Search

Objective: Maralixibat, an ileal bile acid transporter inhibitor, is the first drug approved by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in patients aged ≥3 months with Alagille syndrome (ALGS). Approval was based on reductions in pruritus from the pivotal ICONIC trial, information from two additional trials (ITCH and IMAGO), and long-term extension studies. Although participants in these trials met strict inclusion and exclusion criteria, patients have received maralixibat under broader circumstances as part of an expanded access program or commercially. The expanded access and postapproval settings inform a real-world understanding of effectiveness and safety. The objective was to report on the use of maralixibat in the real-world setting in eight patients who otherwise would not have met entrance criteria for the clinical trials, providing unique insights into its effectiveness in the management of ALGS., Methods: We reviewed records of patients with ALGS who received maralixibat but would have been excluded from trials due to surgical biliary diversion, reduction of antipruritic/cholestatic concomitant medications, administration of medication through a gastrostomy or nasogastric tube, or use in patients under consideration for transplantation., Results: Maralixibat appeared to be effective with reductions in pruritus compared to baseline. Consistent with clinical trials, maralixibat was well tolerated without appreciable gastrointestinal complications. Liver enzyme elevations were observed but were interpreted as consistent with normal fluctuations observed in ALGS, with no increases in bilirubin., Conclusion: Maralixibat may be effective and well tolerated in patients with ALGS in broader clinical contexts than previously reported., (© 2024 The Authors. Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: This study aims to report liver transplantation (LT) outcomes and cardiac disease manifestations in children with Alagille Syndrome (ALGS) in a contemporary cohort., Methods: This project used a novel linkage between the Scientific Registry of Transplant Recipients and Pediatric Health Information System databases. All children ≤21 years undergoing a first LT were identified (2002-2018). The presence of ALGS was identified using Scientific Registry of Transplant Recipients diagnosis coding. Subjects with ALGS were age-matched 1:2 to LT recipients with biliary atresia (BA). The Kaplan-Meier method and log-rank test were used to compare patient and graft survival between groups., Results: A total of 156 LT recipients with ALGS were identified and matched to a control group of 312 LT recipients with BA. Children with ALGS were more likely to have an associated diagnosis of congenital heart disease (80.7% vs 16.4%; P = 0.001) compared with children with BA with 40 (25.6%) children with AGS requiring cardiac intervention (catheter or surgical) either before or after LT. Those patients with ALGS had a higher creatinine, laboratory MELD, and PELD scores before LT. No difference was observed regarding patient or graft survival between children with ALGS and children with BA ( P = 0.08 and P = 0.27, respectively)., Conclusions: Despite increased rate of congenital heart defects and cardiac interventions, higher creatinine, and higher laboratory MELD/PELD scores at time of transplant, this study demonstrates that there is no difference in either patient or graft survival between patients with ALGS and BA., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objective: To evaluate neurodevelopmental status among children with inherited cholestatic liver diseases with native liver and variables predictive of impairment., Methods: Participants with Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), and alpha 1 antitrypsin deficiency (A1AT) enrolled in a longitudinal, multicenter study and completed the Wechsler Preschool and Primary Scale of Intelligence-III or Intelligence Scale for Children-IV. Full Scale Intelligence Quotient (FSIQ) was analyzed continuously and categorically (>100, 85-99, 70-84, <70). Univariate linear regression was performed to study association between FSIQ and risk factors, stratified by disease., Results: Two hundred and fifteen completed testing (ALGS n = 70, PFIC n = 43, A1AT n = 102); median age was 7.6 years (3.0-16.9). Mean FSIQ in ALGS was lower than A1AT (94 vs 101, P = 0.01). Frequency of FSIQ < 85 (>1 standard deviation [SD] below average) was highest in ALGS (29%) versus 18.6% in PFIC and 12.8% in A1AT, and was greater than expected in ALGS based on normal distribution (29% vs 15.9%, P = 0.003). ALGS scored significantly lower than test norms in almost all Wechsler composites; A1AT scored lower on Working Memory and Processing Speed; PFIC was not different from test norms. Total bilirubin, alkaline phosphatase, albumin, hemoglobin, and parental education were significantly associated with FSIQ., Conclusions: Patients with ALGS are at increased risk of lower FSIQ, whereas our data suggest A1AT and PFIC are not. A1AT and ALGS appear vulnerable to working memory and processing speed deficits suggestive of attention/executive function impairment. Malnutrition, liver disease severity, and sociodemographic factors appear related to FSIQ deficits, potentially identifying targets for early interventions., Competing Interests: Conflicts of Interest: D.H.L. reports grant/research support from Abbvie, Gilead, and CF Foundation; he also serves on advisory panels for Merck and Gilead. B.M.K. is a consultant for Mirum, Albireo and Audentes; she has unrestricted educational grants from Mirum and Albireo. V.L.N. is a consultant for Albireo. P.R. reports grants from Gilead, Merck, BMS, AbbVie, Travere Therapeutics, Albireo, and Mirum, Arrowhead; and serving as a consultant for Gilead, Mirum, Albireo, Audentes, and Vertex. R.J.S. reports consulting for Albireo, Mirum/Shire, and Retrophin (all <$10,000 per year). K.M.L. reports consulting for Albireo, Mirum and Retrophin (now known as Travere Therapeutics). The remaining authors report no conflicts of interest. The study sponsors did not have a role in study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the paper for publication., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Aims and Background: Ophthalmic abnormalities are amongst the 5 major criteria required for a diagnosis of Alagille syndrome (ALGS), of which embryotoxon, pseudopapilledema, and hypopigmented retinopathy are the most common. Papilledema with or without intracranial hypertension (ICHT) is rarely described. We report 9 pediatric cases of ALGS with bilateral papilledema, 5 of which were diagnosed with ICHT., Methods: The ophthalmic data from 85 patients with clinically and/or genetically (n = 37) proven ALGS were reviewed. The study inclusion criteria were a positive diagnosis of ALGS and availability of ophthalmic follow-up data. Ophthalmic data from 40 patients after liver transplantation (LT) for other indications were also analyzed., Results: Nine (13.0%) of the 69 patients meeting the inclusion criteria had papilledema. The neurological and neuroimaging results in all 9 patients were normal. These 9 patients were categorized into 4 groups: a nontransplant group (n = 1), a group with pretransplant papilledema persistent after LT (n = 2), a group with papilledema occurring after LT with spontaneous resolution (n = 1), and a group with papilledema and signs of ICHT after LT (n = 5). The patients with ICHT were treated with steroids alone (n = 1) or with acetazolamide (n = 4). A ventriculoperitoneal shunt was placed in 2 of the 5 cases because of progressive visual loss. Pseudopapilledema was present in 10 additional patients (14.5%, 10/69). One (2.5%) of the 40 patients without ALGS developed papilledema after LT., Conclusions: True ICHT may be underdiagnosed in patients with ALGS. Our findings underscore the need for close ophthalmic follow-up before and after LT in these patients.

Objectives: Angiogenic defects secondary to gene mutations of JAG1 and NOTCH2, causing arterial anomalies in Alagille syndrome (AGS), are well described in the literature. The study analyzes the frequency of abdominal arterial anomalies in children with AGS with an emphasis on outcomes following liver transplantation (LT)., Methods: Between 1988 and 2013, 242 children with AGS were treated at our institution. We performed a retrospective analysis of 55 who underwent LT during the study period. Preoperative abdominal arterial findings, operative reports, arterial reconstruction technique, and early as well as late complications following LT were reviewed specifically focusing on arterial thrombosis., Results: Twenty-five patients had preoperative imaging available for analysis. Twelve of these patients showed celiac trunk stenosis (48.0%), 2, a superior mesenteric artery stenosis (8.0%) and one a stenosis of both renal arteries. Twenty patients (36.3%) underwent standard hepatic reconstruction using the native recipient hepatic artery. Thirty-five patients (63.7%) underwent aortic conduit reconstruction (ACR) from the infrarenal aorta using donor arterial conduits. Hepatic artery thrombosis occurred in 9 patients (16.3%). This number was higher in the standard arterial anastomosis group 7/20 (35.0%) than in those with ACR 2/35 (5.7%, P = 0.0079)., Conclusions: In this series, children with AGS pretransplant have a high prevalence of abdominal arterial anomalies. Preoperative abdominal vascular imaging makes it possible to anticipate whether or not a classical arterial revascularization can be performed or whether an ACR is required.

Objectives: Pruritus is a severe symptom accompanying chronic cholestasis. It can be debilitating and difficult to control. In children, first-line treatments are ursodeoxycholic acid and rifampicin. Refractory pruritus may require invasive therapies including liver transplantation. Clinical trials based on small samples of adult patients suggest that serotonin reuptake inhibitors can improve pruritus in cholestatic or uremic disease. We performed a prospective, multicenter study to assess efficiency and safety of the serotonin reuptake inhibitor sertraline in treating children with refractory cholestatic pruritus., Methods: Twenty children experiencing refractory cholestatic pruritus related to Alagille syndrome or progressive familial intrahepatic cholestasis were included from 4 centers between 2007 and 2014, and treated with sertraline at a starting dose of 1 mg · kg · day and thereafter individually adapted up to 4 mg · kg · day. Before and after 3 months with therapy, pruritus was assessed using a visual itching scale graded on 10 points, a skin scratch marks score and a sleeping impairment score., Results: Sertraline was prescribed at a median daily dose of 2.2 mg · kg · day. After 3 months, pruritus improved in 14 out of 20 treated patients, and the median itching score decreased significantly from 8/10 (5-10) to 5/10 (2-10). Likewise, skin scratch marks and sleep quality improved in 9 of these 14 patients. Nonsevere adverse events were reported in 6 children, leading to treatment discontinuation in 3., Conclusion: Our data suggest that sertraline may constitute a useful drug in the management of refractory cholestatic pruritus in children.

Objectives: The aims of the study were to perform a retrospective observational review of the present management and outcome of cholestatic pruritus in children with Alagille syndrome (AGS) at King's College Hospital and to use results to inform appropriate guidelines., Methods: A retrospective review of 62 patients diagnosed as having AGS from January 1995 to November 2010 treated at King's College Hospital was performed. The departmental database of the Paediatric Liver Centre was searched to identify all patients and the clinical records were then analysed., Results: Fifty-one (82.3%) patients experienced pruritus and 50 (80.6%) received antipruritic medication. Ursodeoxycholic acid was the most prescribed drug (n = 40). Other drugs prescribed were rifampicin (n = 39), cholestyramine (n = 18), naltrexone (n = 14), alimemazine (n = 13), nonsedating antihistamine agents (n = 7), ondansetron (n = 5), and phenobarbitone (n = 1). Albumin dialysis using the molecular adsorbent recirculation system was used in 1 patient. Sixteen patients (25.8%) were listed for liver transplantation, and 11 had undergone transplantation by November 2010. Patient survival was high at 95.2%. Pruritus resolved permanently in 39.2% (n = 20) of patients. Fifty-five percent (n = 11) of such patients had undergone liver transplantation. Pruritus was controlled by medication in 41.2% (n = 21). Itching remained a significant problem, affecting quality of life in 19.6% of patients (n = 10)., Conclusions: The management of cholestatic pruritus in AGS is difficult and often suboptimal. Pruritus may remain intractable even with combination medical treatment, and at this stage, surgery or liver transplantation is indicated. At our centre, pruritus was successfully treated in 80.4% of patients with medical and surgical management.

Alagille syndrome (ALGS) is an inherited multisystem disorder in which pancreatic insufficiency (PI) has been regarded a minor but important clinical manifestation. As part of a multicenter prospective study, 42 patients with ALGS underwent fecal elastase (FE) measurement to screen for exocrine PI. FE measurements were normal (>200  μg/g) in 40 (95%) and indeterminate (100-200  μg/g) in 2 (5%). As FE is the most reliable screen for PI, these data suggest that PI is not a prevalent problem in ALGS.

Objective: Fat-soluble vitamin (FSV) deficiencies are common complications in pediatric patients with chronic cholestasis. The aim of the present study was to evaluate the status of FSV deficiencies in patients under present practice and to test the effect of an oral, absorbable, fat-soluble vitamin formulation (OAFSV) in these patients., Methods: We recruited a total of 23 pediatric patients receiving conventional FSV supplementation in a single medical center, with diagnosis of biliary atresia (10), progressive familial intrahepatic cholestasis (9), Alagille syndrome (2), and other conditions (2). Ten patients switched to OAFSV and continued for 3 months. Plasma levels of vitamins A, D, and E and an international normalized ratio (INR) for prothrombin time (PT), a surrogate marker for vitamin K deficiency, were measured., Results: The proportion of patients with FSV A, D, E, and K deficiencies under conventional supplementation was 73.9%, 81.8%, 91.3%, and 20.0%, respectively. In patients with total bilirubin levels ≥3.0  mg/dL, the proportion of at least 1 FSV deficiency was 100%; and the deficiency rates of vitamin A, D, E, and K were 78.6%, 100.0%, 100.0% and 21.4%, respectively. Of the 10 patients receiving standard daily dose of OAFSV for 3 months, no adverse events or overdose effects were found. The rates of vitamin A, D, and E deficiency in the patients receiving OAFSV decreased from 80.0%, 100%, and 100%, respectively, to 70.0%, 60.0%, and 60.0% after 3 months of oral supplementation., Conclusions: High rates of FSV deficiency were found in pediatric patients with chronic cholestasis under present follow-up. OAFSV supplementation is safe and potentially effective in pediatric patients with cholestasis.

Objectives: Alagille syndrome (AGS) frequently presents with neonatal jaundice and can mimic other causes of high gamma-glutamyl transpeptidase (GGT) cholestasis, most notably biliary atresia. As a result infants with AGS may undergo intraoperative cholangiogram and even Kasai procedure. The aim of the study was to assess the hepatic outcomes of children with AGS who underwent the Kasai procedure., Patients and Methods: A retrospective review of the AGS clinical database at the Children's Hospital of Philadelphia was performed to identify clinically defined patients with AGS who underwent a Kasai. A cohort of Alagille control subjects was selected with equivalent symptoms of neonatal jaundice and matched for age and presence of cardiac anomaly. JAGGED1-mutation analysis was performed on available samples. Clinical courses were reviewed. Fisher exact and t tests were used for analysis., Results: Of the 430 patients with AGS, 19 underwent a Kasai procedure (K). The control cohort (C) consisted of 36 patients. Total bilirubin measured between 6 and 10 weeks of age in each cohort was equivalent (K: 9.6 mg/dL, C: 8.7 mg/dL); GGT levels were higher in the control group (K:493.4 U/L, C:574.4 U/L). Of note, the Kasai cohort had a significantly larger number of liver transplants (K: 9 [47.3%], C: 5 [13.9%], P = 0.01) and sustained higher mortality (K: 6 [31.6%], C: 1 [2.8%], P = 0.005). There was no genotype-phenotype correlation between the mutations identified and patients who underwent Kasai., Conclusions: These data suggest that the Kasai procedure, although appropriate for children with biliary atresia, does not benefit children with AGS and actually appears to worsen outcome. The current data suggest that the Kasai is not a marker for underlying severe liver disease, but the procedure itself may have a detrimental effect on outcome. An appropriate medical evaluation and particular consideration of AGS is essential before surgical referral in infants with high GGT cholestasis.

Objectives: : In this retrospective study, we aimed to determine the incidence and distribution of fractures in patients with Alagille syndrome, 1 of the leading inherited causes of pediatric cholestatic liver disease., Materials and Methods: : Surveys regarding growth, nutrition, and organ involvement were distributed to patient families in the Alagille Syndrome Alliance of the Children's Hospital of Philadelphia research database. Patients with a history of fracture were identified by their response to 1 question, and details characterizing each patient's medical, growth, and fracture history were obtained through chart review and telephone contact., Results: : Twelve of 42 patients (28%) reported a total of 27 fractures. Patients experienced fractures at a mean age of 5 years, which contrasts with healthy children, in whom fracture incidence peaks in adolescence. Fractures occurred primarily in the lower extremity long bones (70%) and with little or no trauma (84%). Estimated incidence rate calculations yielded 399.6 total fractures per 10,000 person-years (95% confidence interval 206.5, 698.0) and 127.6 femur fractures per 10,000 person-years (95% confidence interval 42.4, 297.7). There were no differences in sex, age distribution, or organ system involvement between the fracture and no-fracture groups., Conclusions: : Children with Alagille syndrome may be at risk for pathologic fractures, which manifest at an early age and in a unique distribution favoring the lower extremity long bones. Although this preliminary study is limited by small sample size and potential ascertainment bias, the data suggest that larger studies are warranted to further characterize fracture risk and explore factors contributing to bone fragility in these children.

Alagille syndrome is a highly variable, autosomal dominant disorder that affects the liver, heart, eyes, face, skeleton, kidneys, and vascular system. Much has been learned about the genetics of this disorder, which is caused primarily by mutations in the Notch signaling pathway ligand JAGGED1; however, the medical management of this condition is complex and continues to generate controversy. The significant variability of organ involvement requires the managing physician to have an understanding of the breadth and interplay of the variable manifestations. Furthermore, the liver disease in particular requires an appreciation of the natural history and evolution of the profound cholestasis.

Background: Partial external biliary diversion (PEBD) is a promising treatment for children with progressive familial intrahepatic cholestasis (PFIC) and Alagille disease. Little is known about long-term outcomes., Patients and Methods: A retrospective chart review of all patients undergoing PEBD in the University Medical Centre of Groningen (UMCG)., Results: Between 2000 and 2005, PEBD was performed on 14 children with severe pruritus (PFIC 11, mean age 5.3 +/- 4.4 years; Alagille 3, mean age 7.4 +/- 4.2 years). Stature was <-2 standard deviation score (SDS) in 50%. Median preoperative serum bile salt concentration was 318 micromol/L (range 23-527 micromol/L). Twenty-nine percent had severe liver fibrosis and 71% had mild or moderate fibrosis. Median follow-up was 3.1 years (range 2.0-5.7 years). One patient (7%) underwent a liver transplantation at 3.2 years post-PEBD. Two years postoperatively, 50% were without pruritus and 21% had mild pruritus. In 29%, pruritus had not diminished; 3 of them had severe fibrosis preoperatively. In patients with mild or moderate fibrosis, PEBD decreased serum bile salts (105 micromol/L [range 8-269 micromol/L] 2 years postoperatively). Bile salts did not decrease in the patients with severe fibrosis. Two years after PEBD, 27% had a stature below -2 SDS., Conclusions: At median follow-up of 3.1 years after PEBD, pruritus has been relieved in 75%. Bile salts level and growth are improved in most patients. Longer follow-up is needed to determine whether PEBD can postpone or avoid the demand for liver transplantation.

Background: Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder defined by developmental abnormalities of the liver, heart, eye and skeleton. Although visual problems are recognised, the severity of visual loss and its link with idiopathic intracranial hypertension (IIH) has not been reported., Aim: To review the incidence of visual loss and IIH in children with AGS managed at a National Paediatric Liver Unit between 1989 and 2004., Subjects and Methods: Retrospective case note review of children who fulfilled criteria for diagnosis of AGS and had an ophthalmic examination by a paediatric ophthalmologist., Results: Fifty-five children with AGS were evaluated. Of these, 41 children fulfilled diagnostic criteria and had a documented ophthalmic examination. Six children had undergone liver transplantation. Three children had a definite diagnosis of IIH, 2 of whom developed postliver transplant. All 3 were treated medically, but 1 child with IIH required lumboperitoneal shunting. All 3 children with definite IIH have normal vision after treatment. Another child with probable undiagnosed IIH has bilateral optic atrophy and is registered blind. Two children with AGS are registered partially sighted, one with rod cone dystrophy and the other with pigmentary retinopathy and right disc atrophy., Summary: Although visual abnormalities are well described in children with AGS, a minority of children have significant progressive visual loss. Idiopathic intracranial hypertension has been identified as a potentially treatable precipitating factor., Conclusions: We recommend annual fundoscopy in the follow-up of children with AGS to facilitate early detection and appropriate management of IIH to prevent visual loss.

Objectives: To define the spectrum of intracranial events and cerebrovascular lesions in patients with Alagille syndrome using magnetic resonance imaging with angiography of the head and medical histories and to correlate the presence of lesions with the clinical outcome of bleeding or ischemic intracranial events., Methods: 26 patients with Alagille syndrome underwent magnetic resonance imaging with angiography of the head; 22 had no symptoms and underwent study for screening purposes and 4 were symptomatic with neurologic changes. The results of studies and the history of ischemic intracranial events were reviewed., Results: Cerebrovascular abnormalities were detected in 10 of 26 (38%) patients (9 by head magnetic resonance imaging with angiography and 1 by necropsy). The findings included stenoses of the internal carotid arteries unilaterally (n = 5) or bilaterally (n = 3), basilar artery aneurysm (n = 1) and middle cerebral artery aneurysm (n = 1). Among the 9 patients with cerebrovascular abnormalities detected by magnetic resonance imaging with angiography, 5 had no symptoms (23%, 5 of 22) and 4 were symptomatic. Thus, 100% of symptomatic patients had detected abnormalities and 23% of screened, asymptomatic patients had detected anomalies. Screening magnetic resonance imaging with angiography failed to detect vascular anomalies in 2 asymptomatic patients who had fatal ischemic intracranial events years later. There was evidence of progression of vascular abnormalities in 4 patients. Ischemic intracranial events occurred in 10 of 26 (38%) patients and were associated with cerebrovascular abnormalities in 6 of 10 patients., Conclusion: The cerebral vasculopathy of Alagille syndrome predominantly involves the internal carotid arteries. It is more prevalent than would be suggested by the number of symptomatic individuals, appears to be progressive and shares many similarities with moyamoya. Magnetic resonance imaging with angiography is useful to detect these lesions and may have a valuable role in screening for treatable lesions such as aneurysms.

Background: There is controversy about the potential risk of sustained high concentrations of cholesterol and triglyceride in patients with cholestatic chronic liver disease. However, it is currently accepted that cholesterol-lowering therapy may reduce morbidity and mortality rates in hypercholesterolemic patients without preexisting coronary heart disease, as well as in those with coronary heart disease. The objective of this study was to evaluate the effect of cholestyramine on the serum lipid profile of a group of children with Alagille syndrome and hypercholesterolemia., Methods: Five children with Alagille syndrome and basal serum cholesterol concentrations greater than 230 mg/dL were included. Total serum cholesterol, triglyceride, low-density, and high-density lipoprotein cholesterol concentrations were measured on days 0, 10, 20, and 30 after the administration of oral cholestyramine 100, 250, and 500 mg(kg.d), respectively. Lipid fractions were reported as mean +/- 1 SD. Statistical analysis was performed with Friedman analysis of variance., Results: The basal values and those of the three 10-day subsequent 100-, 250-, and 500-mg(kg.d) cholestyramine periods were as follows: total cholesterol: 327.6 +/- 77.1, 305.4 +/- 52.1, 290.6 +/- 24.1, and 320.6 +/- 32.3, respectively (P = 0.668); triglyceride: 136.4 +/- 14.6, 144.8 +/- 41.3, 161 +/- 30.9, and 165.4 +/- 40.7, respectively (P = 0.356); low-density lipoprotein cholesterol: 245.4 +/- 57.8, 239.8 +/- 48.6, 242.2 +/- 68.6, and 246.4 +/- 49.5, respectively (P = 0.782); and high-density lipoprotein cholesterol: 44.4 +/- 11.2, 41.8 +/- 12.8, 44.6.2 +/- 13.2, and 47 +/- 8.5, respectively (P = 0.431)., Conclusion: Under the conditions of the current study, no significant effect of variable doses of cholestyramine could be demonstrated on the serum lipid profile of a series of children with Alagille syndrome. While the controversy on the potential atherogenic risk of low-density lipoprotein hypercholesterolemia in patients with chronic liver disease persists, new, prospective pharmacologic or nutritional trials are required.

Background: Magnesium deficiency may contribute to the metabolic bone disease that complicates chronic cholestatic liver disease. We hypothesized that magnesium deficiency alters vitamin D metabolism by decreasing parathyroid hormone (PTH) response, resulting in decreased serum osteocalcin and decreased bone accretion., Methods: Nine subjects, age 3-22 years, with cholestatic liver disease were evaluated with the magnesium retention test. The response of PTH, 1,25(OH)2 vitamin D, and osteocalcin to provocative stimuli and dual x-ray absorptiometry measurement of bone mineral density (BMD) of the lumbar spine were assessed. Thereafter, subjects were treated with oral magnesium supplements., Results: All nine subjects were magnesium depleted. Repletion with magnesium was successful in seven subjects, and required 4 to 31 (median 14) months with doses of 6 to 34 (median 11) mg/kg/day. Baseline serum PTH was significantly reduced in the cholestatic subjects compared to 15 age-matched controls. Comparison of baseline to repleted provocative testing was performed in six Mg-repleted subjects. Osteocalcin response increased significantly (p = 0.048) with repletion, while PTH response increased (p = 0.061). Lumbar spine BMD increased modestly with repletion (p = 0.093)., Conclusions: This preliminary report suggests that magnesium depletion is extremely common in children with chronic cholestasis. We speculate that magnesium supplementation may be warranted to forestall the progression of metabolic bone disease in chronic cholestasis.