This month in Scandinavian Journal of Gastroenterology

In about 30% of patients irritable bowel syndrome (IBS) seems to be due to bile salt malabsorption (BAM). The mechanism is quite interesting. About 95% of the recirculating pool of bile salts are reabsorbed in the terminal ileum, and the apical bile salt transporter (ASBT) in the ileum is responsible for this. After reabsorption, bile salts bind and activate the farnesoid X-receptor and this causes the transcription of fibroblast growth factor (FGF19). FGF19 travels via the portal blood to the liver where it binds to its receptor FGFR4. For a correct function of FGFR4, one also needs a protein called Klotho beta (KLB). FGF19 signaling in the liver causes the downregulation of CYP7A1, a key enzyme in bile salt synthesis. Recent studies show that BAM can be due to genetic variants of one of these proteins leading to an overproduction of bile salts [1]. Thus, not only a deficiency of ASBT with malabsorption of bile salts but also overproduction of bile salts in the liver can cause BAM. In this issue, Kurien et al. [2] show that BAM is probably an underreported cause of IBS. To detect BAM, they use the SeHCAT test, a validated test that measures retention and loss of bile salts from the enterohepatic circulation. A low value means excessive loss. Loss of bile salts from the ileum to the cecum causes activation of water secretion, reduction of colon transit time and diarrhea. There are a number of diseases wherein BAM is a logical consequence of altered anatomy (Crohn’s disease, ileal resection) but, for other conditions, the cause of BAM is less obvious (IBS and cholecystectomy). In these conditions, the mechanismmost likely resides in acquired (cholecystectomy) or genetic (IBS) causes of malfunction of either bile salt absorption or feedback regulation of CYP7A1. This issue contains more on IBS. IBS can present in various forms and manifestations. Visceral hypersensitivity is one of its hallmarks. Van Hoboken et al. [3] show that visceral hypersensitivity has an anatomical substrate in that it is associated with an increased number of activated mast cells close to nerve endings in the rectum. This is at least true for patients with ulcerative colitis in remission. It would be of interest to investigate this in patients with IBS in general, or in IBS as a postinflammatory condition. Schmidt et al. [4] show that after many years, gallstones can spontaneously disappear from the gallbladder. They re-examined 154 patients who had gallstones in 1983. About 7% had a cholecystectomy but of the remainder only 28% still had gallstones. What caused the spontaneous disappearance of these stones? Were they expelled from the gallbladder or are they dissolved? Many of these patients had abdominal complaints at some point. Biliary colics, either spontaneously or drug-induced, can lead to the movement of gallstones from the gallbladder to the duodenum. Thus perhaps colics, strong enough to clear the gallbladder from stones, have played a role here. The detection by GWAS studies of the interleukin28B polymorphism shed new light on the treatment of patients with chronic hepatitis C. Sixty-nine percent of patients of European ancestry homozygous for the favorable host genotype (rs12979860) (genotype C/C) show sustained virological response (SVR) on treatment with conventional peginterferon–ribavirin combination therapy, even when infected with the relatively treatment-resistant HCV genotype 1. In HCV genotype 1-infected patients with the T/T or C/T host genotype, SVR was only 27% and 33%. For patients with the more favorable HCV genotypes 2 and 3, SVR was 82% in the group with the C/C genotype versus 58% and 75% for the C/T and T/T genotypes [5]. It is likely that detection of the IL28B polymorphism and perhaps other host phenotypes, such as the expression of the HCV receptor CD81 on a subset of blood mononuclear cells [6], will be added to the diagnostic armamentarium of specialized hepatitis C treatment centers. Although this adds extra costs to the already expensive viral tests, identifying patients with little chance to respond to treatment may be cost saving. To make things less expensive, Nakamoto et al. [7] describe a simple genotype assay that detects an SNP close enough to be in linkage disequilibrium with the predictive rs12979860 locus. Thus with this test, one can identify probable responders to therapy. The authors stress that this test should be mainly used for research purposes.