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

Esophageal mucosal integrity improves after laparoscopic antireflux surgery in children with gastroesophageal reflux disease

Background: Esophageal intraluminal baseline impedance reflects the conductivity of the esophageal mucosa and may be an instrument for in vivo evaluation of mucosal integrity in children with gastroesophageal reflux disease (GERD). Laparoscopic antireflux surgery (LARS) is a well-established treatment option for children with proton pump inhibitory (PPI) therapy resistant GERD. The effect of LARS in children on baseline impedance has not been studied in detail. The aim of this study was to evaluate the effect of LARS on baseline impedance in children with GERD. Methods: This is a prospective, multicenter, nationwide cohort study (Dutch national trial registry: NTR2934) including 25 patients [12 males, median age 6 (range 2–18) years] with PPI-resistant GERD scheduled to undergo LARS. Twenty-four hour multichannel intraluminal impedance pH monitoring (MII-pH monitoring) was performed before and 3 months after LARS. Baseline impedance was evaluated during consecutive 2-h intervals in the 24-h tracings. Results: LARS reduced acid exposure time from 8.5 % (6.0–16.2 %) to 0.8 % (0.2–2.8 %), p < 0.001. Distal baseline impedance increased after LARS from 2445 Ω (1147–3277 Ω) to 3792 Ω (3087–4700 Ω), p < 0.001. Preoperative baseline impedance strongly correlated with acid exposure time (r −0.76, p < 0.001); however, no association between symptomatic outcome and baseline impedance was identified. Conclusions: LARS significantly increased baseline impedance likely reflecting recovery of mucosal integrity. As the change in baseline impedance was not associated with the clinical outcome of LARS, other factors besides mucosal integrity may contribute to symptom perception in children with GERD

Benign recurrent intrahepatic cholestasis (BRIC): Evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease characterized by multiple episodes of cholestasis without progression to chronic liver disease. The gene was previously assigned to chromosome 18q21, using a shared segment analysis in three families from the Netherlands. In the present study we report the linkage analysis of an expanded sample of 14 BRIC families, using 15 microsatellite markers from the 18q21 region. Obligate recombinants in two families place the gene in a 7-cM interval, between markers D18S69 and D18S64. All intervening markers had significant LOD scores in two-point linkage analysis. More over, we identified one family in which the BRIC gene seems to be unlinked to the 18q21 region, or that represents incomplete penetrance of the BRIC genotype

Outcomes of Surgical Management of Familial Intrahepatic Cholestasis 1 and Bile Salt Export Protein Deficiencies

Progressive familial intrahepatic cholestasis (PFIC) with normal circulating gamma-glutamyl transpeptidase levels can result from mutations in the ATP8B1 gene (encoding familial intrahepatic cholestasis 1 [FIC1] deficiency) or the ABCB11 gene (bile salt export protein [BSEP] deficiency). We investigated the outcomes of partial external biliary diversion, ileal exclusion, and liver transplantation in these two conditions. We conducted a retrospective multicenter study of 42 patients with FIC1 deficiency (FIC1 patients) and 60 patients with BSEP deficiency (BSEP patients) who had undergone one or more surgical procedures (57 diversions, 6 exclusions, and 57 transplants). For surgeries performed prior to transplantation, BSEP patients were divided into two groups, BSEP-common (bearing common missense mutations D482G or E297G, with likely residual function) and BSEP-other. We evaluated clinical and biochemical outcomes in these patients. Overall, diversion improved biochemical parameters, pruritus, and growth, with substantial variation in individual response. BSEP-common or FIC1 patients survived longer after diversion without developing cirrhosis, being listed for or undergoing liver transplantation, or dying, compared to BSEP-other patients. Transplantation resolved cholestasis in all groups. However, FIC1 patients commonly developed hepatic steatosis, diarrhea, and/or pancreatic disease after transplant accompanied by biochemical abnormalities and often had continued poor growth. In BSEP patients with impaired growth, this generally improved after transplantation. Conclusion: Diversion can improve clinical and biochemical status in FIC1 and BSEP deficiencies, but outcomes differ depending on genetic etiology. For many patients, particularly BSEP-other, diversion is not a permanent solution and transplantation is required. Although transplantation resolves cholestasis in patients with FIC1 and BSEP deficiencies, the overall outcome remains unsatisfactory in many FIC1 patients; this is mainly due to extrahepatic manifestations.Peer reviewe

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