Bile acid malabsorption in patients with graft‐versus‐host disease of the gastrointestinal tract (2012)

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow/granulocyte colony-stimulating factor mobilized blood transplantation. Acute GVHD requiring treatment is associated with substantial morbidity and mortality (Van Lint et al, 2006). Acute GVHD often involves the lower gastrointestinal (GI) tract, inducing diarrhoea, weight loss and abdominal pain. Allogeneic immune cells and the conditioning regimen combine to damage the GI tract leading to inflammation of the mucosa (Hill et al, 1997). Many patients, particularly those with lower GI GVHD, do not respond to intensive immunosuppression (MacMillan et al, 2002). This may be because the process of inflammation is not effectively suppressed by the agents used. Alternatively, additional mechanisms may be at play. Upper and lower GI endoscopy with biopsy are standard investigations of GI GVHD. However many patients have clinical symptoms discordant with the findings from these investigations. In one study, 25% of patients with clinical Glucksberg stage 2–4 GI GVHD had both endoscopic and histological grades <2 (Thompson et al, 2006). This raises the possibility that the symptoms of GI GVHD in some patients may be due to mechanisms other than colitis. One important function of the small bowel is to re-absorb bile acids as part of the enterohepatic circulation. Bile acids are re-absorbed by specific bile acid transporters in the terminal ileum. If this process is disrupted (e.g. by damage to the terminal ileum through Crohn’s disease or surgery) bile acids reach the colon in increased amounts where they cause watery diarrhoea (and abdominal pain) by inducing secretion of sodium and water (Pattni & Walters, 2009). Bile acid malabsorption is investigated using a selenium-75-homocholic acid taurine (SeHCAT) scan in which the radiolabelled bile acid is given orally and the whole body retention is measured at 7 days (Williams et al, 1991; Ford et al, 1992). Treatment with bile acid sequestrants is effective in the majority of cases (Wedlake et al, 2009). Here we report retrospective observational data that suggest that the diarrhoea in GI GVHD may be related to bile acid malabsorption in some patients. We have retrospectively reviewed data from all patients undergoing allogeneic transplantation at St Bartholomew’s Hospital who underwent SeHCAT scans for investigation of persistent diarrhoea in the context of GI GVHD between 2003 and 2011. Retention of <10% of SeHCAT was considered to be diagnostic of bile salt malabsorption. Patients gave written informed consent to undergo the allograft and subsequent investigations. None of the patients had chronic diarrhoea pre-allograft nor had received a prior diagnosis of bile acid malabsorption. Acute GVHD was defined as that occurring before day 100 and chronic GVHD after day 100. Infectious causes of diarrhoea were excluded using standard investigations. Seven patients with a diagnosis of GI GVHD were investigated with SeHCAT scans (Table I). In four of these patients, the diarrhoea was refractory to steroid therapy while in two others the diarrhoea responded initially but recurred once the doses of immunosuppression were weaned. The patients all had bile acid malabsorption as confirmed by SeHCAT scans. Five of seven received therapy with bile acid sequestrants, of whom three had complete resolution of their diarrhoea. The data support the hypothesis that bile acid malabsorption may be a consequence of GI GVHD. This is consistent with studies that indicate that the terminal ileum is frequently involved by GVHD (Kreisel et al, 2011). Corticosteroids increase the expression of bile acid transporters in humans and in so doing may benefit those with GI GVHD in addition to their anti-inflammatory properties (Jung et al, 2004). However, their use is associated with many side effects. Bile acid sequestrants are effective and easy to administer with relatively few side effects (although it should be noted that they can adsorb medications including calcineurin inhibitors and need to be administered at different times from other oral drugs). The use of bile acid sequestrants in patients with GI GVHD may allow a reduction in the use of immunosuppressant medications depending on the involvement of other organs by GVHD. Given that many patients with GVHD die from infective complications, this may be an important consideration. Of note, the SeHCAT scans were performed in our series after the patients had received high doses of corticosteroids and other immunosuppressive agents for prolonged periods. Four patients died from infection; if the diagnosis of bile acid malabsorption had been made earlier it is possible that these infections may have been avoided. SeHCAT scans are not readily available in all centres. If this is the case a therapeutic trial of bile acid sequestrants provides an alternative approach (though it should be noted that sequestrants are hygroscopic and thus reductions in diarrhoea volumes may be unrelated to bile acid sequestration). Although the data are observational, the role of bile acid malabsorption in this setting clearly warrants further study. It is currently unclear what proportion of patients with diarrhoea and GI GVHD have bile acid malabsorption and whether this applies equally to acute and chronic GVHD. The relative contributions of bile acid malabsorption and bowel inflammation to the clinical picture need to be clarified. Most importantly, prospective clinical trials are needed to assess whether bile acid sequestrants can improve the outcomes of patients with GI GVHD. This work was supported by an MRC Clinician Scientist Fellowship (DCT). All authors contributed to acquisition/analysis of data, critical appraisal and approval of the paper. None of the authors have competing interests.