Bile acid malabsorption
Bile acid malabsorption, known also as Bile acid diarrhea, is a cause of several gut-related problems, the main one being chronic diarrhea. It has also been called Bile acid-induced diarrhea, Cholerheic or Choleretic enteropathy and Bile salt malabsorption. It can result from malabsorption secondary to gastro-intestinal disease, or be a primary disorder, associated with excessive bile acid production. Treatment with bile acid sequestrants is often effective.
Bile acid malabsorption was first recognized in patients with ileal disease. When other causes were recognized, and an idiopathic, primary form described, a classification into three types was proposed:
- Type 1: Bile acid malabsorption, secondary to ileal resection, or ileal inflammation (e.g. in Crohn's disease)
- Type 2: Idiopathic bile acid malabsorption, Primary bile acid diarrhea
- Type 3: Secondary to various gastrointestinal diseases including cholecystectomy, vagotomy, small intestinal bacterial overgrowth, radiation enteropathy, celiac disease, chronic pancreatitis, etc.
Mechanisms of disease
Enterohepatic circulation of bile salts
Bile acids (also called bile salts) are produced in the liver, secreted into the biliary system, stored in the gall-bladder and are released after meals stimulated by cholecystokinin. They are important for the digestion and absorption of fats (lipids) in the small intestine. Usually over 95% of the bile acids are absorbed in the terminal ileum and are taken up by the liver and resecreted. This enterohepatic circulation of bile acids takes place 4-6 times in 24 hours and usually less than 0.5g /24h of bile acids enter the large intestine. When larger amounts of bile acids enter the large intestine, they stimulate water secretion and intestinal motility in the colon, which causes symptoms of chronic diarrhea.
Intestinal absorption of bile acids
The ileum is very efficient at absorbing the glyco- and taurine-conjugated forms of the bile salts. The apical sodium-dependent bile salt transporter (ASBT, IBAT, gene symbol SLC10A2) is the first step in absorption at the brush-border membrane. The cytoplasmic ileal bile acid binding protein (IBABP, ILBP, gene symbol FABP6) and the basolateral heterodimer of OSTα and OSTβ transfer bile acids through and out of the cell where they eventually enter the portal vein. These bile acid transporters are all highly expressed in the ileum but not in the liver, jejunum or colon. When expression of these specialized transporters is reduced, the intestine is less efficient at bile acid reabsorption (Type 1 bile acid malabsorption). If intestinal motility is affected by gastro-intestinal surgery, or bile acids are deconjugated by small intestinal bacterial overgrowth, absorption is less efficient (Type 3 bile acid malabsorption). A very small proportion of the patients with no obvious disease (Type 2 bile acid malabsorption) may have mutations in ASBT, but this mutation is not more common in most patients and does not affect function.
Overproduction of bile acids
Primary bile acid diarrhea (Type 2 bile acid "malabsorption") may be caused by an overproduction of bile acids. Several groups of workers have failed to show any defect in ileal bile acid absorption in these patients, and they have an enlarged bile acid pool, rather than the reduced pool expected with malabsorption. The synthesis of bile acids in the liver is negatively regulated by the ileal hormone fibroblast growth factor 19 (FGF19), and lower levels of this hormone result in overproduction of bile acids, which are more than the ileum can absorb.
Several methods have been developed to identify the disorder but there are difficulties with all of them. Fecal bile acid quantification is unpleasant for both the patient and laboratory. Diagnosis of bile acid malabsorption is easily and reliably made by the SeHCAT test. This nuclear medicine test involves two scans a week apart and so measures multiple cycles of bile acid excretion and reabsorption. There is limited radiation exposure (0.3mSv). Retention of SeHCAT at 7 days is normally above 15%; values less than 15%, 10% and 5% predict respectively mild, moderate and severe abnormal retention and an increasing likelihood of response to bile acid sequestrants. This test is not licensed in the USA, and is underutilized even where it is available. Older methods such as the 14C-glycocholic breath test are no longer in routine clinical use.
Measurement of 7 alpha-hydroxy-4-cholesten-3-one, a bile acid precursor, in serum, shows the increased bile acid synthesis found in bile acid malabsorption. This test is an alternative diagnostic means when available. Fasting blood FGF19 values may have value in the recognition of the disease and prediction of response.
Bile acid malabsorption is common in Crohn's disease but not always recognised. Most patients with previous ileal resection and chronic diarrhea will have abnormal SeHCAT tests and can benefit from bile acid sequestrants.
Patients with primary bile acid diarrhea are frequently misdiagnosed as having the irritable bowel syndrome as clinicians fail to recognize the condition. When SeHCAT testing is performed, the diagnosis of primary bile acid diarrhea is commonly made. In a review of 18 studies of the use of SeHCAT testing in diarrhea-predominant irritable bowel syndrome patients, 32% of 1223 patients had a SeHCAT 7-day retention of less than 10%, and 80% of these reported a response to cholestyramine, a bile acid sequestrant.
Estimates of the population prevalence taken from this review  suggest that 1% of the adult population could have primary bile acid diarrhea (Type 2 bile acid malabsorption).
Bile acid sequestrants are the main agents used to treat bile acid malabsorption. Cholestyramine and colestipol, both in powder form, have been used for many years. Unfortunately many patients find them difficult to tolerate; although the diarrhea may improve, other symptoms such as pain and bloating may worsen. Colesevelam is a tablet and some patients tolerate this more easily. A proof of concept study of the farnesoid X receptor agonist obeticholic acid has shown clinical and biochemical benefit.
- Hofmann, AF (1967). "The syndrome of ileal disease and the broken enterohepatic circulation: cholerheic enteropathy.". Gastroenterology 52 (4): 752–7. PMID 5337211.
- Thaysen, EH; Pedersen, L (1976). "Idiopathic bile acid catharsis.". Gut 17 (12): 965–70. PMC 1411224. PMID 1017717. doi:10.1136/gut.17.12.965.
- Fromm, H; Malavolti, M (1986). "Bile acid-induced diarrhoea". Clinics in gastroenterology 15 (3): 567–82. PMID 3742841.
- Dawson, PA; Lan, T; Rao, A (2009). "Bile acid transporters". Journal of lipid research 50 (12): 2340–57. PMC 2781307. PMID 19498215. doi:10.1194/jlr.R900012-JLR200.
- Oelkers, P; Kirby, LC, Heubi, JE, Dawson, PA (1997). "Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2)". The Journal of Clinical Investigation 99 (8): 1880–7. PMC 508012. PMID 9109432. doi:10.1172/JCI119355.
- Montagnani, M; Love, MW, Rössel, P, Dawson, PA, Qvist, P (2001). "Absence of dysfunctional ileal sodium-bile acid cotransporter gene mutations in patients with adult-onset idiopathic bile acid malabsorption". Scandinavian journal of gastroenterology 36 (10): 1077–80. PMID 11589382. doi:10.1080/003655201750422693.
- Hofmann, AF (2009). "Chronic diarrhea caused by idiopathic bile acid malabsorption: an explanation at last". Expert review of gastroenterology & hepatology 3 (5): 461–4. PMID 19817666. doi:10.1586/egh.09.49.
- Walters, JR; Tasleem, AM, Omer, O S, Brydon, WG, Dew, T, le Roux, CW (2009). "A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis". Clinical gastroenterology and hepatology 7 (11): 1189–94. PMID 19426836. doi:10.1016/j.cgh.2009.04.024.
- van Tilburg, AJ; de Rooij, FW, van den Berg, JW, van Blankenstein, M (1992). "Primary bile acid malabsorption: a pathophysiologic and clinical entity?". Scandinavian journal of gastroenterology. Supplement 194: 66–70. PMID 1298051.
- Vijayvargiya P, Camilleri M, Shin A, Saenger A (2013). "Methods for diagnosis of bile acid malabsorption in clinical practice". Clin. Gastroenterol. Hepatol. 11 (10): 1232–9. PMC 3783593. PMID 23644387. doi:10.1016/j.cgh.2013.04.029.
- Wedlake L, A'Hern R, Russell D, Thomas K, Walters JR, Andreyev HJ (2009). "Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome". Aliment. Pharmacol. Ther. 30 (7): 707–17. PMID 19570102. doi:10.1111/j.1365-2036.2009.04081.x.
- Walters, JR (2010). "Defining primary bile acid diarrhea: making the diagnosis and recognizing the disorder". Expert review of gastroenterology & hepatology 4 (5): 561–7. PMID 20932141. doi:10.1586/egh.10.54.
- Khalid, U; Lalji, A; Stafferton, R; Andreyev, J (2010). "Bile acid malabsorption: a forgotten diagnosis?". Clinical Medicine (London) 10 (2): 124–6. PMID 20437979. doi:10.7861/clinmedicine.10-2-124.
- Brydon, WG; Nyhlin, H; Eastwood, MA; Merrick, MV (1996). "Serum 7 alpha-hydroxy-4-cholesten-3-one and selenohomocholyltaurine (SeHCAT) whole body retention in the assessment of bile acid induced diarrhoea". European journal of gastroenterology & hepatology 8 (2): 117–23. PMID 8723414. doi:10.1097/00042737-199602000-00005.
- Pattni SS, Brydon WG, Dew T, Johnston IM, Nolan JD, Srinivas M, Basumani P, Bardhan KD, Walters JR (2013). "Fibroblast growth factor 19 in patients with bile acid diarrhoea: a prospective comparison of FGF19 serum assay and SeHCAT retention". Aliment. Pharmacol. Ther. 38 (8): 967–76. PMID 23981126. doi:10.1111/apt.12466.
- Wilcox C, Turner J, Green J (May 2014). "Systematic review: the management of chronic diarrhoea due to bile acid malabsorption". Aliment. Pharmacol. Ther. 39 (9): 923–39. PMID 24602022. doi:10.1111/apt.12684.
- Wedlake, L; Thomas, K; Lalji, A; Anagnostopoulos, C; Andreyev, HJ (2009). "Effectiveness and tolerability of colesevelam hydrochloride for bile-acid malabsorption in patients with cancer: a retrospective chart review and patient questionnaire". Clinical therapeutics 31 (11): 2549–58. PMID 20109999. doi:10.1016/j.clinthera.2009.11.027.
- NICE. "Bile acid malabsorption: colesevelam". Retrieved 17 August 2014.
- Beigel F, Teich N, Howaldt S, Lammert F, Maul J, Breiteneicher S et al. (November 2014). "Colesevelam for the treatment of bile acid malabsorption-associated diarrhea in patients with Crohn's disease: A randomized, double-blind, placebo-controlled study". J Crohns Colitis 8 (11): 1471–9. PMID 24953836. doi:10.1016/j.crohns.2014.05.009.
- Walters JR, Johnston IM, Nolan JD, Vassie C, Pruzanski ME, Shapiro DA (January 2015). "The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid". Aliment. Pharmacol. Ther. 41 (1): 54–64. PMID 25329562. doi:10.1111/apt.12999.