Advances in understanding of bile acid diarrhea

Abstract

Bile acids (BA) are actively reabsorbed in the terminal ileum by the apical Na⁺-dependent bile salt transporter. This review addresses the epidemiology, pathophysiology, diagnosis and treatment of BA diarrhea (BAD). BAD is typically caused by ileal resection or disease; 25–33% of patients with chronic functional diarrhea or irritable bowel syndrome-diarrhea (IBS-D) have BAD, possibly from deficiency in the ileal hormone, FGF-19, which normally provides feedback inhibition of BA synthesis. Diagnosis of BAD is typically based on reduced BA retention of radiolabeled BA (⁷⁵SeHCAT), increased BA synthesis (serum C4) or increased fecal BA loss. In clinical practice, diagnosis is often based on response to BA sequestrants (e.g., cholestyramine or colesevelam). Diagnostic tests for BA malabsorption (BAM) need to be used more extensively in clinical practice. In the future, farnesoid X receptor agonists that stimulate ileal production of FGF-19 may be alternative treatments of BAD.

Keywords::

• ASBT
• CDCA
• colesevelam
• DCA
• FGF-19
• FXR
• IBAT
• obeticholic acid
• secretion
• sequestrants

Acknowledgements

The author thanks Cindy Stanislav for secretarial support.

Financial & competing interests disclosure

The work has been supported by grant NIH R01-DK92179. M Camilleri had filed a provisional patent on treatment of constipation with delayed release preparation of bile acids. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Bile acid diarrhea (BAD) is an important clinical entity that may account for up to a third of patients with chronic diarrhea or diarrhea-predominant irritable bowel syndrome.

• At present, the strongest evidence suggests that BAD results from failure of feedback regulation of hepatic synthesis by the ileal hormone FGF-19.

• There is a wide array of molecules involved in feedback regulation of BA synthesis, including nuclear receptors and membrane transporters in the ileal enterocyte and hepatocyte that may lead to disturbances in the absorption, synthesis and secretion of BA.

• The current diagnosis of BAD is based on either a therapeutic trial with BA binders or measurement of BA retention using ⁷⁵SeHCAT; simpler serological screening tests are measurement of C4 and possibly FGF-19, farnesoid X receptor (FXR) agonists have the potential to become alternative treatments for BAD in addition to BA binders such as cholestyramine and colesevelam.

Notes