Changes in bile acid synthesis in gallstone disease: Cause, consequence, or neither?
Authors: Marco Bertolotti, Chiara Gabbi, Claudia Anzivino, Lucia Carulli, Nicola Carulli
Journal: Hepatology (2007)

The relationship between hepatic lipid homeostasis and gallstone formation is intriguing. The reduction of the activity of cholesterol 7α-hydroxylase (CYP7A1), the limiting enzyme of bile acid synthesis, has long been claimed as a possible cause of gallstone formation.1, 2 More recent evidence from fibric acid derivatives has confirmed an association between decreased bile acid synthesis and increased biliary cholesterol secretion.3, 4 Finally, anecdotal evidence from a family with a congenital defect in CYP7A1 has also shown increased prevalence of gallstone disease.5 An article by Castro et al.6 recently published in HEPATOLOGY, confirming previous evidence that they had reported,7 shows, on the other hand, an increase in circulating 7α-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, and in hepatic CYP7A1 messenger RNA in gallstone patients. This is also correlated with increased hepatic activity of the microsomal triglyceride transfer protein, which is critical for hepatic lipoprotein production. In our opinion, different scenarios can be envisioned in the reciprocal relationships between bile acid synthesis and gallstone formation. In a few specific conditions, reduced degradation of cholesterol to bile acid, either congenital or secondary to drug treatment, may result in an increased concentration of free cholesterol recruitable for biliary secretion; this can therefore be regarded as a cause of increased cholesterol saturation and gallstone formation.3-5 In other patient subsets, bile acid malabsorption may occur, and the increases in bile acid synthesis, 7α-hydroxy-4-cholesten-3-one levels, and CYP7A1 expression need to be considered instead as results of an underlying metabolic defect, an epiphenomenon of gallstone disease. Indeed, this peculiar condition has been described mainly in Chilean Hispanic subjects.6, 7 It would be interesting to assess whether the relationships linking intestinal bile acid uptake and malabsorption, hepatic lipoprotein production (considered a cause of primary hypertriglyceridemia),8 and gallstone disease also hold true in different patient settings. In a vast majority of untreated subjects, on the other hand, no specific defects in any of the metabolic pathways controlling hepatic cholesterol homeostasis, that is, cholesterol synthesis, esterification, and bile acid synthesis, have been disclosed,9 and this is in agreement with our own data on hepatic CYP7A1 expression and 7α-hydroxy-4-cholesten-3-one levels.10 This leads us to conclude that in many instances cholesterol gallstone disease is multifactorial and is likely to require the concomitant presence of genetic (probably polygenic) and environmental factors, unfortunately in the absence of reliable and measurable biomarkers. Hepatic nuclear receptors can control many metabolic steps of cholesterol and bile acid homeostasis and may certainly represent a molecular link between bile acid and lipoprotein production.6 Changes in nuclear receptor expression and changes in the expression and activity of related target genes, such as hepatobiliary transporters, may occur in gallstone disease, as suggested by preliminary data from our group.10, 11 It would be interesting to know whether changes in the tissue expression of farnesoid X receptor or related genes are present in this particular subset of gallstone patients and whether they are associated with changes in microsomal triglyceride transfer protein expression and activity. It is hoped that further exploration of the metabolic relevance of nuclear receptors for hepatic cholesterol and bile acid metabolism and for biliary lipid secretion will provide new clues in terms of pathophysiology and novel molecular approaches. In the meantime, more than 30 years after the utilization of the first (then unrecognized) farnesoid X receptor agonist, chenodeoxycholic acid, for stone dissolution, the causal relationship between bile acid synthesis and gallstone disease in humans still has a high degree of uncertainty. Marco Bertolotti*, Chiara Gabbi*, Claudia Anzivino*, Lucia Carulli*, Nicola Carulli*, * Dipartimento di Medicina, Endocrinologia, Metabolismo e Geriatria, Università degli Studi di Modena e Reggio Emilia, Modena, Italy.