Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis

Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are rare, inherited cholestatic liver disorders that manifest in infants and children and are associated with impaired bile flow (ie cholestasis), pruritus and potentially fatal liver disease. There are no effective or approved pharmacologic treatments for these diseases (standard medical treatments are supportive only), and new, noninvasive options would be valuable. Typically, bile acids undergo biliary secretion and intestinal reabsorption (ie enterohepatic circulation). However, in these diseases, disrupted secretion of bile acids leads to their accumulation in the liver, which is thought to underlie pruritus and liver-damaging inflammation. One approach to reducing pathologic bile acid accumulation in the body is surgical biliary diversion, which interrupts the enterohepatic circulation (eg by diverting bile acids to an external stoma). These procedures can normalize serum bile acids, reduce pruritus and liver injury and improve quality of life. A novel, nonsurgical approach to interrupting the enterohepatic circulation is inhibition of the ileal bile acid transporter (IBAT), a key molecule in the enterohepatic circulation that reabsorbs bile acids from the intestine. IBAT inhibition has been shown to reduce serum bile acids and pruritus in trials of paediatric cholestatic liver diseases. This review explores the rationale of inhibition of the IBAT as a therapeutic target, describes IBAT inhibitors in development and summarizes the current data on interrupting the enterohepatic circulation as treatment for cholestatic liver diseases including ALGS and PFIC

Dietary supplementation with multiple micronutrients: No beneficial effects in pediatric cystic fibrosis patients

AbstractBackgroundCystic fibrosis (CF) patients are subjected to increased oxidative stress due to chronic pulmonary inflammation and recurrent infections. Additionally, these patients have diminished skeletal muscle performance and exercise capacity. We hypothesize that a mixture of multiple micronutrients could have beneficial effects on pulmonary function and muscle performance.MethodsA double-blind, randomized, placebo controlled, cross-over trial with a mixture of multiple micronutrients (ML1) was performed in 22 CF patients (12.9±2.5 yrs) with predominantly mild lung disease. Anthropometric measures, pulmonary function, exercise performance by bicycle ergometry, muscular strength and vitamins A and E were determined.ResultsAnalysis was performed using the paired Student t-test comparing the change in each parameter during ML1 and placebo. Plasma vitamin E and A levels increased during ML1 when compared to placebo. However, no significant difference between the effect of the ML1 or placebo was observed neither for FEV1, FVC, anthropometry, nor for the parameters for muscle performance.ConclusionsThe micronutrient mixture was not superior to placebo with respect to changes in pulmonary function or muscle performance in pediatric CF patients, despite a significant increase in plasma vitamin E concentrations

Starreveld scoring method in diagnosing childhood constipation

Four scoring methods exist to assess severity of fecal loading on plain abdominal radiographs in constipated patients (Barr-, Starreveld-, Blethyn- and Leech). So far, the Starreveld score was used only in adult patients. To determine accuracy and intra- and inter-observer agreement of the Starreveld scoring method in the diagnosis of functional constipation among pediatric patients. In addition, we compared the Starreveld with the Barr scoring method. Thirty-four constipated and 34 non-constipated children were included. Abdominal radiographs, obtained before treatment, were rated (Starreveld- and Barr) by 4 observers. A second observation after 4 weeks was done by 3 observers. Cut-off level for the Starreveld score, accuracy as measured by the area under the receiver operator characteristics curve, and inter- and intra-observer agreement were calculated. Cut-off value for the Starreveld score was 10. AUC for Starreveld score was 0.54 and for Barr score 0.38, indicating poor discriminating power. Inter-observer agreement was 0.49-0.52 4 (Starreveld) and 0.44 (Barr), which is considered moderate. Intra-observer agreement was 0.52-0.71 (Starreveld) and 0.62- 0.76 (Barr). The Starreveld scoring method to assess fecal loading on a plain abdominal radiograph is of limited value in the diagnosis of childhood constipatio

Intestinal Obstruction Syndromes in Cystic Fibrosis: Meconium Ileus, Distal Intestinal Obstruction Syndrome, and Constipation

Meconium ileus at birth, distal intestinal obstruction syndrome (DIOS), and constipation are an interrelated group of intestinal obstruction syndromes with a variable severity of obstruction that occurs in cystic fibrosis patients. Long-term follow-up studies show that today meconium ileus is not a risk factor for impaired nutritional status, pulmonary function, or survival. DIOS and constipation are frequently seen in cystic fibrosis patients, especially later in life; genetic, dietary, and other associations have been explored. Diagnosis of DIOS is based on suggestive symptoms, with a right lower quadrant mass confirmed on abdominal radiography, whereas symptoms of constipation are milder and of longer standing. In DIOS, early aggressive laxative treatment with oral laxatives (polyethylene glycol) or intestinal lavage with balanced osmotic electrolyte solution and rehydration is required, which now makes the need for surgical interventions rare. Constipation can generally be well controlled with polyethylene glycol maintenance treatment

Systematic review of progressive familial intrahepatic cholestasis

BACKGROUND AND AIMS: Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of rare genetic disorders associated with bile acid secretion or transport defects. This is the first systematic review of the epidemiology, natural history and burden of PFIC. METHODS: MEDLINE and Embase were searched for publications on PFIC prevalence, incidence or natural history, and the economic burden or health-related quality of life (HRQoL) of patients with PFIC. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. RESULTS: Of 1269 records screened, 20 were eligible (epidemiology, 17; humanistic burden, 5; both, 2). Incidence of intrahepatic cholestasis, including but not limited to PFIC, was 1/18 000 live births in one study that did not use genetic testing. In two studies of infants and children (2-18 years) with cholestasis, 12-13% had genetically diagnosed PFIC. Of the three main PFIC subtypes, PFIC2 was the most common (21-91% of patients). Common symptoms (e.g. pruritus, jaundice, hepatomegaly, splenomegaly) generally appeared at about 3 months of age and tended to emerge earliest in patients with PFIC2. Patients reported that pruritus was often severe and led to dermal damage and reduced HRQoL. Disease progression led to complications including liver failure and hepatocellular carcinoma, with 20-83% of patients requiring liver transplantation. Mortality was 0-87% across 10 studies (treatment varied among studies), with a median age at death of ~4 years in one study. CONCLUSIONS: Patients with PFIC face debilitating symptoms and poor prognosis. Further research is needed to inform patient management and clinical trial design. Published data on the epidemiology and socioeconomic burden of PFIC is limited

Influence of allopurinol on thiopurine associated toxicity: A retrospective population-based cohort study

Aims: Thiopurines are important for treating inflammatory bowel disease, but are often discontinued due to adverse effects. Concomitant use of allopurinol might lower the risk of these unwanted effects, but large studies in the general population are lacking. The aims of this study were to evaluate rates of hepatotoxicity, myelotoxicity, pancreas toxicity and therapy persistence in adult thiopurine users with or without allopurinol. Methods: A retrospective population-based cohort study was conducted within current thiopurine users (Clinical Practice Research Datalink). Among these patients, co-use of allopurinol was compared to non-use. Hazard ratios (HRs) for hepatotoxicity, myelotoxicity and pancreatitis were derived using time-dependent Cox proportional hazards models, and were adjusted for potential confounders. Persistence of thiopurine use was evaluated using Log-rank statistics. Results: Patients using thiopurines (n = 37 360) were identified of which 1077 were concomitantly taking allopurinol. A 58% decreased risk of hepatotoxicity was observed in those concomitantly taking allopurinol (HR 0.42; 95% CI 0.30–0.60; NNT 46). Rate of myelotoxicity (HR 0.96; 95% CI 0.89–1.03) was not influenced. Risk of pancreatitis was increased (HR 3.00; 95% CI 1.01–8.93; NNH 337), but was only seen in those with active gout (suggesting confounding by indication). Finally, allopurinol co-users were able to maintain thiopurine therapy over twice as long as those not on allopurinol (3.9 years vs. 1.8 years, P < 0.0001). Conclusion: In thiopurine users, allopurinol is associated with a 58% reduced risk of hepatotoxicity. In addition, thiopurine persistence was prolonged by 2.1 years in allopurinol users. These data support the use of allopurinol in individuals requiring thiopurine therapy

Impact of Paediatric Versus Adult Care Setting on Health Care Utilization in Adolescents With Inflammatory Bowel Disease

OBJECTIVE: Paediatric-onset inflammatory bowel disease (IBD) is different from adult-onset IBD with respect to disease severity and its effect on growth and development. Care of paediatric IBD patients in some countries is dispersed among paediatricians and adult care providers, which may result in different outcomes. This study aims to assess the effect of care setting (paediatric vs adult-oriented) on health care utilization in adolescent IBD patients. METHODS: This is a Dutch population-based cohort study based on an insurance claims database covering 4.2 million insurees (approximately 25% of the Dutch population). We identified IBD patients ages 16 to 18 years and followed them until the age of 19 years or transfer to adult care, whichever came first. We categorized patients according to care setting: paediatric versus adult-oriented. We defined outcomes as corticosteroid use, IBD-related hospital admission, IBD-related surgery, and biological use. We estimated Cox proportional hazards regression models to control for confounding by indication. RESULTS: Among 626 patients, 380 (61%) were in paediatric and 246 (39%) in adult-oriented care. In paediatric care, patients were less likely to be treated with corticosteroids (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.52-0.99) or biologicals (HR 0.57, 95% CI 0.34-0.97), and had fewer IBD-related hospital admissions (HR 0.58, 95% CI 0.37-0.92). CONCLUSION: In a large and representative community cohort of adolescents with IBD, treatment in paediatric care setting was associated with significantly lower steroid and biological use, without increase in hospital admissions. These results might be used to optimize clinical care for adolescents with IBD