Bile acid malabsorption

Last updated
Bile acid diarrhea / Bile acid malabsorption
Other namesBile acid-induced diarrhea, cholerheic or choleretic enteropathy, bile salt diarrhea, bile salt malabsorption
Specialty Gastroenterology
Symptoms Bowel movement frequency, soft or watery stools, diarrhea, urgency [1]
Complications Anxiety, fecal incontinence
Usual onsetAny age
DurationChronic (longlasting, persistent)
TypesPrimary or secondary or types 1, 2 and 3
CausesSurgical resection of ileum, cholecystectomy, idiopathic
Risk factors Pelvic radiation disease, small intestinal bacterial overgrowth
Diagnostic method Fecal bile acids, SeHCAT, 7α-hydroxy-4-cholesten-3-one
Differential diagnosis Irritable bowel syndrome, microscopic colitis
Medication Bile acid sequestrants
Prognosis Good with treatment
Frequency1 in 100 of population
DeathsNon-fatal

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 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.

Contents

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, increased frequency and urgency of defecation are common manifestations, often with fecal incontinence and other gastrointestinal symptoms such as abdominal swelling, bloating and abdominal pain. [2] [3] [1] [4]

People with this disorder often report impairments of mental health and well-being, including fatigue, dizziness, anxiety about leaving home (primarily due to fear of fecal incontinence), depression, one survey reports. [1] It contributes in delays in diagnosis. [1]

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 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 four–six 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. [5]

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. These bile acid transporters are all highly expressed in the ileum but not in the liver, jejunum or colon. [6] 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, [7] but this mutation is not more common in most patients and does not affect function. [8]

Overproduction of bile acids

Primary bile acid diarrhea (Type 2 bile acid "malabsorption") may be caused by an overproduction of bile acids. [5] [9] 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. [10] 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. [9]

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. [11] The underlying mechanisms are not fully understood. Furthermore, gut microbiome composition differs from that of people who do not suffer from bile acid diarrhea. [12] [13] [14]

Diagnosis

Several methods have been developed to identify the disorder but there are difficulties with all of them. [15] 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. [16] This test is not licensed in the USA, and is underutilized even where it is available. [17] [18] Older methods such as the 14C-glycocholic breath test are no longer in routine clinical use. [19]

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. [20] 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. [21]

The various biomarkers give similar diagnostic yields of around 25% in patients with functional bowel disorders with diarrhea. [19] In countries such as the US, where SeHCAT is not available, fecal bile acids and C4 are available to make the diagnosis. [19]

Classification

Bile acid malabsorption was first recognized in patients with ileal disease. [22] When other causes were recognized, and an idiopathic, primary form described, [23] a classification into three types was proposed: [24]

Treatment

Bile acid sequestrants are the main agents used to treat bile acid malabsorption. [25] 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 which is well tolerated and has been shown in placebo-controlled, randomized clinical trials to be effective. [26] [27] [28] [29]

The farnesoid X receptor agonist obeticholic acid has shown clinical and biochemical benefits in a proof of concept study. [30] Tropifexor is another farnesoid X receptor agonist that has been studied, showing improvements in biochemistry and colonic transit. [31]

Liraglutide, a GLP-1 receptor agonist had unexpected effects in clinical cases with co-existing bile acid diarrhoea [32] which led to a randomised, double-blind, active-comparator, non-inferiority clinical trial. [33] 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. [4]

People with primary bile acid diarrhea are frequently misdiagnosed as having irritable bowel syndrome. [17] 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. [16]

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. [34]

Estimates of the population prevalence suggest that 1% of the adult population could have primary bile acid diarrhea (Type 2 bile acid malabsorption). [16]

A nationwide cohort study indicates an association between bile acid diarrhea and gastrointestinal cancers. [35]

Related Research Articles

<span class="mw-page-title-main">Diarrhea</span> Loose or liquid bowel movements

Diarrhea, also spelled diarrhoea or diarrhœa, 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 due to fluid loss. Signs of dehydration often begin with loss of the normal stretchiness of the skin and irritable behaviour. This can progress to decreased urination, loss of skin color, a fast heart rate, and a decrease in responsiveness as it becomes more severe. Loose but non-watery stools in babies who are exclusively breastfed, however, are normal.

<span class="mw-page-title-main">Crohn's disease</span> Type of inflammatory bowel 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 gastrointestinal tract may include anemia, skin rashes, arthritis, inflammation of the eye, and fatigue. The skin rashes may be due to infections as well as pyoderma gangrenosum or erythema nodosum. Bowel obstruction may occur as a complication of chronic inflammation, and those with the disease are at greater risk of colon cancer and small bowel cancer.

<span class="mw-page-title-main">Irritable bowel syndrome</span> Functional gastrointestinal disorder

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 occur over a long time, sometimes for years. IBS can negatively affect quality of life and may result in missed school or work or reduced productivity at work. Disorders such as anxiety, major depression, and chronic fatigue syndrome are common among people with IBS.

The bile acid sequestrants are a group of resins used to bind certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by combining with bile constituents and preventing their reabsorption from the gut. In general, they are classified as hypolipidemic agents, although they may be used for purposes other than lowering cholesterol. They are used in the treatment of chronic diarrhea due to bile acid malabsorption.

<span class="mw-page-title-main">Malabsorption</span> Abnormality in absorption of food nutrients across the gastrointestinal tract

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 variety of anaemias.

<span class="mw-page-title-main">Primary sclerosing cholangitis</span> Hardening of the bile ducts due to scarring and inflammation

Primary sclerosing cholangitis (PSC) is a long-term progressive disease of the liver and gallbladder characterized by inflammation and scarring of the bile ducts, which normally allow bile to drain from the gallbladder. Affected individuals may have no symptoms or may experience signs and symptoms of liver disease, such as yellow discoloration of the skin and eyes, itching, and abdominal pain.

<span class="mw-page-title-main">Small intestinal bacterial overgrowth</span> Medical condition

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, which is rich with bacteria, the small bowel usually has fewer than 100,000 organisms per millilitre. Patients with bacterial overgrowth typically develop symptoms which may include nausea, bloating, vomiting, diarrhea, malnutrition, weight loss, and malabsorption by various mechanisms.

<span class="mw-page-title-main">Colestyramine</span> Pharmaceutical drug

Colestyramine (INN) or cholestyramine (USAN) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them strongly in the resin matrix. The functional group of the anion exchange resin is a quaternary ammonium group attached to an inert styrene-divinylbenzene copolymer.

<span class="mw-page-title-main">Cholestasis</span> Medical condition

Cholestasis is a condition where the flow of bile from the liver to the duodenum is impaired. The two basic distinctions are:

<span class="mw-page-title-main">Bile acid</span> Steroid acid found predominantly in the bile of mammals and other vertebrates

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.

Postcholecystectomy syndrome (PCS) describes the presence of abdominal symptoms after a cholecystectomy.

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 prostate cancer; it has also been termed pelvic radiation disease with radiation proctitis being one of the principal features.

<span class="mw-page-title-main">Colesevelam</span> Pharmaceutical drug

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 Cholestagel. In Canada, it is marketed by Valeant as Lodalis.

Jejunoileal bypass (JIB) was a surgical weight-loss procedure performed for the relief of morbid obesity from the 1950s through the 1970s in which all but 30 cm (12 in) to 45 cm (18 in) of the small bowel were detached and set to the side.

<span class="mw-page-title-main">Ileal sodium/bile acid cotransporter</span> Protein-coding gene in the species Homo sapiens

Ileal sodium/bile acid cotransporter, also known as apical sodium–bile acid transporter (ASBT) and ileal bile acid transporter (IBAT), is a bile acid:sodium symporter protein that in humans is encoded by the SLC10A2 gene.

<span class="mw-page-title-main">FGF19</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor 19 is a protein that in humans is encoded by the FGF19 gene. It functions as a hormone, regulating bile acid synthesis, with effects on glucose and lipid metabolism. Reduced synthesis, and blood levels, may be a factor in chronic bile acid diarrhea and in certain metabolic disorders.

<span class="mw-page-title-main">SeHCAT</span> Chemical compound

SeHCAT is a drug used in a clinical test to diagnose bile acid malabsorption.

<span class="mw-page-title-main">7α-Hydroxy-4-cholesten-3-one</span> Chemical compound

7α-Hydroxy-4-cholesten-3-one is an intermediate in the biochemical synthesis of bile acids from cholesterol. Its precursor, 7α-hydroxycholesterol, is produced from cholesterol by hepatic cholesterol 7α-hydroxylase (CYP7A1).

<span class="mw-page-title-main">Obeticholic acid</span> Chemical compound

Obeticholic acid (OCA), sold under the brand name Ocaliva, is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It is used as a medication used to treat primary biliary cholangitis. Intercept Pharmaceuticals Inc. hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma.

<span class="mw-page-title-main">Alan Hofmann</span> American physician (1931–2021)

Alan Frederick Hofmann was a gastrointestinal physiologist, biochemist and clinician who was notable for his extensive basic, translational and clinical research on bile acids and lipid digestion. From 1977, he was a member of the Division of Gastroenterology at University of California, San Diego. He influenced and mentored a large number of researchers with his ideas, knowledge and support.

References

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  32. ↑ Kårhus, M L; Brønden, A; Røder, M E (Aug 2019). "Remission of Bile Acid Malabsorption Symptoms Following Treatment With the Glucagon-Like Peptide 1 Receptor Agonist Liraglutide". Gastroenterology. 157 (2): 569–571. doi:10.1053/j.gastro.2019.04.002. PMID   30965026.
  33. ↑ Kårhus ML, Brønden A, Forman JL, Haaber A, Knudsen E, Langholz E, Dragsted LO, Hansen SH, Krakauer M, Vilsbøll T, Sonne DP, Knop FK (October 2022). "Safety and efficacy of liraglutide versus colesevelam for the treatment of bile acid diarrhoea: a randomised, double-blind, active-comparator, non-inferiority clinical trial". The Lancet. Gastroenterology & Hepatology. 7 (10): 922–931. doi:10.1016/S2468-1253(22)00198-4. PMID   35868334.
  34. ↑ Kårhus, M L; Ellegaard, A; Winther-Jensen, M (Dec 2023). "The Epidemiology of Bile Acid Diarrhea in Denmark". Clin Epidemiol. 15: 1173–1181. doi: 10.2147/CLEP.S442054 . PMC   10712339 . PMID   38089008.
  35. ↑ Ellegaard AM, Kårhus ML, Winther-Jensen M, Knop FK, Kårhus LL (May 2024). "Bile Acid Diarrhea Is Associated With an Increased Incidence of Gastrointestinal Cancers". Am J Gastroenterol. doi:10.14309/ajg.0000000000002859. PMID   38717021.
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