Elevated Levels of Toxic Bile Acids in Serum of Cystic Fibrosis Patients with CFTR Mutations Causing Pancreatic Insufficiency

Abstract

Hepatobiliary involvement is a hallmark in cystic fibrosis (CF), as the causative CF Transmembrane Conductance Regulator (CFTR) defect is expressed in the biliary tree. However, bile acid (BA) compositions in regard to pancreatic insufficiency, which is present at an early stage in about 85% of CF patients, have not been satisfactorily understood. We assess the pattern of serum BAs in people with CF (pwCF) without CFTR modulator therapy in regard to pancreatic insufficiency and the CFTR genotype. In 47 pwCF, 10 free and 12 taurine- and glycine-conjugated BAs in serum were prospectively assessed. Findings were related to genotype, pancreatic insufficiency prevalence (PIP)-score, and hepatic involvement indicated by serum liver enzymes, as well as clinical and ultrasound criteria for CF-related liver disease. Serum concentrations of total primary BAs and free cholic acid (CA) were significantly higher in pwCF with higher PIP-scores (p = 0.025, p = 0.009, respectively). Higher total BAs were seen in pwCF with PIP-scores ≥0.88 (p = 0.033) and with pancreatic insufficiency (p = 0.034). Free CA was higher in patients with CF-related liver involvement without cirrhosis, compared to pwCF without liver disease (2.3-fold, p = 0.036). pwCF with severe CFTR genotypes, as assessed by the PIP-score, reveals more toxic BA compositions in serum. Subsequent studies assessing changes in BA homeostasis during new highly effective CFTR-modulating therapies are of high interest.

Scoring Abdominal Symptoms in People with Cystic Fibrosis

“…Untreated EPI results in maldigestion, malabsorption, and failure to thrive, together with deficient absorption of fat-soluble vitamins and other nutrients. Intestinal CFTR deficiency further aggravates enterocyte dysfunction, which breaks the digestive balance leading to stool abnormalities, intestinal obstruction [ 7 ], disruption of the intestinal flora [ 8 ], and defective bile acid absorption with a specific cholestatic pattern in pwCF [ 9 , 10 , 11 , 12 ]. Thereby, CFTR-mRNA expression is highest in the Brunner glands of the proximal duodenum, which produce intestinal mucus and it decreases towards the distal intestine [ 13 , 14 ].…”

“…Frequent antibiotic treatment of pulmonary pathogen colonization and altered intestinal passage times [ 18 ] contribute to the CF-specific AS pattern, which is complemented by changes in bile acid profiles, gallstones, and an impaired enterohepatic circuit [ 19 ]. The defective CFTR channel in the bile ducts adds to the pathogenesis of CF-related liver disease (CFLD), initially featuring a toxic cholestatic pattern [ 9 ] and progressing to focal or multifocal biliary cirrhosis and end-stage liver cirrhosis that contributes to the appearance of other complications such as portal hypertension, ascites, esophageal varices, and in some cases to liver failure [ 20 ].…”