New treatment for bile salt malabsorption

Currently available binding resins used for symptomatic bile salt malabsorption are generally poorly tolerated because of unpalatability and associated gastrointestinal side effects. We suggest that there is now a viable alternative, colesevelam hydrochloride (WelChol, Sankyo Pharmaceuticals Inc., Japan).

A 30 year old man presented with steatorrhoea, progressive weight loss, marked abdominal bloating, and lethargy after a right hemicolectomy following a road traffic accident in 1966.

Physical examination, relevant blood tests, barium follow through, colonoscopy, and microscopic examination of colonic biopsies were normal. A trial of cholestyramine in preference to a SeCHAT scan caused cessation of diarrhoea on one sachet per day. However, his abdominal bloating continued unabated and he found the treatment unpalatable. Cholestyramine was therefore changed to colesevelam 2.5 g/3.75 g on alternate days. This was well tolerated, with complete cessation of his steatorrhoea and lethargy, and no side effects. In addition, he rapidly gained weight.

A further four patients with markedly symptomatic bile salt malabsorption resistant to antidiarrhoeal agents and intolerant of cholestyramine were subsequently commenced on colesevelam (table 1 ▶). In all of these cases colesevelam was well tolerated with no side effects.

Table 1.

 Characteristics of four patients with markedly symptomatic bile salt malabsorption resistant to antidiarrhoeal agents and intolerant of cholestyramine given colesevelam

Age (y)	Sex	Reason for bile salt malabsorption	Outcome with cholestyramine	Outcome with colesevelam	Duration of colesevelam treatment (months)	Current dose of colesevelam
37	M	Idiopathic	Diarrhoea improved but not tolerated because it induced severe dyspepsia	Diarrhoea resolved, no side effects	7	3.75 g/day
59	F	Right hemicolectomy	Diarrhoea improved but not tolerated due to unpalatability	Diarrhoea resolved, no side effects	3	3.75 g/day
68	F	Radiation enteritis and right hemicolectomy	Diarrhoea improved although suffered intractable vomiting	Diarrhoea resolved, no side effects	2	2.5 g/day
40	F	Radiation enteritis	Diarrhoea improved although suffered intractable nausea	Diarrhoea resolved, no side effects	2	1.25 g/day

Colesevelam is a non-absorbed water insoluble polymer which sequesters bile.¹ It has been approved for usage by the US FDA, and has been received as a valuable alternative for lowering cholesterol.² Colesevelam has high affinity for dihydroxy and trihydroxy bile acids in the intestine which causes increased faecal bile acid secretion, reducing the enterohepatic circulation of bile acids.² This allows 7-hydroxylase, the rate limiting enzyme in bile acid synthesis, to increase the conversion of hepatic cholesterol to bile acids.² It has not yet been approved for use in the UK. One abstract suggests that colesevelam may be beneficial for patients with diarrhoea who have undergone small bowel resection for Crohn’s disease.³ There are no other published data to support its role in bile salt induced diarrhoea. Colesevelam is reported to be 4–6 times as potent as traditional bile salt sequestrants, possibly due to its greater binding affinity for glycocholic acid.⁴ It is administered in tablet form, and in one study the rate of compliance with colesevelam was 93%.⁴ The unique hydrogel polymeric structure enables greater tolerability with less potential drug interactions than with resins.¹

Reported adverse events from the largest clinical trial to date include flatulence, dyspepsia, and diarrhoea although the incidence of adverse events does differ significantly from that observed with placebo, and is lower than with cholestyramine.² It is rarely associated with constipation, unlike cholestyramine.⁴ Colesevelam is non-absorbed and is excreted entirely via the gastrointestinal tract, preventing systemic side effects.⁵ Furthermore, there is little evidence for clinically significant interactions involving colesevelam.⁴ Pharmacokinetic studies with colesevelam have not shown clinically significant effects of absorption of six other coadministered drugs.⁶

There is a theoretical risk of fat soluble vitamin deficiency following such efficient bile acid sequestration. None of our patients developed any significant change in fasting triglycerides or fat soluble vitamin levels to date.

Each film coated tablet contains colesevelam 625 mg (active ingredient).² The recommended starting dose for monotherapy for hypercholesteraemia is 3.75 g once a day or 1.875 g twice per day, although the optimal dose is 4.375 g in adults.² The optimal dose for bile salt malabsorption is not clear but an effective dose has varied between two and six tablets/day in our series. Colesevelam was obtained from IDIS Ltd.

Thus colesevelam is a novel bile acid binding resin in tablet form that maintains the benefits of cholestyramine, yet is palatable, associated with decreased adverse effects, and has greater potency. It provides a very attractive alternative therapy for patients with bile salt malabsorption and further study is warranted.