Bile acid malabsorption (BAM), 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, bile salt diarrhea or bile salt malabsorption. It can result from
malabsorption secondary to
gastrointestinal disease, or be a primary disorder, associated with excessive
bile acid
Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.
Primary b ...
production. Treatment with
bile acid sequestrants is often effective.
Signs and symptoms
A persistent (chronic) history of
diarrhea, with watery or mushy, unformed stools, (types 6 and 7 on the
Bristol stool scale), sometimes with
steatorrhea
Steatorrhea (or steatorrhoea) is the presence of excess fat in feces. Stools may be bulky and difficult to flush, have a pale and oily appearance, and can be especially foul-smelling. An oily anal leakage or some level of fecal incontinence may oc ...
, increased frequency and urgency of
defecation
Defecation (or defaecation) follows digestion, and is a necessary process by which organisms eliminate a solid, semisolid, or liquid waste material known as feces from the digestive tract via the anus. The act has a variety of names ranging f ...
are common manifestations, often with
fecal incontinence and other gastrointestinal symptoms such as abdominal swelling,
bloating and
abdominal pain.
People with this disorder often report impairments of
mental health and
well-being, including
fatigue
Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
,
dizziness,
anxiety about leaving home (primarily due to fear of
fecal incontinence),
depression, one survey reports.
[ It contributes in delays in diagnosis.][
]
Pathogenesis
Enterohepatic circulation of bile salts
Bile acids (also called bile salts) are produced in the liver, secreted into the biliary system, stored in the gallbladder and are released after meals stimulated by cholecystokinin. They are important for the digestion and absorption
Absorption may refer to:
Chemistry and biology
* Absorption (biology), digestion
**Absorption (small intestine)
*Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials
*Absorption (skin), a route by which ...
of fats (lipids) in the small intestine
The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the p ...
. 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 0.5 g of bile acids enter the large intestine per 24 h. 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
The portal vein or hepatic portal vein (HPV) is a blood vessel that carries blood from the gastrointestinal tract, gallbladder, pancreas and spleen to the liver. This blood contains nutrients and toxins extracted from digested contents. Approxima ...
. 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.[
]
Diagnosis
Several methods have been developed to identify the disorder but there are difficulties with all of them. 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 (0.3 mSv). 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 7α-Hydroxy-4-cholesten-3-one, (C4), 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.
The various biomarkers give similar diagnostic yields of around 25% in patients with functional bowel disorders with diarrhea. In countries such as the USA, where SeHCAT is not available, fecal bile acids and C4 are available to make the diagnosis.[
]
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 disease
Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...
)
* Type 2: Idiopathic bile acid malabsorption, Primary bile acid diarrhea
* Type 3: Secondary to various gastrointestinal diseases including cholecystectomy
Cholecystectomy is the surgical removal of the gallbladder. Cholecystectomy is a common treatment of symptomatic gallstones and other gallbladder conditions. In 2011, cholecystectomy was the eighth most common operating room procedure performed i ...
, vagotomy, small intestinal bacterial overgrowth, radiation enteropathy, celiac disease, chronic pancreatitis
Chronic pancreatitis is a long-standing inflammation of the pancreas that alters the organ's normal structure and functions. It can present as episodes of acute inflammation in a previously injured pancreas, or as chronic damage with persistent pa ...
, etc.
Treatment
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 abdominal 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
The bile acid receptor (BAR), also known as farnesoid X receptor (FXR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4), is a nuclear receptor that is encoded by the ''NR1H4'' gene in humans.
Function
FXR is expressed at high levels ...
agonist obeticholic acid has shown clinical and biochemical benefit.
As of March 15, 2016, Novartis Pharmaceuticals is conducting a phase II clinical study involving a farnesoid X receptor agonist named LJN452.
Epidemiology
Bile acid malabsorption is common in Crohn's disease
Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...
but not always recognized. Most people with previous ileal resection and chronic diarrhea will have abnormal SeHCAT tests and can benefit from bile acid sequestrants.[
People with primary bile acid diarrhea are frequently misdiagnosed as having irritable bowel syndrome.][ 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 people 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 suggest that 1% of the adult population could have primary bile acid diarrhea (Type 2 bile acid malabsorption).][
]
References
External links
{{DEFAULTSORT:Bile Acid Malabsorption
Diseases of intestines
*
Gastrointestinal tract disorders