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Letter: hydroxypropyl cellulose as therapy for chronic diarrhoea in patients with bile acid malabsorption – possible mechanisms

2016; Wiley; Volume: 44; Issue: 3 Linguagem: Inglês

10.1111/apt.13678

1365-2036

W. G. Brydon, Julian R.F. Walters, Subrata Ghosh, Pearl Culbert,

Pediatric Hepatobiliary Diseases and Treatments

We were interested to see the randomised clinical trial of colestyramine compared with hydroxypropyl cellulose (HPC) in patients with functional chronic watery diarrhoea.1 Fernández-Bañares et al. demonstrated in their patients with low SeHCAT values, indicative of bile acid malabsorption/diarrhoea, that HPC significantly reduced the number of stools, especially watery stools, together with improvements in quality of life scores. This trial was originally conceived to employ HPC, which is a widely used food additive, as a placebo in the investigation of the efficacy of colestyramine, an established, although incompletely studied, bile acid sequestrant. Colestyramine had a greater benefit on some end-points, but was also associated with significantly more adverse events. At the review stage, the authors recognised that there was evidence that HPC could be an active agent. We discuss this further here. Ruseler-van Embden et al.2 reported in 1998 that HPC reduced daily stool number in five patients with Crohn's disease, and also improved stool consistency. Subsequent communications determined that these patients had ileal disease with partial resections. Brydon et al.3 reported in abstract form in 2003 that 5/5 patients with ileal disease and 4/5 patients with idiopathic bile acid malabsorption who were intolerant of colestyramine had reduced stool frequency (mean 56%, P = 0.001) on HPC 1–1.5 g/day (Klucel, Aqualon). To explore possible mechanisms for HPC effects, serum 7α-hydroxy-4-cholesten-3-one (7αHCO, also known as C4), a measure of new bile acid synthesis, and a biomarker for bile acid diarrhoea,4 was determined in 10 patients before and during HPC ingestion. No significant increase was observed (see Figure 1). This is in contrast to colestyramine, which caused large increases in 7αHCO, coupled with decreases in serum fibroblast growth factor 19 (FGF19) in normal subjects.5 FGF19 is produced in the ileum in response to bile acid absorption. Impaired FGF19 production results in increased new bile acid synthesis, as shown by a raised serum 7αHCO in bile acid diarrhoea.6 Although colestyramine may be binding bile acids in the ileum, adversely reducing FGF19 and consequently the negative feedback control of bile acid synthesis, HPC may be acting only in the colon, without restricting ileal bile acid absorption. Furthermore, in vitro studies have reported aggregation of deoxycholate (a secondary bile acid) with HPC in solution.7 Recent work has studied these interactions more fully, showing more efficient adsorption of taurodeoxycholate than taurocholate with HPC.8 We conclude that there is an interaction between HPC, which is not degraded within the GI tract, with more hydrophobic secondary bile acids in the colon. Such interactions could reduce the propensity of raised concentrations of these bile acids to stimulate colonic epithelial water secretion. An agent which prevents the diarrhoeal effects of bile acids without interfering with their normal physiological functions, including enterohepatic circulation and FGF19 regulation of new synthesis, may have some advantages in the treatment of patients, especially those intolerant of other bile acid sequestrants. Declaration of personal and funding interests: JW has served as a speaker, consultant and advisory board member for Albireo, GE Healthcare, Intercept, Novartis and Pendopharm, and has received research funding from Albireo and Intercept.