Screening strategy for gastrointestinal and hepatopancreatobiliary cancers in cystic fibrosis

Based on systematic review and meta-analysis, the risk for developing cancers in patients with cystic fibrosis (CF) is known to be significantly greater than in the general population, including site-specific cancers of the esophagus, small bowel, colon, liver, biliary tract, and pancreas. An even higher risk has been found in patients who have severe CF transmembrane conductance regulator (CFTR) genotypes or who have undergone organ transplantation and are immunosuppressed. The risk continues to rise as life expectancies steadily climb due to advancements in medical care and treatment for CF. The colorectal cancer risk is at such a high level that CF has now been declared a hereditary colon cancer syndrome by the Cystic Fibrosis Foundation. The CFTR gene has been strongly-associated with the development of gastrointestinal (GI) cancers and mortality in the CF population. Even CF carriers have shown an increased rate of GI cancers compared to the general population. Several limitations exist with the reported guidelines for screening of GI and hepatopancreatobiliary cancers in the CF population, which are largely universal and are still emerging. There is a need for more precise screening based on specific risk factors, including CFTR mutation, medical co-morbidities (such as gastroesophageal reflux disease, distal intestinal obstruction syndrome, and diabetes mellitus), familial risks for each cancer, gender, age, and other factors. In this review, we propose changes to the guidelines for GI screening of patients with CF. With the development of CFTR modulators, additional studies are necessary to elucidate if there is an effect on cancer risk.     

Chilaiditi syndrome in pediatric patients - Symptomatic hepatodiaphragmatic interposition of colon: A case report and review of literature

BACKGROUNDChilaiditi syndrome is a rare disorder characterized by the hepatodiaphragmatic interposition of the intestine.CASE SUMMARYHere we report a case of a 12-year-old male who was admitted to the pediatric intensive care unit secondary to abdominal pain and severe respiratory distress. He was treated conservatively but the symptoms persisted requiring a surgical approach. While there have been several cases of Chilaiditi syndrome reported in adults, there is a scarcity of cases reported in the pediatric population. Our review of the literature found only 30 pediatric cases, including our reported case, with Chilaiditi syndrome, 19 (63%) of which were male. The median age of diagnosis was 4.5 years old with an interquartile range of 2.0-10.0 years. In our review, we found that the most common predisposing factors in children are aerophagia (12/30 cases) and constipation (13/30 cases). Ninety percent of the cases presented with complete intestinal interposition, in 100% of which, the colon was involved. Three of the 30 cases were associated with volvulus.CONCLUSIONIn the pediatric population, conservative (21/30 cases) and surgical (8/30 cases) treatment approaches have produced satisfactory outcomes for all the patients, regardless of approach.     

Anterior pituitary hormone effects on hepatic functions in infants with congenital hypopituitarism

Background: Congenital hypopituitarism is an uncommon cause of neonatal cholestasis. Little is known about the effect of anterior pituitary hormone on hepatic functions.Methods: A retrospective review of the medical charts of eight infants with congenital hypopituitarism and neonatal cholestasis was performed. The results of endocrinological investigations, eye examinations, and magnetic resonance imaging were used to classify these infants.Results: Eight infants (4 male and 4 female; mean age, 1.7 weeks) who presented with cholestatic jaundice subsequently (mean age, 7.6 weeks) developed isolated or multiple anterior pituitary hormone deficiencies. Persistent hypoglycemia, ocular abnormalities, and microphallus were often clinical signs prompting further endocrinological and radiological investigations. Septo-optic dysplasia was prevalent, occurring in five cases. Cholestasis and hepatosplenomegaly resolved within a mean of 9.7 and 10 weeks, respectively, in the majority of cases after replacement of glucocorticoid and thyroid hormones. However, transaminase levels remained high after hormone replacement. Cortisol deficiency and hypoglycemia were noted in all cases, often following stress. Hyperlipidemia persisted in one case after the resolution of cholestasis and after corticosteroid and thyroid hormone replacement therapy. Growth hormone deficiency was not corrected due to the absence of hypoglycemia after corticosteroid hormone, an infant’s age, and/or a lack of financial resources.Conclusions: In our series, it appears that glucocorticoid and thyroid hormones play a significant role in the resolution of cholestasis and hepatosplenomegaly. A persistently elevated transaminase level and hyperlipidemia after corticosteroid and thyroid hormone replacement may indicate the need for long-term follow-up and/or growth hormone therapy.     

Disaccharidase activities in dyspeptic children: biochemical and molecular investigations of maltase-glucoamylase activity

BACKGROUND: Maltase-glucoamylase enzyme plays an important role in starch digestion. Glucoamylase deficiency is reported to cause chronic diarrhea in infants, but its role in dyspeptic children is unknown. METHODS: Glucoamylase and other disaccharidase specific activities were assayed from duodenal biopsy specimens in 44 children aged 0.5-18 years (mean, 10 +/- 5 years) undergoing endoscopy to evaluate dyspeptic symptoms. All subjects had normal duodenal histology. Intestinal organ culture was used to evaluate synthesis and processing of maltase-glucoamylase. Sequencing of the maltase-glucoamylase coding region was performed in subjects with low activity or variation of isoform in organ culture. RESULTS: Twenty-two of the dyspeptic children had one or more disaccharidases with low specific activity. Twelve subjects (28%) had low activity of glucoamylase. Eight subjects had low activities of glucoamylase, sucrase, and lactase. Low glucoamylase activity was not correlated with the isoform phenotype of maltase-glucoamylase as described by metabolic labeling and sodium dodecyl sulfate electrophoresis. Novel nucleotide changes were not detected in one subject with low glucoamylase activity or in two subjects with variant isoforms of maltase-glucoamylase peptides. CONCLUSION: Twelve of 44 dyspeptic children had low specific activity of duodenal maltase-glucoamylase. Eight of these children had low specific activity of all measured disaccharidases.     

Congenital maltase-glucoamylase deficiency associated with lactase and sucrase deficiencies

BACKGROUND: Multiple enzyme deficiencies have been reported in some cases of congenital glucoamylase, sucrase, or lactase deficiency. Here we describe such a case and the investigations that we have made to determine the cause of this deficiency. METHODS AND RESULTS: A 2.5 month-old infant, admitted with congenital lactase deficiency, failed to gain weight on a glucose oligomer formula (Nutramigen). Jejunal mucosal biopsy at 4 and 12 months revealed normal histology with decreased maltase-glucoamylase, sucrase-isomaltase, and lactase-phlorizin hydrolase activities. Testing with a C-starch/breath CO loading test confirmed proximal starch malabsorption. Sequencing of maltase-glucoamylase cDNA revealed homozygosity for a nucleotide change (C1673T) in the infant, which causes an amino acid substitution (S542L) 12 amino acids after the N-terminal catalytic aspartic acid. The introduction of this mutation into "wildtype" N-terminus maltase-glucoamylase cDNA was not associated with obvious loss of maltase-glucoamylase enzyme activities when expressed in COS 1 cells and this amino-acid change was subsequently found in other people. Sequencing of the promoter region revealed no nucleotide changes. Maltase-glucoamylase, lactase, and sucrase-isomaltase were each normally synthesized and processed in organ culture. CONCLUSIONS: The lack of evidence for a causal nucleotide change in the maltase-glucoamylase gene in this patient, and the concomitant low levels of lactase and sucrase activity, suggest that the depletion of mucosal maltase-glucoamylase activity and starch digestion was caused by shared, pleiotropic regulatory factors.     

Pediatric perspectives on treating uncommon genotypes of hepatitis C in the United States

Rationale: Hepatitis C in the pediatric population is a large health burden globally. With its diverse genotypes as well as genotypic subtypes, there is a discrepancy in the genotypes used in research compared to their prevalence. HCV genotype 6 which is endemic to South China and Southeast Asia comprises approximately one-third of all HCV infections worldwide, but make up a minority of cases studied in HCV research. Patient concerns: We report a case of HCV-6 seen in an 11-yearold Burmese immigrant to the U.S. and describe the new direct acting antiviral treatment guidelines for pediatrics with HCV genotype 6.Interventions: The patient completed a 12-week course of ledipasvir/sofosbuvir(90 mg/400 mg), per FDA weight-based recommendations for treatment-naive HCV genotypes 4-6, without any complications. Outcomes: The patient was treated successfully with an undetectable HCV viral load one month after treatment completion. Lessons: HCV-6, although previously uncommon in the U.S., is becoming more prevalent. Updated guidelines include the use of direct acting antivirals, which have been proven effective for HCV-6. Lessons on barriers to care in the immigrant population as well as the value of HCV genotyping are also discussed.