The young infant has only primary bile acids in the bile. The anaerobic flora of the colon develop sometime during the first year, signaled by the presence of DCA in bile. The proportion of DCA increases with age, and it is the dominant biliary bile acid in some adults. Bile acids are identical in men and women.
A schematic depiction of the enterohepatic circulation of bile acids in humans is shown in Figure 2. Bacterial enzymes undo the work of hepatic enzymes. Bile acid formation involves hydroxylation and conjugation; bacterial modification in the colon involves deconjugation and dehydroxylation. Hydroxylation and conjugation render bile acids soluble; conversely, deconjugation and dehydroxylation in the distal intestine make bile acids virtually insoluble and thereby lower the aqueous concentration and bacteriostatic effect of bile acids.
This process should be useful in herbivorous animals, which depend on bacterial production of short-chain fatty acids in the colon as a key energy source. Because conjugated bile acids are fully ionized at a physiological pH level, they are membrane impermeable. In addition, the bile acid molecule is also too large to pass through the junctional complexes between cells. The impermeability of the conjugated bile acid anion to the epithelium of the biliary tract and small intestine permits high intraluminal concentrations to be maintained.
Conjugation with glycine or taurine also affects the physicochemical properties of bile acids. Conjugated bile acids are more soluble at acidic pH levels than are their corresponding unconjugated derivatives. They are also more resistant to precipitation in the presence of high concentrations of calcium ions. The resistance to acidity prevents bile acids from precipitating from solution as the insoluble protonated acid in the duodenum, which is occasionally quite acidic.
The resistance to high calcium concentrations prevents bile salts from precipitating from solution as the calcium salt during concentration in the gallbladder. The addition of hydroxy groups to the cholesterol molecule during bile acid biosynthesis is restricted to 1 face of the bile acid molecule.
The bile acid molecule has a hydrophobic face without hydroxy substituents and a hydrophilic face with hydroxy substituents. Bile acids are planar, surface-active amphipathic molecules. Above a certain concentration—the critical micellization concentration—bile acids self-associate to form small polymolecular aggregates called micelles.
Micelles composed solely of bile acid molecules do not occur in the body. Rather, when present in sufficient concentration, conjugated bile acid molecules solubilize other lipids to form mixed micelles. Not all types of lipids are solubilized by bile acids.
The only lipids that readily form mixed micelles with bile acid anions are lipids that, by themselves, form bilayers in water: molecules such as phosphatidylcholine PC , fatty acid—fatty acid anion soap mixtures, and monoglycerides, for which bile acids are the most potent solubilizing agents known; conventional detergents are much weaker.
The arrangement of molecules in the bile acid—PC mixed micelle has been the subject of intense investigation. Recent work using the complex physical technique of small-angle neutron scattering indicates that the micelle is cylindrically shaped.
At high lipid and bile acid proportions, the micelle may become worm shaped, like a piece of spaghetti with the PC molecules arranged radially. The broad bile acid molecules are forced down between the heads of the PC molecules.
There is a continuous exchange of molecules between mixed micelles, mostly by micelle-micelle collision. There is also a small exchange through the aqueous phase surrounding the mixed micelles. The mixed micelle that is present in small intestinal content contains fatty acids and monoglycerides that have been solubilized by bile acids. These are formed by the action of pancreatic lipase on dietary triglyceride. The molecular arrangement of the bile acid—fatty acid—monoglyceride mixed micelle is identical to that of the bile acid—PC mixed micelle.
However, because fatty acids have a greater aqueous solubility than does PC, the concentration of fatty acids in monomeric form in the aqueous phase between micelles is higher than that of PC between bile acid—PC mixed micelles.
The conversion of PC-cholesterol vesicles and bilayers of fatty acid and monoglyceride to mixed micelles is illustrated in Figure 3. The movement of bile acid molecules in enterohepatic circulation can be considered to begin with the canaliculus. Here, adenosine triphosphate—stimulated transporters the major one is termed the canalicular bile salt export pump pump bile acids into the canaliculus.
The osmotic activity of the bile acids pulls water and filterable solutes into the canaliculus, which is then squeezed by the actin spiral.
Initially vesicles are formed, but in the presence of a supramicellar concentration of bile acids, the vesicles are transformed into mixed micelles. The canaliculus is a network of intercellular spaces with a blind end at the pericentral zone, where the canalicular channels empty via the canals of Hering into the finest radicals of the biliary tract. The osmotic forces generated by bile acid secretion, together with the contraction of the pericanalicular filaments, generate a pressure of about 30 cm of water.
Bile flows down the biliary tract. If pressure in the common bile duct is greater than in the cystic duct, bile enters the gallbladder. During overnight fasting, the sphincter of Oddi contracts and relaxes. Results of the limited studies that are available suggest that about half of the bile secreted by the liver is stored in the gallbladder.
Because some bile acids are absorbed from the proximal small intestine, bile acids gradually accumulate in the gallbladder. The volume of water removed by the concentration of gallbladder bile is replaced by entering bile. Thus, during overnight fasting, the gallbladder can remain constant in size yet store a progressively increasing fraction of the circulating bile acid pool. When a meal is eaten, cholecystokinin is released from the endocrine cells of the intestinal mucosa.
The hormone acts on vagal afferents or the nerve ganglia innervating the gallbladder and induces gallbladder contraction. At the same time, it acts on the nerves innervating the sphincter of Oddi, causing it to relax.
The end result is that gallbladder bile is delivered to the duodenum. Conjugated bile acids move along the small intestine via intestinal propulsive activity. Their absorption is predominantly carrier mediated, the most important of which is in enterocytes present in the terminal ileum.
This consists of an apical sodium-dependent cotransporter called the "apical bile salt transporter" and a basolateral transporter that is an anion exchanger. Based on results of animal studies, there is likely to be a second transporter in the proximal small intestine that transports dihydroxy conjugates preferentially.
The importance is this carrier in humans is not known. Not all bile acid absorption is carrier mediated; passive absorption from the distal intestine involves only unconjugated bile acids that are formed by bacterial deconjugation of conjugated bile acids. Unconjugated dihydroxy bile acids, being less hydrophilic than cholic acid, are absorbed much more rapidly.
Absorption occurs by passive flip-flop of the nonionized bile acid molecule across the lipid bilayer. Bile acids return to the liver in portal blood.
About three fourths of the trihydroxy bile acids are protein bound, mostly to albumin. A sodium-dependent cotransporter and a sodium-independent transporter are present in the sinusoidal membrane, but their relative importance in conjugated bile acid uptake is not yet clarified.
The concentration of bile acids at any place in enterohepatic circulation depends on the relation of the rates of input of bile acids and surrounding aqueous fluid. All of these concentrations are sufficiently high that bile acids are present in micellar form. The concentration of bile acids in plasma is always low. Because the first-pass extraction of bile acids is constant, when more bile acids are absorbed during digestion, the concentration of bile acids in systemic plasma rises severalfold.
Cholesterol and conjugated bile acid molecules that enter the small intestine during the secretion of bile have quite different fates. Only one fourth to one half of cholesterol is absorbed, whereas bile acids are efficiently absorbed. For a meal in which the bile acid pool might circulate twice, nine tenths of the bile acids are absorbed.
Bile acids that are not absorbed from the colon are eliminated in the stool. Fecal elimination is balanced by biosynthesis from cholesterol.
Because the concentration of bile acids in systemic venous plasma is low, and because bile acids are bound to albumin, the amount of bile acids entering the glomerular filtrate is small. The ileal bile acid transport system is also located in the proximal renal tubule, where it efficiently reabsorbs most bile acids present in tubular fluid.
As a consequence, in the healthy person, virtually no bile acids are eliminated in urine. In the adult, about two thirds of cholesterol is eliminated as cholesterol and about one third as bile acids. Bile acids are cytotoxic when their concentrations increase to abnormally high levels, either intracellularly or extracellularly. Bile acid cytotoxicity is strongly affected by its structure: the greater the hydrophobicity, the greater the cytotoxicity.
Hydrophobicity is defined operationally by the extent to which bile acids bind to hydrophobic surfaces, and this can be determined by measuring the retention time during liquid chromatography using a hydrophobic adsorbent.
Ursodeoxycholic acid, although a dihydroxy bile acid, does not bind to the adsorbent, has a short retention time, is hydrophilic, and devoid of cytotoxic properties in most model systems. Cholic acid is intermediate, being noncytotoxic at low concentrations, but cytotoxic at very high concentrations.
Intracellular toxicity caused by conjugated bile acids occurs in the intact cell only when a transporter is present in the cell membrane that permits conjugated bile acids to enter the cell. To date, intracellular toxicity attributable to conjugated bile acids has been clearly established only for the hepatocyte. In the hepatocyte of the healthy person, uptake is followed by rapid elimination, and cytosolic proteins that bind bile acids are likely to be present.
When elimination is impaired, bile acids accumulate intracellularly. When their concentration exceeds the binding capacity of the cytosolic proteins, bile acids enter other organelles, possibly interfering with their activity, and damage the canalicular membrane.
In the hepatocyte, the accumulation of bile acids leads to mitochondrial damage and ultimately to apoptosis or necrosis. Unconjugated bile acids, being membrane permeable, are highly cytotoxic to isolated cells in vitro because unconjugated bile acids can readily accumulate to pathological levels.
However, cytotoxicity attributable to unconjugated bile acids in vivo has not been clearly shown. For cells that lack a bile acid transporter, conjugated bile acids are not usually cytotoxic until their concentration is sufficiently high to attack the membrane of the cell. This concentration is close to the critical micellization concentration of the bile acid. Because CDCA and DCA have a lower critical micellization concentration than does cholic acid, they are more cytotoxic for a given concentration.
In the presence of other lipids, such as PC or fatty acids, the monomeric concentration of bile acids depends on their association with these lipids to form mixed micelles. Such mixed micelle formation occurs at a concentration well below the cytotoxic concentration, explaining the lack of cytotoxicity of bile acids in the biliary tract and small intestine in healthy people.
In patients and knockout mice lacking the canalicular PC transporter, PC is absent from bile, the monomeric concentration of bile acids is increased, and damage to the biliary epithelial cells occurs.
Disturbances of the enterohepatic circulation may be classified into 4 groups: 1 disturbances of circulation ie, movement between organs , 2 disturbances of bile acid formation synthesis and conjugation , 3 disturbances in membrane transport of bile acids, and 4 disturbances involving bacterial deconjugation and dehydroxylation. Biliary obstruction, eg, a stone obstructing the common duct, causes bile acid retention in the hepatocyte, leading to hepatocyte necrosis or apoptosis.
Sulfated and unsulfated bile acids regurgitate from the hepatocyte and are eliminated in urine. Plasma concentrations of bile acids rise to fold. In time, with total obstruction, bile acid biosynthesis decreases and is balanced by urinary loss. Biliary lipids such as phospholipids and cholesterol regurgitate from bile into plasma, causing increased plasma levels of phospholipids and cholesterol.
With complete obstruction, bile acids are not present in the small intestine, fat-soluble vitamins are not absorbed, and dietary triglyceride is inefficiently absorbed see below.
Because bile acids do not enter the intestine, secondary bile acids are not formed. When biliary obstruction is incomplete, secretion of bile acids into the intestine decreases. Despite this, ileal absorption continues, and the return of cytotoxic bile acids to the liver promotes liver damage.
Such continuing ileal absorption in cholestatic disease may be considered inappropriate and has been termed organ warfare. Bile acid sequestrants are administered to decrease the efficiency of ileal absorption. If ileal absorption is sufficiently efficient, less bile acids may enter the colon. Secondary bile acids are formed in decreased amounts, and fecal bile acid output also decreases. In a patient with a biliary fistula, bile acids are diverted to the outside instead of entering the small intestine.
Because bile acid biosynthesis is controlled by negative feedback, bile acid synthesis increases markedly—up to fold. Because bile acids are made from cholesterol, cholesterol biosynthesis must have a parellel increase.
When no bile acids are in the small intestine, fat-soluble vitamins and lipid-soluble drugs such as cyclosporine have little or no absorption. Lipolysis of dietary triglyceride is nonetheless complete, but the uptake of fatty acids is slowed because micelles are not present, and the site of absorption extends throughout the small intestine.
Because unsaturated fatty acids have a greater aqueous solubility than saturated fatty acids, their absorption is less disturbed by an absence of bile acids.
For infants with cholestatic liver disease, formula feedings usually contain triglycerides rich in medium-chain fatty acids, which are water soluble and can be absorbed efficiently in the absence of conjugated bile acids.
A common clinical occurrence of a biliary fistula is after orthotopic liver transplantation. The transplanted liver increases its bile acid biosynthesis slowly, presumably because of its ischemic damage during storage before transplantation.
This greatly decreases the flux of bile acids through the transplanted liver; also, there is an increased load of bilirubin for excretion in the cholestatic recipient. It is unclear whether bile acid supplementation with UDCA to increase the flux of bile acids through the recovering hepatocytes would be of therapeutic value. Some groups 21 have reported benefit; others 22 have not. In patients in whom the gallbladder has been removed, the bile acid pool is stored in the small intestine during the fasting state.
When a meal is ingested, the pool moves to the terminal ileum, where it is actively absorbed. Bile acids return to the liver and are immediately secreted into bile. The overall effect of cholecystectomy on biliary secretion is small, and daily bile acid secretion after cholecystectomy is not very different than in the healthy person. This is clinically manifest as diarrhea and generally responds to administration of a bile acid sequestrant.
Resection of the terminal ileum causes bile acid malabsorption. If the resection is small, the effect on bile acid metabolism is minimal. Increased biosynthesis occurs to compensate for increased loss. With larger resections, bile acid synthesis increases even further—up to 20 times the usual rate. In this new steady state, unabsorbed bile acids, water, and electrolytes enter the colon in greatly increased amounts. In some patients, bile acids act on the colonic epithelium to inhibit water absorption or induce frank secretion.
The result is a mild, watery diarrhea. Symptomatic response is obtained by cholestyramine resin administration.
The bile acid pool becomes progressively depleted during the day. Because of the lack of micelles, fat malabsorption occurs. Increased fatty acids passing into the colon inhibit water absorption. The loss of water and electrolyte conservation by the distal small intestine, together with the inhibition of colonic water absorption, result in severe diarrhea and steatorrhea. If the diarrhea is sufficiently large, and if there is malabsorption of other nutrients, the patient may be diagnosed as having "short-bowel syndrome.
In some patients, fecal weight and frequency is reduced by the elimination of fat from the diet. Conjugated bile acid replacement therapy is being explored to increase fat absorption see below.
Other therapeutic approaches include proton pump inhibitors, low osmolar diets, growth factors, and glutamine. When patients have portal systemic venous shunting because of portal hypertension or a surgical portal caval anastomosis, bile acids enter the systemic circulation. There are two fundamentally important functions of bile in all species:.
Adult humans produce to ml of bile daily, and other animals proportionately similar amounts. The secretion of bile can be considered to occur in two stages:.
In species with a gallbladder man and most domestic animals except horses and rats , further modification of bile occurs in that organ. The gall bladder stores and concentrates bile during the fasting state. Typically, bile is concentrated five-fold in the gall bladder by absorption of water and small electrolytes - virtually all of the organic molecules are retained. Secretion into bile is a major route for eliminating cholesterol. Free cholesterol is virtually insoluble in aqueous solutions, but in bile, it is made soluble by bile acids and lipids like lecithin.
Gallstones , most of which are composed predominantly of cholesterol, result from processes that allow cholesterol to precipitate from solution in bile. Bile acids are derivatives of cholesterol synthesized in the hepatocyte. Cholesterol, ingested as part of the diet or derived from hepatic synthesis is converted into the bile acids cholic and chenodeoxycholic acids, which are then conjugated to an amino acid glycine or taurine to yield the conjugated form that is actively secreted into cannaliculi.
Symptoms 4. Treatment 5. Support 6. This factsheet is about bile acid malabsorption Bile contains bile acids which are used for two main purposes.
Causes of bile acid malabsorption There are three different causes of bile acid malabsorption and these are categorised into types: Type I: this is when there is a problem in the part of the small intestine ileum where re-absorption takes place.
Type II: this is when no definitive cause can be found and is known as primary bile acid malabsorption. Type III: this can result from other diseases or conditions within the abdomen such as gallbladder removal, coeliac disease, chronic pancreatitis, radiotherapy or small bowel bacteria overgrowth.
What are the usual symptoms of bile acid malabsorption? Diarrhoea: this is the main symptom. When bile acids are not properly re-absorbed from the ileum, they pass instead into the large intestine colon , irritating the lining of the colon and stimulating salt and water secretion.
Diarrhoea is usually frequent during the day and sometimes at night. It may be pale, greasy and hard to flush away or may be unusually coloured green or orange.
Stomach problems: these include bloating, cramping abdominal pain and excessive wind. Unfortunately, many symptoms of bile acid malabsorption mimic those of Irritable Bowel Syndrome IBS and some IBS patients may actually have undiagnosed bile acid malabsorption. How is Bile Acid Malabsorption diagnosed?
What treatment is available for bile acid malabsorption? Medications These work by binding to the bile acid in the small intestine and preventing them from irritating the large intestine. The main medications include: Colestyramine and colestipol — these medications only come in powder form.
Unfortunately, some people may find them unpalatable and if the dose is too high, it can cause constipation, so it is important to adjust the dose according to symptoms. Colesevelam — this is a newer medication and comes in a tablet form. Some patients find it easier to take than colestyramine. Due to current cost and drug licensing colesevelam may not be widely available. Diet Following a diagnosis of bile acid malabsorption, a referral to a dietitian may be advised, and a key piece of dietary advice may be to keep to a strict low-fat diet 40g of fat per day.
Does bile acid malabsorption need to be monitored and, if so, how? How can bile acid malabsorption affect you? What to ask your doctor about bile acid malabsorption? Do I need to be referred to a dietitian to see if there are any changes to my diet that may help with my symptoms?
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