High Concentrations Of Bile Acids Research Articles

Pituitary-dependent hyperadrenocorticism in a cockatoo

A 13-year-old female intact Moluccan cockatoo (Cacatua moluccensis) was evaluated because of coelomic distention, presumed to be secondary to an abdominal hernia. The patient also had a history of rapid weight gain and polyuria and polydipsia. Ultrasonography was used to confirm the existence of a pseudohernia that appeared to contain the small intestines, pancreas, and reproductive tract. Results of plasma biochemical analysis revealed hyperglycemia, hypophosphatemia, and high nonfasting bile acid concentrations and aspartate aminotransferase activity. A CBC revealed a relative heterophilia with a concomitant lymphopenia and mild monocytosis. Histologic evaluation of a liver biopsy specimen indicated chronic hepatic lipidosis. Despite a strong clinical suspicion of hyperadrenocorticism, ACTH stimulation test results were equivocal. The pseudohernia was strengthened with a prolene mesh. Despite ongoing medical and surgical care, the patient developed complications associated with the herniorrhaphy and was euthanatized. The clinical suspicion of hyperadrenocorticism was confirmed on the basis of histologic evaluation of the pituitary gland by use of special stains. To our knowledge, pituitary-dependent hyperadrenocorticism has not been previously confirmed in Psittaciformes. The condition should be considered in birds with clinical signs consistent with those observed in mammals. For the cockatoo of this report, ACTH stimulation test results were equivocal and additional diagnostic tests should be developed for avian patients.

Bile Acids Promote the Expression of Hepatitis C Virus in Replicon-Harboring Cells

Hepatitis C virus (HCV) is a cause of chronic liver disease, with more than 170 million persistently infected individuals worldwide. Although the combination therapy of alpha interferon (IFN-alpha) and ribavirin is effective for chronic HCV infection, around half of all patients infected with HCV genotype 1 fail to show sustained virologic responses and remain chronically infected. Previously, we demonstrated that bile acids were essential for growth of porcine enteric calicivirus in cell culture in association with down-regulation of IFN responses. Because hepatocytes are exposed to high concentrations of bile acids in the liver, we hypothesized that bile acids have similar effects on HCV replication. We incubated HCV replicon-harboring cells (genotype 1b, Con1) in the presence of various bile acids and monitored the expression of HCV RNA and protein (NS5B). The addition of an individual bile acid (deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, or glycochenodeoxycholic acid) in the medium increased the levels of HCV RNA and proteins up to fivefold at 48 h of incubation. An antagonist of bile acid receptor farnesoid X receptor (FXR), Z-guggulsterone, reduced the bile acid-mediated increase of HCV RNA. When IFN (alpha or gamma) and each bile acid were incubated together, we observed that bile acid significantly reduced the anti-HCV effect of IFN. These results indicated that bile acids are factors in the failure of IFN treatment for certain patients infected with HCV genotype 1. Our finding may also contribute to the establishment of better regimens for treatment of chronic HCV infections by including agents altering the bile acid-mediated FXR pathway.

Gastric duodenal metaplasia in duodenal adenomas

Backgound: In cases of known aetiology, gastric duodenal metaplasia (GMD) is a reversible lesion. In cases of unknown aetiology, the fate of GMD remains elusive. GMD was recently found in...

Bile acid interactions with cholangiocytes

Cholangiocytes are exposed to high concentrations of bile acids at their apical membrane. A selective transporter for bile acids, the Apical Sodium Bile Acid Cotransporter (ASBT) (also referred to as Ibat; gene name Slc10a2) is localized on the cholangiocyte apical membrane. On the basolateral membrane, four transport systems have been identified (t-ASBT, multidrug resistance (MDR)3, an unidentified anion exchanger system and organic solute transporter (Ost) heteromeric transporter, Ostalpha-Ostbeta. Together, these transporters unidirectionally move bile acids from ductal bile to the circulation. Bile acids absorbed by cholangiocytes recycle via the peribiliary plexus back to hepatocytes for re-secretion into bile. This recycling of bile acids between hepatocytes and cholangiocytes is referred to as the cholehepatic shunt pathway. Recent studies suggest that the cholehepatic shunt pathway may contribute in overall hepatobiliary transport of bile acids and to the adaptation to chronic cholestasis due to extrahepatic obstruction. ASBT is acutely regulated by an adenosine 3', 5'-monophosphate (cAMP)-dependent translocation to the apical membrane and by phosphorylation-dependent ubiquitination and proteasome degradation. ASBT is chronically regulated by changes in gene expression in response to biliary bile acid concentration and inflammatory cytokines. Another potential function of cholangiocyte ASBT is to allow cholangiocytes to sample biliary bile acids in order to activate intracellular signaling pathways. Bile acids trigger changes in intracellular calcium, protein kinase C (PKC), phosphoinositide 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and extracellular signal-regulated protein kinase (ERK) intracellular signals. Bile acids significantly alter cholangiocyte secretion, proliferation and survival. Different bile acids have differential effects on cholangiocyte intracellular signals, and in some instances trigger opposing effects on cholangiocyte secretion, proliferation and survival. Based upon these concepts and observations, the cholangiocyte has been proposed to be the principle target cell for bile acids in the liver.

α-Crystallin Is a Target Gene of the Farnesoid X-activated Receptor in Human Livers

Alpha-crystallins comprise 35% of soluble proteins in the ocular lens and possess chaperone-like functions. Furthermore, the alphaA subunit (alphaA-crystallin) of alpha crystallin is thought to be "lens-specific" as only very low levels of expression were detected in a few non-lenticular tissues. Here we report that human alphaA-crystallin is expressed in human livers and is regulated by farnesoid X-activated receptor (FXR) in response to FXR agonists. AlphaA-crystallin was identified in a microarray screen as one of the most highly induced genes after treatment of HepG2 cells with the synthetic FXR ligand GW4064. Northern blot and quantitative real-time PCR analyses confirmed that alphaA-crystallin expression was induced in HepG2-derived cell lines and human primary hepatocytes and hepatic stellate cells in response to either natural or synthetic FXR ligands. Transient transfection studies and electrophoretic mobility shift assays revealed a functional FXR response element located in intron 1 of the human alphaA-crystallin gene. Importantly, immunohistochemical staining of human liver sections showed increased alphaA-crystallin expression in cholangiocytes and hepatocytes. As a member of the small heat shock protein family possessing chaperone-like activity, alphaA-crystallin may be involved in protection of hepatocytes from the toxic effects of high concentrations of bile acids, as would occur in disease states such as cholestasis.

Acquired Portosystemic Shunting in 2 Cats Secondary to Congenital Hepatic Fibrosis

Case 1. A 2-year-old female crossbred cat was referred to Utrecht University Companion Animal Clinic with a 2-month history of episodic vomiting, constipation, decreased appetite, apathy, and decreased activity. The vomiting was treated successfully with cisapride (0.25 mg/kg PO q8h). Physical examination disclosed no abnormalities and a full CBC and serum biochemistry tests were performed. These evaluations showed a leukocytosis (18.6 3 109/L; reference range, 4.3–16.2 3 109/L), increased bile acid concentration (132 mmol/L [53.88 mg/mL]; reference range, 1– 13 mmol/L) and a low BUN concentration (3.6 mmol/L [10.08 mg/dL]; reference range, 6.1–12.8 mmol/L). The combination of high bile-acid concentration and low BUN concentration indicated possible portosystemic shunting. Fasting venous blood ammonia concentration was measured and was increased (196 mmol/L [354 mg/dL]; reference range, ,50 mmol/L). Abdominal ultrasonography was performed for the further diagnosis and identification of portosystemic shunting. Abdominal ultrasonography revealed several small cortical cysts in both kidneys compatible with polycystic kidney disease (PKD). Otherwise, the size and structure of both kidneys and the liver were considered normal. An anomalous tortuous vessel with hepatofugal flow was seen originating from the portal vein in the region where the splenic vein enters the trunk of the portal vein. It was not possible to follow the shunting vessel to its termination. The direction of blood flow was hepatofugal in the portal vein cranial to the origin of the anomalous vein and was hepatopetal caudal to it. The left ovarian vein was dilated. A very small amount of free abdominal fluid was seen. The spleen was ultrasonographically normal. The tortuous anomalous vein was suspected to be an acquired portosystemic collateral, therefore ultrasound-guided core biopsiesa of the liver were taken. The liver biopsies were processed routinely and stained with hematoxylin-eosin, Von Gieson, and a reticulin stain according to the method of Gordon and Sweet. Histological

Increased GADD gene expression in human colon epithelial cells exposed to deoxycholate.

The colonic epithelium is often exposed to high concentrations of secondary bile acids, which stresses the epithelial cells, leading potentially to activation of stress-response genes. To examine this possibility in vitro, the purpose of this study was to determine if expression of certain growth arrest and DNA damage-inducible genes (GADD) is upregulated in human colonic epithelial cells exposed to deoxycholate (DOC). DNA macroarray screening of a small cluster of stress/apoptosis-related genes in DOC-treated HCT-116 colonocytes revealed clearly higher expression of only GADD45, which was confirmed by gene-specific relative RT-PCR analysis. Subsequently, it was found that DOC also increased GADD34 mRNA expression. However, mRNA expression of GADD153 was increased most markedly in DOC-treated HCT-116 colonocytes, which express wild-type p53. However, the upregulation of GADD34, GADD45, and GADD153 mRNA expression apparently did not require p53, based on the finding that DOC increased expression of all three GADD genes in HCT-15 colonocytes, which express mutant p53. In further studying GADD153 in particular, the effect of DOC on GADD153 mRNA was prevented by actinomycin-D (Act-D), but not by antioxidants or MAPK inhibitors. DOC also caused GADD153 protein to be expressed in close parallel with increased GADD153 mRNA expression. Induction of GADD153 protein by DOC was prevented by either anisomycin or cycloheximide. These findings suggest that DOC-induced upregulation of GADD153 mRNA expression occurred at the level of transcription without involving reactive oxygen species and MAPK signaling, and that the expression of GADD153 protein was due also to translation of pre-existing, and not just newly synthesized, mRNA.

Intestinal steroids in rats are influenced by the structural parameters of pectin

We investigated the effects of pectin with different degrees of methylation (34.5, 70.8, and 92.6%, respectively) on the composition and concentration of intestinal and fecal bile acids and neutral sterols in conventional and germfree rats. Diets containing 6.5% pectin (galacturonan) were given for 3 weeks. High concentrations of free and secondary bile acids appeared in cecum and colon of conventional rats. With increasing degree of methylation, more bile acids were transported into lower parts of intestinal tract and excreted whereas the proportion of secondary bile acids decreased. In contrast, the composition of bile acids in intestinal contents and feces was relatively unchanged in germfree rats. Exclusively cholesterol was found as a neutral sterol in germfree rats. Coprostanol appeared in cecum of conventional rats and additionally coprostanone in colon. Amounts of neutral sterols increased with increasing degree of methylation of pectin. Additionally, concentrations of bile acids in plasma decreased if the pectin-containing diets were given. Besides the degree of methylation, the molecular weight of pectin used in the diets influenced concentration and composition of intestinal and fecal steroids in rats.

Duodenogastric Bile Reflux Is Common in Cystic Fibrosis

ABSTRACTBackgroundPatients with cystic fibrosis (CF) have a high incidence of gastroesophageal reflux disease, but few cases of mucosal injury are reported. Duodenogastric reflux has not been studied in CF but has been suggested to have a pathogenic role in producing alkaline injury to the esophageal mucosa. The aim of this study was to analyze the presence of duodenogastric reflux in patients with CF.Patients and MethodsTen patients with CF and 7 healthy volunteers participated in the study. Gastroduodenal manometry and intragastric perfusion were performed in all subjects. Gastric perfusate was analyzed for bilirubin and bile acids. Only patients and controls exhibiting normal migrating motor complexes were evaluated.ResultsEight patients with CF had normal motility recordings and had significantly higher gastric bilirubin levels compared with healthy subjects (P = 0.003). The bilirubin concentration was associated with bile acid regurgitation in five patients with CF. All bile acids were conjugated with a high glycine/taurine ratio and low levels of secondary bile acids. Small amounts of keto bile acids were found in two patients.ConclusionThe patients with CF had an increased incidence of duodenogastric reflux compared with healthy subjects. The bile acid composition was typical for CF with low levels of secondary bile acids. Although high bile acid concentration was found in the duodenogastric reflux in most patients with CF, the less toxic profile of the bile acids might possibly contribute to the low frequency of Barrett's esophagus in CF.

Duodenogastric bile reflux is common in cystic fibrosis.

Patients with cystic fibrosis (CF) have a high incidence of gastroesophageal reflux disease, but few cases of mucosal injury are reported. Duodenogastric reflux has not been studied in CF but has been suggested to have a pathogenic role in producing alkaline injury to the esophageal mucosa. The aim of this study was to analyze the presence of duodenogastric reflux in patients with CF. Ten patients with CF and 7 healthy volunteers participated in the study. Gastroduodenal manometry and intragastric perfusion were performed in all subjects. Gastric perfusate was analyzed for bilirubin and bile acids. Only patients and controls exhibiting normal migrating motor complexes were evaluated. Eight patients with CF had normal motility recordings and had significantly higher gastric bilirubin levels compared with healthy subjects (P = 0.003). The bilirubin concentration was associated with bile acid regurgitation in five patients with CF. All bile acids were conjugated with a high glycine/taurine ratio and low levels of secondary bile acids. Small amounts of keto bile acids were found in two patients. The patients with CF had an increased incidence of duodenogastric reflux compared with healthy subjects. The bile acid composition was typical for CF with low levels of secondary bile acids. Although high bile acid concentration was found in the duodenogastric reflux in most patients with CF, the less toxic profile of the bile acids might possibly contribute to the low frequency of Barrett's esophagus in CF.

High serum and urinary unconjugated bile acid concentrations are associated with homozygous mutation in bile acid coenzyme A: Amino acid N-acyltransferase (BAAT)

The final step in bile acid synthesis involves conjugation with the amino acids glycine and taurine. Conjugated bile acids have low pKa values and self-associate efficiently to form micelles and facilitate fat absorption. Recently, we discovered two Amish children, aged 2 and 5, with pruritus, fat malabsorption and vitamin K coagulopathy and high serum bile acid concentrations. Both showed homozygous mutation in BAAT, an enzyme that conjugates bile acids with glycine and taurine. Total serum bile acid concentrations were elevated (53.05 and 9.55 mg/ml, respectively; 1.4 mg/ml in control children, and 53.4 and 45.6 mg/ml after treatment with 300 mg/day ursodeoxycholic acid). No amino acid conjugates were found. in contrast, a cholestaric pauent with BRIC (due to a mutation in FIC1) showed elevated serum bile acid concentrations (151 mg/ml) that were almost entirely (96%) amino acid conjugated. Urinary bile acid outputs in the Amish patients were 30.3 and 17.3 mg/ml, respectively, with 18 and 34% unconjugated and the rest as glucuronide/sulfates. The patient with BRIC had 192.1 mg/ml bile acids in the anne, but more than 50% were glycine and taurine conjugated. These resuhs suggest that the bile salt export pump has a requirement for amino acid conjugated bile acids in order to transport them from liver into the bile. Patients that are homozygous for BAAT mutation show high levels of serum unconjugated bile acids and increased urinary excretion of bile acids, composed chiefly of unconjugated and glucuronidated/sulfated bile acids, in contrast, patients with BRIC also show elevated serum and urinary bile acids, but these are predominantly conjugated with glycine and taurine. The presence of unconjugated bile acids leads to their backup and overflow into the serum and excretion into urine. Clinically, elevated serum unconjugated bile acids are associated with pruritus while the deficiency of amino acid conjugated bile acids in the intestine results in tat malabsorption and vitamin K coagulopathy.

Cord liver function and bile acids in actively managed obstetric cholestasis (OC) are not abnormal

Obstetric cholestasis (OC) is associated with increased fetal morbidity and mortality. Active management (delivery by 38 weeks) may reduce this. Poor fetal outcome may be linked to high concentrations of bile acids in the maternal or fetal circulation. This study compared maternal and fetal liver function in a group of actively managed women with OC. Matched cord and maternal (day of delivery) serum was obtained from women with: (i) OC [n = 43, 16 ursodeoxycholic acid (UDCA)], (ii) pruritus gravidarum (PG, n = 28) and (iii) healthy controls (n = 9). Women with OC were delivered by 38 weeks; there were no stillbirths. Bile acids, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutathione S-transferase alpha 1-1 (GSTA1-1) were measured. Maternal liver function parameters were raised in OC and not reduced significantly by UDCA treatment (P = 0.748, 95% CI= 0.934–1.099). In OC, cord serum liver function values were no different to controls and PG. Cord serum ALT, AST and GSTA1-1 in OC were lower than the maternal serum. Cord serum bile acid concentrations (µm) in the OC group were 16.97 ± 1.13 and in maternal blood 18.57 ± 3.20 compared to 12.89 ± 1.00 and 7.24 ± 1.2 in PG and 15.99 ± 1.95 and 6.76 ± 0.96 in controls, respectively.

Development and molecular characterization of HCT-116 cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate.

Evidence from live cell bioassays shows that the flat mucosa from patients with colon cancer exhibits resistance to bile salt-induced apoptosis. Three independent cell lines derived from the colonic epithelial cell line HCT-116 were selected for resistance to bile salt-induced apoptosis. These cell lines were developed as tissue culture models of apoptosis resistance. Selection was carried out for resistance to apoptosis induced by sodium deoxycholate (NaDOC), the bile salt found in highest concentrations in human fecal water. Cultures of HCT-116 cells were serially passaged in the presence of increasing concentrations of NaDOC. The resulting apoptosis resistant cells were able to grow at concentrations of NaDOC (0.5 mM) that cause apoptosis in a few hours in unselected HCT-116 cells. These cells were then analyzed for changes in gene expression. Observations from cDNA microarray, 2-D gel electrophoresis/MALDI-mass spectroscopy, and confocal microscopy of immunofluorescently stained preparations indicated underexpression or overexpression of numerous genes at either the protein or mRNA level. Genes that may play a role in apoptosis and early stage carcinogenesis have been identified as upregulated in these cell lines, including Grp78, Bcl-2, NF-kappaB(p50), NF-kappaB(p65), thioredoxin peroxidase (peroxiredoxin) 2, peroxiredoxin 4, maspin, guanylate cyclase activating protein-1, PKCzeta, EGFR, Ras family members, PKA, PI(4,5)K, TRAF2 and BIRC1 (IAP protein). Under-expressed mRNAs included BNIP3, caspase-6, caspase-3 and serine protease 11. NF-kappaB was constitutively activated in all three resistant cell lines, and was responsible, in part, for the observed apoptosis resistance, determined using antisense oligonucleotide strategies. Molecular and cellular analyses of these resistant cell lines has suggested potential mechanisms by which apoptosis resistance may develop in the colonic epithelium in response to high concentrations of hydrophobic bile acids that are associated with a Western-style diet. These analyses provide the rationale for the development of hypothesis-driven intermediate biomarkers to assess colon cancer risk on an individual basis.

Intractable diarrhea after liver transplantation for Byler's disease: successful treatment with bile adsorptive resin.

Intractable diarrhea and prolonged growth retardation after liver transplantation for Byler's disease are serious complications limiting the ultimate outcome of liver transplantation for this disease. However, details of these complications have not been documented thoroughly. Six patients with Byler's disease developed intractable diarrhea after living donor liver transplantation. Because of high bile acid concentrations in stool, four patients were treated with bile acid adsorptive resin for bile acid diarrhea, and all showed improved bowel movements. Four of these patients who were followed up for 1 year registered a significant height gain. Also, the cause of postoperative diarrhea and growth retardation in patients with Byler's disease after liver transplantation is discussed.

Portovenogram findings in cases of elevated bile acid concentrations following correction of portosystemic shunts.

The case records of 36 cats and dogs undergoing surgical correction of a single extrahepatic portosystemic shunt were reviewed. In 12 animals, the shunt was fully ligated during the first surgical procedure, while, in the remaining 24, the shunting vessel could only be partially ligated. Assessment of serum bile acid concentrations demonstrated complete shunt occlusion in 15 of these latter 24 animals (63 per cent) between one and six months postoperatively. Ten animals (28 per cent) had persistently high serum bile acid concentrations postoperatively. Portovenogram findings in these individuals revealed six that demonstrated shunting solely through the original vessel; In five of these, full shunt attenuation was achieved at second surgery. Further shunt manipulation was not possible in the sixth case due to extensive adhesion formation. In the remaining four animals with raised bile acid concentrations, the portovenogram demonstrated shunting through the original vessel as well as the development of multiple acquired shunts.

Fetal Bile Acid Metabolism: Analysis of Urinary 3β-Monohydroxy-Δ5 Bile Acid in Preterm Infants

To elucidate the urinary concentration of total bile acids after birth and the profile of the usual and unusual urinary bile acids, especially 3β-hydroxy-5-cholen-24-oic acid (Δ⁵-3β-ol), we measured the concentrations of 13 bile acids in the urine from preterm infants vs. full-term controls by gas chromatography-mass spectrometry. The urinary concentration of total bile acids in early preterm infants below 32 weeks of gestational age significantly exceeded that of the late preterm and full-term infants (p < 0.0005). The major urinary bile acids in early preterm infants were cholic acid, 1β,3α,7α,12α-tetrahydroxy-5β-cholan-24-oic acid and Δ⁵-3β-ol. In conclusion, the high urinary concentrations of total bile acids in preterm infants may be due to an overproduction, or more likely to a low hepatic bile acid clearance. An alternative fetal pathway, the acidic pathway, may be a major route of bile acid biosynthesis in preterm infants.

Iatrogenic copper deficiency associated with long-term copper chelation for treatment of copper storage disease in a Bedlington Terrier

A 9-year-old Bedlington Terrier was evaluated because of weight loss, inappetence, and hematemesis. Copper storage disease had been diagnosed previously on the basis of high hepatic copper concentration. Treatment had included dietary copper restriction and administration of trientine for chelation of copper. A CBC revealed microcytic hypochromic anemia. High serum activities of liver enzymes, high bile acid concentrations, and low BUN and albumin concentrations were detected. Vomiting resolved temporarily with treatment, but the clinicopathologic abnormalities persisted. Results of transcolonic portal scintigraphy suggested an abnormal shunt fraction. Results of liver biopsy and copper quantification revealed glycogen accumulation and extremely low hepatic copper concentration. Serum and hair copper concentrations were also low. Chelation and dietary copper restriction were tapered and discontinued. Clinical signs and all clinicopathologic abnormalities improved during a period of several months.

Duodenogastric reflux is associated with antral metaplastic gastritis

Background: It has long been suspected that duodenogastric reflux plays a role in the pathogenesis of intestinal metaplasia (IM), although recent studies have demonstrated a close association between Helicobacter pylori infection and gastroduodenal diseases, including IM. The objective of this study was to investigate the relation among IM and duodenogastric reflux, H pylori infection, and smoking. Methods: Subjects with “marked” characteristics of IM, all with extensive prepyloric distribution at endoscopy that was confirmed histologically, were studied as an IM group (27 men, 26 women; mean age, 64 years). A control group was comprised by subjects without characteristics of IM (29 men, 28 women; mean age, 63 years). Fasting pH, total bile acid concentration, and ammonia concentration were measured in the gastric juice of all participants. Histologic examination endoscopic biopsy specimens were evaluated histologically. H pylori infection was determined by serum antibody and urease testing, and by histology. Serum gastrin and pepsinogen concentrations, and gastric emptying time were measured. Dietary, drinking, and smoking habits were recorded. Comparisons were made between groups and analyzed statistically. Results: The pH and total bile acid concentrations were significantly higher in the IM group than the control group (p < 0.01). No significant difference in H pylori infection was found between the IM and control group. Smoking was associated with IM (odds ratio [OR], 15.74; 95% CI, 3.96 to 62.50). Conclusions: A high pH and total bile acid concentration and smoking were associated with “marked” IM, suggesting that these factors may play a role in the development of IM. (Gastrointest Endosc 2001;53:53-9.)

Advances in familial and congenital cholestatic diseases. Clinical and diagnostic implications

Recent progress in liver cell biology and molecular genetics revealed that a number of familial and congenital cholestatic disorders are caused by mutations in genes coding for hepatobiliary-transporter or for signalling proteins involved in morphogenesis. The status of the field is reviewed in the light of its impact on current diagnostic and clinical practice. The heterogeneous progressive familial intrahepatic cholestasis can now be separated into different genetic diseases. FIC1-defective progressive familial intrahepatic cholestasis (previously Byler disease) is determined by mutations in the FIC1 gene, coding for P-type ATPases of unknown physiological function, while a second form (bile salt export pump defective progressive familial intrahepatic cholestatic) is caused by a defective function of the canalicular bile salt export pump. Furthermore, a group of progressive familial intrahepatic cholestasis patients with high serum gamma glutamyltranspeptidase have mutations in the gene (PGY3) coding for the MDR3 protein, a canalicular ATP-dependent phopshatidylcholine translocator. Recurrent intrahepatic cholestasis (previously benign recurrent cholestasis), is also linked to specific mutations in the FIC1 gene. Finally, in Alagille syndrome, mutations in the JAG1 gene cause deficiency Jagged 1, a ligand for Notch 1, a receptor determining cell fate during early embryogenesis. Diagnosis of Alagille syndrome, a condition that should be suspected in all patients with unexplained cholestasis, will thus be confirmed by genetic analysis for mutations of JAG1. In children with cholestasis and low serum bile acid levels, an inborn error of bile acid synthesis should be excluded by urinary bile acid analysis by means of fast atom bombardment-ionization mass-spectrometry. In contrast, in children with cholestasis and high serum bile acid concentrations, a high serum gamma glutamyltranspeptidase value would indicate MDR3 deficiency, which should be excluded through biliary phospholipid determination and genetic analysis of PGY3 gene. Finally, in those children with cholestasis, high serum bile acids and low gamma glutamyltranspeptidase activity, analysis of mutation in FIC1 and bile salt export pump genes may lead to the diagnosis of progressive familial intrahepatic cholestasis either from bile salt export pump or FIC1 deficiency.

The continuing importance of bile acids in liver and intestinal disease.

Bile acids, the water-soluble, amphipathic end products of cholesterol metabolism, are involved in liver, biliary, and intestinal disease. Formed in the liver, bile acids are absorbed actively from the small intestine, with each molecule undergoing multiple enterohepatic circulations before being excreted. After their synthesis from cholesterol, bile acids are conjugated with glycine or taurine, a process that makes them impermeable to cell membranes and permits high concentrations to persist in bile and intestinal content. The relation between the chemical structure and the multiple physiological functions of bile acids is reviewed. Bile acids induce biliary lipid secretion and solubilize cholesterol in bile, promoting its elimination. In the small intestine, bile acids solubilize dietary lipids promoting their absorption. Bile acids are cytotoxic when present in abnormally high concentrations. This may occur intracellularly, as occurs in the hepatocyte in cholestasis, or extracellularly, as occurs in the colon in patients with bile acid malabsorption. Disturbances in bile acid metabolism can be caused by (1) defective biosynthesis from cholesterol or defective conjugation, (2) defective membrane transport in the hepatocyte or ileal enterocyte, (3) defective transport between organs or biliary diversion, and (4) increased bacterial degradation during enterohepatic cycling. Bile acid therapy involves bile acid replacement in deficiency states or bile acid displacement by ursodeoxycholic acid, a noncytotoxic bile acid. In cholestatic liver disease, administration of ursodeoxycholic acid decreases hepatocyte injury by retained bile acids, improving liver tests, and slowing disease progression. Bile acid malabsorption may lead to high concentrations of bile acids in the colon and impaired colonic mucosal function; bile acid sequestrants provide symptomatic benefit for diarrhea. A knowledge of bile acid physiology and the perturbations of bile acid metabolism in liver and digestive disease should be useful for the internist.