Increased synthesis of bile acids in gallstone disease is a global finding and not a “peculiar condition” solely in Chile
Authors: Mats Rudling
Journal: Hepatology (2008)

In the November issue of HEPATOLOGY, Bertolotti and colleagues1 claim that previous findings2 of an increased synthesis of bile acids (BAs) in subjects with gallstone disease is a "peculiar condition" "described mainly in Chilean Hispanic subjects". It was further stated that in a vast majority of untreated subjects, no specific defects in cholesterol homeostasis have been disclosed. As evidence, 2 papers were referred to. The first3 compared 11 gallstone patients with 9 controls. The second study4 compared 27 gallstone subjects with 13 controls. Considering subject numbers in these studies, it is difficult not to deem them anecdotal. However, they are representative for studies on this topic that usually have 2 major problems in common: (1) they are severely underpowered and (2) controls are not healthy. Using 7α-hydroxy-4-cholesten-3-one (C4)5 as measure of BA synthesis can unwind these problems, allowing for the inclusion of sufficient numbers of both patients and healthy controls. The Chilean study referred to2 had 80 healthy controls and 45 subjects with gallstones. BA synthesis was 37% higher in subjects with gallstones. There is also a Swedish study6 on 72 subjects who were gallstone-free and 41 subjects with gallstones where BA synthesis was 40% higher in subjects with gallstones. Further, analysis of 2 German studies7, 8 made by one research group on 106 healthy controls7 and 51 subjects with gallstones8 reveal that BA synthesis is 31% higher in subjects with gallstones. In addition, in the Chilean study,2 40 Mapuche Indians had very high BA synthesis regardless whether stones were present, suggesting that increased BA synthesis is present prior to stone formation. Thus, in Swedes,6 Germans,7, 8 and Chileans,2 data from 395 subjects (258 normal and 137 with gallstones) consistently show that BA synthesis is 31%–40% higher in gallstone disease. These data strongly suggest that increased BA synthesis in gallstone disease is a global finding. This finding together with previous well-documented facts that the pool of BAs is reduced in gallstone disease whereas the turnover of BAs is increased suggests that the initial event causing gallstone disease may be in the intestine, commencing with a fecal loss of BAs that cannot be adequately compensated for, thereby facilitating gallstone precipitation. Interestingly, studies on wild mice9 support this concept.2 Wild mice develop gallstones with a seasonal variation and the gallstone prevalence strongly relates to fecal BAs (Fig. 1). From analysis of gastric contents it was concluded9 that the intake of dietary fiber may contribute to the fecal loss of BAs, providing a potential physiologic and nutritional mechanism for cholesterol gallstone formation. Seasonal gallstone prevalence in wild deer mice as a function of seasonal fecal bile acid (BA) content. Seasonal fecal BA contents have been phase-advanced 3 months. Data derived from Ginnett et al.9 The seasons for collection of mice for gallstone prevalence determination are indicated. Direct measures of the fecal excretion of BAs in human subjects with gallstone disease are now warranted to confirm if an increased fecal excretion of BAs in gallstone disease as reported10 remains when investigated on large series of patients. Mats Rudling M.D., Ph.D. Professor* , * Karolinska Institute, Center for Endocrinology, Metabolism, and Diabetes, Department of Medicine, Karolinska University Hospital, Huddinge, Stockholm, Sweden, Molecular Nutrition Unit, Department of Biosciences and Nutrition, Huddinge, Stockholm, Sweden.