Potential conflict of interest: Nothing to report.
Article first published online: 25 APR 2008
Copyright © 2008 American Association for the study of Liver Diseases
Volume 47, Issue 5, pages 1797–1798, May 2008
How to Cite
Bertolotti, M., Gabbi, C., Anzivino, C., Carulli, L. and Carulli, N. (2008), Reply:. Hepatology, 47: 1797–1798. doi: 10.1002/hep.22260
- Issue published online: 25 APR 2008
- Article first published online: 25 APR 2008
We deeply appreciate the interest of Dr. Rudling in our short comment. As correctly pointed out, the numbers of subjects described in individual studies where hepatic tissue sampling is required are necessarily limited. Studies using surrogate markers of bile acid synthesis such as 7α-hydroxy-4-cholesten-3-one (C4) can allow for inclusion of patient numbers of an almost “epidemiological” size.
Such evidence leads to consideration of bile acid malabsorption, and consequently increased bile acid synthesis, as a risk factor for gallstone formation. We completely agree with this view, already supported by older evidence in the literature of patients with small bowel disease.1
What we disagree on is the view of this as a general (and therefore, global) finding in patients with gallstones, and as a major, or only, cause of gallstone formation; the fact itself that such large numbers are required to disclose statistical significance on a 30%–40% difference points to an epidemiological association more than to a universal pathophysiological cause-and-effect relationship.
Indeed, a look at the literature reveals a body of evidence that is against an increase in bile acid synthesis as a prominent feature in gallstone disease. In older papers by Nilsell et al.2 and Berr et al.,3 when bile acid synthesis was measured in vivo by isotope techniques, no difference in total primary bile acid synthesis was detected between patients with gallstones and control patients. Once again, in individual studies the numbers are not impressive, but this is the evidence that can be collected in human studies of such complexity.
Moving to in vitro studies, none of the pieces of evidence reported up to now, as far as we know, have shown increased CYP7A1 activity in gallstone disease, with some studies suggesting a reduced rate4–6 and others showing no differences.7–9
No significant differences were detected in tissue messenger RNA expression of CYP7A1 in our own data (Bertolotti et al.10, and unpublished data, summing up 13 control subjects and 16 patients with gallstones) and in a recent paper by Jiang et al. on 22 Chinese patients with gallstones compared with 13 matched controls.11
Adding up all figures derived from these studies, we total nearly 40 patients in each experimental group in the two in vivo studies, and nearly 100 control subjects versus more than 130 patients with gallstones with data in vitro. Even keeping in mind the extreme heterogeneity among these studies and the fact that most of them were performed decades ago, such evidence is far more than anecdotal.
Is there any reason why indirect measurement of CYP7A1 activity by assay of plasma C4 levels should yield results which are discrepant with in vitro assay of CYP7A1 expression and activity, or with other measurements of bile acid synthesis? This cannot be excluded, but as far as we know there is no evidence supporting this view.
The data provided by Rudling on mice are interesting and thought-provoking; once again, other pieces of evidence where mice overexpressing CYP7A1 show reduced risk for gallstone formation reveals another side to this story.12
In the article by Muhrbeck et al.,13 quoted by Rudling, the authors themselves conclude that “the increased biliary cholesterol saturation and cholesterol secretion in patients with gallstones is not the result of a single monogenic defect but rather the aetiology of cholesterol gallstones is multifactorial”. A recent review on the genetic background of cholesterol cholelithiasis14 is also in line with this view.
We believe that, in close analogy with other chronic diseases (for example, atherosclerosis), the etiology of cholesterol gallstone disease is to be considered multifactorial; in this context, we all agree that some “risk factors” may be identified, among which are defects in bile acid absorption. Such conditions, much like dyslipidemia or hypertension for cardiovascular diseases, may certainly be relevant even if not universally present. It is not paradoxical that reduced bile acid synthesis may also represent a risk factor in specific situations, for example, patients receiving fibrate treatment or with the extremely rare condition of genetic deficit of CYP7A1 already mentioned in our letter.
Further research on the interrelationships underlying the control of bile acid recirculation along the enterohepatic axis is certainly required to provide clearer insight in this field. Because the observed changes, as pointed out by Dr. Rudling, may precede gallstone formation, proper identification of the subgroups of patients with higher risk for gallstone development might be relevant in the perspective of prevention.
- 6Biliary lipid synthesis and secretion in gallstone patients before and during treatment with chenodeoxycholic acid. J Lab Clin Med 1980; 96: 816–826., , , , .
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.