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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, 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.

Malnutrition in children with chronic cholestasis is a prevalent issue and a major risk factor for adverse outcomes. Fat soluble vitamin (FSV) deficiency is an integral feature of cholestatic disease in children, often occurring within the first months of life in those with neonatal cholestasis and malnutrition. This review focuses on FSVs in cholestasis, with particular emphasis on a practical approach to surveillance and supplementation that includes approaches that account for differing local resources. The overarching strategy suggested is to incorporate recognition of FSV deficiencies in cholestatic children in order to develop practical plans for close monitoring and aggressive FSV repletion. Routine attention to FSV assessment and supplementation in cholestatic infants will reduce long periods of inadequate levels and subsequent adverse clinical sequalae.

OBJECTIVES Cholestasis is caused by a wide variety of etiologies, often genetic in origin. Broad overlap in clinical presentations, particularly in newborns, renders prioritizing diagnostic investigations challenging. In this setting, a timely, comprehensive assessment using a multigene panel by a clinical diagnostic laboratory would likely prove useful. We summarize initial findings from a testing program designed to discover genetic causes of cholestasis. METHODS A neonatal/adult sequencing panel containing 66 genes (originally 57; nine added March 2017) relevant to cholestasis was used. A broad range of eligible patients were enrolled with current/history of cholestasis without an identified cause, or unexplained chronic liver disease. DNA sequencing utilized a custom-designed capture library, and variants were classified and reported as benign, likely benign, variant of unknown significance (VOUS), likely pathogenic (LP), or pathogenic (P), according to the clinical interpretation workflow at EGL Genetics (Tucker, GA). RESULTS A total of 2433 samples were submitted between February 2016 and December 2017; 2171 results were reported. Median turnaround time was 21 days. Results from the 2171 subjects (57%

Osteopenia and bone fractures are significant causes of morbidity in children with cholestatic liver disease. Dual-energy X-ray absorptiometry (DXA) analysis was performed in children with intrahepatic cholestatic diseases who were enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis in the Childhood Liver Disease Research Network. DXA was performed on participants aged >5 years (with native liver) diagnosed with bile acid synthetic disorder (BASD), alpha-1 antitrypsin deficiency (A1AT), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Weight, height, and body mass index Z scores were lowest in CIC and ALGS. Total bilirubin (TB) and serum bile acids (SBA) were highest in ALGS. Bone mineral density (BMD) and bone mineral content (BMC) Z scores were significantly lower in CIC and ALGS than in BASD and A1AT (P < 0.001). After anthropometric adjustment, bone deficits persisted in CIC but were no longer noted in ALGS. In ALGS, height-adjusted and weight-adjusted subtotal BMD and BMC Z scores were negatively correlated with TB (P < 0.001) and SBA (P = 0.02). Mean height-adjusted and weight-adjusted subtotal BMC Z scores were lower in ALGS participants with a history of bone fractures. DXA measures did not correlate significantly with biliary diversion status. Conclusion: CIC patients had significant bone deficits that persisted after adjustment for height and weight and generally did not correlate with degree of cholestasis. In ALGS, low BMD and BMC reference Z scores were explained by poor growth. Anthropometrically adjusted DXA measures in ALGS correlate with markers of cholestasis and bone fracture history. Reduced bone density in this population is multifactorial and related to growth, degree of cholestasis, fracture vulnerability, and contribution of underlying genetic etiology.

Vitamin D-deficiency rickets, not responding to large treatment doses of oral vitamin D, suggest rare receptor mutations, malabsorption, or hepatobiliary dysfunction. We present a set of twins of Hispanic origin who presented with refractory vitamin D-deficiency rickets and failure to thrive (FTT) at 6 months of age. On follow-up, mild elevations in serum alanine transaminases and normal aspartate aminotransferase were noted. Subsequently, patients manifested fat-soluble vitamin deficiencies. More targeted evaluations revealed a diagnosis of 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency. Treatment with oral bile acid replacement with cholic acid resolved rickets and promoted weight gain. Bile acid synthesis disorders should be suspected in refractory rickets in infancy, particularly in a clinical setting of FTT, even in the absence of substantial abnormalities in liver-function tests.

OBJECTIVES To advance our understanding of monogenic forms of intrahepatic cholestasis. METHODS Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data. RESULTS Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported. CONCLUSIONS In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.

Background Biallelic variants in HSD3B7 cause 3β-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) deficiency, a life-threatening but treatable liver disease. The goal of this study was to obtain detailed information on the correlation between the genotype and phenotype of HSD3B7 deficiency and to report on responses to primary bile acid therapy. Methods The medical records of a cohort of 39 unrelated patients with genetically and biochemically confirmed HSD3B7 deficiency were examined to determine whether there exist genotype-phenotype relationships in this bile acid synthesis disorder. Results In all, 34 of the 44 variants identified in HSD3B7 were novel. A total of 32 patients presented early with neonatal cholestasis, and 7 presented after 1-year of age with liver failure (n = 1), liver cirrhosis (n = 3), cholestasis (n = 1), renal cysts and abnormal liver biochemistries (n = 1), and coagulopathy from vitamin K1 deficiency and abnormal liver biochemistries (n = 1). Renal lesions, including renal cysts, renal stones, calcium deposition and renal enlargement were observed in 10 of 35 patients. Thirty-three patients were treated with oral chenodeoxycholic acid (CDCA) resulting in normalization of liver biochemistries in 24, while 2 showed a significant clinical improvement, and 7 underwent liver transplantation or died. Remarkably, renal lesions in 6 patients resolved after CDCA treatment, or liver transplantation. There were no significant correlations between genotype and clinical outcomes. Conclusions In what is the largest cohort of patients with HSD3B7 deficiency thus far studied, renal lesions were a notable clinical feature of HSD3B7 deficiency and these were resolved with suppression of atypical bile acids by oral CDCA administration.

Background Zellweger spectrum disorders (ZSDs) are a rare, heterogenous group of autosomal recessively inherited disorders characterized by reduced peroxisomes numbers, impaired peroxisomal formation, and/or defective peroxisomal functioning. In the absence of functional peroxisomes, bile acid synthesis is disrupted, and multisystem disease ensues with abnormalities in the brain, liver, kidneys, muscle, eyes, ears, and nervous system. Main body Liver disease may play an important role in morbidity and mortality, with hepatic fibrosis that can develop as early as the postnatal period and often progressing to cirrhosis within the first year of life. Because hepatic dysfunction can have numerous secondary effects on other organ systems, thereby impacting the overall disease severity, the treatment of liver disease in patients with ZSD is an important focus of disease management. Cholbam® (cholic acid), approved by the U.S. Food and Drug Administration in March 2015, is currently the only therapy approved as adjunctive treatment for patients with ZSDs and single enzyme bile acid synthesis disorders. This review will focus on the use of CA therapy in the treatment of liver disease associated with ZSDs, including recommendations for initiating and maintaining CA therapy and the limitations of available clinical data supporting its use in this patient population. Conclusions Cholbam is a safe and well-tolerated treatment for patients with ZSDs that has been shown to improve liver chemistries and reduce toxic bile acid intermediates in the majority of patients with ZSD. Due to the systemic impacts of hepatic damage, Cholbam should be initiated in patients without signs of advanced liver disease.

Cholestasis is caused by a wide variety of etiologies, often genetic in origin. Broad overlap in clinical presentations, particularly in newborns, renders prioritizing diagnostic investigations challenging. In this setting, a timely, comprehensive assessment using a multigene panel by a clinical diagnostic laboratory would likely prove useful. We summarize initial findings from a testing program designed to discover genetic causes of cholestasis.A neonatal/adult sequencing panel containing 66 genes (originally 57; nine added March 2017) relevant to cholestasis was used. A broad range of eligible patients were enrolled with current/history of cholestasis without an identified cause, or unexplained chronic liver disease. DNA sequencing utilized a custom-designed capture library, and variants were classified and reported as benign, likely benign, variant of unknown significance (VOUS), likely pathogenic (LP), or pathogenic (P), according to the clinical interpretation workflow at EGL Genetics (Tucker, GA).A total of 2433 samples were submitted between February 2016 and December 2017; 2171 results were reported. Median turnaround time was 21 days. Results from the 2171 subjects (57%1 year old) included 583 P variants, 79 LP variants, and 3117 VOUS; 166 P/LP variants and 415 VOUS were novel. The panel's overall diagnostic yield was 12% (n = 265/2171) representing 32 genes. The top five genetic diagnoses for the group, in order: JAG1 + NOTCH2 (Alagille syndrome), ABCB11, SERPINA1, ABCB4, and POLG.These findings support the utility of comprehensive rapid multigene testing in diagnosing cholestasis and highlight the evolving understanding of genetic variants contributing to the pathogenesis of cholestasis.

Bile acids are synthesized by the liver from cholesterol through a complex series of reactions involving at least 14 enzymatic steps. A failure to perform any of these reactions will block bile acid production with failure to produce "normal bile acids" and, instead, result in the accumulation of unusual bile acids and intermediary metabolites. Failure to synthesize bile acids leads to reduced bile flow and decreased intraluminal solubilization of fat and fat-soluble vitamins. In some circumstances, the intermediates created because of blockade in the bile acid biosynthetic pathway may be toxic to hepatocytes. Nine recognized inborn errors of bile acid metabolism have been identified that lead to enzyme deficiencies and impaired bile acid synthesis in infants, children, and adults. Patients may present with neonatal cholestasis, neurologic disease, or fat and fat-soluble vitamin malabsorption. If untreated, progressive liver disease may develop or reduced intestinal bile acid concentrations may lead to serious morbidity or mortality. This review focuses on a description of the disorders of bile acid synthesis that are directly related to single defects in the metabolic pathway, their proposed pathogenesis, treatment, and prognosis.

Zellweger spectrum disorders (ZSDs), a subgroup of peroxisomal biogenesis disorders, have a generalized defect in peroxisome function. Liver disease in ZSDs has been linked to accumulation of C27-bile acid intermediates due to the lack of peroxisomal β-oxidation of these intermediates to form primary C24-bile acids. Oral treatment with primary bile acid, cholic acid (CA), inhibits formation of hepatotoxic C27-bile acids by restoring normal physiologic feedback inhibition on bile acid synthesis. We present the long-term CA treatment and liver-related outcomes for 3 pediatric patients with ZSDs who have received CA treatment for ≥15 years. Ongoing CA treatment was associated with stabilized liver function, as shown by serum biochemistries and liver histopathology, and no treatment-related adverse effects were observed. All 3 patients have attended regular school with classroom accommodations and attained a good quality of life. Our patient outcomes suggest that early and ongoing CA therapy may sustain liver function in patients with ZSDs.

The aim of the study is to describe pancreatic enzyme practices during the first year of life in infants with cystic fibrosis (CF) and evaluate associations between dosing and outcomes, including growth and gastrointestinal (GI) symptoms.We analyzed data from a subset of infants who were in a prospective cohort study conducted at 28 US CF centers. Anthropometric measurements and medications were recorded at each visit. Diaries with infant diet, pancreatic enzyme replacement therapy (PERT) dosing, stool frequency and consistency, and pain were completed by a parent/guardian for 3 days before each visit.Two hundred and thirty-one infants were enrolled in the main study; 205 of these met criteria for pancreatic insufficiency (PI). PERT dose between birth and 6 months was on average 1882 LU/kg per meal (range: 492-3727) and was similar between 6 and 12 months (mean: 1842 LU/kg per mean, range: 313-3612). PERT dose had a weak, negative association with weight z score at 3 and 6 months (r = -0.16, 95% confidence interval [CI] -0.29 to -0.02 and r = -0.18, 95% CI -0.31 to -0.04, respectively) but not at 12 months. There was not a clear relationship between PERT dosing and number of stools per day, stool consistency or pain. One hundred and forty-four infants (70%) were placed on acid suppression medication. Weight z score mean was 0.37 higher in infants using proton pump inhibitors (PPIs) exclusively versus those using histamine-2 blockers exclusively (95% CI -0.02 to 0.76, P = 0.06).We did not observe that centers with a higher PERT dosing strategy yielded greater clinical benefit than dosing at the lower end of the recommended range.

Objectives: Patients with bile acid synthesis disorders (BASDs) due to single enzyme defects (SEDs) or Zellweger spectrum disorders (ZSDs) accumulate hepatotoxic atypical bile acids resulting in potentially fatal progressive liver disease. We evaluated the efficacy and safety of oral cholic acid in patients with BASD. Methods: In this phase 3, open-label, single-arm, nonrandomized, noncomparative study conducted over 18 years, patients were administered cholic acid orally 10 to 15 mg · kg−1 · day−1. The primary efficacy variables were changes from pre- to post-treatment in atypical urinary bile acids, liver chemistries (serum aspartate aminotransferase, alanine aminotransferase), and height and weight. Additional efficacy variables included changes in serum bilirubin and liver histology. Results: Of the 85 enrolled patients (63 with SED and 22 with ZSD), 79 received at least 1 dose of study medication; 70 patients (50 with SED and 20 with ZSD) were included in the modified intent-to-treat dataset. Cholic acid significantly improved urine bile acid metabolite scores (P

Objectives To identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere. Study design The Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected. Results We enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding neonatal cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for neonatal cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score. Conclusions Portal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of neonatal cholestasis is a weak predictor of severe disease.

Objectives Poor adherence to medication following pediatric liver transplantation remains a major challenge, with some estimates suggesting that 50% of adolescent liver transplant recipients exhibit reduced medication adherence. To date, no gold standard has emerged to address this challenge; however, system interventions are most likely to be successful. We sought to implement a system to identify and address adherence barriers in a liver transplant clinic. Methods Using structured quality improvement methods, including multiple plan-do-study-act cycles, we developed a system to screen for patients at risk of poor adherence, identify patient- and/or parent-reported barriers to adherence, and partner with patients to overcome identified barriers. We developed a process to track key outcomes, including the variability in tacrolimus trough levels and episodes of late acute cellular rejection. Results The practice saw a total of 85 patients over 6 months, and about half were females. Over this period, the improvement team implemented this system-level process with high reliability (>90% of patients received the bundle of interventions). The most commonly identified adherence barrier by patients and caregivers was "forgetting." The second most commonly identified adherence barrier by patients was that the medication "gets in the way of their activities," whereas by caregivers, it was "difficulty swallowing pills." Discussion We identified challenges and opportunities to screen for poor adherence and identify patient- and/or caregiver-reported barriers to immunosuppression adherence. Identifying such barriers and partnering with patients to overcome those barriers using patient-centered, barrier-specific interventions could improve long-term graft survival through improved medication adherence.

Background We determined qualitative and quantitative serum unconjugated bile acid (SUBA) levels among children with history of intestinal failure (IF) and suspected small bowel bacterial overgrowth (SBBO). Methods This was a single-center, case-control pilot study conducted at Cincinnati Children's Hospital Medical Center. Children with history of IF and suspected SBBO were enrolled as subjects. Age-matched children without IF or suspected SBBO served as controls. All participants underwent small bowel fluid sampling for microbial culture analysis. Additionally, serum fractionated and total bile acids were measured by liquid chromatography-mass spectrometry at enrollment and following treatment for SBBO. Results SUBA concentrations were elevated in IF subjects (median 1.16 μM, range 0.43-10.65 μM) compared with controls (median 0.10 μM, range 0.05-0.18 μM, P = 0.001). Among SUBA, chenodeoxycholic acid (CDCA) was significantly elevated in subjects (median 0.8 μM, range 0-7.08 μM) compared with controls (median 0 μM, range 0-0.03 μM, P = 0.012). When controls were excluded from analysis, IF subjects with positive aspirates for SBBO demonstrated higher concentration of CDCA (median 7.36 μM, range 1.1-8.28 μM) compared with IF subjects with negative aspirates (median 0.18 μM, range 0-1.06 μM, P = 0.017). Treatment for SBBO did not alter SUBA concentration. Conclusions SUBA concentrations are elevated in children with history of IF and presumed SBBO compared with non-IF controls. CDCA was more prevalent in IF subjects with positive aspirates for SBBO compared with IF subjects with negative aspirates. The determination of SUBA concentration may be a useful surrogate to small bowel fluid aspiration in the diagnosis of SBBO in children with history of IF.

On the occasion of the 50th anniversary of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), its close partner associations submitted comments and felicitations which are presented here. These include words from the Latin American (LASPGHAN), North American (NASPGHAN) and Panarabian Societies (PASPGHAN) and the Commonwealth Association (CAPGHAN) of Paediatric Gastroenterology, Hepatology and Nutrition, the Federation of International Societies of Paediatric Gastroenterology, Hepatology and Nutrition (FISPGHAN), the European Academy of Pediatrics (EAP), the European Pediatric Association/Union of National Pediatric Societies (EPA-UNEPSA), the International Pediatric Association (IPA), the European Crohn's and Colitis Organisation (ECCO), European Society for Clinical Nutrition and Metabolism (ESPEN) , the Federation of European Nutrition Societies (FENS), and United European Gastroenterology (UEG).

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

OBJECTIVES α-1-Antitrypsin (A1AT) deficiency is a common genetic disease with an unpredictable and highly variable course. The Childhood Liver Disease Research and Education Network is a National Institutes of Health, multicenter, longitudinal consortium studying pediatric liver diseases, with the objective of prospectively defining natural history and identifying disease modifiers. METHODS Longitudinal, cohort study of A1AT patients' birth through 25 years diagnosed as having liver disease, type PIZZ or PISZ. Medical history, physical examination, laboratory, imaging, and standardized survey tool data were collected during the provision of standard of care. RESULTS In the present report of the cohort at baseline, 269 subjects were enrolled between November 2008 and October 2012 (208 with their native livers and 61 postliver transplant). Subjects with mild disease (native livers and no portal hypertension [PHT]) compared to severe disease (with PHT or postliver transplant) were not different in age at presentation. A total of 57% of subjects with mild disease and 76% with severe disease were jaundiced at presentation (P = 0.0024). A total of 29% of subjects with native livers had PHT, but age at diagnosis and growth were not different between the no-PHT and PHT groups (P > 0.05). Subjects with native livers and PHT were more likely to have elevated bilirubin, ALT, AST, INR, and GGTP than the no-PHT group (P <

Malnutrition is one of the earliest clinical manifestations of cystic fibrosis (CF) and is associated with poorer pulmonary and cognitive outcomes and survival later in life. Infant growth can be a responsive measure for clinical research in this age group if obtained and characterized accurately. We report here the methods to standardize and implement research-quality anthropometric measurement of infants with cystic fibrosis in the Baby Observational Nutrition Study multicenter trial.

Fat-soluble vitamin (FSV) deficiency is a well-recognized consequence of cholestatic liver disease and reduced intestinal intraluminal bile acid. We hypothesized that serum bile acid (SBA) would predict biochemical FSV deficiency better than serum total bilirubin (TB) level in infants with biliary atresia.Infants enrolled in the Trial of Corticosteroid Therapy in Infants with Biliary Atresia after hepatoportoenterostomy were the subjects of this investigation. Infants received standardized FSV supplementation and monitoring of TB, SBA, and vitamin levels at 1, 3, and 6 months. A logistic regression model was used with the binary indicator variable insufficient/sufficient as the outcome variable. Linear and nonparametric correlations were made between specific vitamin measurement levels and either TB or SBA.The degree of correlation for any particular vitamin at a specific time point was higher with TB than with SBA (higher for TB in 31 circumstances vs 3 circumstances for SBA). Receiver operating characteristic curve shows that TB performed better than SBA (area under the curve 0.998 vs 0.821). Including both TB and SBA did not perform better than TB alone (area under the curve 0.998).We found that TB was a better predictor of FSV deficiency than SBA in infants with biliary atresia. The role of SBA as a surrogate marker of FSV deficiency in other cholestatic liver diseases, such as progressive familial intrahepatic cholestasis, α-1-antitrypsin deficiency, and Alagille syndrome in which the pathophysiology is dominated by intrahepatic cholestasis, warrants further study.

Early diagnosis of bile acid synthesis disorders (BASDs) is important because, untreated, these conditions can be fatal. Our objectives were to screen children with cholestasis or unexplained liver disease for BASD and in those with confirmed BASD to evaluate the effectiveness of cholic acid therapy.A routine serum total bile acid measurement was performed on children with cholestasis, liver cirrhosis, and liver failure. Patients were screened for BASD by fast atom bombardment ionization-mass spectrometry (FAB-MS) analysis of urine, and molecular analysis confirmed diagnosis. Treatment response to oral cholic acid (10-15 mg/kg bw/day) was assessed from liver function tests and fat-soluble vitamin levels. FAB-MS analysis of urine was used to monitor compliance and biochemical response.Between 2007 and 2016, 626 patients were evaluated; 450 with infantile cholestasis. Fifteen cases of BASD were diagnosed: 12 presented with infantile cholestasis (2.7%, 7 boys), an 8-year-old boy presented with cirrhosis, and two 18-month-old boys presented with hepatomegaly and rickets. Eleven were caused by 3β-hydroxy-Δ-C27-steroid oxidoreductase dehydrogenase deficiency, 3 from Δ-3-oxosteroid 5β-reductase deficiency, and 1 had Zellweger spectrum disorder. In all but 1, serum total bile acids were normal or low. With cholic acid therapy, 10 are alive and healthy with their native liver. Liver failure developed in 3 infants despite therapy; 2 died and 1 underwent liver transplantation.BASDs are rare but treatable causes of metabolic liver disease in Saudi Arabia. BASD should be considered in infants with cholestasis and low or normal serum total bile acid concentrations.

To assess neurodevelopmental outcomes among participants with biliary atresia with their native liver at ages 12 months (group 1) and 24 months (group 2), and to evaluate variables predictive of neurodevelopmental impairment.Participants enrolled in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with either the Bayley Scales of Infant Development, 2nd edition, or Bayley Scales of Infant and Toddler Development, 3rd edition. Scores (normative mean = 100 ± 15) were categorized as ≥100, 85-99, and85 for χThere were 148 children who completed 217 Bayley Scales of Infant and Toddler Development, 3rd edition, examinations (group 1, n = 132; group 2, n = 85). Neurodevelopmental score distributions significantly shifted downward compared with test norms at 1 and 2 years of age. Multivariate analysis identified ascites (OR, 3.17; P = .01) and low length z-scores at time of testing (OR, 0.70; P .04) as risk factors for physical/motor impairment; low weight z-score (OR, 0.57; P = .001) and ascites (OR, 2.89; P = .01) for mental/cognitive/language impairment at 1 year of age. An unsuccessful hepatoportoenterostomy was predictive of both physical/motor (OR, 4.88; P .02) and mental/cognitive/language impairment (OR, 4.76; P = .02) at 2 years of age.Participants with biliary atresia surviving with native livers after hepatoportoenterostomy are at increased risk for neurodevelopmental delays at 12 and 24 months of age. Those with unsuccessful hepatoportoenterostomy are4 times more likely to have neurodevelopmental impairment compared with those with successful hepatoportoenterostomy. Growth delays and/or complications indicating advanced liver disease should alert clinicians to the risk for neurodevelopmental delays, and expedite appropriate interventions.Clinicaltrials.gov: NCT00061828 and NCT00294684.

Background: Evidence shows that physicians and medical students who engage in healthy lifestyle habits are more likely to counsel patients about such behaviors. Yet medical school is a challenging time that may bring about undesired changes to health and lifestyle habits.Aims: This study assessed changes in students’ health and lifestyle behaviors during medical school. Subjects and Methods: In a longitudinal study, students were assessed at both the beginning and end of medical school. Anthropometric, metabolic, and lifestyle variables were measured at a clinical research center. Data were collected from 2006 to 2011, and analyzed in 2013–2014 with SAS version 9.3. Pearson’s correlations were used to assess associations between variables and a generalized linear model was used to measure change over time.Results: Seventy‑eight percent (97/125) of participants completed both visits. At baseline, mean anthropometric and clinical measures were at or near healthy values and did not change over time, with the exception of increased diastolic blood pressure (P = 0.01), high‑density lipoprotein‑cholesterol (P < 0.001), and insulin (P < 0.001). Self‑reported diet and physical activity habits were congruent with national goals, except for Vitamin D and sodium. Dietary intake did not change over time, with the exceptions of decreased carbohydrate (percent of total energy) (P < 0.001) and sodium (P = 0.04) and increased fat (percent of total energy) and Vitamin D (both P < 0.01). Cardiovascular fitness showed a trend toward declining, while self‑reported physical activity increased (P < 0.001). Conclusions: Students’ clinical measures and lifestyle behaviors remain generally healthy throughout medical school; yet some students exhibit cardiometabolic risk and diet and activity habits not aligned with national recommendations. Curricula that include personal health and lifestyle assessment may motivate students to adopt healthier practices and serve as role models for patients.Keywords: Lifestyle, Medical school, Medical students, Nutrition, Prevention

Importance Since the implementation of universal newborn screening (NBS) for cystic fibrosis (CF), the timing and magnitude of growth deficiency or its association with correlates of disease among infants with CF who underwent NBS has not been well described. Objective To examine incremental weight gain, linear growth, and clinical features in the first year of life among infants with CF who underwent NBS. Design, Setting, and Participants The Baby Observational and Nutrition Study (BONUS), a multicenter, longitudinal, observational cohort study, was conducted during regular CF clinic visits in the first 12 months of life at 28 US Cystic Fibrosis Foundation–accredited Care Centers from January 7, 2012, through May 31, 2015. Participants included 231 infants younger than 3.5 months who underwent NBS and had confirmed CF, with a gestational age of at least 35 weeks, birth weight of at least 2.5 kg, and toleration of full oral feeds. Of these, 222 infants (96.1%) had follow-up beyond 6 months of age and 215 (93.1%) completed 12 months of follow-up. Exposure Cystic fibrosis. Main Outcome and Measures Attained weight and length for age and World Health Organization normative z scores at ages 1 to 6 and 8, 10, and 12 months (defined a priori). Results Of the 231 infants enrolled, 110 infants (47.6%) were female and 121 (52.4%) were male, with a mean (SD) age of 2.58 (0.69) months. BONUS infants had lower than mean birth weights (mean z score, −0.15; 95% CI, −0.27 to −0.04) and higher birth lengths (mean z score, 0.44; 95% CI, 0.26 to 0.62). They achieved normal weight by 12 months, a significant improvement over a prescreening cohort of newborns with CF from 20 years before the contemporary cohort (mean z score increase, 0.57; 95% CI, 0.37-0.77). However, length was lower than the mean at 12 months (mean z score, −0.56; 95% CI, −0.70 to −0.42). Only 30 infants (13.6%) were at less than the 10th percentile of weight for age, whereas 53 (23.9%) were at less than the 10th percentile of length for age at more than half their visits. Male sex, pancreatic insufficiency, meconium ileus, histamine blocker use, and respiratory Pseudomonas aeruginosa infection were associated with lower weight or length during the first year. Insulinlike growth factor 1 levels were significantly lower among low-length infants. Persistently low-weight infants consumed significantly more calories, and weight and length z scores were negatively correlated with caloric intake. Conclusions and Relevance Since initiation of universal NBS for CF, significant improvement has occurred in nutritional status, with normalization of weight in the first year of life. However, length stunting remains common.

Background: Incorporating comprehension testing into the informed consent process has been suggested as a method to verify that subjects understand the risks and requirements of research protocols. We analyzed our informed consent process and examined the utility of comprehension testing in a complex clinical study using subjective and objective measures. Methods: Healthy subjects taking part in a study of cholesterol absorption and metabolism were recruited for this sub-study and completed the informed consent process, which included a 20-item comprehension test evaluating study-specific risks and procedures. After completing the clinical study, they were reevaluated by a separate 47-item knowledge test that included general informed consent items, the identical 20-item comprehension test, and a self-assessment. Results: Twenty-five of 28 eligible subjects completed the study. All subjects scored well on the comprehension test (mean: 95.1%), and again when the same test was administered a year later (mea...

Secoisolariciresinol-diglycoside (SDG), a natural dietary lignan of flaxseeds now available in dietary supplements, is converted by intestinal bacteria to the mammalian lignans enterodiol and enterolactone. High levels of these lignans in blood and urine are associated with reduced risk of many chronic diseases. Our objective was to determine the bioavailability and pharmacokinetics of SDG in purified flaxseed extracts under dose-ranging and steady-state conditions, and to examine whether differences in secoisolariciresinol-diglycoside purity influence bioavailability. Pharmacokinetic studies were performed on healthy postmenopausal women after oral intake of 25, 50, 75, 86 and 172 mg of secoisolariciresinol-diglycoside. Extracts differing in secoisolariciresinol-diglycoside purity were compared, and steady-state lignan concentrations measured after daily intake for one week. Blood and urine samples were collected at timed intervals and secoisolariciresinol, enterodiol and enterolactone concentrations measured by mass spectrometry. Secoisolariciresinol-diglycoside was efficiently hydrolyzed and converted to secoisolariciresinol. Serum concentrations increased rapidly after oral intake, peaking after 5-7 h and disappearing with a plasma elimination half-life of 4.8 h. Maximum serum concentrations of the biologically active metabolites, enterodiol and enterolactone were attained after 12-24 h and 24-36 h, respectively, and the half-lives were 9.4 h and 13.2 h. Linear dose-responses were observed and secoisolariciresinol bioavailability correlated (r(2) = 0.835) with cumulative lignan excretion. There were no significant differences in the pharmacokinetics of extracts differing in purity, and steady-state serum lignan concentrations were obtained after one-week of daily dosing. In conclusion, this study defines the pharmacokinetics of secoisolariciresinol-diglycoside and shows it is first hydrolyzed and then metabolized in a time-dependent sequence to secoisolariciresinol, enterodiol and ultimately enterolactone, and these metabolites are efficiently absorbed.

Researchers designed learner-directed journal clubs to develop literature evaluation skills in preclinical students. Sessions balanced student-led discussion with structured objectives and faculty support. During the pilot with preclinical MD/PhD students, self-rated mastery improved over all 17 measured objectives. Six exercises have since been incorporated into the full medical school curriculum.

S-(-)equol, an intestinally derived metabolite of the soy isoflavone daidzein, is proposed to enhance the efficacy of soy diets. Adults differ in their ability to produce equol when consuming soy foods for reasons that remain unclear. Therefore, we performed a comprehensive dietary analysis of 143 macro- and micronutrients in 159 healthy adults in the United States (n = 89) and Australia (n = 70) to determine whether the intake of specific nutrients favors equol production. Three-d diet records were collected and analyzed using Nutrition Data System for Research software and S-(-)equol was measured in urine by mass spectrometry. Additionally, in a subset of equol producers and nonproducers (n = 10/group), we examined the long-term stability of equol producer status by retesting 12, 18, and 24 mo later. Finally, the effect of oral administration of the antibiotic metronidazole (500 mg/d for 7 d) on equol production was examined in 5 adults monitored during a 4-mo follow-up period. Equol producers accounted for 30.3% and 28.6% of the United States and Australian participants, respectively (overall frequency, 29.6%). No significant differences were observed for total protein, carbohydrate, fat, saturated fat, or fiber intakes between equol producers and nonproducers. However, principal component analysis revealed differences in several nutrients, including higher intakes of polyunsaturated fatty acids (P = 0.039), maltose (P = 0.02), and vitamins A (P = 0.01) and E (P = 0.035) and a lower intake of total cholesterol (P = 0.010) in equol producers. During a 2-y period, equol producer status remained unchanged in all nonproducers and in 80% of equol producers, whereas metronidazole abolished equol production in only 20% of participants. In conclusion, these findings suggest that major differences in the macronutrient content of the diet appear not to influence equol production, but subtle differences in some nutrients may influence the ability to produce equol, which was a relatively stable phenomenon.

Aims Investigate the efficacy of risedronate sodium (Procter and Gamble, Cincinnati, USA) for treating reduced lumbar spine (LS) bone mineral density (BMD) in non-ambulatory patients. Methods Nine (10-39 years, mean age 23.0 years, 7 males) in the risedronate arm and 10 (10-35 years, mean age 21.4 years, 8 males) in the placebo arm completed 24 months of therapy at baseline, 6, 12, 18, and 24 months. The primary outcome was change in LS BMD assessed by dual energy x-ray absorptiometry (DXA). Secondary outcomes included changes in serum bone markers, bone specific alkaline phosphatase, osteocalcin, and N-telopeptides. Mixed models examined group, time, and the group by time interaction for the 4 post-baseline time points. Results The change in LS BMD score from baseline to 24 months was 0.069 (95% CI 0.014 to 0.124) in risedronate participants compared to -0.015 (95% CI -0.073 to 0.042) (t Value = -2.40, P > t=0.03) in the controls. When controlling for baseline scores, the difference was consistent across four post-baseline time points tested (F=5.67, Pr > F=0.03). No differences in serum bone markers were observed. Conclusions Risedronate increases LS BMD in non-ambulatory patients with minimal side effects.

Although exclusively breastfed infants are at increased risk of vitamin D (vit D) deficiency if vit D supplementation is lacking and sun exposure is limited, assessment of both risk factors in the first year of life is lacking. We evaluated the contribution of vit D intake and sunlight exposure to vit D status in 120 healthy, breastfeeding mother-infant dyads, who were followed up for 1 year. Vitamin D intake and skin sunlight exposure were evaluated using questionnaires. Serum 25-hydroxyvitamin D, parathyroid hormone (PTH) and alkaline phosphatase levels were determined post-natally in mothers at 4 weeks and in infants at 4, 26 and 52 weeks. Vitamin D supplementation was low (

Background: Human and animal studies have produced conflicting results with regard to the effect of soy isoflavones on breast cancer risk. This may be due to differences in isoflavone metabolism. Objective: The objective of this study was to determine whether soy isoflavone phase II metabolism differs between humans and rodents. Design: Circulating total and unconjugated isoflavone concentrations were determined by mass spectrometry in plasma samples from 7 separate studies: 1) in Sprague-Dawley rats and in 3 strains of mice fed commercial soy-containing diets; 2) in Sprague-Dawley rats gavaged with genistein; 3) in healthy adults who consumed single servings of soy nuts, soy milk, and tempeh; 4) in healthy adults subchronically given soy milk; 5) in healthy women orally administered 50 mg genistein; 6) in healthy women orally administered 20 mg pure S-(-)equol; and 7) in 6-mo-old infants fed soy infant formula and later, at age 3 y, a soy germ isoflavone supplement. Results: The proportion of unconjugated genistein in plasma from adults and infants who consumed different soy foods, pure genistein, or an isoflavone supplement was

Surgical interposition of distal ileum into the proximal jejunum is a bariatric procedure that improves the metabolic syndrome. Changes in intestinal and hepatic physiology after ileal interposition (transposition) surgery (IIS) are not well understood. Our aim was to elucidate the adaptation of the interposed ileum, which we hypothesized, would lead to early bile acid reabsorption in the interposed ileum, thus short circuiting enterohepatic bile acid recycling to more proximal bowel segments. Rats with diet-induced obesity were randomized to IIS, with 10 cm of ileum repositioned distal to the duodenum, or sham surgery. A subgroup of sham rats was pair-fed to IIS rats. Physiological parameters were measured until 6 wk postsurgery. IIS rats ate less and lost more weight for the first 2 wk postsurgery. At study completion, body weights were not different, but IIS rats had reversed components of the metabolic syndrome. The interposed ileal segment adapted to a more jejunum-like villi length, mucosal surface area, and GATA4/ILBP mRNA. The interposed segment retained capacity for bile acid reabsorption and anorectic hormone secretion with the presence of ASBT and glucagon-like-peptide-1-positive cells in the villi. IIS rats had reduced primary bile acid levels in the proximal intestinal tract and higher primary bile acid levels in the serum, suggesting an early and efficient reabsorption of primary bile acids. IIS rats also had increased taurine and glycine-conjugated serum bile acids and reduced fecal bile acid loss. There was decreased hepatic Cyp27A1 mRNA with no changes in hepatic FXR, SHP, or NTCP expression. IIS protects against the metabolic syndrome through short-circuiting enterohepatic bile acid recycling. There is early reabsorption of primary bile acids despite selective “jejunization” of the interposed ileal segment. Changes in serum bile acids or bile acid enterohepatic recycling may mediate the metabolic benefits seen after bariatric surgery.

Objectives—The “gold standard” for the diagnosis of fat malabsorption, the 72 hour fat balance study, requires a three day collection to generate a coefficient of fat absorption (CFA). We hypothesized that, a new test using behenic acid (behenate test) as a nonabsorbable lipid marker may provide a facile means to assess fat absorption. The study proposed to answer two questions: 1) whether the “behenate test” correlated with the “gold standard” and 2) whether the CFA improved when taking pancreatic enzymes during meals instead of prior to them. Methods—The study compared the “behenate test” with the gold standard in 15 cystic fibrosis patients during three arms which require 3–4 day hospitalizations: one taking pancreatic enzymes prior to meals, one taking pancreatic enzymes during meals, and one off of pancreatic enzymes. Results—The mean CFA was 78.3% when pancreatic enzymes were taken during meals and 80.4% when pancreatic enzymes were taken prior to meals. Correlation between the CFA and the “behenate test” for collections during all 3 arms was r 2 = 0.219 (p= 0.001). Conclusion—1) Timing of ingestion of pancreatic enzymes does not significantly alter the CFA. 2) Although the CFA correlates with the “behenate test”, the correlation is not robust enough to justify its replacement of the “gold standard.” It is unclear whether the poor correlation between tests relates to intermeal variability in fat excretion,or other factors; however the “behenate test” may be suitable as a screening test for detection of fat malabsorption.

Background: The nonsteroidal estrogen equol occurs as diastereoisomers, S-(−)equol and R-(+)equol, both of which have significant biological actions. S-(−)equol, the naturally occurring enantiomer produced by 20–30% of adults consuming soy foods, has selective affinity for estrogen receptor-β, whereas both enantiomers modulate androgen action. Little is known about the pharmacokinetics of the diastereoisomers, despite current interest in developing equol as a nutraceutical or pharmaceutical agent. Objective: The objective was to compare the pharmacokinetics of S-(−)equol and R-(+)equol by using [13C] stable-isotope-labeled tracers to facilitate the optimization of clinical studies aimed at evaluating the potential of these diastereoisomers in the prevention and treatment of estrogen- and androgen-dependent conditions. Design: A randomized, crossover, open-label study in 12 healthy adults (6 men and 6 women) compared the plasma and urinary pharmacokinetics of orally administered enantiomeric pure forms of S-(−)[2-13C]equol, R-(+)[2-13C]equol, and the racemic mixture. Plasma and urinary [13C]R-equol and [13C]S-equol concentrations were measured by tandem mass spectrometry. Results: Plasma [13C]equol concentration appearance and disappearance curves showed that both enantiomers were rapidly absorbed, attained high circulating concentrations, and had a similar terminal elimination half-life of 7–8 h. The systemic bioavailability and fractional absorption of R-(+)[2-13C]equol were higher than those of S-(−)[2-13C]equol or the racemate. The pharmacokinetics of racemic (±)[2-13C]equol were different from those of the individual enantiomers: slower absorption, lower peak plasma concentrations, and lower systemic bioavailability. Conclusions: The high bioavailability of both diastereoisomers contrasts with previous findings for the soy isoflavones daidzein and genistein, both of which have relatively poor bioavailability, and suggests that low doses of equol taken twice daily may be sufficient to achieve biological effects.

Prothrombin time (PT), a surrogate marker of vitamin K deficiency, may underestimate the prevalence of vitamin K deficiency in cholestatic liver disease. This study investigated the frequency of vitamin K deficiency in children and adults with cholestatic liver disease by determining plasma protein induced in vitamin K absence II (PIVKA-II), and assessed the relation between plasma PIVKA-II levels and markers of cholestasis, measured PT, international normalized ratio (INR), serum undercarboxylated osteocalcin (ucOC), serum vitamins A and E, and serum 25-hydroxyvitamin D levels.Blood was collected from patients with cholestatic liver disease for liver biochemistries, PT, INR, bile acids, 25-hydroxyvitamin D, vitamin A, vitamin E, ucOC, and PIVKA-II.Thirty-one patients were enrolled (age range 0.5-54 years, median age 5.7 years, 17 females). Nine patients (29%) had increased INRs, whereas 21 (68%) had elevated plasma PIVKA-II levels. All patients with increased INRs had increased plasma PIVKA-II. Fifteen of 21 patients with increased plasma PIVKA-II were receiving supplemental vitamin K therapy (range 7.8-700 mug/kg/day). Plasma PIVKA-II levels were positively correlated with serum conjugated bilirubin, bile acids, aspartate aminotransferase, alanine aminotransferase, PT, INR, and serum ucOC (Por= 0.02) and negatively correlated with serum 25-hydroxyvitamin D levels (P = 0.01). Twenty-two patients (71%) had vitamin D deficiency, 9 patients (29%) had vitamin A deficiency, and 2 patients (6%) had vitamin E deficiency.Despite vitamin K supplementation, elevation of plasma PIVKA-II suggesting ongoing vitamin K deficiency is common in cholestatic liver disease. Better strategies for vitamin K supplementation and dosing guidelines are needed.