Gallbladder bile supersaturated with cholesterol in gallstone patients preferentially develops from shortage of bile acids

Abstract

supersaturated with cholesterol (1-3). A common way to monitor this is from a cholesterol saturation index (CSI), calculated from the mol% (mole percent) values of the three major lipids in GB bile: bile acids (BAs), cholesterol, and phospholipids (PLs) together with the total lipids (4). CSI is an established indicator of GSD risk. However, a high CSI value does not indicate whether increased cholesterol levels, reduced BA levels, and/or reduced PL levels in GB bile are causing it, a crucial question for identification of the major most common cause for supersaturated bile. Nevertheless, a frequent view is that increased CSI in GB bile is primarily due to hepatic hypersecretion of cholesterol into bile (5-10). In studies on lipid levels in GB bile, authors often compare mol% data of GB lipids from patients with and without GSs. From such comparisons, authors frequently conclude that the mol% of cholesterol is increased in GB bile from patients with GSD, a finding often considered to support that hypersecretion of cholesterol is the primary and major cause for why GB bile from patients with GSD is supersaturated with cholesterol (2, 9, 11-14). We hypothesized that such comparisons of the relative mol% data of GB lipids (12, 13, 15, 16) do not provide information as to whether cholesterol supersaturation results from excess hepatic secretion of biliary cholesterol, decreased biliary secretion of BAs or PLs, or a combination of both. We reasoned that straightforward mmol/l (millimole per liter) levels of GB bile lipids should instead provide more relevant direct information to answer this question. To investigate this, we compared the mmol/l levels of GB lipids in GS and GS-free (GSF) patients with the results obtained using the corresponding mol% values. This was possible because we had access to data from a previously Abstract Gallstone (GS) formation requires that bile is supersaturated with cholesterol, which is estimated by a cholesterol saturation index (CSI) calculated from gallbladder (GB) total lipids and the mol% (mole percent) of bile acids (BAs), cholesterol, and phospholipids (PLs). Whereas CSI indicates GS risk, we hypothesized that additional comparisons of GB lipid mol% data are inappropriate to identify why CSI is increased in GS disease. We anticipated that GB lipid mmol/l (millimole per liter) levels should instead identify that, and therefore retrieved GB mmol/l data for BAs, cholesterol, and PLs from a study on 145 GS and 87 GS-free patients and compared them with the corresponding mol% data. BA and PL mmol/l levels were 33% and 31% lower in GS patients, while cholesterol was unaltered. CSI was higher in GS patients and correlated inversely with GB levels of BAs and PLs, but not with cholesterol. A literature search confirmed, in 13 studies from 11 countries, that GB BA levels and, to a certain extent, PLs are strongly reduced in GS patients, while cholesterol levels are not elevated. Our findings show that a shortage of BAs is a major reason why GB bile is supersaturated with cholesterol in GS...

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