Bile acid malabsorption
Encyclopedia
Bile acid malabsorption is a cause of chronic diarrhea
. It can result from malabsorption
secondary to gastro-intestinal disease or be a primary disorder. Treatment with bile acid sequestrants is often effective.
, 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
.
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 number of patients with no obvious disease (Type 2 bile acid malabsorption) may have mutations in ASBT but this is not more common in most patients and does not affect function.
), and lower levels of this hormone result in overproduction of bile acids, which are more than the ileum can absorb.
test. This nuclear medicine
test involves two scans a week apart and only very limited radiation exposure. Retention of SeHCAT at 7 days is normally above 15%. Values less than 15% predict a response to bile acid sequestrants. Older methods such as fecal bile acid quantfication or the 14C-glycocholic breath test are no longer in routine clinical use. The SeHCAT test measures multiple cycles of bile acid excretion and reabsorption over 7 days. This test is not licensed in the USA, and is underutilized even where it is available.
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.
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).
is a tablet and some patients tolerate this more easily
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
. It can result from malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
secondary to gastro-intestinal disease or be a primary disorder. Treatment with bile acid sequestrants is often effective.
Classification
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 diseaseCrohn's diseaseCrohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
) - Type 2: Idiopathic bile acid malabsorption, Primary bile acid diarrhea
- Type 3: Secondary to various gastrointestinal diseases including cholecystectomyCholecystectomyCholecystectomy is the surgical removal of the gallbladder. It is the most common method for treating symptomatic gallstones. Surgical options include the standard procedure, called laparoscopic cholecystectomy, and an older more invasive procedure, called open cholecystectomy.-Open surgery:A...
, vagotomyVagotomyA vagotomy is a surgical procedure that involves resection of the vagus nerve.-Applications:Truncal vagotomy is a treatment option for chronic duodenal ulcers...
, small intestinal bacterial overgrowth, radiation enteropathyRadiation enteropathyRadiation enteropathy or radiation enteritis is the syndrome that develops after the intestine is exposed to radiation....
, celiac disease, chronic pancreatitisChronic pancreatitisChronic pancreatitis is a long-standing inflammation of the pancreas that alters its normal structure and functions. It can present as episodes of acute inflammation in a previously injured pancreas, or as chronic damage with persistent pain or malabsorption....
, etc.
Enterohepatic circulation of bile salts
Bile acids (also called bile salts) are produced in the liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, secreted into the biliary system, stored in the gall-bladder and are released after meals stimulated by cholecystokinin
Cholecystokinin
Cholecystokinin is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein...
. They are important for the digestion
Digestion
Digestion is the mechanical and chemical breakdown of food into smaller components that are more easily absorbed into a blood stream, for instance. Digestion is a form of catabolism: a breakdown of large food molecules to smaller ones....
and absorption
Absorption
Absorption may refer to:- Chemistry and biology :* Absorption , absorption of particles of gas or liquid in liquid or solid material* Absorption , a route by which substances can enter the body through the skin...
of fats (lipids) in the small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...
. Usually over 95% of the bile acids are absorbed in the terminal ileum
Ileum
The ileum is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine may be used instead of ileum.The ileum follows the duodenum...
and are taken up by the liver and resecreted. This enterohepatic circulation
Enterohepatic circulation
Enterohepatic circulation refers to the circulation of biliary acids from the liver, where they are produced and secreted in the bile, to the small intestine, where it aids in digestion of fats and other substances, back to the liver....
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
Large intestine
The large intestine is the third-to-last part of the digestive system — — in vertebrate animals. Its function is to absorb water from the remaining indigestible food matter, and then to pass useless waste material from the body...
. When larger amounts of bile acids enter the large intestine
Large intestine
The large intestine is the third-to-last part of the digestive system — — in vertebrate animals. Its function is to absorb water from the remaining indigestible food matter, and then to pass useless waste material from the body...
, they stimulate water secretion and intestinal motility in the colon
Colon (anatomy)
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
, which causes symptoms of chronic diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
.
Intestinal absorption of bile acids
The ileumIleum
The ileum is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine may be used instead of ileum.The ileum follows the duodenum...
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
SLC10A2
Ileal sodium/bile acid cotransporter also known as ileal sodium-dependent bile acid transporter is a protein that in humans is encoded by the SLC10A2 gene.-Further reading:...
) 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 number of patients with no obvious disease (Type 2 bile acid malabsorption) may have mutations in ASBT but this 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 (FGF19FGF19
Fibroblast growth factor 19 is a protein that in humans is encoded by the FGF19 gene.-Further reading:...
), and lower levels of this hormone result in overproduction of bile acids, which are more than the ileum can absorb.
Diagnosis
Diagnosis of bile acid malabsorption is easily and reliably made by the SeHCATSeHCAT
SeHCAT is the usual name for 23-seleno-25-homo-tauro-cholic acid . It is used in a clinical test to diagnose bile acid malabsorption.-Development:...
test. This nuclear medicine
Nuclear medicine
In nuclear medicine procedures, elemental radionuclides are combined with other elements to form chemical compounds, or else combined with existing pharmaceutical compounds, to form radiopharmaceuticals. These radiopharmaceuticals, once administered to the patient, can localize to specific organs...
test involves two scans a week apart and only very limited radiation exposure. Retention of SeHCAT at 7 days is normally above 15%. Values less than 15% predict a response to bile acid sequestrants. Older methods such as fecal bile acid quantfication or the 14C-glycocholic breath test are no longer in routine clinical use. The SeHCAT test measures multiple cycles of bile acid excretion and reabsorption over 7 days. This test is not licensed in the USA, and is underutilized even where it is available.
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.
Prevalence
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 SeHCATSeHCAT
SeHCAT is the usual name for 23-seleno-25-homo-tauro-cholic acid . It is used in a clinical test to diagnose bile acid malabsorption.-Development:...
tests and can benefit from bile acid sequestrants.
Patients with primary bile acid diarrhea are frequently misdiagnosed as having the irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
as clinicians fail to recognize the condition. When SeHCAT
SeHCAT
SeHCAT is the usual name for 23-seleno-25-homo-tauro-cholic acid . It is used in a clinical test to diagnose bile acid malabsorption.-Development:...
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
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
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
Bile acid sequestrant
The bile acid sequestrants are a group of medications used to bind certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by sequestering them and preventing their reabsorption from the gut. In general, they are classified as hypolipidemic...
.
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).
Treatment
Bile acid sequestrants are the main agents used to treat bile acid malabsorption. Cholestyramine and colestipol 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. ColesevelamColesevelam
Colesevelam is a bile acid sequestrant administered orally. It is developed by Genzyme and marketed in the US by Daiichi Sankyo under the brand name WelChol and elsewhere by Genzyme under the tradename Cholestagel.-Clinical use:...
is a tablet and some patients tolerate this more easily