This resembled the biochemical picture seen in patients with known defects in hepatic fatty acid oxidation, such as the acyl-CoA dehydrogenase deficiencies.[10] Studies done at CCHMC uncovered a link between Reye’s syndrome and aspirin administration, resulting in significant media attention.[11, 12] This led to warning labels on aspirin preparations and a dramatic decline in the incidence of Reye’s syndrome beginning Selleckchem BTK inhibitor in the late 1980s. Thus, a dramatic life-threatening disorder was virtually eliminated. In addition, insight into genetic defects in the synthesis of mitochondrial proteins and enzymes affecting multiple organ systems, including the brain and skeletal/cardiac

muscle, had been elucidated.[7, 9, 13] Therefore, this disease JQ1 research buy served as a model

for mitochondrial disorders, as subsequently seen in fialuridine-induced mitochondrial inhibition.[14] This “public health triumph,” likely the first major development in the field of Pediatric Hepatology, stimulated the unification of individuals interested in the care and investigation of children with liver diseases. One of the early research challenges presented to me by Bill Schubert was to solve the problem of Donald—an infant with persistent, intractable diarrhea beginning on the second day of life, which caused failure to thrive. At 4 months of age he weighed 3.5 kg, well below his birth weight of 4.4 kg. Attempts at refeeding with a variety of elemental diets resulted in watery diarrhea, dehydration, acidosis, and shock; thus, he was total parenteral nutrition-dependent. Daily stool weight averaged >500 gm/day (normal <100) and fecal fat excretion was >50% of the daily intake. His serum cholesterol concentration was markedly depressed (<70 mg/dL). After several months of evaluation and fruitless investigations I came across an article by Alan Hofmann that described the clinical consequences of resection of the ileum, the main site of bile acid reabsorption.[15] Donald manifested some of these clinical features; thus, my naïve thought was that he may well be malabsorbing

Ureohydrolase bile acids. Indeed, a short-term trial of cholestyramine resulted in an initial improvement of his diarrhea, followed by a gradual exacerbation of his steatorrhea. This biphasic response supported the hypothesis that bile acid malabsorption might well be the cause of his prolonged diarrhea. We designed a study to prove that theory. Evaluation of bile acid kinetics in this patient with severe refractory diarrhea confirmed our hypothesis that bile acid transport in the terminal ileum was altered. Fecal excretion of labeled bile acid (I4C-24-cholic acid) was increased, with the ratio of excretion of bile acid comparable to that of a nonabsorbable marker, consistent with primary bile acid malabsorption.[16] The magnitude of loss of cholic acid was similar to that observed in infants who had undergone ileal resection.