Bile acid malabsorption (BAM), known also as bile acid diarrhea, is a cause of several gut-related problems, the main one being chronic
diarrhea
Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
. 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
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a varie ...
secondary to
gastrointestinal disease
Gastrointestinal diseases (abbrev. GI diseases or GI illnesses) refer to diseases involving the Human gastrointestinal tract, gastrointestinal tract, namely the esophagus, stomach, small intestine, large intestine and rectum; and the accessory or ...
, 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 in peroxisomes. Bile acids are conjugated with taurine or glycine residues to give anions called bile ...
production. Treatment with
bile acid sequestrants is often effective. Depending on the severity of symptoms, it may be recognised as a disability in the United Kingdom under the Equality Act 2010.
Signs and symptoms
A persistent (chronic) history of
diarrhea
Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
, 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 Human feces, 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 incon ...
, increased frequency and urgency of
defecation
Defecation (or defaecation) follows digestion and is the necessary biological process by which organisms eliminate a solid, semisolid, or liquid metabolic waste, waste material known as feces (or faeces) from the digestive tract via the anus o ...
are common manifestations, often with
fecal incontinence
Fecal incontinence (FI), or in some forms, encopresis, is a lack of control over defecation, leading to involuntary loss of bowel contents—including flatus (gas), liquid stool elements and mucus, or solid feces. FI is a sign or a symptom ...
and other gastrointestinal symptoms such as abdominal swelling,
bloating
Abdominal bloating (or simply bloating) is a short-term disease that affects the gastrointestinal tract. Bloating is generally characterized by an excess buildup of gas, air or fluids in the stomach. A person may have feelings of tightness, pressu ...
and
abdominal pain
Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...
.
People with this disorder often report impairments of
mental health
Mental health is often mistakenly equated with the absence of mental illness. However, mental health refers to a person's overall emotional, psychological, and social well-being. It influences how individuals think, feel, and behave, and how t ...
and
well-being
Well-being is what is Intrinsic value (ethics), ultimately good for a person. Also called "welfare" and "quality of life", it is a measure of how well life is going for someone. It is a central goal of many individual and societal endeavors.
...
, including
fatigue
Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself.
Fatigue (in the medical sense) is sometimes associated wit ...
,
dizziness
Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness.
Dizziness is a ...
,
anxiety
Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...
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
Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver in peroxisomes. Bile acids are conjugated with taurine or glycine residues to give anions called bile ...
(also called
bile salts
Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver in peroxisomes. Bile acids are conjugated with taurine or glycine residues to give anions called bile ...
) are produced in the
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
, secreted into the
biliary system, stored in the
gallbladder
In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow Organ (anatomy), organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath t ...
and are released after meals stimulated by
cholecystokinin
Cholecystokinin (CCK or CCK-PZ; from Greek ''chole'', "bile"; ''cysto'', "sac"; ''kinin'', "move"; hence, ''move the bile-sac (gallbladder)'') is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat a ...
. They are important for the
digestion
Digestion is the breakdown of large insoluble food compounds into small water-soluble components so that they can be absorbed into the blood plasma. In certain organisms, these smaller substances are absorbed through the small intestine into th ...
and
absorption of fats (lipids) in the
small intestine
The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...
. Usually over 95% of the bile acids are absorbed in the terminal
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 ...
and are taken up by the liver and resecreted. This
enterohepatic circulation
Enterohepatic circulation is the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver. Enterohepa ...
of bile acids takes place four–six times in 24 hours and usually less than 0.5 g of bile acids enter the
large intestine
The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the Digestion, digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces befor ...
per 24 h. When larger amounts of bile acids enter the
large intestine
The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the Digestion, digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces befor ...
, they stimulate water secretion and
intestinal motility
Gastrointestinal physiology is the branch of human physiology that addresses the physical function of the gastrointestinal (GI) tract. The function of the GI tract is to process ingested food by mechanical and chemical means, extract nutrients an ...
in the
colon, which causes symptoms of chronic
diarrhea
Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
.
Intestinal absorption of bile acids
The
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 ...
is very efficient at absorbing the glyco- and
taurine
Taurine (), or 2-aminoethanesulfonic acid, is a naturally occurring amino sulfonic acid that is widely distributed in animal tissues. It is a major constituent of bile and can be found in the large intestine. It is named after Latin (cogna ...
-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
Gastrointestinal physiology is the branch of human physiology that addresses the physical function of the gastrointestinal (GI) tract. The function of the GI tract is to process ingested food by mechanical and chemical means, extract nutrients an ...
is affected by gastro-intestinal surgery, or bile acids are deconjugated by
small intestinal bacterial overgrowth
Small intestinal bacterial overgrowth (SIBO), also termed bacterial overgrowth, or small bowel bacterial overgrowth syndrome (SBBOS), is a disorder of excessive bacterial growth in the small intestine. Unlike the colon (or large bowel), which is r ...
, 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.
[
]
Dysmetabolism and gut microbiome
A study found that patients suffering from bile acid diarrhea are characterized by a dysmetabolic and prediabetic-like profile, with higher postprandial concentrations of glucose, insulin and glucagon, compared with matched healthy controls. The underlying mechanisms are not fully understood. Furthermore, gut microbiome composition differs from that of people who do not suffer from bile acid diarrhea.
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
Nuclear medicine (nuclear radiology, nucleology), is a medical specialty involving the application of radioactivity, radioactive substances in the diagnosis and treatment of disease. Nuclear imaging is, in a sense, ''radiology done inside out'', ...
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 US, 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, fever, abdominal distension, and weight loss. Complications outside of the ...
)
* 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
Small intestinal bacterial overgrowth (SIBO), also termed bacterial overgrowth, or small bowel bacterial overgrowth syndrome (SBBOS), is a disorder of excessive bacterial growth in the small intestine. Unlike the colon (or large bowel), which is r ...
, radiation enteropathy
:''(Redirected from "Pelvic Radiation Disease")''
Radiation enteropathy is a syndrome that may develop following abdominal or pelvic radiation therapy for cancer. Many affected people are cancer survivors who had treatment for cervical cancer or ...
, celiac disease
Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine. Patients develop intolerance to gluten, which is present in foods such as wheat, rye, spel ...
, 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 p ...
, etc.
Treatment
Bile acid sequestrants are the main agents used to treat bile acid malabsorption. Cholestyramine
Colestyramine ( INN) or cholestyramine ( USAN) (trade names Questran, Questran Light, Cholybar, Olestyr, Quantalan, Vasosan) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong i ...
and colestipol
Colestipol (trade names Colestid, Cholestabyl) is a bile acid sequestrant used to lower blood cholesterol, specifically low-density lipoprotein (LDL). It is also used to reduce stool volume and frequency, and in the treatment of chronic diarrhea. ...
, 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
Colesevelam is a bile acid sequestrant administered orally. It was developed by GelTex Pharmaceuticals and later acquired by Genzyme. It is marketed in the US by Daiichi Sankyo under the brand name Welchol and elsewhere by Genzyme as Cholesta ...
is a tablet which is well tolerated and has been shown in placebo-controlled, randomized clinical trials to be effective.
The farnesoid X receptor agonist obeticholic acid has shown clinical and biochemical benefits in a proof of concept study. Tropifexor is another farnesoid X receptor agonist that has been studied, showing improvements in biochemistry and colonic transit.
Liraglutide, a GLP-1 receptor agonist had unexpected effects in clinical cases with co-existing bile acid diarrhoea which led to a randomised, double-blind, active-comparator, non-inferiority clinical trial. This trial demonstrated superiority in favour of liraglutide compared with colesevelam in reducing stool frequency and improved pathophysiological markers, suggesting it may be a new, safe and more effective treatment compared with current established, cheaper treatment modalities.
Epidemiology
Bile acid malabsorption is common in Crohn's disease 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
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating, and changes in the consistency of bowel movements. These symptoms may ...
.[ 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.]
A study from 2023 investigating the epidemiology of bile acid diarrhea in Denmark, found that people suffering from bile acid diarrhea seemed to have more co-morbidities, lower levels of income and education and more health care contacts compared with matches not suffering from bile acid diarrhea.
Estimates of the population prevalence suggest that 1% of the adult population could have primary bile acid diarrhea (Type 2 bile acid malabsorption).
A nationwide cohort study indicates an association between bile acid diarrhea and gastrointestinal cancer
Gastrointestinal cancer refers to malignant conditions of the Human gastrointestinal tract, gastrointestinal tract (GI tract) and accessory organs of digestion, including the esophagus, stomach, biliary system, pancreas, small intestine, large in ...
s.
References
External links
{{DEFAULTSORT:Bile Acid Malabsorption
Diseases of intestines
*
Gastrointestinal tract disorders
Steatorrhea-related diseases