Bile acids are nature’s laxatives. So said Dr Alan Hoffman, for many years a world expert on bile acids. So might malabsorption of bile acids be a major factor in IBS diarrhoea?
Bile acids are synthesized from cholesterol in the liver and are released along with other components of bile into the small intestine, where they disperse fat rendering it capable of being digested by pancreatic juice. They then convey the digestive products to the cells lining the small intestine and assist their absorption, before shuttling back to pick up more fat. In this way they are key players in ensuring adequate fat absorption.
Bile acids continue to do their conveyancing as the meal travels the 20 feet of small intestine, but when they get to the last section, which is called the ileum, they combine with a receptor and are themselves transported across the intestinal wall into the veins that drain into the liver and are used again to help digest the next meal. Under healthy conditions, only about 5% of bile acid is lost into the colon, where it is converted by bacteria into highly irritant secondary bile acids, which stimulate secretion and peristalsis – nature’s laxative. This entero-hepatic circulation of bile acid is disrupted if the ileum is inflamed by Crohn’s disease, has been surgically resected or if the passage through the ileum is too quick for complete absorption to take place. Then the secretion and peristalsis caused by an excessive influx of larger amounts of bile acid, can overwhelm the ability fo the colon to salvage salt and water and diarrhea can ensue. This is know as bile acid malabsorption (BAM).
The most frequent method of testing for BAM is to administer by mouth a small dose of radioactively tagged bile acid, which mixes with the circulating pool of bile acid. Then after a week the body is scanned to determine the amount retained. This is known as the SeHCAT test. Normally upwards of 20% of the label is retained after a week but anything less than 15% indicates bile acid malabsorption.
Although this test has been available for about thirty years, few diagnostic centres use it. The reason for this is not clear. Perhaps it is considered too cumbersome, perhaps there is some anxiety over the dose of radioactivity (which is actually less than background radiation), perhaps doctors do not appreciate that BAM is so common.
Bile acid malabsorption as detected by SeHCAT testing occurs in a third to a half of patients with idiopathic/IBS diarrhoea, and most people with low SeHCAT retention (49 to 83%) respond to bile acid sequestrants, resins that adsorb or stick to bile acids and remove them from the body without causing irritation. There are several sequestrants available: colestyramine (questran), colesevelam and colestipol. Colestyramine is the one that is most commonly used. I prefer to prescribe it since patients learn to take it half an hour before a meal and can easily subdivide the dose titrating it with the size of the meal and the response of the symptoms. Not everybody likes Questran, finding it gluey or gritty in the mouth, but if it is mixed with orange juice and swallowed quickly, it goes down well.
So to use common parlance, we might say that treating IBS diarrhoea with Questran or other bile acid sequestrants is a ‘no brainer’. Not so! Questran is licensed for reducing cholesterol, not for treating diarrhea, yet when IBS diarrhea is associated with urgency, it can work very well. Those of us , who believe that BAM is a major factor in IBS-diarrhoea, might often use a trial of Questran as a diagnostic therapy, but we would struggle to convince other medical practitioners without evidence that the patient has BAM. But how can we prove that BAM is a significant factor if the SeHCAT test is not generally available or recommended by NICE and the treatment is not licensed for that indication? It’s not just a double bind, but a triple bind.
The water has been rather muddied in recent years by the discovery of a ‘gut hormone’, FGF-19, which is released from the ileum and stimulates bile acid synthesis in the liver. FGF-19 is inhibited when bile acid is absorbed, preventing new bile acid synthesis, but bile acid malabsorption from whatever cause releases FGF19 from inhibition and feeds back to the liver stimulating additional synthesis of bile acid, which enters the colon in larger amounts causing more diarrhoea. This discovery has led to the notion that IBS might be associated with a primary overproduction of FGF-19 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2850200/FGF19) instead of reduced absorption due to rapid ileal transit, yet it has been know for many years that IBS-diarrhoea is associated with rapid small bowel transit.
So if you have diarrhoea associated with IBS and it does not respond to restricting FODMAPs, do consider whether food and bile acids are passing too quickly through your small intestine and irritating the your sensitive colon and whether you would be better treated with Questran.
Most studies and many letters received by The IBS Network would support the use of colestyramine and other bile acid sequestrants, but doctors are unlikely to prescribe these unless there is evidence of bile acid malabsorption. If the NICE committee could acknowledge that bile acid malabsorption as detected by SeHCAT testing is common in IBS-diarrhoea and responds to bile acid sequestrants, it might allow patients to receive an effective treatment, doctors to use an effective test and clinic investigators to carry out more research.