Intestinal Bile Acid Malabsorption in Cystic Fibrosis: a Primary Mucosal Cell Defect

Pediatr. Res. 16: 494-498 (1982) Intestinal Bile Acid Malabsorption in Cystic Fibrosis: a Primary Mucosal Cell Defect JOSEPH D. FONDACAR0'35', JAMES E. HEUBI, AND FRANK W. KELLOGG Departments of Physiology and Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio and Children's Hospital Clinical Research Center, Cincinnati, Ohio U S A Summary Bile acid malabsorption in cystic fibrosis reduces intraluminal bile acid concentration and may impair fat absorption. The cause of this malabsorption is unknown but it is believed due to intraluminal inhibition of uptake by undigested dietary nutrients. The purpose of this study was to determine the bile acid absorptive capability of cystic fibrosis intestine in a physiologic environment. Direct ileal mucosal taurocholic acid uptake was examined in vitro in seven patients with cystic fibrosis, and seven children and adolescents with ileostomies as controls. Jejunal uptake was studied in five normal individuals. A Crosby-Kugler biopsy capsule was used to obtain all tissues. Tissue was incubated in Krebs buffer, 10 mM glucose, and taurocholic acid at 0.1, 1.0 and 10.0 mM with shaking at 37OC. Significant reduction of taurocholic acid uptake was present in every cystic fibrosis patient with mean uptake rates being 24%, 38%, and 29% of control ileum, respectively, at the three concentrations. Values paralleled those for passive jejunal taurocholic acid uptake in controls. These data illustrate a marked reduction in taurocholic acid uptake capability of cystic fibrosis ileal mucosa and may indicate a cellular defect suggestive of a primary lesion in this disease. The most widely accepted view suggests that undigested dietary nutrients (present intraluminally due to pancreatic insufficiency) in some way bind or sequester bile acids, thus preventing normal absorption (3, 15, 21, 33); however, definitive studies have not been reported and the precise mechanism remains conjectural. The present study was designed to determine if ileal mucosa from CF patients, when removed from the abnormal intraluminal environment of the CF intestine, has the normal capacity to absorb bile acid in vitro. Results from such experiments will either suggest that the bile acid malabsorption in CF is caused by an intraluminal event or will point toward a basic cellular defect for bile acid absorption in the ileal mucosa. MATERIALS AND METHODS Patients. Seven patients (two males, five females) with cystic fibrosis, CF(Il), age 4-8/12 years to 25 years (mean 16.7 years) were studied. All had sweat chloride concentrations exceeding 80 mEq/liter on repeated tests, pulmonary disease confirmed by pulmonary function studies and chest radiographs, and pancreatic insufficiency defined as absent stool tryptic activity and improvement of diarrhea with pancreatic enzyme supplements. All patients were hospitalized for aggressive pulmonary toilet and broad spectrum intravenous antibiotics including a semisynthetic penicillin Speculation and an aminoglycoside. Before discharge, during a 7-10 day ~ e s u l tof s the present study suggest that bile acid malabsorption course of antibiotics, the present study was performed. All patients in cystic fibrosis may be due to a primary f~nctionaldefect of the were below the 5th percentile for weight and/or height. ileal mucosal cells in this disease. This is demonstrated in vitro by ~h~ first control group, C(I 11, consisted of seven patients (three the reduced uptake rates for taurocholic acid by ileal mucosa males, four females) ages 6/12 to 27 years (mean 1 1.1 years) who taken from cystic fibrosis patients when compared to controls. had well adapted ileostomies (at least 12 months postresection) Furthermore, the taurocholic acid uptake rate in cystic fibrosis after total co~ectomyfor ulcerative colitis (six patients) or ~~~h~~~ ileal mucosa are comparable to that of jejunal mucosa from health colitis (one patient). All were in excellent health, and all mucosae volunteers. This suggests that active transport mechanisms for were histologically normal. We believe this is the most reasonable bile acid absorption are absent in cystic fibrosis intestine. Although control group to study because peroral ileal biopsy in normal these studies do not impugn an intral~minalmechanism, they point healthy children of this age is neither feasible nor ethical. to a primary functional ileal mucosal cell defect as the ~ a t h o ~ h ~ s -Four females and one male, ages 26-43 years (mean 31 years), iologic mechanism of bile acid malabsorption in cystic fibrosis. in good health and with no gastrointestinal symptoms, were studied as a jejunal control group, C(Je). All mucosae were Cystic fibrosis (CF) is an autosomal, recessively transmitted histologically normal. Informed consent was obtained from either the patient or his/ disease affecting multiple organs including the mucous glands of the tracheobronchial tree, the exocrine pancreas, and the gastroin- her parents before entering the study. Protocol for the study was testinal mucosa (15). Clinically significant intestinal malabsorp- approved by the Committee on Human Research of the University tion of various substrates including bile acids is a consistent of Cincinnati, College of Medicine, and by the Committee on Research Involving Human Subjects of the Children's Hospital finding in C F (1, 3, 5, 12, 16, 21, 25, 28, 30, 33). Several studies have been carried out attempting to define the Medical Center, Cincinnati, Ohio. Biopsyprocedure. Peroral biopsies were taken from the ileum in pathophysiology and the severity of bile acid malabsorption in CF. Total bile acid pool size is contracted in CF patients unsup- seven C F patients and from the jejunum in the five normal plemented with pancreatic enzymes, which reverses with supple- volunteers using a 3.0 mrn port Crosby-Kugler biopsy capsule. mentation (30). Fecal bile acid loss in CF, which directly correlates Proximal jejunal biopsies were performed as previously described with the degree of pancreatic insufficiency (32), can be excessive (23). Ileal biopsies were performed according to the following due to interruption of the normal enterohepatic circulation of bile procedure. After an overnight fast, an Argyl nasogastric tube was passed through the nose and the tip retrieved through the month acids. There are several theories regarding the factor or factors that with a McGill forceps. The proximal end of a polyethylene tube might account for the inhibition of bile acid absorption in CF. (180-240 cm in length) attached to the biopsy capsule, was then 494 49 5 BILE ACID AND CF pulled back through the nose. The patients swallowed the capsule with the tubing extended out through the nose. Passage of the capsule through the pylorus was facilitated by patient positioning. The patient was allowed to eat and the capsule moved distally with peristalsis. The position of the capsule was verified periodically using abdominal x-ray wi (...truncated)