Letter: Hydroxypropyl cellulose as therapy for chronic diarrhoea in patients with bile acid malabsorption—possible mechanisms.

W.G. Brydon*, J.R.F. Walters†, S. Ghosh*, P. Culbert*.

*Western General Hospital, Edinburgh

†Imperial College London.

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Sirs: 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 colestyramine, an established, though incompletely studied, bile acid sequestrant. Colestyramine had somewhat 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 improved stool consistency. Subsequent communications (with WGB) 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 1–1.5g/d (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 ten patients before and during HPC ingestion. No significant increase was observed (see Figure). This is in contrast to colestyramine, which caused large 18-fold 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 Whereas 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.

ACKNOWLEDGEMENT

Declaration of personal and funding interests: None.

REFERENCES:

1. Fernandez-Banares F, Rosinach M, Piqueras M et al. Randomised Clinical Trial: colestyramine vs hydroxypropyl cellulose in patients with functional chronic watery diarrhoea. Aliment Pharmacol Ther 2015; 41:1132-40.

2.Ruseler-van Embden JGH, van Lieshout LMC, Binnema DJ, Hazenberg MP

Isolation and characterisation of the viscous, high molecular mass microbial carbohydrate fraction from faeces of healthy subjects and patients with Crohn’s disease and the consequences for a therapeutic approach. Clin Science 1998; 95: 425-433

3. Brydon G, Ganguly R, Ghosh S. The effect of hydroxypropylcellulose on bile acid induced watery diarrhoea. Gut 2003; 52(Suppl. 1): A116.

4. Brydon WG, Culbert P, Kingstone K et al. An evaluation of the use of serum 7-alpha-hydroxycholestenone as a diagnostic test of bile acid malabsorption causing watery diarrhoea. Can J Gastroenterol 2011; 25: 319-323.

5. Lundasen T, Galman C, Angelin B, Rudling M. Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J Intern Med 2006; 260: 530-536.

6. Walters JRF. Bile acid diarrhoea and FGF19: new views on diagnosis, pathogenesis and therapy. Nat Rev Gastroenterol Hepatol 2014; 11: 426-34.

7. Martins RM, da Silva CA, Becker CM et al. Anionic surfactant aggregation with hydroxypropylcellulose in the presence of added salt. J Brazil Chem Soc 2006; 17: 829-831

8. Torcello-Gómez A, Fernández Fraguas C, Ridout MJ, Woodward NC, Wilde PB, Foster TJ. Effect of substituent pattern and molecular weight of cellulose ethers on interactions with different bile salts. Food Funct 2015; 6: 730-39.

Figure. Serum 7α-hydroxy-4-cholesten-3-one (7aHCO) in ten patients at baseline and on treatment with hydroxypropylcellulose (HPC). Wilcoxon matched pairs signed rank test (p=0.09).