Abstract
Objective: A Malabsorption Blood Test (MBT) is proposed as an alternative method to the 72-hour stool and dietary collection for assessing the degree of fat malabsorption in people with pancreatic insufficiency. The MBT consists of a simultaneous oral dose of pentadecanoic acid (PA), a free fatty acid, and triheptadecanoic acid (THA), a triglyceride with three heptadecanoic (HA) saturated fatty acids requiring hydrolysis by pancreatic lipase before HA can be intestinally absorbed. The aim of this study is to demonstrate the ability of MBT to detect fat malabsorption in healthy adult subjects using the pancreatic lipase (PL) inhibitor Orlistat (Xenical®), and in subjects with CF and PI while on and off routine pancreatic enzyme doses. Materials and methods: The MBT with the PA and THA were delivered in a breakfast test meal (2.5 g PA and either 5 g or 8 g THA) to healthy adult subjects (ages 18 – 50 years, BMI 21 – 30) and to subjects with CF (> 12 years, FEV1% predicted > 40%), after a 12-hour fast and 24 hours without dairy foods. Serum levels of PA and HA were assessed by gas-liquid chromatography, from blood samples drawn prior to MBT and then hourly for 8 hours. For healthy subjects, the MBT was administered before and after Orlistat treatment, and in subjects with CF, both with subjects receiving routine pancreatic lipase treatment (“on enzyme”) and also “off enzyme” treatment. Treatment groups were compared for baseline (C0) and maximum (Cmax) plasma concentrations of PA and HA over 8 hours: area under the curve (AUC) was calculated using linear trapezoid method. The ratio of HA to PA Cmax and AUC was also calculated and compared. Results: For the healthy subjects (n = 15, 60% female, ages 21 – 49 years), absorption of HA was reduced 71% for Cmax (p < 0.001) and 65% for AUC (p = 0.001) after Orlistat treatment, and absorption of PA was unchanged. For subjects with CF (n = 6, 50% female, ages 13 – 19 years), absorption of HA was minimal with subjects “off enzymes” and increased significantly with subjects “on enzymes” while absorption of PA did not differ between groups. Enzyme administration resulted in increased Cmax HA/PA ratios from 0.02 to 0.92 and from 0.05 to 0.73 in subjects with CF receiving 5.0 g and 8.0 g of THA, respectively. AUC HA/PA ratios showed similar increases. Conclusions: In this pilot and feasibility proof-of-concept study, the MBT, utilizing the relative absorption of HA to PA, two odd-chained fatty acids, responds to changes in fat absorption in healthy subjects using a lipase inhibitor and in subjects with CF while on or off enzyme therapy. The MBT holds promise to provide a more accurate, specific and acceptable alternative to the 72-hour stool collection to quantify pancreatic-based fat malabsorption in a variety of clinical and research contexts.
Highlights
Optimum utilization of dietary fat requires a complex digestive process in which dietary fat moieties are hydrolyzed and repackaged within the gut lumen for absorption and transport into the body
Acquired causes of lipase insufficiency may result from chronic enteropathy such as celiac disease, and this usually resolves once the celiac disease is treated
The 95% confidence intervals (CI) for AUC ratios were calculated via bootstrapping. Subject characteristics for both the healthy subjects in the Lipase Inhibitor Study and the subjects with cystic fibrosis (CF) in the CF Pharmacokinetic Study are presented in Table 1, both for the total samples and separately by gender. 60% of the healthy subjects were female and 50% of the subjects with CF
Summary
Optimum utilization of dietary fat requires a complex digestive process in which dietary fat moieties are hydrolyzed and repackaged within the gut lumen for absorption and transport into the body. PA and HA pharmacokinetic characteristics in combination, and the HA/PA ratio, can be used to evaluate pancreatic-based fat malabsorption in patients and research subjects These two odd-chained fatty acids were selected for the MBT for the following reasons: 1) they are found in small amounts only in dairy foods; 2) the vast majority of individuals have very low serum concentrations of PA and HA; 3). They are safe to administer in larger doses than typically found in the diet; and 4) they are identified in the serum by well-established laboratory methods, and absorption pharmacokinetics can be readily described. The results of these initial experiments are expected to guide the MBT development as a diagnostic for malabsorption in subjects with CF and other pancreatic based malabsorption disorders
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