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Results for “Cholestasis, Intrahepatic”

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PubMed1991

Serum copper in intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy is characterised by clinical and biochemical fluctuations and further diagnostic tools are required. The aim of this study was to investigate serum copper and copper oxidase during the course of intrahepatic cholestasis of pregnancy (ICP). Twenty eight ICP patients and twenty healty pregnant women were included. Routine liver tests, fasting serum bile acids (FSBA), serum copper and serum copper oxidase were measured. In ICP, serum copper was significantly higher than in controls (274 +/- 49 micrograms/dl vs 176 +/- 34 micrograms/dl, p less than 0.001). Copper oxidase rose in ICP (78 +/- 15 mg/dl) different than healthy pregnant women (64 +/- 8 mg/dl); p less than 0.02. In contrast to marked oscillations in FSBA, serum copper remained elevated during the follow-up with only minor fluctuations and no correlation was demonstrated between changes in FSBA and those noted in serum copper (r:0.17, NS). At labor, a significant rise in serum copper was demonstrated in ICP (from 251 +/- 50 micrograms/dl to 297 +/- 55 micrograms/dl, p less than 0.01) and in controls (from 168 +/- 34 to 192 +/- 42 micrograms/dl, p less than 0.01). This increment in serum copper was associated with a peak in serum copper oxidase activity. Serum copper and copper oxidase are elevated in ICP and may be considered as adjuvant diagnostic tests. Disturbances in copper metabolism reported in this study are consistent with the hypothesis that normal pregnancy is associated with a mild cholestasis effect and ICP represent a form of improperly controlled response.

Adolescent↗

PubMed1996

Locus heterogeneity in progressive familial intrahepatic cholestasis.

Progressive familial intrahepatic cholestasis (PFIC or Byler disease) is a rare autosomal recessive form of severe and fatal cholestatic liver disease. A locus for PFIC has recently been mapped to chromosome 18q21-q22 in the original Byler pedigree. This region harbours the locus for a related phenotype, benign recurrent intrahepatic cholestasis (BRIC), suggesting that these traits are allelic. Linkage analysis was undertaken in five consanguineous PFIC pedigrees from Saudi Arabia using marker loci (D18S69, D18S41, D18S64, D18S38, D18S42, D18S55, D18S68, and D18S61) which span the Byler disease/BRIC region on 18q21-q22. In this family set the disease locus was excluded from this region, showing that locus heterogeneity exists for the PFIC phenotype.

Cholestasis, Intrahepatic↗

PubMed2005

Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic condition that may affect women during the third trimester of pregnancy. Symptoms experienced by these women generally resolve spontaneously following delivery, but prior to delivery the fetus is at increased risk of intrauterine distress and sudden intrauterine death. The genetic etiology of most cases of ICP is unknown, although heterozygous carriers of mutations causing progressive familial intrahepatic cholestasis (PFIC) diseases may experience ICP. When examining linkage to known cholestasis genes, affected members of four Finnish ICP families shared haplotypes around ATP8B1, the gene responsible for PFIC1. This gene was subsequently screened in 176 familial and sporadic ICP patients. A total of 17 sequence changes were detected, five exonic and 12 intronic. No intronic change was associated with ICP in sporadic cases. Four intronic changes segregated with ICP in three families, a different change in each of two families and three changes in another family, although the significance of this is currently unknown. Three exonic changes were nonsynonymous, one (in exon 23) is probably a polymorphism while two predict novel amino-acid replacements (N45T and K203R). These changes, in exons 2 and 7, were detected in one individual each, and may have predisposed these individuals to ICP. In conclusion, although the exon 2 and 7 changes may have functioned as risk alleles, ATP8B1 is probably not a major gene contributing to the occurrence of ICP.

Adenosine Triphosphatases↗

PubMed2004

[Intrahepatic cholestasis of pregnancy].

Intrahepatic cholestasis of pregnancy is a rare disorder of unknown origin with a symptomatically distressing maternal course with pruritus and icterus as the chief complaints. The disease poses little medical risk to the mother, but poses significantly risk to the fetus of perinatal mortality, preterm delivery, fetal distress, and meconium staining. The authors demonstrate the epidemiology, pathomechanism, prognosis of the disease. The clinical picture, the possibilities of diagnostics and differential diagnostics as well as the therapy of the disease are particularly discussed. On the basis of the data in the literature and on own observations the authors recommend the ursodeoxycholic acid treatment in the management of intrahepatic cholestasis of pregnancy.

Cholagogues and Choleretics↗

PubMed1995

Autosomal-recessive inheritance of benign recurrent intrahepatic cholestasis.

Benign recurrent intrahepatic cholestasis (BRIC) is a rare disorder characterized by recurrent episodes of cholestasis without permanent liver damage. Familial and sporadic cases have been described. Based on existing evidence, both autosomal-recessive and autosomal-dominant inheritance have been considered. We describe a large Dutch pedigree with 4 patients, strongly suggesting autosomal-recessive inheritance.

Cholestasis, Intrahepatic↗

PubMed2006

Nasobiliary drainage induces long-lasting remission in benign recurrent intrahepatic cholestasis.

Benign recurrent intrahepatic cholestasis (BRIC) is characterized by episodic cholestasis and pruritus without anatomical obstruction. Effective medical treatment is not available. We report complete and long-lasting disappearance of pruritus and normalization of serum bile salt concentrations in cholestatic BRIC patients within 24 hours after endoscopic nasobiliary drainage (NBD). Relative amounts of phospholipids and bile salts in bile collected during NBD appeared to be normal, but phospholipids other than phosphatidylcholine (especially sphingomyelin) were increased. In conclusion, we propose that temporary endoscopic nasobiliary drainage should be considered in cholestatic BRIC patients.

Adult↗

PubMed1997

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↗

PubMed2005

Benign recurrent intrahepatic cholestasis.

Benign recurrent intrahepatic cholestasis (BRIC) is a rare cause of cholestasis in children. The disease may start in infancy or early childhood. Jaundice persists or recurs throughout life but does not lead to chronic liver disease or cirrhosis. Treatment is mostly symptomatic. The condition has not been reported in Indian children. We report an interesting case of BRIC in a 9-year-old boy who had recurrent episodes of jaundice since when he was 1 yr old.

Child↗

PubMed2006

A new ABCB11 mutation in two Italian children with familial intrahepatic cholestasis.

Progressive familial intrahepatic cholestasis (PFIC) syndromes are characterized by defects in transporters of conjugated bile acids into the bile canaliculus. Three genes (ATP8B1, ABCB11, ABCB4) are associated with the different forms, but no easy genotype-phenotype correlations help in the prioritization for gene testing. We developed a denaturing high-performance liquid chromatography (DHPLC) method to screen patients with PFIC for mutations in ATP8B1 and ABCB11, and combined genetic analyses with immunolabeling in liver for the ABCB11 and ABCB4 gene products. Used in combination with commercially available antibodies on liver specimens, the DHPLC approach allowed us to confirm the clinical diagnosis in two Italian sisters and to identify a novel missesnse mutation in ABCB11. Our findings are expected to facilitate detection of the molecular cause of PFIC in affected families.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Living related liver transplantation in 13 cases of progressive familial intrahepatic cholestasis.

Progressive familial intrahepatic cholestasis (PFIC) is a heterogenous group of disorders with various etiologies. Recent molecular and genetic studies have categorized the spectrum of types. Liver transplantation is a curative modality of treatment in this disease. We report our experience with 13 patients with PFIC who underwent living related liver transplantation. The follow-up periods ranged from 12 to 50 months. Two children died at 1 and 2 years posttransplantation, leading to a decrease in survival rate from 100% in the first year to 84.6%.

Child, Preschool↗

PubMed1998

Intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a disease of the third trimester of pregnancy involving pruritus and elevated bile acid levels. Its pathogenesis likely involves a genetic hypersensitivity to estrogen. Once thought to be benign for both mother and fetus, ICP has been associated with increased rates of fetal morbidity and mortality and an increased risk of maternal coagulopathy. Optimal obstetric management includes delivery after establishment of fetal lung maturity. Many treatments have been proposed for the maternal medical management of ICP, none of which is ideal.

Cholestasis, Intrahepatic↗

PubMed1999

Benign recurrent intrahepatic cholestasis.

Benign recurrent intrahepatic cholestasis is a rare autosomal recessive disorder characterized by repeated episodes of intense pruritus and jaundice. Each attack lasts from several weeks to months before resolving spontaneously. Patients are completely asymptomatic for months to years between symptomatic periods. The disorder does not lead to progressive liver disease. Although attacks seem to be associated with a viral prodrome, an inciting viral agent or toxin has not been defined. Genetic studies have mapped the defect of this disorder to the long arm of chromosome 18 and a gene that codes for a P-type ATPase, which appears to be involved in aminophospholipid transport. Therapy during symptomatic periods is supportive and aimed at relief of severe pruritus until the episode resolves spontaneously.

Adenosine Triphosphatases↗

PubMed1999

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.

Bile Acids and Salts↗

PubMed1999

Progressive familial intrahepatic cholestasis.

Progressive familial intrahepatic cholestasis (PFIC), also known as Byler disease, is an inherited disorder of childhood in which cholestasis of hepatocellular origin often presents in the neonatal period and leads to death from liver failure before adolescence. The pattern of appearance of affected children within families is consistent with autosomal recessive inheritance. Several studies have provided support for the heterogeneity of this clinical entity suggesting the existence of different types due to different disorders affecting the hepatocyte and related to defects of bile acid secretion or bile acid metabolism. Recent molecular and genetic studies have identified genes responsible for three types of PFIC and have shown that PFIC was related to mutations in hepatocellular transport system genes involved in bile formation. These findings now provide specific diagnostic tools for the investigation of children with PFIC and should allow prenatal diagnosis in the future. Genotype-phenotype correlations performed in patients treated with ursodeoxycholic acid or biliary diversion should allow those PFIC patients who could benefit from these therapies to be precisely identified. In the future, other therapies, such as cell and gene therapies, might be considered and could also represent an alternative to liver transplantation.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2006

Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder that usually develops in the third trimester of pregnancy and persists until delivery. The cause of ICP remains elusive, but there is evidence that mutations in the canalicular ABC transporter phospholipid flippase (MDR3) and in the bile salt export pump (BSEP) can predispose for the development of ICP. MDR3 and BSEP were investigated by gene sequencing and immunofluorescence microscopy in a patient with severe ICP of early onset. ICP was diagnosed in a patient in the first trimester of pregnancy with severe pruritus, elevated levels of bile salts, and 48-fold elevation of transaminase levels. A liver biopsy specimen showed diminished canalicular expression of the bile salt export pump BSEP, while the expression and localization of the phospholipid flippase MDR3 was normal. Gene sequencing revealed a homozygous MDR3 gene mutation (S320F). The patient was also homozygous for the common BSEP polymorphism V444A. Treatment with ursodeoxycholate normalized transaminase levels but could not prevent further elevation of bile salt levels and preterm delivery. The combined homozygous alterations of the canalicular transporters may explain the early onset and severity of ICP in this patient. The common BSEP polymorphism V444A accounts for the reduced canalicular BSEP expression. Reduced bile salt secretion through BSEP may explain the persistence of elevated bile salt levels and incomplete efficacy of ursodeoxycholate treatment.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2004

Diagnosis and therapy of intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is characterized by the occurrence of pruritus mostly in the third trimenon. Diagnosis is based on the presence of pruritus and elevated levels of serum bile acids in the absence of pruritic skin diseases. There is strong evidence of a genetic predisposition for ICP. Numerous studies have investigated the association of known cholestasis genes such as ABCB4 (also designated MDR3), ABCB11 ( BSEP) and ATP8B1 ( FIC1) with ICP. The results of these studies implicate a heterogeneous etiology of this syndrome. ICP increases the risk of preterm delivery and fetal loss. Furthermore, intense pruritus may necessitate premature induction of labor with its known higher frequency of complications for mother and child. Therefore, ICP pregnancies should be managed as high-risk pregnancies. Pharmaceuticals to alleviate pruritus or improve cholestasis like antihistamines, phenobarbital, anion exchange resins, dexamethasone or S-adenosylmethionine are not widely accepted because of questionable efficacy or side effects. Recent randomized studies have shown beneficial effects of ursodeoxycholic acid (UDCA) on laboratory data and pruritus in patients with ICP. Improved knowledge about the diagnostic classification of different types and pathophysiological mechanisms of ICP may allow for a more targeted treatment of this disease in future.

Bile Acids and Salts↗

PubMed2004

Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder associated with increased risk of intrauterine fetal death and prematurity. There is increasing evidence that genetically determined dysfunction in the canalicular ABC transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein 3 (MDR3, ABCB4) might be risk factors for ICP development. This study aimed to (i). describe the extent of genetic variability in BSEP and MDR3 in ICP and (ii). identify new disease-causing mutations. Twenty-one women with ICP and 40 women with uneventful pregnancies were recruited between April 2001 and April 2003. Sequencing of BSEP and MDR3 spanned 8-10 kb per gene and comprised the promoter region and 100-350 bp of the flanking intronic region around each exon. DNA sequencing of polymerase chain reaction fragments was performed on an ABI3700 capillary sequencer. MDR3 promoter activity of promoter constructs carrying different ICP-specific mutations was studied using reporter assays. A total of 37 and 51 variant sites were detected in BSEP and MDR3, respectively. Three non-synonymous sites in codons for evolutionarily conserved amino acids were specific for the ICP collective (BSEP, N591S; MDR3, S320F and G762E). Furthermore, four ICP-specific splicing mutations were detected in MDR3 [intron 21, G(+1)A; intron 25, G(+5)C and C(-3)G; and intron 26, T(+2)A]. Activity of the mutated MDR3 promoter was similar to that observed for the wild-type promoter. Our data further support an involvement of MDR3 genetic variation in the pathogenesis of ICP, whereas analysis of BSEP sequence variation indicates that this gene is probably less important for the development of pregnancy-associated cholestasis.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2006

Safety of living-related liver transplantation for progressive familial intrahepatic cholestasis.

Progressive familial intrahepatic cholestasis (PFIC) is a severe cholestatic liver disease of early life often requiring liver transplantation. Organ shortage leads to consider living-related liver transplantation. Because of possible partial metabolic defect in heterozygotes, the use of familial donors might be questionable. We therefore evaluated the safety of this procedure, for both donors and recipients. We compared a series of seven parental-children pairs, having participated in the living related liver transplant program for PFIC between 1994 and 2001, with that of a series of seven parental-children pairs, performed for biliary atresia (BA) during the same period. No primary graft dysfunction was observed. There was no difference in the course of transaminases, gamma-glutamyl transpeptidase and bilirubin levels after transplantation in both donor and recipient series. Thirteen recipients and 14 donors are alive and well 3-10 yr post-surgery. One PFIC recipient died nine months post-orthotopic liver transplantation from sepsis. We conclude that PFIC heterozygote status of the donor does not increase the risk of liver dysfunction in either recipients or donors, with a similar course compared with BA recipients and donors.

Adolescent↗