequencing were performed on the patients and the family members. Results: Idiopathic or viral hepatitis was diagnosed in 34%, metabolic disease in 20%, total parenteral nutrition induced cholestasis in 16%, extrahepatic biliary atresia in 14%, genetic disease in 10%, neonatal lupus in 2%, congenital syphilis in 2%, and choledochal cyst in 2% of the patients. The patient with progressive familial intrahepatic cholestasis had novel heterozygous mutations of ABCB11 c.11C>G (p.Ser4*) and c.1543A>G (p.Asn515Asp). The patient with benign recurrent intrahepatic cholestasis had homozygous mutations of ABCB11 c.1331T>C (p.Val444Ala) and heterozygous, c.3084A>G (p.Ala1028Ala). Genetic confirmation of ABCB11 spectrum liver disorder led to early liver transplantation in the progressive familial intrahepatic cholestasis patient. In addition, the atypically severe benign recurrent intrahepatic cholestasis patient was able to avoid unnecessary liver transplantation after genetic analysis. Conclusion: ABCB11 spectrum liver disorders can be clinically indistinguishable as they share similar characteristics related to acute episodes. A comprehensive genetic analysis will facilitate optimal diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive disorder resulting from biallelic mutations of the SLC25A13 gene. Due to the lack of well-recognized clinical or biochemical diagnostic criteria, the definitive diagnosis of this disease relies on the genetic analysis of SLC25A13 at present. As novel large deletion/insertion mutations of the SLC25A13 gene are difficult to detect using routine DNA analytic approaches, the timely diagnosis of patients with these types of mutations remains a challenge. The present study aimed to examine SLC25A13 mutations in an infant with a suspected diagnosis of NICCD. DNA was extracted from blood samples, and SLC25A13 mutations were examined by screening for high-frequency mutations and Sanger sequencing. Reverse transcription-polymerase chain reaction and cDNA cloning analyses were then performed using peripheral blood lymphocytes (PBLs) to identify the obscure mutation. The results demonstrated that the infant was heterozygous for a paternally-inherited mutation, c.851_854del4, and a maternally-inherited large deletion, c.1019_1177+893del, which has not been reported previously. A positive diagnosis of NICCD was made, and the infant responded favorably to a galactose-free and medium-chain triglyceride-enriched formula. The present study confirmed the effectiveness of this formula in NICCD therapy, enriched the SLC25A13 mutational spectrum and supported the feasibility of cDNA cloning analysis using PBLs as a molecular tool for facilitating the identification of large SLC25A13 deletions. [ABSTRACT FROM AUTHOR]

Aim of work: To estimate the frequency of mutations involving exons 6, 8 and 9 of Adenosine triphosphate-binding cassette, subfamily B, member 4 (ABCB4) gene among children with progressive intrahepatic cholestasis with high γ-GT activity (PFIC3). Subjects and methods: Cross sectional study was conducted on 30 children with PFIC3. Genotyping was performed by sequencing analysis of exons 6, 8 and exon 9 of ABCB4 gene. Results: Heterozygous synonymous polymorphic variant was detected in exon 6 (rs 1202283) and in exon 8 (rs 2109505). No mutations in studied exons were detected. Conclusion: Exons 6, 8 and 9 mutations of ABCB4 gene are not common among Egyptian children with PFIC3. [ABSTRACT FROM PUBLISHER]

LT for PFIC type 1 is often complicated by postoperative diarrhea and recurrent graft steatosis. A 26-month-old female child with cholestatic jaundice, pruritus, diarrhea, and growth retardation revealed total bilirubin 9.1 mg/dL, gamma-glutamyl transpeptidase 64 IU/L, and TBA 295.8 μmol/L. Genetic analysis confirmed ATP8B1 defects. A LT (segment 2, 3 graft) from the heterozygous father was performed. Biliary diversion was performed by a 35-cm jejunum conduit between the graft hepatic duct and the mid-transverse colon. Stools became pigmented immediately. Follow-up at 138 days revealed resolution of jaundice and pruritus and soft-to-hard stools (6-8 daily). Radioisotope hepato-biliary scintigraphy (days 26, 68, and 139) confirmed unobstructed bile drainage into the colon (t1/2 34, 27, and 19 minutes, respectively). Contrast meal follow-through at day 62 confirmed the absence of any colo-jejuno-hepatic reflux. At 140 days, contrast follow-through via the biliary stent revealed patent jejuno-colonic anastomosis and satisfactory transit. Graft biopsy at LT, 138 days, and 9 months follow-up revealed comparable grades of macrovesicular steatosis (<20%). TIBD during LT may be a clinically effective stoma-free biliary diversion and may prevent recurrent graft steatosis following LT for PFIC type 1. [ABSTRACT FROM AUTHOR]

Background and Aims: Large indels are commonly identified in patients but are not detectable by routine Sanger sequencing and panel sequencing. We specially designed a multi-gene panel that could simultaneously test known large indels in addition to ordinary variants, and reported the diagnostic yield in patients with intrahepatic cholestasis. Methods: The panel contains 61 genes associated with cholestasis and 25 known recurrent large indels. The amplicon library was sequenced on Ion PGM system. Sequencing data were analyzed using a routine data analysis protocol and an internal program encoded for large indels test simultaneously. The validation phase was performed using 54 patients with known genetic diagnosis, including 5 with large insertions. At implement phase, 141 patients with intrahepatic cholestasis were evaluated. Results: At validation phase, 99.6% of the variations identified by Sanger sequencing could be detected by panel sequencing. Following the routine protocol, 99.8% of false positives could be filtered and 98.8% of retained variations were true positives. Large insertions in the 5 patients with known genetic diagnosis could be correctly detected using the internal program. At implementation phase, 96.9% of the retained variations, following the routine protocol, were confirmed to be true. Twenty-nine patients received a potential genetic diagnosis when panel sequencing data were analyzed using the routine protocol. Two additional patients, who were found to harbor large insertions in SLC25A13, obtained a potential genetic diagnosis when sequencing data were further analyzed using the internal program. A total of 31 (22.0%) patients obtained a potential genetic diagnosis. Nine different genetic disorders were diagnosed, and citrin deficiency was the commonest. Conclusion: Specially designed multi-gene panel can correctly detect large indels simultaneously. By using it, we assigned a potential genetic diagnosis to 22.0% of patients with intrahepatic cholestasis. [ABSTRACT FROM AUTHOR]

Summary Biliary Atresia and other cholestatic childhood diseases are rare conditions affecting the function and/or anatomy along the canalicular-bile duct continuum, characterised by onset of persistent cholestatic jaundice during the neonatal period. Biliary atresia (BA) is the most common among these, but still has an incidence of only 1 in 10–19,000 in Europe and North America. Other diseases such as the genetic conditions, Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC), are less common. Choledochal malformations are amenable to surgical correction and require a high index of suspicion. The low incidence of such diseases hinder patient-based studies that include large cohorts, while the limited numbers of animal models of disease that recapitulate the spectrum of disease phenotypes hinders both basic research and the development of new treatments. Despite their individual rarity, collectively BA and other cholestatic childhood diseases are the commonest indications for liver transplantation during childhood. Here, we review the recent advances in basic research and clinical progress in these diseases, as well as the research needs. For the various diseases, we formulate current key questions and controversies and identify top priorities to guide future research. [ABSTRACT FROM AUTHOR]

Background & Aims Liver disease in Alagille syndrome is highly variable. Many of the patients presenting with severe cholestasis early in life improve spontaneously; 10-20%, however, have progressive disease. It is currently not possible to predict long-term hepatic outcomes in Alagille syndrome. This international, multicentre study was aimed at identifying early life predictors of liver disease outcome. Methods Retrospective clinical, laboratory and radiographic data from a cohort of 144 Alagille syndrome patients, whose long-term hepatic outcomes had been determined a priori based on previously published criteria, were collected. Results Sixty-seven patients had mild and 77 had severe hepatic outcome. Univariate analysis demonstrated that cholestasis and fibrosis on biopsy, as well as the presence of xanthomata were significantly different between the groups ( P < 0.05 for all). Mixed model analysis revealed that total serum bilirubin and serum cholesterol were also associated with outcome ( P = 0.001 and P = 0.002, respectively). Graphical representation of the data revealed a change in total bilirubin levels between 12 and 24 months of age in the mild group. Recursive partitioning identified a threshold for total bilirubin of 3.8 mg/dl (65 mmol/L) in that age-frame that differentiated between outcomes. A multivariable logistic regression model was developed using fibrosis, xanthomata and the total bilirubin cut-off of 3.8 mg/dl (65 mmol/L), which generated an area under the ROC curve of 0.792. Conclusions The long-term hepatic outcomes of patients with Alagille syndrome can be predicted based on serum total bilirubin between the ages of 12-24 months combined with fibrosis on liver biopsy and the presence of xanthomata on physical examination. [ABSTRACT FROM AUTHOR]

Aim Single gene mutations cause syndromes of intrahepatic cholestasis, but previous multi-gene mutation screening in children with idiopathic cholestasis failed to fulfill diagnostic criteria in approximately two-thirds of children. In adults with fibrosing cholestatic disease, heterozygous ABCB4 mutations were present in 34% of patients. Here, we hypothesized that children with idiopathic cholestasis have a higher frequency of heterozygous non-synonymous gene sequence variants. Methods We analyzed the frequency and types of variants in 717 children in whom high-throughput sequencing of the genes SERPINA1, JAG1, ATP8B1, ABCB11 and ABCB4 was performed as part of an evaluation for idiopathic intrahepatic cholestasis cholestasis. The frequency of non-synonymous variants (NSV) was compared with those of 1092 control subjects enrolled in the 1000 Genome Project. Results The frequency of NSV in single genes was similar between disease (25%) and controls (26%, P = 0.518). In contrast, double or triple NSV in two or more genes were more frequent in disease ( n = 7%) than controls ( n = 4.7%, P = 0.028). Detailed review of clinical and laboratory information in a subgroup of double or triple heterozygous patients revealed variable γ-glutamyltransferase levels and severity of pruritus, with liver biopsies showing stage 2-3 fibrosis. Conclusion Children with idiopathic intrahepatic cholestasis have a higher frequency of double or triple NSV in SERPINA1, JAG1, ATPB1, ABCB11 or ABCB4. These findings raise the potential role for gene-gene relationships in determining the phenotype of cholestatic liver disease in children. [ABSTRACT FROM AUTHOR]

Cholestasis results from impairment in the excretion of bile, which may be due to mechanical obstruction of bile flow or impairment of excretion of bile components into the bile canaliculus. When present, cholestasis warrants prompt diagnosis and treatment. The differential diagnosis of cholestasis beyond the neonatal period is broad and includes congenital and acquired etiologies. It is imperative that the clinician differentiates between intrahepatic and extrahepatic origin of cholestasis. Treatment may be supportive or curative and depends on the etiology. Recent literature shows that optimal nutritional and medical support also plays an integral role in the management of pediatric patients with chronic cholestasis. This review will provide a broad overview of the pathophysiology, diagnostic approach, and management of cholestasis beyond the neonatal and infancy periods. [ABSTRACT FROM AUTHOR]

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Background & Aims Monoallelic defects in ABCB4, which encodes the canalicular floppase for phosphatidylcholine MDR3, have been encountered in association with a variety of hepatobiliary disorders, particularly in adult subjects. In this study, we examined the presence of heterozygous ABCB4 variants in a cohort of children with chronic cholestasis and assessed the pathogenicity of the missense changes identified. Methods Sixty-seven children with chronic liver dysfunction were studied by the sequencing of ABCB4 and multiplex ligation-dependent probe amplification analysis. The molecular defects arising from missense variants were analysed in MDCK- II and AD-293 cells. Results Defects in a single allele of ABCB4 were identified in nine subjects. They included one small insertion (p.I1242Nfs), one nonsense mutation (p.R144X) and six missense changes (p.T175A, p.G228R, p.A250T, p.S320F, p.P352L and p.A934T). In four children, these defects in ABCB4 co-existed with various medical conditions. In vitro phenotyping of the six missense variants revealed that four (T175A, G228R, S320F and A934T) led to reduced MDR3 protein levels. Two mutations (G228R and A934T) resulted in trapping of the protein in the endoplasmic reticulum. Phosphatidylcholine efflux activity was decreased to 56-18% of reference levels for MDR3 mutants T175A, A250T and S320F. The G228R, P352L and A934T mutants were found to be non-functional. Conclusions These results illustrate the varying effects of ABCB4 missense mutations and suggest that even a modest reduction in MDR3 activity may contribute or predispose to the onset of cholestatic liver disease in the paediatric age. [ABSTRACT FROM AUTHOR]

Gabriela, 8 years old, was admitted in the 1st Pediatric Clinic, Timisoara for the evaluation of cholestasis syndrome. She was known with hypotonic cerebral palsy, epilepsy with polymorphic seizures partial controlled by anticonvulsants and 5 atraumatic leg fractures occurred in the last 3 years. At admission, she had pale skin, absent subcutaneous tissue and muscle atrophy with muscle atrophy. She had splint cast in the left lower limb and pseudoarthrosis in the 1/3 distal of the right leg. The biological investigations revealed normal liver enzymes except alkaline phosphatase, an abnormal coagulation and bone markers and the presence of starch and fiber in the stool, while the other tests were normal. The radiography of extremities showed osteolysis injuries and old left clavicle, upper third diaphysis of left humerus and femur and lower third diaphysis of right tibia fractures, with vicious callus secondary to Osteogenesis Imperfecta. We considered that all these fractures were manifestations of osteoporosis secondary to malabsorption syndrome, malnutrition, vitamin D and K deficiencies, chronic anticonvulsant therapy and Osteogenesis Imperfecta. The evolution was favorable under treated with calcium gluconate, vitamin D and K with the reduction of alkaline phosphatase and normalization of coagulation. The initiation of bisphosphonate therapy was taken into account. Case particularity: The association of osteoporosis and Osteogenesis Imperfecta responsible for the production of fractures in a patient with cerebral palsy and epilepsy. [ABSTRACT FROM AUTHOR]

Intractable pruritus secondary to bile salts retention in Progressive Familial Intrahepatic Cholestasis (PFIC) can be relieved surgically by diverting bile drainage from ileum to reduce bile salts reabsorption into entero-hepatic circulation. We are reporting on the successful biliary diversion in a child with PFIC, with the use of the appendix as a conduit to drain bile from gallbladder to the colon (cholecysto-appendicostomy). [ABSTRACT FROM AUTHOR]

Familial intrahepatic cholestases (FICs) are a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. Three distinct forms are described: FIC1 and FIC2, associated with low/normal GGT level in serum, which are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and defects in ABCB11 encoding bile salt export pump protein, respectively; FIC3, linked to high GGT level, involves impaired biliary phospholipid secretion due to defects in ABCB4, encoding multidrug resistance 3 protein. Different mutations in these genes may cause either a progressive familial intrahepatic cholestasis (PFIC) or a benign recurrent intrahepatic cholestasis (BRIC). For the purposes of the present study we genotyped 27 children with intrahepatic cholestasis, diagnosed on either a clinical or histological basis. Two BRIC, 23 PFIC and 2 BRIC/PFIC were identified. Thirty-four different mutations were found of which 11 were novel. One was a 2Mb deletion (5’UTR- exon 18) in ATP8B1. In another case microsatellite analysis of chromosome 2, including ABCB11, showed uniparental disomy. Two cases were compound heterozygous for BRIC/PFIC2 mutations. Our results highlight the importance of the pathogenic role of novel mutations in the three genes and unusual modes of their transmission. [ABSTRACT FROM AUTHOR]

Cholestasis is a multifactorial disorder with various biological, infectious, toxic, genetic and metabolic manifestations, its principal feature presented as reduced bile flow or abnormalities in bile formation. It has lately been accepted that some specific biological markers would shorten the period needed to establish a positive diagnosis, as currently it is necessary to navigate through a complex diagnostic protocol for this disorder. The purpose of this study was to establish some biological parameters and biomarkers useful for cholestasis management in children. Two hundred thirty-two children with cholestasis were selected, during a six-year study. The biological indicators followed were serum bilirubin, gamma-glutamyl transpeptidase, aspartate transaminase, alkaline phosphatase, lactate dehydrogenase, serum cholesterol and triglycerides. Our data showed that certain biological parameters are more often involved in the various forms of cholestasis, and the conclusions of this study could be useful in the early detection of cholestasis and appropriate disease management. [ABSTRACT FROM AUTHOR]

Background Untreated, progressive familial intrahepatic cholestasis (PFIC) results in fibrosis, cirrhosis, and liver failure. It has been shown that partial external biliary diversion (PEBD) may prevent from liver transplantation in patients without cirrhosis. The aim of this study is to present a new laparoscopic technique using a button instead of a bowel conduit for PEBD. Patients and Methods Two boys with PFIC (patient 1, 17 months; patient 2, 12 years) underwent laparoscopic button cholecystostomy using a 3-trocar technique by insertion of a 14 FrenchMIC KEY button (Kimberly-ClarkWorldwide, Inc, Draper, Utah, United States) at the gallbladder fundus secured with two absorbable purse-string sutures. Beside the suitability of the procedure, end points included course of serum bile acids, total bilirubin, liver enzymes, and pruritus at a follow-up of 6 months. Results No complications related to the operation occurred. Relieve of pruritus was achieved in both the children, due to adequate bile drainage during a follow-up period of 6 months. In patient 2, a 10-mm gallstone was removed simultaneously. In patient 1, serum bile acids decreased from 12.3 to 6.6 μmol/L and in patient 2, serum bile acids decreased from 106.3 to 2.9 μmol/L. Total bilirubin, aspartate amino transferase, alanine amino transferase, and gamma-glutamyltransferase are kept in normal ranges during follow-up. Patient's and parent's acceptance with the button was excellent. Conclusion Laparoscopic button cholecystostomy is a simple, safe, and sufficient technique for PEBD in patients with PFIC. It achieves an adequate bile flow with consecutive relief of pruritus and avoids an enteric anastomosis. [ABSTRACT FROM AUTHOR]

Introduction: Prolonged Total Parental Nutrition (TPN) is associated with life-threatening complications in the pediatric population, being cholestasis one of the most important ones. The source of fatty acids, the amount of phytosterols and the dose of lipids in the nutritional support, have been linked to the development of this complication. Purpose: To describe the behavior of liver function tests in pediatric patients with TPN where lipid based omega 3 fatty acids (Omegaven®) were used. Methods: A retrospective research was made in a population of children under 18 years old where omega 3 fatty acids were used for a minimum of 8 days. Patients were initially classified into two groups: cholestasis and abnormal liver tests. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), direct bilirubin (DB) gamma glutamyl transferase (GGT) and alkaline phosphatase (AP) before and after treatment with Omegaven® was evaluated. Results: 33 patients met the inclusion criteria. At the end of treatment with Omegaven®, 82.4% of patients who initially presented cholestasis showed resolution or improvement. The group of patients with abnormal liver tests 18.8% progressed to cholestasis. Conclusions: Our study suggests that the use of Omegaven® in pediatric patients with TPN and DB ≥ 2 mg/dL, seem to reverse or improve cholestasis while in patients with abnormal liver tests we still don´t have clear effect. [ABSTRACT FROM AUTHOR]

Progressive familial intrahepatic cholestasis (PFIC) is a group of rare disorders which are caused by defect in bile secretion and present with intrahepatic cholestasis, usually in infancy and childhood. These are autosomal recessive in inheritance. The estimated incidence is about 1 per 50,000 to 1 per 100,000 births, although exact prevalence is not known. These diseases affect both the genders equally and have been reported from all geographical areas. Based on clinical presentation, laboratory findings, liver histology and genetic defect, these are broadly divided into three types—PFIC type 1, PFIC type 2 and PFIC type 3. The defect is in ATP8B1 gene encoding the FIC1 protein, ABCB 11 gene encoding BSEP protein and ABCB4 gene encoding MDR3 protein in PFIC1, 2 and 3 respectively. The basic defect is impaired bile salt secretion in PFIC1/2 whereas in PFIC3, it is reduced biliary phospholipid secretion. The main clinical presentation is in the form of cholestatic jaundice and pruritus. Serum gamma glutamyl transpeptidase (GGT) is normal in patients with PFIC1/2 while it is raised in patients with PFIC3. Treatment includes nutritional support (adequate calories, supplementation of fat soluble vitamins and medium chain triglycerides) and use of medications to relieve pruritus as initial therapy followed by biliary diversion procedures in selected patients. Ultimately liver transplantation is needed in most patients as they develop progressive liver fibrosis, cirrhosis and end stage liver disease. Due to the high risk of developing liver tumors in PFIC2 patients, monitoring is recommended from infancy. Mutation targeted pharmacotherapy, gene therapy and hepatocyte transplantation are being explored as future therapeutic options. [ABSTRACT FROM AUTHOR]

We present a case of a 7-year-old boy who had cholestasis after trimethoprim-sulfamethoxazole combination therapy. Liver biopsy was performed 36 days after the onset of jaundice because of no evidence of improving cholestasis. Liver histology revealed portal inflammation, bile plug, and biliary stasis around the central vein with the loss of the interlobular bile ducts. Immunohistochemical stains for cytokeratin 7 and 19 were negative. These findings were consistent with those of vanishing bile duct syndrome (VBDS). Chlestasis was progressively improved with dose increment of urosodeoxycholic acid from conventional to high dose. This is the first case report of trimethoprime-sulfamethoxazole associated VBDS in Korean children. The case suggests that differential diagnosis of VBDS should be considered in case of progressive cholestatic hepatitis with elevation of alkaline phosphatase and gamma-glutamyl transpeptidase after or during taking medicine to treat nonhepatobiliary diseases illness. [ABSTRACT FROM AUTHOR]

The measurement of aminotransferases levels has become part of the routine biochemical tests done in children regardless of their clinical symptoms. Aminotransferases (ALT, AST) are tissue necrosis markers which change in both hepatic and extra-hepatic conditions. The aim of this study was to establish the etiology and clinical significance of the cytolysis syndrome without cholestasis in children hospitalized for various pediatric conditions. The study group consisted of 394 children (aged between 1.5 months and 16 years) with elevated values of ALT, AST. The investigation protocol applied included history, full physical examination, complete biological investigations, viral markers and liver ultrasounds. Depending on the aminotransferases values as compared to the normal value (NV), the patients were included in 3 study subgroups: 222 patients with slightly elevated transaminases values (< 2xNV) (subgroup I), 164 patients with ALT and AST values between 2-3xNV (subgroup II) and 8 patients with TGP, TGO values > 3 x NV (subgroup III). The ALT and AST values were determined monthly during the first 3 months, and then every 2 to 6 months. In all groups the etiology was dominated by acute bacterial (respiratory, urinary, digestive) and viral (Epstein Barr, Citomegalovirus infection) conditions. Other causes of cytolysis syndrome were nutritional and metabolic diseases (obesity, mellitus diabetes, phenyl-ketonuria, cystic fibrosis, congenital hypotiroidism). The etiology remained unclear in 20.31% of the cases, yet the transaminase values returned to normal after 6 months with diet and hepatoprotective therapy. Slightly elevated ALT and AST values do not require thorough investigations, as they usually return to normal within the first three months. On the other hand, mildly and severe increases, which persist after three months therapy require further investigation to determine the etiology (viral infections, autoimmune, nutritional and metabolic diseases). [ABSTRACT FROM AUTHOR]

Background/Aims: Stent migration occurs frequently, but the prevention of complications resulting from covered self-expandable metal stents (C-SEMSs) remains unresolved. We prospectively assessed a newly developed C-SEMS, a modified covered Zeo stent (m-CZS), in terms of its antimigration effect. Methods: Between February 2010 and January 2011, an m-CZS was inserted into 42 patients (31 initial drainage cases and 11 reintervention cases) at a tertiary referral center and three affiliated hospitals. The laser-cut stent was flared for 1.5 cm at both ends, with a 1 cm raised bank located 1 cm in from each flared end. The main outcome of this study was the rate of stent migration, and secondary outcomes were the rate of recurrent biliary obstruction (RBO), the time to RBO, the frequencies of complications, and overall survival. Results: Of the 31 patients with initial drainage, stent migration occurred in four (12.9%, 95% confidence interval, 5.1% to 29.0%), with a mean time of 131 days. RBO occurred in 18 (58%), with a median time to RBO of 107 days. Following previous C-SEMS migration, seven of 10 patients (70%) did not experience m-CZS migration until death. Conclusions: m-CZSs with antimigration properties effectively, although not completely, prevented stent migration after stent insertion. [ABSTRACT FROM AUTHOR]

Introduction. Percutaneous liver biopsy and histomorphological analysis of liver tissue is an important diagnostic procedure in the investigation of neonates and infants with cholestatic syndrome. This study has been aimed at determining whether there is a difference in the incidence of complications after liver biopsy performed by Menghini technique using a needle of 1.6 mm as compared to 1.2 mm diameter and if there is a difference in the sample representativeness of liver tissue after liver biopsy with those two different needle diameters. Material and Methods. We retrospectively reviewed medical records of 156 neonates and infants with chronic cholestatic syndrome, hospitalized at Mother and Child Health Care Institute, Serbia. Results. One hundred and fifty six children underwent liver biopsy. There was no difference in frequency of liver biopsy complications performed by Menghini technique using a larger diameter needle (1.6 mm) as compared to 1.2 mm diameter. The mortality after liver biopsy was 0% while the frequency of complications with a needle of 1.6 mm in diameter was 3.8%, the percentage of serious complications being 0.6%. Among the samples of liver biopsy taken by a larger diameter needle (1.6 mm), 108/109 were representative samples (> 5 portal areas), and among those taken by a smaller diameter needle (1.2 mm), 34/47 were representative samples. Of 109 liver biopsy specimens obtained by Menghini technique using a needle of larger diameter (1.6 mm), 109/109 were representative samples (> 3 portal areas), and when a smaller diameter needle (1.2 mm) was used, 42/47 were representative samples. Conclusion. Our results indicate that the sample representativeness was significantly higher when a larger diameter needle was used for liver biopsy by Menghini technique; however, no difference in the incidence of complications was observed. [ABSTRACT FROM AUTHOR]

Merli L, Grimaldi C, Monti L, Nobili V, Francalanci P, de Ville de Goyet J. Liver transplantation for refractory severe pruritus related to widespread multifocal hepatic focal nodular hyperplasia (FNH) in a child: Case report and review of literature. Pediatr Transplantation 2011. © 2011 John Wiley & Sons A/S. Abstract: FNH is a rare and benign tumor of the liver. It is not a conventional indication for liver transplantation, and no transplant for FNH in a child has been reported to date. Multifocal FNH growing in adolescent age to a widespread tumor invading the whole liver and associated with severe refractory pruritus was an unusual indication for transplantation in a 13-yr-old girl. The operation and the follow-up were uneventful, allowing full recovery and disappearance of pruritus. [ABSTRACT FROM AUTHOR]

We report on how adefovir-induced membranous nephropathy related to hepatitis B was caused by lamivudine-resistant virus after a liver transplant due to Byler's disease. In 1980, a 2-year-old girl was diagnosed with Byler's disease (familial progressive familial intrahepatic cholestasis). In 1994 (at the age of 14 years) she underwent a liver transplant with her father as the donor. In 2003, hematuria and proteinuria appeared and shortly afterwards her renal function rapidly decreased. A renal biopsy showed atypical membranous nephropathy, which suggested the possibility of a secondary renal disease. The patient had suffered from chronic hepatitis type B (HBV). In 2001 she was administered lamivudine which is an antiviral drug; it was around this time that hematuria and proteinuria appeared as well as an increase of the virus titer. We believed the HBV-related membranous nephropathy was the cause of the virus titer and the renal histology. We concluded that the patient's condition had become resistant to lamivudine medication. Therefore, in February 2004 we administered adefovir, a new drug at the time, to treat the HBV. In April 2004, the HB virus titer decreased and the hematuria and proteinuria decreased. The patient's renal function also showed improvement. HBV-associated nephropathy is caused by HBV antigen deposition in the glomeruli. Generally the first choice of treatment is antivirus therapy. There are many reports demonstrating that administration of interferon and lamivudine are effective; however, there are few reports that show adefovir as an effective treatment for HBV-associated nephropathy. [ABSTRACT FROM AUTHOR]

Background & Aims: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is due to mutations in ABCB11 encoding the canalicular bile salt export pump (BSEP) of hepatocyte. Liver transplantation is usually required. 4-phenylbutyrate (4-PB) has been shown in vitro to retarget some selected mutated apical transporters. After an in vitro study in a hepatocellular polarized line, we tested 4-PB treatment in a child with a homozygous p.T1210P BSEP mutation. Methods: Can 10 cells were transfected with plasmids encoding wild type Bsep (Bsepwt) and mutated p.T1210P Bsep (BsepT1210P), both tagged with GFP. Then, cells were treated with 4-PB at 37 or 27°C, immunostained and analyzed using confocal microscopy. The child received 4-PB orally in two divided doses and BSEP liver immunostaining was performed before and after 4-PB as well as bile analysis. Results: In Can 10 cells, in contrast to Bsepwt-GFP, BsepT1210P-GFP was not detected at the canalicular membrane but in the endoplasmic reticulum. 4-PB as well as incubation at 27°C partially corrected BsepT1210P–GFP targeting to the canalicular membrane, while combined treatments resulted in normal canalicular localization. In the child, we showed that 4-PB improved clinical and biological parameters of cholestasis and liver function. Also, canalicular expression of p.T1210P BSEP mutant was partially corrected as was biliary bile acid excretion. Conclusions: The results illustrate for the first time the therapeutic potential of a clinically approved chaperone drug in a selected patient with PFIC2 and support that bile secretion improvement might be due to the ability of 4-PB to retarget mutated BSEP. [ABSTRACT FROM AUTHOR]

Objectives: to determine the survival rate and type of morbidity during the first year of life of infants with necrotizing enterocolitis (NEC) who underwent to surgical treatment. Methods: a comparative and descriptive study was performed. Thirty two children with NEC (19 deaths and 13 survivals) who underwent to surgery during neonatal period were studied. Perinatal conditions, surgical procedures and findings, morbidity and survival rate during the first year of life were registered. Results: all patients underwent to laparotomy, except three patients who died and were managed with peritoneal drainage only. During the first year of life, cholestasis and intestinal obstruction were the main causes of morbidity in survivals and deaths. Survival rate during neonatal period was 78 %, and 40.6 % in the first year of life. Conclusions: morbidities during the first year of life were related to surgery. In this series, there was a high survival rate in neonatal period, which diminished in the first year of life. [ABSTRACT FROM AUTHOR]

Symptomatic choledocholithiasis in infancy is not common. It usually presents with jaundice and acholic stools and is diagnosed on abdominal ultrasonography. Favourable outcome of conservative management has been reported, but specific management guidelines are not well defined in the literature. We describe three cases using a combination of ursodeoxycholic acid and antibiotics as a treatment paradigm, which could potentially negate more invasive treatment. All three patients had ultrasonography proven choledocholithiasis with concomitant obstructive liver function test. They were treated with a combination of ursodeoxycolic acid and antibiotics. Patient 1 had an Escherichia coli urinary tract infection and was treated with oral bactrim. Intravenous amoxicillin, gentamicin and metronidazole were used for the other two patients. All three patients responded with a return to normal-coloured stools within 48 h of combination treatment. Repeat ultrasonography done within 11 days after the first study for all three patients confirmed complete resolution of choledocholithiasis. It is postulated that this improvement is as a result of a reduction in inflammation and oedema, associated with a low-grade cholangitis, following antibiotic treatment. This is coupled with improved bile flow with ursodeoxycholic acid therapy. The findings suggest the potential application of this safe, non-invasive therapeutic strategy as initial management in infants with this condition. A follow-up prospective randomised controlled trial may be an answer to prove the validity of this observation but due to the rarity of this problem, it would be a challenge to recruit sufficient number of patients. [ABSTRACT FROM AUTHOR]

This study was aimed to determine prevalence of Vitamin D deficiency and rickets in children with cholestatic liver diseases. Forty eight children with established cholestatic liver disease who referred to gastrointestinal clinic of Children Medical Center (Tehran, Iran) between April 2010 and March 2011 were enrolled in a cross-sectional study. Laboratory analysis including calcium, phosphate, albumin, total and direct bilirubin, aminotransferases, alkalinephosphatase (ALP), prothrombin time (PT), parathyroid hormone (PTH), total protein determined by routine laboratory techniques. Mean age of participants was 299.1 ± 676.8 days (range 2-3600 days) whereas twenty one were female (43.8%) and 27 (56.3%) were male. Twenty two (45.8%) had evidences of rickets in X-ray evaluation. Three children with rickets and two with normal X-ray had Vitamin D deficiency while ten in rickets group and 16 in normal group had Vitamin D insufficiency. The main underlying diseases were anatomical biliary atresia in cases with rickets and idiopathic in other group. Rickets and Vitamin D deficiency should be considered in chronic cholestatic children. [ABSTRACT FROM AUTHOR]

During the newborn and infancy period, it is an important to demonstrate the condition which causes cholestatic liver diseases. If direct bilirubin level is more than 20% of total bilirübin, it is defined as cholestasis. Especially early diagnosis of diseases including biliary atresia, tyrosinaemia, galactosaemia is crucial for prevention of permanent damage in the future and for benefit from early treatment. Therefore, total, direct and indirect bilirübin levels should be measured in all newborns with jaundice lasting more than two weeks. If 20% of total bilirubin is direct bilirubin, liverrelated disorders should be questioned. In this review, we aimed to show which clinical and laboratory features should be considered to demonstrate the cause of cholestatic diseases. (Turk Arch Ped 2012; 47: 1-7) [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Cholestatic liver disease (CLD) is the main indication for liver transplantation in children. This retrospective study evaluated the outcomes of living donor liver transplantation (LDLT) in children with CLD. Methods: One hundred fifty-nine children with CLD who underwent 164 LDLT between May 2001 and May 2011 were evaluated. Their original diseases were biliary atresia (n = 145, 91%), Alagille syndrome (n = 8, 5%), primary sclerosing cholangitis (n = 2), and the others (n = 4). The mean age and body weight of the recipients at LDLT was 42 ± 53 months and 14.0 ± 11.0 kg, respectively. Results: Parents were living donors in 98%. The left lateral segment was the most common type of graft (77%). There were no reoperations and no mortality in any living donor. Recipients'' postoperative surgical complications consisted mainly of hepatic arterial problems (7%), hepatic vein stenosis (5%), portal vein stenosis (13%), biliary stricture (18%), intestinal perforation (3%). The overall rejection rate was 31%. Cytomegalovirus infection and Epstein-Barr virus disease were observed in 26% and 5%, respectively. Retransplantation was performed five times in four patients; the main cause was hepatic vein stenosis (n = 3). Four patients died; the main cause was gastrointestinal perforation (n = 2). The body height of Alagille syndrome patients less than 2 years old significantly improved compared with older patients after LDLT. The 1-, 5-, and 10-year patient survival rates were 98%, 97%, and 97%, respectively. Conclusions: LDLT for CLD is an effective treatment with excellent long-term outcomes. [Copyright &y& Elsevier]

Abstract: Background/Purpose: The surgical treatment for patients with progressive familial intrahepatic cholestasis (PFIC) is either liver transplantation (LTX) or partial external biliary diversion (PEBD). Both procedures achieve a good short-term outcome. However, the treatment strategy for these children remains controversial because the long-term outcome after PEBD is unknown. The aim of our study was to assess the long-term outcome and complications after PEBD in our institution. Methods: We retrospectively analyzed the characteristics of all patients with PFIC undergoing PEBD in our department from 1994 to 2008. The course of serum bile acids, pruritus, and liver enzymes was assessed in a regular follow-up. Results: Twenty-four patients underwent PEBD. Thirteen patients (54%) improved significantly, with a normalization of serum bile acids (P < .001 vs postoperatively) and lessened pruritus (P < .05 vs preoperatively) at 12 months after PEBD. None of these patients showed progression of cholestasis during a median follow-up of 9.8 years (range, 1.6-14.3 years). Partial external biliary diversion failed to normalize bile acids in 11 patients, of whom 9 required secondary LTX at a 1-year follow-up, with a median interval of 1.9 years (range, 0.5-3.8 years). All 7 patients (100%) with liver cirrhosis at the time of PEBD and 2 of 17 patients without cirrhosis (12%) required secondary LTX (P < .001). Conclusions: Clinical improvement with normalization of serum bile acids within 1 year was associated with an excellent long-term outcome in patients with PEBD. The presence of liver cirrhosis at the time of PEBD indicated an unfavorable outcome. Thus, we recommend primary LTX only in PFIC patients with liver cirrhosis. [Copyright &y& Elsevier]

Myotubular myopathy is a rare congenital disease characterized by hypotonia and respiratory compromise at birth in affected males. It causes high neonatal mortality. Most surviving newborns need prolonged ventilation and have significantly delayed motor development. Although all patients with congenital myotubular myopathy have respiratory problems such as atelectasis and recurrent lung infections, concurrent neonatal intrahepatic cholestasis is rare. We report a newborn with a myotubular myopathy, ventilator dependency, recurrent lung infections and pleural effusion, facial diplegia, ophthalmoplegia, and progressive intrahepatic cholestasis. A genetic study showed a novel mutation of the MTM1gene: c.1142 G>A (R381Q). We suggest that physicians consider probable concurrent disorders of other organs in neonates with congenital myotubular myopathy. [ABSTRACT FROM PUBLISHER]

Abstract: Objective: The aim of this study was to review evidence-based data addressing key clinical questions regarding parenteral nutrition–associated cholestasis (PNAC) and parenteral nutrition–associated liver disease (PNALD) in children. Data Source: Data were obtained from PubMed, Medicine databases of the English literature (up to October 2010), and the Cochrane Database of Systematic Reviews. Study Selection: The review of PNAC/PNALD has been divided into 4 areas to simplify one''s understanding of the current knowledge regarding the pathogenesis and treatment of this disease: (1) nonnutrient risk factors associated with PNAC, (2) PNAC and lipid emulsions, (3) nutritional (nonlipid) considerations in the prevention of PNAC, and (4) supplemental medications in the prevention and treatment of PNAC. Results: The data for each topic area relevant to the clinical practice of pediatric surgery were reviewed, evaluated, graded, and summarized. Conclusions: Although the conditions of PNAC and PNALD have been well recognized for more than 30 years, only a few concrete associations and treatment protocols have been established. [Copyright &y& Elsevier]

Abstract: Microvillous inclusion disease is a congenital intestinal epithelial cell disorder leading to lifelong intestinal failure. In this report, we discuss the use of a fish oil–based lipid emulsion in the treatment of 3 patients with microvillous inclusion disease who developed parenteral nutrition–associated liver disease. [Copyright &y& Elsevier]