Crigler-Najjar type II syndrome may result from several types and combinations of mutations in the UGT1A1 gene.
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Amino Acid Substitution↗
Biomedical subjects
A Myara
Publications and source records attributed to A Myara.
Bifidobacterium animalis strain DN-173 010 shortens the colonic transit time in healthy women: a double-blind, randomized, controlled study.
BACKGROUND: A previous study has suggested that Bifidobacterium animalis DN-173 010 shortens the colonic transit time in women. AIM: To confirm this effect and to determine whether modifications of the faecal bacterial mass and/or faecal secondary bile salts may be the explanation. METHODS: A double-blind, cross-over study was performed. Thirty-six healthy women were studied in four consecutive 10-day periods. During periods 2 and 4, they ingested three 125 g cups per day of a fermented milk which was either a product containing B. animalis DN-173 010 or a control without bifidobacteria. Periods 1 and 3 were run-in and washout periods, respectively. The total and segmental colonic transit times were assessed using a pellet method. In 12 subjects, all stools were collected and analysed for pH, faecal weight, bacterial mass and bile acids. RESULTS: The total and sigmoid transit times were significantly shorter during dosing with B. animalis compared to the control period. The other transit times, faecal weight, pH, bacterial mass and bile acids were not significantly affected. CONCLUSIONS: B. animalis DN-173 010 shortens the colonic transit time in healthy women. This effect is not explained by modifications of the faecal bacterial mass or secondary bile acids.
Adult↗
[Evidence of daily stability of fasting serum bile acid levels in healthy volunteers].
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Adolescent↗
[Pediatric liver diseases].
Pediatric liver diseases usually manifest as jaundice, hepatomegaly, ascites or edema and can reflect a metabolic or nonmetabolic condition. In unconjugated hyperbilirubinemia, hemolysis can be distinguished from transient or inherited glucuronidation deficiencies. Jaundice with conjugated hyperbilirubinemia should suggest extrahepatic bile duct obstruction (requiring immediate surgery) or intrahepatic mechanical or metabolic cholestasis. Hepatomegaly or hepatocellular necrosis suggests diseases characterized by hepatocyte damage or overload. Appropriate investigations and a painstaking physical examination are essential to establish the diagnosis and to identify the cause, since immediate treatment is needed in some cases.
Cholestasis↗
[Biological examination in the diagnosis and monitoring of liver disease. Algorithms to aid the decision].
The goal of this article is to describe a rational step-wise strategy for using standard laboratory tests to obtain diagnostic orientation for a liver disorder; establish, support, or rule out a liver disorder; and monitor the course of treated and untreated patients with liver disorders.
Algorithms↗
Serum C24 bile acids in the developing human fetus.
The C24 bile acids (BA) in the serum of 22 healthy human fetuses between weeks 20 and 37 of gestation were determined by capillary GC-MS. Fetal blood samples were taken in utero from the umbilical cord monitored by echography. There was no correlation between total bile acids (TBA) and gestational age. The TBA concentration was 5.14 +/- 2.13 microM. Primary BA (cholic acid and chenodeoxycholic acid) were the main BA (66.78 +/- 13.47%) with chenodeoxycholic acid being the main one. There were low concentrations of secondary BA (deoxycholic acid and lithocholic acid) (10.28 +/- 7.85%), which formed by intestinal bacterial 7 alpha-dehydroxylation of primary BA in the adult, despite the germ-free gut. The tertiary BA (ursodeoxycholic acid) was also detected (12.06 +/- 9.64%). There was 6 alpha-hydroxylation of chenodeoxycholic acid and of lithocholic acid to produce hyocholic acid and hyodeoxycholic acid respectively. Two 1 beta-hydroxylated BA were detected at different times of gestation. Cholic acid was rarely found in the 6 alpha- and 1 beta-hydroxylated forms. These additional hydroxylations could help to protect the fetal liver against the accumulation of cytotoxic bile acids at a time when other detoxification pathways are poorly developed. Traces of unsaturated bile acids like 3 beta-hydroxy-5-cholenoic acid were detected, showing that 27-hydroxylation of cholesterol does occur.
Alkaline Phosphatase↗
Evidence for survival and metabolic activity of encapsulated xenogeneic hepatocytes transplanted without immunosuppression in Gunn rats.
BACKGROUND: Hepatocyte transplantation could be an alternative to whole organ transplantation to correct enzymatic disorders. To this end, it would be of major importance to use xenogeneic cells without immunosuppression. The aim of this study was to investigate the survival and metabolic activity of encapsulated xenogeneic hepatocytes in the absence of immunosuppression. For this purpose, we used Gunn rats genetically incapable of bilirubin conjugation. METHODS: Xenogeneic (from guinea pigs) and allogeneic (from Lewis rats) hepatocytes (2x10(7)) were isolated, macroencapsulated in hydrogel hollow fibers made with an acrylonitrile-sodium methallyl-sulfonate copolymer, and transplanted into the peritoneum of Gunn rats without any immunosuppression. Plasma bilirubin levels were evaluated weekly. Bilirubin conjugates in bile and cell morphology were studied after 5 and 12 weeks, respectively. RESULTS: In Gunn rats transplanted with xenogeneic hepatocytes, a significant decrease in the serum bilirubin level was observed between 3 and 9 weeks after transplantation when compared with controls transplanted with empty hollow fibers: it fell to 62% of the initial level at weeks 5-7 (P < 0.01). A comparable result was observed in Gunn rats transplanted with encapsulated allogeneic cells. Bilirubin conjugates were observed in bile samples of rats transplanted with encapsulated hepatocytes. After explantation, hollow fibers appeared intact with minimal fibrosis. Cell viability and hepatocyte morphology were preserved. CONCLUSIONS: These results indicate that macroencapsulated xenogeneic hepatocytes can survive and remain functional for more than 2 months when transplanted in vivo in the absence of any immunosuppression.
Acrylic Resins↗
Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis.
Progressive familial intrahepatic cholestasis (PFIC) is a lethal inherited childhood cholestasis of hepatocellular origin. Different subtypes of PFIC have been described according to serum gamma-glutamyl transpeptidase (GGT) activity. There is currently no effective medical therapy available for children with PFIC. We report on 39 patients with PFIC who received ursodeoxycholic acid (UDCA) orally (20-30 mg/kg b.w./day) for a period of 2 to 4 years. Group 1 (n = 26) consisted of children with normal GGT activity, and group 2 (n = 13) of children with high GGT activity. Within group 1, liver tests normalized in 11 children, improved in 5, and stabilized or worsened in 10. Within group 2, liver tests normalized in six children, improved in four, and stabilized or worsened in three. Improvement of parameters was associated with an enrichment of the circulating pool of bile acids with UDCA. Hepatosplenomegaly and pruritus disappeared or diminished in children in whom liver tests normalized. In nine of these children, liver tests worsened and normalized again after stopping and restarting UDCA. Liver histology assessed in four children after normalization of liver tests and 2 years of treatment showed a decrease in fibrosis. We conclude that UDCA should be considered in the initial therapeutic management of children with PFIC, because it appears effective in resolving or improving the liver function and the clinical status of a fair proportion of children. Chronic UDCA therapy might thus avoid the need for liver transplantation in some children with PFIC.
Alanine Transaminase↗
Severe CPT-11 toxicity in patients with Gilbert's syndrome: two case reports.
BACKGROUND: CPT-11 is hydrolyzed to its active metabolite SN-38, which is mainly eliminated through conjugation by hepatic uridine diphosphate glucuronosyl transferases (UGTs) to the glucuronide (SN-38G) derivative. Preclinical studies showed that UGT*1.1 is the isozyme responsible for SN-38 glucuronidation. Patients with Gilbert's syndrome have deficient UGT*1.1 activity, therefore may have an increased risk for related CPT-11 toxicity. PATIENTS AND METHODS: Two patients with metastatic colon cancer and Gilbert's syndrome were treated with CPT-11 based chemotherapy. CPT-11, SN-38 and SN-38G pharmacokinetics parameters were obtained. Serum bilirubin was analysed by alkaline methanolysis and HPLC. RESULTS: Both patients presented grade 4 neutropenia and/or diarrhea (NCI-CTC) in every treatment cycle. Biliary index (after Gupta et al) values were well above 4000. CONCLUSION: We present the first clinical evidence linking bilirubin glucuronidation status and CPT-11 related toxicity. The severe toxicity experienced by the two patients with Gilbert's syndrome treated with CPT-11 based chemotherapy has a genetic basis. Individuals with Gilbert's syndrome have an enhanced risk for CPT-11 toxicity. Unconjugated serum bilirubin could be predictive parameter of CPT-11 toxicity.
Bilirubin↗
Early changes in cutaneous bilirubin and serum bilirubin isomers during intensive phototherapy of jaundiced neonates with blue and green light.
We measured the changes in cutaneous bilirubin (Br) and serum Br photoisomers in two groups of 5 jaundiced newborn infants treated by intensive phototherapy (IP), one with blue light and the other with green light. Cutaneous Br was measured with a transcutaneous jaundice meter and photoisomers were measured by HPLC. Cutaneous Br decreased in the two groups as soon as IP began, and the skin was completely bleached within 3 h with blue light only. Rebound occurred which was more marked after blue light IP. The main serum photoproduct was the 4Z-15E isomer, which reached a steady-state level within 1 h in both groups, whereas the lumirubin and 4E-15Z Br concentrations were slightly higher after green light IP. These data indicate that blue light is more suitable for IP, although this is not clearly explained by the production of more lumirubin.
Bilirubin↗
The optimized use of gas chromatography-mass spectrometry and high performance liquid chromatography to analyse the serum bile acids of patients with metabolic cholestasis and peroxisomal disorders.
We have measured the bile acids in human serum as methyl ester-trimethylsilyl ethers by gas chromatography-mass spectrometry (GC-MS) using an electron ionization procedure. The overall method was validated and the detection limit (0.4 mumol/l), linearity (2-30 mumol/l), intra-day and inter-day precision, accuracy and recovery (96.2% for nor-23-deoxycholic acid as internal standard) were measured. Serum C24-bile acids profiles from 43 cholestatic patients were measured by GC-MS and by HPLC. The results obtained with the two methods were well correlated and the criteria for selecting either HPLC or GC-MS identified. The serum C24- and C27-bile acids and C29 dicarboxylic bile acid profiles for patients with generalized peroxisomal deficiencies, like Zellweger syndrome (n = 5), neonatal adrenoleukodystrophy (n = 1), infantile Refsum disease (n = 2) and from a single peroxisomal deficiency (n = 1) were also measured by GC-MS.
Adrenoleukodystrophy↗
Immunosuppressive effects of endotoxins and bile acids in vivo in the rat.
Cell-mediated immunity is impaired during cholestasis. The aim of this study was to evaluate in vivo the effects on this immune defect of high serum levels of endotoxin and bile acids. Heterotopic cardiac allotransplantations were performed in the DA/Lewis rat combination. Cholestasis, induced by ligation/section of the common bile duct, was responsible for a significant delay in the rejection time (16 +/- 0.5 vs. 7.1 +/- 0.4 days in controls, P < 0.01). Elimination of Gram-negative intestinal bacteria from cholestatic rats by a vancocin/colimycin/tobramycin (VCT) mixture induced a significant reduction in endotoxin levels and a reduction in rejection times (9.5 +/- 1.0 days, P < 0.01) that remained, however, significantly longer than those of controls (P < 0.05). Oral administration of chenodeoxycholic acid in non-cholestatic rats significantly enhanced the serum concentration of total bile acids (60.6 +/- 15.3 mumol L(-1) vs. 17.4 +/- 1.9 mol L(-1) in controls, P < 0.01) and postponed allograft rejection (10.7 +/- 0.6 days, P < 0.01 vs. controls). These data suggest that increased endotoxin level and serum bile acid concentration may play a role in the immunosuppressive effect of cholestasis.
Animals↗
Cyclosporin A-mediated cholestasis in patients with chronic hepatitis after heart transplantation.
Viral chronic hepatitis often occurs in heart transplant recipients receiving cyclosporin. This essential immunosuppressive drug may induce cholestasis. We investigated the effect of treatment with cyclosporin on serum conjugated bile acids in patients with chronic hepatitis developing after heart transplantation. Fifty-nine patients were studied: 17 with chronic hepatitis, 15 heart transplant patients with normal alanine aminotransferase activity, and 27 heart transplant patients with chronic hepatitis, the last two groups receiving cyclosporin. Hepatic biochemical tests and total bile acid concentration were determined on fasting blood samples. The individual glyco- and tauroconjugated bile acids were quantified by high-performance liquid chromatography and direct spectrometry. In patients taking cyclosporin the bilirubin concentration and the alkaline phosphatase activity were increased only when hepatitis was present, in association with a slight increase in cholic acid level (5.13 microM vs. 0.68 microM; P < 0.01). Conjugated lithocholate concentration was dramatically higher when hepatitis and immunosuppression with cyclosporin were associated (1.17 microM vs. 0.03 and 0.04 microM; P < 0.01). Chenodeoxycholate was the main circulating bile acid only in the heart transplant patients treated with cyclosporin but without hepatitis. These results suggest that the mechanisms which explain the cyclosporin-associated modifications of the bile acid pool are different according to the presence or absence of hepatitis. The occurrence of hepatitis in patients on cyclosporin led to an increase in serum lithocholate and primary bile acid concentrations. Further studies are required to assess the effect of ursodeoxycholic acid for this cholestasis.
Adult↗
Serum conjugated bile acid profile during intrahepatic cholestasis of pregnancy.
BACKGROUND/AIMS: Intrahepatic cholestasis of pregnancy is a specific liver disease of pregnancy of unknown cause. The serum bile acid profile has not been clearly described in this disease and the aim of this study was to investigate the serum conjugated bile acid profile. METHODS: Thirteen patients with intrahepatic cholestasis of pregnancy were studied. Ten patients had been treated with natural progestatin before the onset of pruritus. The glyco- and tauroconjugated bile acids were quantified by high-performance liquid chromatography and direct spectrometric detection at 199 nm. RESULTS: There was no difference between total bile acid concentrations measured by high-performance liquid chromatography (43.5 +/- 22.6 microM, mean +/- S.D.) or by an enzymatic procedure (43.4 +/- 24.6 microM), indicating a low concentration of free bile acids. Primary bile acids represented 88% of total bile acids, i.e. 72.7% for cholic acid and 15.3% for chenodeoxycholic acid. For both cholic and chenodeoxycholic acids glyco- and tauroconjugates were equivalent. Secondary bile acids represented 11.3% of total bile acids. Ursodeoxycholic acid was identified at very low concentrations in only three samples. CONCLUSIONS: We conclude that in intrahepatic cholestasis of pregnancy primary bile acids are very predominant.
Adult↗
[Recent aspects of liver biochemistry: from physiopathology to functional liver exploration].
The advent of liver transplantation and the availability of effective medical therapeutics have recently made possible treatments of chronic liver diseases. These improvements have evidenced new needs for evaluation of the treated patients. In this review, authors present new biochemical liver tests proposed for a better monitoring in the course of the disease, to assess the therapeutic response in clinical trials and to reduce the number of liver biopsies. The different aspects of this paper concern the evaluation of hepatic uptake and biliary elimination, cholestasis, jaundice, cellular injury, fibrosis and liver tumor.
Aspartate Aminotransferases↗
Genetic heterogeneity of Crigler-Najjar syndrome type I: a study of 14 cases.
Crigler-Najjar syndrome type I (CN-I) is an autosomal recessive condition characterized by severe unconjugated hyperbilirubinemia caused by the lack of bilirubin-UDP-glucuronosyltransferase (B-UGT) activity in the liver. Two B-UGTs are coded for by a gene complex (UGT1) that maps to chromosome 2q37 and that also encodes two phenol-UDP-glucuronosyltransferases. Here, we report eleven mutations (including nine novel mutations) of the B-UGT1 gene in a large series of 14 unrelated CN-I children of various geographic origins: France (seven patients: A401P, Q357X, W335X, A368T, 1223insG, A291V, K426E, K437X); Portugal (two patients: G308E); Tunisia (two patients; Q357R); Turkey (one patient: S381R); italy (two siblings: S381R). Interestingly, 6/14 mutant alleles carried by unrelated probands of French ancestry bore the A401P mutation, indicating a founder effect; this effect is probably also present in Portugal, Turkey, and Tunisia. Since mutations occurred in exons 2-5 shared by all mRNAs species of the gene, a combined deficiency of B-UGT and P-UGT was observed in the liver of five patients in whom these activities were measured. The present study confirms that CN-I is genetically heterogeneous and suggests that different founder effects are involved in Western Europe, the Middle East, and North Africa.
Crigler-Najjar Syndrome↗
[Reliability of conjugated bilirubin determination in the neonatal period].
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Bilirubin↗
Cholelithiasis in infancy: a study of 40 cases.
During a 17-year period, 40 infants less than 1 year of age were investigated for cholelithiasis; 32 infants were seen within the past 10 years. Seventeen of them had no recognizable predisposing factors. In 6 infants, gallbladder lithiasis was a fortuitous finding on a plain radiograph or sonogram with no signs of common bile duct obstruction; under conservative management, no complications of lithiasis were observed on follow-up of 3 infants and spontaneous resolution occurred in 2 others. In the remaining 34 infants with lithiasis of the common duct or cystic duct or both, the initial symptoms were cholestatic jaundice in 21, acholic stools in 8, sepsis in 4, and abdominal pain in 1. Ultrasonography, performed in 33 of them, showed dilation of the biliary tract in 28, and stones in the gallbladder in 13 and in the bile ducts in 10. Percutaneous transhepatic cholangiography or operative cholangiography in 26 infants showed stones in the bile ducts in 23. In 3 infants, no lithiasis was visible, suggesting the spontaneous elimination of stones. Treatment was initially surgical in 9 infants, but starting in 1981 interventional radiologic procedures were attempted in 15 infants and were successful in 12. Spontaneous resolution of cholelithiasis occurred in 10 other infants with cholestasis. Recurrence of biliary stones was observed in 3 infants only after a follow-up of 7 months to 10 years. These results suggest that common bile duct lithiasis should be considered among the causes of cholestatic jaundice in infancy, and that some of the gallbladder calculi found in older children may have resulted from a lithogenic process that occurred during fetal life or shortly after birth. Percutaneous cholangiography with biliary drainage appears to be an effective means of treatment of infants with common bile duct obstruction; surgery can then be restricted to a limited number of cases, especially those with associated strictures of the bile ducts.
Bile↗