Excess Bile Acids Research Articles

Recycling rate of bile acids in the enterohepatic recirculation as a major determinant of whole body 75SeHCAT retention

Measurement of the whole body retention of orally administered (75)SeHCAT is used to investigate patients with unexplained diarrhoea. Retention values of <15 % at 7 days post-administration are taken to indicate bile acid malabsorption (BAM). Whilst idiopathic BAM is frequently diagnosed with (75)SeHCAT, functional and morphological studies of the terminal ileum rarely show any abnormality, so the disorder may be more appropriately termed bile acid diarrhoea (BAD). In addition to malabsorption, excess bile acid may reach the colon, where the events leading to diarrhoea take place, as a result firstly of increased bile acid synthesis and secondly of an increased recycling rate of bile acids. Increased recycling has been largely ignored as a cause of BAD, but, as shown in this study, can readily result in excess bile acids reaching the colon even when ileal absorption efficiency is normal (i.e. 95-97 %). There needs to be a re-evaluation of the causes of BAD in patients without a history of previous intestinal resection or evidence of ileal pathology, such as Crohn's disease.

PTU-193 A Novel, Rational Approach to Treating Primary Bile Acid Diarrhoea: a Proof of Concept Study of the FXR Agonist Obeticholic Acid

IntroductionPrimary (idiopathic) bile acid diarrhoea (PBAD) is a common chronic diarrhoeal condition, affecting ~1% of the population, and a large proportion of patients otherwise diagnosed with IBS-D. We showed that...

New Insights into Bile Acid Malabsorption

Bile acid malabsorption occurs when there is impaired absorption of bile acids in the terminal ileum, so interrupting the normal enterohepatic circulation. The excess bile acids in the colon cause diarrhea, and treatment with bile acid sequestrants is beneficial. The condition can be diagnosed with difficulty by measuring fecal bile acids, or more easily by retention of selenohomocholyltaurine (SeHCAT), where this is available. Chronic diarrhea caused by primary bile acid diarrhea appears to be common, but is under-recognized where SeHCAT testing is not performed. Measuring excessive bile acid synthesis with 7α-hydroxy-4-cholesten-3-one may be an alternative means of diagnosis. It appears that there is no absorption defect in primary bile acid diarrhea but, instead, an overproduction of bile acids. Fibroblast growth factor 19 (FGF19) inhibits hepatic bile acid synthesis. Defective production of FGF19 from the ileum may be the cause of primary bile acid diarrhea.

Ostα depletion protects liver from oral bile acid load

Bile acid homeostasis is tightly maintained through interactions between the liver, intestine, and kidney. During cholestasis, the liver is incapable of properly clearing bile acids from the circulation, and alternative excretory pathways are utilized. In obstructive cholestasis, urinary elimination is often increased, and this pathway is further enhanced after bile duct ligation in mice that are genetically deficient in the heteromeric, basolateral organic solute transporter alpha-beta (Ostα-Ostβ). In this study, we examined renal and intestinal function in Ostα-deficient and wild-type mice in a model of bile acid overload. After 1% cholic acid feeding, Ostα-deficient mice had significantly lower serum ALT levels compared with wild-type controls, indicating partial protection from liver injury. Urinary clearance of bile acids, but not clearance of [(3)H]inulin, was significantly higher in cholic acid-fed Ostα-deficient mice compared with wild-type mice but was not sufficient to account for the protection. Fecal excretion of bile acids over the 5 days of cholic acid feeding was responsible for almost all of the bile acid loss in Ostα-deficient mice, suggesting that intestinal losses of bile acids accounted for the protection from liver injury. Thus fecal loss of bile acids after bile acid overload reduced the need for the kidney to filter and excrete the excess bile acids. In conclusion, Ostα-deficient mice efficiently eliminate excess bile acids via the feces. Inhibition of intestinal bile acid absorption might be an effective therapeutic target in early stages of cholestasis when bile acids are still excreted into bile.

Molecular and cellular pathways associated with chromosome 1p deletions during colon carcinogenesis.

Chromosomal instability is a major pathway of sporadic colon carcinogenesis. Chromosome arm 1p appears to be one of the “hot spots” in the non-neoplastic mucosa that, when deleted, is associated with the initiation of carcinogenesis. Chromosome arm 1p contains genes associated with DNA repair, spindle checkpoint function, apoptosis, multiple microRNAs, the Wnt signaling pathway, tumor suppression, antioxidant activities, and defense against environmental toxins. Loss of 1p is dangerous since it would likely contribute to genomic instability leading to tumorigenesis. The 1p deletion-associated colon carcinogenesis pathways are reviewed at the molecular and cellular levels. Sporadic colon cancer is strongly linked to a high-fat/low-vegetable/low-micronutrient, Western-style diet. We also consider how selected dietary-related compounds (eg, excess hydrophobic bile acids, and low levels of folic acid, niacin, plant-derived antioxidants, and other modulatory compounds) might affect processes leading to chromosomal deletions, and to the molecular and cellular pathways specifically altered by chromosome 1p loss.

A Study of the Prevalence of Genetic Polymorphisms in Bile Acid Diarrhea Patients

Introduction Bile acid diarrhoea (BAD) is a common cause of chronic diarrhoea and results from high concentrations of bile acids in the colon. It has recently been suggested that impaired production of fibroblast growth factor 19 (FGF19) in the ileum can result in excessive hepatic bile acid synthesis through reduced negative feedback regulation, and this, rather than malabsorption, is the cause of the diarrhoea. The reason for the reduced ileal FGF19 production remains unclear but it has been established that ileal FGF19 synthesis is markedly stimulated by bile acids binding to the farnesoid X receptor (FXR). In the liver, FGF19 acts through the FGFR4 receptor and its co-receptor Klotho β. Organic solute transporter α (OSTα) is the ileal basolateral bile acid transporter. The aim of this study was to determine the prevalence of 6 common single nucleotide polymorphisms (SNPs) in four genes involved in bile acid metabolism and FGF19 action, comparing the prevalence in patients with primary BAD, a similar number of controls with diarrhoea, and a larger numbers of healthy controls. Methods Two common SNPs (rs948992 and rs1789170) in the FGF19 gene were analysed as well as 2 SNPs (M173T, rs61755050 and −1g>t, rs56163822) in the FXR gene. Mutations in FXR are implicated in patients with obstetric cholestasis and have been shown to reduce function and translation efficiency of FXR. A SNP in Klotho β (rs17618244) has been associated with colonic transit in IBS-D patients. A further SNP in the OSTα gene (rs939885) was also studied. Genomic DNA was extracted from 92 primary BAD patients diagnosed on the basis of an abnormal ( Results Polymorphisms in all the genes studied were detectable in controls and in cases. No significant differences in the genotypes and allele frequencies were found in the Caucasian cohorts in the control and primary BAD groups (p > 0.1). Further analysis of patients of different ethnic origin again did not show significant differences in the allele frequencies. Conclusion Major differences in the frequency of genetic polymorphisms in four candidate genes involved with FGF19 and bile acid metabolism are unlikely to be associated with primary BAD. However, the SNPs identified may contribute small effects, with a combination of SNPs in several genes producing a cumulative effect. Larger numbers of cases are required to define specific interactions or minor effects. At present the cause of the reduced FGF19 action in BAD remains uncertain.

* A study of the prevalence of genetic polymorphisms in bile acid diarrhoea patients

IntroductionBile acid diarrhoea (BAD) is a common cause of chronic diarrhoea and results from high concentrations of bile acids in the colon. It has recently been suggested that impaired production...

The role of phosphatidylethanolamine methyltransferase in a mouse model of intrahepatic cholestasis

Intrahepatic cholestasis eventually leads to liver failure. We report here a condition that decreases liver damage in intrahepatic cholestasis based on a mouse model that lacks multiple drug resistant protein 2 (ABCB4). We found that lack of phosphatidylethanolamine N-methyltransferase (PEMT) decreased liver damage in Abcb4 −/− mice caused by exposure of the liver to excess bile acids. The protective effect was not related to hepatic ratio of phosphatidylcholine to phosphatidylethanolamine or the level of cholesterol. The decreased concentration of bile acids in liver was related to impaired re-absorption of bile acids in intestine and increased disposal of bile acids in feces in Abcb4 −/− /Pemt −/− mice as compared to Abcb4 −/− mice. PEMT deficiency affected intestinal Na + absorption resulting in an impaired Na + concentration gradient along the length of the small intestine and abnormal absorption of bile acids mediated by apical sodium-dependent bile acid transporter (ASBT). The findings of this study suggest that inhibition of PEMT and/or reduction of intestinal sodium concentration may be helpful in attenuating liver damage and prolonging hepatic function in intrahepatic cholestasis.

New Treatment Options for Chronic Constipation: Mechanisms, Efficacy and Safety

The present review has several objectives, the first of which is to review the pharmacology and selectivity of serotonergic agents to contrast the older serotonergic agents (which were withdrawn because of cardiac or vascular adverse effects) with the newer generation serotonin receptor subtype 4 agonists. Second, the chloride ion secretagogues that act through the guanylate cyclase C receptor are appraised and their pharmacology is compared with the approved medication, lubiprostone. Third, the efficacy and safety of the application of bile acid modulation to treat constipation are addressed. The long-term studies of surgically induced excess bile acid delivery to the colon are reviewed to ascertain the safety of this therapeutic approach. Finally, the new drugs for opiate-induced constipation are introduced. Assuming these drugs are approved, practitioners will have a choice; however, patient responsiveness will be based on trial and error. Nevertheless, the spectrum of mechanisms and demonstrated efficacy and safety augur well for satisfactory treatment outcomes.

New Treatment Options for Chronic Constipation: Mechanisms, Efficacy and Safety

The present review has several objectives, the first of which is to review the pharmacology and selectivity of serotonergic agents to contrast the older serotonergic agents (which were withdrawn because of cardiac or vascular adverse effects) with the newer generation serotonin receptor subtype 4 agonists. Second, the chloride ion secretagogues that act through the guanylate cyclase C receptor are appraised and their pharmacology is compared with the approved medication, lubiprostone. Third, the efficacy and safety of the application of bile acid modulation to treat constipation are addressed. The long-term studies of surgically induced excess bile acid delivery to the colon are reviewed to ascertain the safety of this therapeutic approach. Finally, the new drugs for opiate-induced constipation are introduced. Assuming these drugs are approved, practitioners will have a choice; however, patient responsiveness will be based on trial and error. Nevertheless, the spectrum of mechanisms and demonstrated efficacy and safety augur well for satisfactory treatment outcomes.

Managing bile acid diarrhoea.

Bowel symptoms including diarrhoea can be produced when excess bile acids (BA) are present in the colon. This condition, known as bile acid or bile salt malabsorption, has been under recognized, as the best diagnostic method, the (75)Se-homocholic acid taurine (SeHCAT) test, is not available in many countries and is not fully utilized in others. Reduced SeHCAT retention establishes that this is a complication of many other gastrointestinal diseases. Repeated studies show SeHCAT tests are abnormal in about 30% of patients otherwise diagnosed as diarrhoea-predominant irritable bowel syndrome or functional diarrhoea, with an estimated population prevalence of around 1%. Recent work suggests that the condition previously called idiopathic bile acid malabsorption (BAM) is not in fact due to a defect in absorption, but results from an overproduction of BA because of defective feedback inhibition of hepatic bile acid synthesis, a function of the ileal hormone fibroblast growth factor 19 (FGF19). The approach to treatment currently depends on binding excess BA, to reduce their secretory actions, using colestyramine, colestipol and, most recently, colesevelam. Colesevelam has a number of potential advantages that merit further investigation in trials directed at patients with bile acid diarrhoea.

PP-020 A prospective study of fibroblast growth factor 19 in patients with chronic diarrhoea and possible bile acid malabsorption

Introduction Chronic diarrhoea resulting from excess bile acids in the colon (“bile acid malabsorption”, BAM) is usually diagnosed by the selenium homocholic acid taurine (SeHCAT) test and responds to bile acid sequestrants. Other tests for BAM including serum levels of 7α-hydroxy-4-cholesten-3-one are not widely available. Our group suggested that disordered negative feedback inhibition by Fibroblast Growth Factor 19 (FGF19), produced by the ileum, of hepatic bile acid synthesis results in an excess of bile acids entering the colon, causing bile acid diarrhoea. We aim to examine further the role of FGF19 in a larger group of patients with chronic diarrhoea. Methods 62 patients have been prospectively recruited with chronic diarrhoea. All patients had routine investigations for chronic diarrhoea to exclude other causes and all had SeHCAT tests. Three different patient groups were defined according to the diagnosis based on SeHCAT results: SeHCAT 15% (n=28). All patient demographics and symptoms were recorded and fasting blood samples for FGF19 were collected and available in 54 patients. Serum FGF19 was quantified by ELISA using a commercially available kit. Results Fasting FGF19 levels were significantly lower in patients with primary and secondary BAM compared with the chronic diarrhoea group with normal SeHCAT results (medians 160 vs 139 vs 276 pg/ml, p Conclusion This study confirms that serum levels of an easily measurable hormone, FGF19, are significantly reduced in patients with bile acid diarrhoea, and are not affected by chronic diarrhoea per se. These patients also have a higher BMI. Other symptoms such as faecal incontinence, urgency abdominal pain, bloating and steatorrhoea are also common findings in these patients. These results provide further evidence that there is a disruption of a homeostatic mechanism in the control of bile acid synthesis with an overproduction of bile acids leading to chronic watery diarrhoea.

Recent advances in the understanding of bile acid malabsorption

Bile acid malabsorption (BAM) is a syndrome of chronic watery diarrhoea with excess faecal bile acids. Disruption of the enterohepatic circulation of bile acids following surgical resection is a common cause of BAM. The condition is easily diagnosed by the selenium homocholic acid taurine (SeHCAT) test and responds to bile acid sequestrants. Idiopathic BAM (IBAM, primary bile acid diarrhoea) is the condition where no definitive cause for low SeHCAT retention can be identified. Review of PubMed and major journals. Evidence is accumulating that BAM is more prevalent than first thought. Management of chronic diarrhoea involves excluding secondary causes. Treatment of the condition is with bile acid binders. SeHCAT testing is not widely performed, limiting awareness of how common this condition can be. The underlying mechanism for IBAM has been unclear. Increasing awareness of the condition is important. Alternative mechanisms of IBAM have been suggested which involve an increased bile acid pool size and reduced negative feedback regulation of bile acid synthesis by FGF19. New sequestrants are available. Further research into the precise mechanism of IBAM is needed. Improvements in the recognition of the condition and optimization of treatment are required.

Chronic Diarrhea Due to Excessive Bile Acid Synthesis and Not Defective Ileal Transport: A New Syndrome of Defective Fibroblast Growth Factor 19 Release

Elsewhere in this issue Julian Walters and his colleagues report a major advance in our understanding of the pathogenesis of chronic diarrhea associated with idiopathic bile acid malabsorption.1 The story is a fascinating one and unites longstanding and very recent discoveries in physiology, biochemistry, and molecular biology.

A New Mechanism for Bile Acid Diarrhea: Defective Feedback Inhibition of Bile Acid Biosynthesis

Primary (idiopathic) bile acid malabsorption (BAM) is a common, yet underrecognized, chronic diarrheal syndrome. Diagnosis is difficult without selenium homocholic acid taurine (SeHCAT) testing. The diarrhea results from excess colonic bile acids, but the pathogenesis is unclear. Fibroblast growth factor 19 (FGF19), produced in the ileum in response to bile acid absorption, regulates hepatic bile acid synthesis. We proposed that FGF19 is involved in bile acid diarrhea and measured its levels in patients with BAM. Blood was collected from fasting patients with chronic diarrhea; BAM was diagnosed by SeHCAT. Serum FGF19 was measured by enzyme-linked immunosorbent assay. Serum 7alpha-hydroxy-4-cholesten-3-one (C4) was determined using high-performance liquid chromatography, to quantify bile acid synthesis. Data were compared between patients and subjects without diarrhea (controls). Samples were taken repeatedly after meals from several subjects. The median C4 level was significantly higher in patients with primary BAM than in controls (51 vs 18 ng/mL; P < .0001). The median FGF19 level was significantly lower in patients with BAM (120 vs 231 pg/mL; P < .0005). There was a significant inverse relationship between FGF19 and C4 levels (P < .0004). Low levels of FGF19 were also found in patients with postcholecystectomy and secondary bile acid diarrhea. Abnormal patterns of FGF19 levels were observed throughout the day in some patients with primary BAM. Patients with BAM have reduced serum FGF19 which may be useful in diagnosis. We propose a mechanism whereby impaired FGF19 feedback inhibition causes excessive bile acid synthesis that exceeds the normal capacity for ileal reabsorption, producing bile acid diarrhea.

FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption

Bile acid malabsorption, which in patients leads to excessive fecal bile acid excretion and diarrhea, is characterized by a vicious cycle in which the feedback regulation of bile acid synthesis is interrupted, resulting in additional bile acid production. Feedback regulation of bile acid synthesis is under the control of an endocrine pathway wherein activation of the nuclear bile acid receptor, farnesoid X receptor (FXR), induces enteric expression of the hormone, fibroblast growth factor 15 (FGF15). In liver, FGF15 acts together with FXR-mediated expression of small heterodimer partner to repress bile acid synthesis. Here, we show that the FXR-FGF15 pathway is disrupted in mice lacking apical ileal bile acid transporter, a model of bile acid malabsorption. Treatment of Asbt-/- mice with either a synthetic FXR agonist or FGF15 downregulates hepatic cholesterol 7alpha-hydroxylase mRNA levels, decreases bile acid pool size, and reduces fecal bile acid excretion. These findings suggest that FXR agonists or FGF15 could be used therapeutically to interrupt the cycle of excessive bile acid production in patients with bile acid malabsorption.

Bile acids and post-vagotomy diarrhoea.

Abstract Cholecystectomy increases the risk of post-vagotomy diarrhoea and bile acid binding agents may relieve it, suggesting a role for bile acids in its pathogenesis. The faecal bile acid loss in 15 patients with episodic diarrhoea after vagotomy and drainage was not raised when compared with 12 normal subjects, except on days when diarrhoea occurred. This elevation was caused by an increase in stool weight rather than bile acid concentration, suggesting that the increased bile acid loss during attacks was not causally related. Asymptomatic vagotomy patients excreted normal amounts of bile acids. Seven patients with episodic diarrhoea after vagotomy and drainage with cholecystectomy continuously excreted excessive amounts of bile acids when compared with normal subjects and asymptomatic patients. The concentration of bile acid in their stools was higher than that observed in symptomatic patients after vagotomy and drainage alone. The continuous presence of excess bile acid may prime the colon to react more readily to stimuli caused by disturbed gastric emptying and rapid small bowel transit, without being the main factor in causing the condition. These findings may explain the increased risk of diarrhoea when cholecystectomy is combined with vagotomy.

Endothelin B receptor–Mediated protection against anoxia-reoxygenation injury in perfused rat liver: Nitric oxide–Dependent and –Independent mechanisms

This study aimed to investigate the roles of endothelin (ET) receptors in biliary dysfunction and cell injury in postischemic livers. Rat livers perfused with oxygenated Krebs-Henseleit solution were exposed to reoxygenation following 20-minute hypoxia. The anoxic perfusion decreased bile output and reduced cyclic guanosine monophosphate (cGMP) contents, an index of nitric oxide (NO) generation. Upon reoxygenation, the decreased bile was not fully recovered, and the resistance increased biphasically: an early transient spike accompanied by an elevated release of ET-1 and a rise accompanied by a cGMP elevation in the later period. The initial vasoconstriction appeared to be mediated by both ETA and ETB receptors, as judged by inhibitory effects of their antagonists, BQ-485 and BQ–788, respectively, while the late elevation of the resistance was not attenuated by these reagents, but rather enhanced by the ETB blockade. The BQ-788 treatment attenuated the reoxygenation-induced cGMP elevation and induced bile acid–dependent choleresis. However, such a change upon the ETB blockade coincided with dissociation of a recovery of phospholipids and aggravation of cell injury. The BQ-788–elicited deterioration of reoxygenation-elicited changes was attenuated by NO supplement with S-nitroso-N-acetyl penicillamine. Nω-Nitro-L-arginine methyl ester, an NO synthase inhibitor, mimicked biliary changes elicited by the ETB blockade but without causing notable cell injury. Under these circumstances, coadministration of clotrimazole, an inhibitor of cytochrome P450 mono-oxygenases, elicited the injury comparable with that observed under the ETB blockade. These results suggest that ETB-mediated signaling limits excessive bile acid excretion and plays a protective role against reoxygenation injury through mechanisms involving both NO-dependent and -independent processes. (HEPATOLOGY 2001;33:894-901.)

INTRAHEPATIC CHOLESTASIS OF PREGNANCY

Intrahepatic cholestasis of pregnancy is one of the primary disorders of the liver that adversely affects maternal well-being and fetal outcome. Early identification of this condition, careful interdisciplinary monitoring, and prompt delivery at fetal maturity can improve outcomes in the mother and child. Although the cause is unclear, IHCP probably arises from a genetic predisposition for increased sensitivity to estrogens and progestogens and altered membrane composition and expression of bile ducts, hepatocytes, and canalicular transport systems. As a result, the elevations in maternal levels of bile acids and their molar ratios seen in healthy pregnancy rise further in IHCP patients. Also, as the normal fetal-to-maternal transfer of bile acids across the trophoblast is impaired, the excess bile acids with abnormal profiles accumulate and are toxic to the fetus. The management of IHCP is dictated by the increased risks of fetal distress, spontaneous preterm delivery, and sudden death, as well as by alleviating pruritus in the mother. These risks to the fetus rise progressively to delivery, regardless of serum levels of bile acids and ALT. Close monitoring of these markers is essential but does not prevent sudden fetal distress and death. Provision should be made to induce labor as soon as fetal lung maturity has been established. Ursodeoxycholic acid is the only therapy that has proven effective, albeit in small studies, in alleviating pruritus and restoring towards normal the abnormal profiles of bile acids and sulfated steroids in serum and other body fluids. Ursodeoxycholic acid seems to have no obvious adverse effects on the fetus, but experience is insufficient to draw conclusions regarding teratogenicity and prevention of adverse outcomes.

The synthesis of taurine‐conjugated bile acids and bile acid sulfates labeled with 14C or 3H in the taurine moiety

Studies of bile acid transport systems require radio-labeled taurine-conjugated bile acids with high specific activity. An established synthetic procedure was optimized to provide mild, fast, and effective conjugation of radio-labeled taurine with different types of bile acids, including those with labile 7α-hydroxy-3-oxo-Δ4 or 3β,7α-dihydroxy-Δ5 structures. Taurine labeled with 14C or 3H was reacted with excess bile acid anhydride formed from the tributylamine salt and ethylchloroformate (2/1 M/M) in aqueous dioxane for 15 min at room temperature. The yields were higher than 95% and less than 2% side products were formed. Bile acid sulfates were conjugated with 14C- or 3H- labeled taurine by using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline as the coupling reagent. The products were effectively purified by chromatography of the sodium salts on Sephadex LH-20. The yields of taurine-conjugated bile acid sulfates were 65–70%. © 1997 John Wiley & Sons, Ltd.