Bile Acids: an Underrecognized and Underappreciated Cause of Chronic Diarrhea

NINFLAMMATORYUTRITION ISSUES BOWEL IN GASTROENTEROLO DISEASE: A PRACTICALGY, SERIES APPROACH, #110 SERIES #73 Carol Rees Parrish, M.S., R.D., Series Editor Bile Acids: An Underrecognized and Underappreciated Cause of Chronic Diarrhea Rafiul Sameer Islam John K. DiBaise Bile acid malabsorption is a common cause of chronic watery diarrhea; however, its role appears to be poorly appreciated among clinicians. As such, bile acid diarrhea remains an underrecognized cause of chronic diarrhea, resulting in many patients incorrectly diagnosed and interfering and delaying proper treatment. In this review, we briefly discuss the synthesis, enterohepatic circulation, and function of bile acids. We then focus on the role of bile acids in bile acid malabsorption including the diagnostic and treatment options. By recognizing that bile acid malabsorption is a relatively common cause of chronic diarrhea, we hope that more physicians will more effectively evaluate and treat patients with this condition. INTRODUCTION iarrhea caused by bile acids was first recognized patients are diagnosed with other causes of diarrhea in 1967, when Alan Hofmann described this or are considered to have irritable bowel syndrome or Dphenomenon as cholerhetic enteropathy.1 functional diarrhea by exclusion, thereby interfering Despite more than 40 years since the initial report, with, and delaying proper treatment. The goal of this bile acid diarrhea remains an underrecognized and review is to raise awareness of this clinical condition so underappreciated cause of chronic diarrhea. One recent that it may be considered in the differential diagnosis of report found that only 6% of British gastroenterologists chronic diarrhea. We will first review bile acid synthesis investigate for bile acid malabsorption (BAM) as and enterohepatic circulation, followed by a discussion part of the first-line testing in patients with chronic of specific disorders involving BAM including their diarrhea, while 61% consider the diagnosis only in diagnosis and treatment. selected patients or not at all.2 As a consequence, many Bile Acid Synthesis Rafiul Sameer Islam, MD, Gastroenterology Bile acids are produced in the liver as end products and Hepatology Fellow. John K. DiBaise, MD, of cholesterol metabolism. Bile acid synthesis occurs Professor of Medicine, Division of by two pathways: the classical (neutral) pathway via Gastroenterology. Mayo Clinic, Scottsdale, AZ (continued on page 34) 32 Practical GastroenteroloGy • october 2012 Parrish_Oct_12.indd 32 10/10/12 7:15 AM Bile Acids NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #110 NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #110 (continued from page 32) microsomal cholesterol 7α-hydroxylase (CYP7A1), Cholic acid or the alternative (acidic) pathway via mitochondrial 5β-cholestane-3α,7α,12α-triol sterol 27-hydroxylase (CYP27A1). The classical 7α,12α-dihydroxy-4-cholesten-3-one pathway, which is responsible for 90-95% of bile acid synthesis in humans, begins with 7α-hydroxylation of 12-α-hydroxylase cholesterol catalyzed by CYP7A1, the rate-limiting Cholesterol 7-α-hydroxycholesterol 7-α-hydroxy-4-cholesten-3-one(C4) 3 step (Figure 1). This pathway occurs exclusively 5β-cholestane-3α,7α-diol in the liver and gives rise to two primary bile acids: Chenodeoxycholic acid cholate and chenodeoxycholate. Newly synthesized bile acids are conjugated with glycine or taurine and secreted into the biliary tree; in humans, most of the bile acids are conjugated to glycine.4 Conjugation is a very Figure 1. Classical pathway of bile acid synthesis. Note important step in bile acid synthesis converting weak the production of the primary bile acids, cholic acid and acids to strong acids, which are fully ionized at biliary chenodeoxycholic acid, and the intermediate, C4. and intestinal pH, making them hydrophobic (lipid soluble) and membrane impermeable. These properties acid pool of about 2-3 g which typically cycles 4-6 aid in digestion of lipids and also decrease the passive times/day.10 diffusion of bile acids across cell membranes during The size of the bile acid pool is tightly controlled their transit through the biliary tree and small intestine.5 by a complex regulatory pathway. Bile acid synthesis This allows maximum lipid absorption throughout the is under negative feedback regulation by which bile small intestine without sacrificing bile acid loss. acids downregulate their own biosynthesis by binding to the nuclear receptor, farnesoid X receptor (FXR), Enterohepatic Circulation thereby inducing the synthesis of a repressor protein After their involvement in micelle formation, about which downregulates the rate-limiting enzyme in bile 95% of the conjugated bile salts are reabsorbed in acid synthesis, CYP7A1.11 Recently, fibroblast growth the terminal ileum and returned to the liver via the factor 19 (FGF19), acting via FXR, was shown to be portal venous system for eventual recirculation in a stimulated by bile acids in the ileal enterocyte.12 FGF19 process known as enterohepatic circulation; only a small is then released from the enterocyte and travels to the proportion (3-5%) are excreted into the feces.6, 7 liver where, acting together with ß-klotho, it activates Enterohepatic circulation requires carrier-mediated the FGF receptor 4 (FGFR4) on the hepatocyte leading transport by the terminal ileal enterocytes and the to a phosphorylation cascade that downregulates bile hepatocytes by means of both apical and basolateral acid synthesis (Figure 2).13 transporters.8 First, the bile acids are actively transported As previously noted, a small proportion of the from the intestinal lumen into the enterocyte via a secreted bile acids reach the colon where they are network of efficient sodium-dependent apically located deconjugated (removing the taurine or glycine) and co-transporters (ileal bile acid transporters) (6,7) in the dehydroxylated (removing the 7-OH group) by bacteria distal ileum up to 100 cm proximal to the ileocecal valve.9 to produce the secondary bile acids, deoxycholate and The bile acids are then transported into the portal venous lithocholate. A small fraction of these secondary bile system via a basolateral transport system consisting acids are absorbed by the colonic epithelium; however, of 2 proteins, organic solute transporter (OST)-α and most are eliminated in the feces. OST-ß, and returned to the liver. In the liver, they are efficiently extracted by basolateral transporters on the Bile Acid Function hepatocytes and added to the bile acid pool. The liver Bile acids play a key role in the absorption of lipids must then only replace the small amount of bile acids in the small intestine. Upon stimulation by a meal that are not recirculated and instead excreted into the (via cholecystokinin release), bile acids are expelled feces (about 0.3-0.5 g/day). In humans, approximately from the gallbladder into the bile duct and then enter 12 g of bile acids are secreted into the intestine daily. the lumen of the small intestine where they solubilize Efficient recycling allows the maintenance of a bile dietary lipids in a multistep process.14 First, they 34 PracticalGastroenteroloGy • october2012 Parrish_Oct_12.indd 34 10/10/12 7:15 AM Bile Acids NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #110 NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #110 emulsify the lipids, allowing the droplets to disperse diarrhea.21, 22 Interestingly, a recent study suggests that and increasing the surface area for digestive enzymes. low concentrations of bile acids downregulate colon Next, they form micelles with the products of lipid secretion and promote fluid and electrolyte absorption.23 digestion, allowing the normally hydrophobic lipids In contrast, when colonic luminal concentrations of bile to dissolve into the aqueous luminal environment. The acids are high, as is seen in BAM, bile acids induce micelles then diffuse to the brush-border membrane of prosecretory and promotility effects, manifesting the intestinal epithelium whereby the lipids are released clinically as diarrhea. from the micelles and diffuse down their concentration gradients into the cells. Once released, the bile acids Prevalence of Bile Acid Diarrhea are left behind in the intestinal lumen until they are Due to the limited availability of diagnostic tests for absorbed in the terminal ileum. Their presence in the BAM, its prevalence remains unclear. The availability intestinal lumen allows maximal absorption of lipids of the 75Selenium-homocholic acid taurine (SeHCAT) throughout the small intestine; however, the majority retention test (see below) in Europe has, nevertheless, of fat absorption occurs in the proximal 100 cm of the allowed an estimate of its prevalence, at least in the jejunum. Western world. A systematic review of studies that Multiple other functions of bile acids have also estimated the prevalence of primary bile acid diarrhea been described.1 including: using the SeHCAT test in patients with chronic unexplained diarrhea [most of whom were classified · Contributing to cholesterol metabolism by as diarrhea-predominant irritable bowel syndrome promoting the excretion of cholesterol (D-IBS)] identified 18 studies involving 1223 patients.24 · Denaturing dietary proteins, thereby At the best confidence interval (<10%) for SeHCAT retention percentage, one-third of patients had an accelerating their breakdown by pancreatic 15 abnormal result suggesting BAM. Using this figure, proteases. these investigators have estimated the population · Having direct and indirect antimicrobial

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