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At least 19 recordsLinked to original sources
PubMed2004

Molecular basis of intrahepatic cholestasis.

Intrahepatic cholestasis, or impairment of bile flow, is an important manifestation of inherited and acquired liver disease. In recent years, human genetic and molecular studies have identified several genes, the disruption of which results in cholestasis. ATP8B1 (FIC1), ABCB11 (BSEP), and ABCB4 (MDR3) are disrupted in forms of progressive familial intrahepatic cholestasis (PFIC) and related disorders. Mutations in BAAT, TJP2 (ZO-2), and EPHX1 have been identified in patients with hypercholanemia. A CLDN1 mutation was recently reported in patients with ichthyosis, leukocyte vacuoles, alopecia and sclerosing cholangitis (ILVASC), and North American Indian childhood cirrhosis (NAIC) is associated with a missense mutation in CIRH1A. Alagille syndrome patients carry mutations in JAG1, and mutations in VPS33B have been identified in patients with arthrogryposis, renal dysfunction and cholestasis syndrome (ARC). Identification of these genes, and characterization of the proteins they encode, is enhancing our understanding of the biology of the enterohepatic circulation in health and disease.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1979

Immaturity of the biliary excretory system predisposes neonates to intrahepatic cholestasis.

Intrahepatic cholestasis associated with both gram-negative bacterial infections and total parenteral nutrition (TPN) is observed more frequently in neonates than in older children or adults. Factors involved in the pathogenesis of this syndrome are uncertain. The cholestatic effects of gram-negative bacterial infections appear to result from the inhibitory effects of endotoxin on bile flow. Since the adverse effects of both endotoxin and TPN on bile flow involve primarily the bile acid-independent portion, the immaturity of the neonatal hepatic excretory system which an inadequate bile acid-dependent fraction of bile would explain the increased susceptibility of the neonate to endotoxin- and, perhaps, to TPN-induced cholestasis.

Bacterial Infections↗
PubMed1976

Familial benign recurrent intrahepatic cholestasis. Interrelation with intrahepatic cholestasis of pregnancy and from oral contraceptives?

A family study was prompted by the presence of benign recurrent intrahepatic cholestasis in three members and probably in a fourth. Pruritus and/or jaundice occurred during pregnancy in nine members. Two additional members suffered from pruritus while using oral contraceptives. The literature on benign recurrent intrahepatic cholestasis since 1959 describes at least 57 cases. A familial form of this condition proved to be fairly common. There seems to be a relation to the intrahepatic cholestasis sometimes seen during pregnancy and during oral contraceptive use. The data of the family study are suggestive for an interrelation of the three types of intrahepatic cholestasis, although a common denominator remains obscure.

Adult↗
PubMed1975

[Intrahepatic cholestasis].

Intrahepatic cholestasis has become a very important aspect of liver disease. The author, in the light of electron microscopy and the theory of filtration-reabsorption of bile secretion proposes that the disease may be explained by obstructions situated at various levels of the inter-cellular spaces of the liver. This obstruction is functional at first, but is maintained by a duodeno-hepatic inhibitory reflex, the existence of which has been demonstrated by the author. In the light of facts and documents presented here, one may see that from Monneret until now, various authors have come very close to the true mechanism of this type of jaundice, each discovering some aspect of the truth.

Cholestasis↗
PubMed2002

Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum.

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease, characterised by intermittent attacks of cholestasis, which can start at any age and last for several weeks to months. Characteristically serum GGT activity is low and normal liver structure is preserved. Progressive familial intrahepatic cholestasis (PFIC) is another liver disease, characterised by severe cholestasis, starting almost invariably before 6 months of age. All patients progress to cirrhosis, liver failure and death, unless a liver transplantation is performed. We now identified four patients who presented in childhood with recurrent attacks of cholestasis, while in the course of the disease the cholestasis gradually became permanent. Although liver biopsies performed in the early stages of the disease showed normal liver architecture, late stage biopsies revealed evident fibrosis with porto-portal septa formation. In conclusion, the disease of these patients started with the clinical and histopathological characteristics of BRIC but progressed to PFIC.

Adolescent↗
PubMed1981

Studies on intrahepatic cholestasis in drug-induced allergic hepatitis: intrahepatic cholestasis induced in the rat by the culture supernatant of activated lymphocytes.

A marked reduction in bile flow and bile acid excretion was whenever peripheral lymphocytes from patients with drug-induced allergic intrahepatic cholestasis were stimulated with a specific drug in vitro in the presence of a soluble liver-specific antigen fraction, and their culture supernatant injected into the mesenteric vein of rats. A gel filtration study of the active fraction of the supernatant that caused a reduction in bile flow, suggested that the molecular size of this active principle is similar to that of the macrophage migration inhibitory factor (MIF). Histologically, dilated bile canaliculi with decreased microvilli were observed via electron microscopy in rat liver after injection of culture supernatant. No such changes were observed in rats after injection of the supernatant of a lymphocyte culture similarly prepared from normal individuals. These results strongly suggested that sensitized lymphocytes obtained from patients with drug-induced intrahepatic cholestasis produce a factor (of factors) causing cholestasis when stimulated with a specific drug in the presence of liver-specific antigen fractions.

Animals↗
PubMed1996

[Intrahepatic cholestasis].

The intrahepatic cholestasis is not an common syndrome, in particular way in people between 50 and 60 years of age. It is often unknown or confused, because of itching, with allergic or dermatologic diseases. The most frequent causes of intrahepatic cholestasis are primary sclerosing cholestasis, primary biliary cirrhosis and hepatic cirrhosis. The pathogenetic mechanism is the faulty secretion of bile and, more bile salts. The diagnosis is allowed by anamnesis, objective examination and, above all, biochemical markers of cholestasis, echography, TC, NMR and liver biopsy. Therapy consist of generic (hypolipidic diet, liposoluble vitamin and others) and specific (UDCA, SAMe) measures.

Cholestasis, Intrahepatic↗
PubMed1995

Mapping of a locus for progressive familial intrahepatic cholestasis (Byler disease) to 18q21-q22, the benign recurrent intrahepatic cholestasis region.

A locus for progressive familial intrahepatic cholestasis (PFIC), also known as Byler disease, has been mapped to a 19 cM region of chromosome 18 by a search for shared segments, using patients from the Amish kindred in which the disorder was originally described. A similar liver disease, benign recurrent intrahepatic cholestasis (BRIC), recently has been mapped to the same region, suggesting that these two diseases are caused by mutations in the same gene. Although PFIC and BRIC are clinically distinct diseases, episodic attacks of jaundice and pruritus, with elevated concentrations of bile acid in serum, are seen in both disorders. In PFIC patients, these attacks result in progressive liver damage and death. The clinical and biochemical features of PFIC and BRIC are suggestive of a defect in primary bile acid secretion. The biology of bile secretion is of great interest because of its vital importance in digestion of dietary fats as well as in secretion of xenobiotics and metabolic waste products. Cloning of the gene (or genes) responsible for PFIC and BRIC will likely provide important insights into this pathway.

Alleles↗
PubMedDate not supplied

[Recurrent benign familial intrahepatic cholestasis].

Benign recurrent intrahepatic cholestasis is a disorder described 3 decades ago. The literature describes at least 60 cases. This syndrome is characterized by attacks of jaundice with obstructive features recurring over a number of years. Though the etiology remains, obscure the coincidence in members of a family or brothers suggests that this may be a constitutional form of jaundice. We describe the case of a young man who presented two episodes of obstructive jaundice. The serologic tests were negative for hepatitis and the biopsy revealed a severe intrahepatic cholestasis without histologic inflammatory changes and preserved lobulillar architecture. Inquest of the family were negative, but parents were possibly related, this factor may be important if a genetic defect is implicated. We conclude that from the clinical biochemical and histological findings this case of jaundice is due to intermittent intrahepatic cholestasis. The most common causes of intrahepatic cholestasis--viral hepatitis and certain drugs--; can be ruled out in this patient. Finally we have to suspect this syndrome, even though very rare, when we have a patient as we described.

Adolescent↗
PubMed2000

Long-term outcome after partial external biliary diversion for intractable pruritus in patients with intrahepatic cholestasis.

BACKGROUND: Chronic intrahepatic cholestasis is associated with severe pruritus that is often refractory to maximal medical management and leads to significantly impaired quality of life. The hypothesis in this study was that partial external biliary diversion (PEBD) can substantially improve intractable pruritus secondary to intrahepatic cholestasis with subsequent improvement of functional quality of life. METHODS: Parents' and/or patients' clinical rating of pruritus, growth percentiles, biochemical parameters, and liver biopsies performed before and after surgery were compared in a retrospective medical record review. RESULTS: Eight children underwent PEBD from 1990 through 1997. Complete follow-up data were available for seven patients. Before surgery, all patients had intense pruritus, which was not responsive to maximal medical therapy. Specimens obtained in preoperative liver biopsies showed moderate (n = 1), minimal (n = 6), or no (n = 1) portal fibrosis. After PEBD, all patients received ursodeoxycholic acid (10-15 mg/kg/dose two to three times daily) until resolution of pruritus. Of the seven patients with complete follow-up data, six had complete resolution of pruritus and sustained resolution up to 8 years after surgery. The patient with mild to moderate residual pruritus was the youngest to undergo PEBD. Growth improved from below the 5th percentile before surgery to the 5th through the 25th percentiles for five of six patients with more than 6 years' follow-up. All families reported improved quality of life, defined by school attendance and ability to resume normal activity with peers. There has been no clinical evidence of progression of liver disease. CONCLUSION: Partial external biliary diversion is effective in the long-term treatment of pruritus refractory to medical therapy and provides a favorable outcome in a select group of patients with chronic intrahepatic cholestasis without cirrhosis.

Bile Acids and Salts↗
PubMed2006

Plasma lipid profiles of women with intrahepatic cholestasis of pregnancy.

OBJECTIVE: Intrahepatic cholestasis of pregnancy is associated with dyslipidemia, but the gestational lipid profile in relation to clinical diagnosis of the disease is unknown. The aim of this study was to undertake a detailed analysis of plasma lipids in women presenting with intrahepatic cholestasis of pregnancy and pruritus gravidarum. METHODS: Plasma lipid concentrations were assessed in nonfasting blood samples from 63 women with intrahepatic cholestasis of pregnancy (n = 54, recruited at the time of diagnosis, and n = 9, who later developed the disease), 43 women with pruritus gravidarum, and 26 healthy pregnant controls during pregnancy and at 4-6 weeks postpartum. RESULTS: Intrahepatic cholestasis of pregnancy was associated with an abnormal lipid profile. Low-density lipoprotein (LDL) cholesterol, apolipoprotein B-100, and total cholesterol concentrations were significantly raised during pregnancy in women with intrahepatic cholestasis of pregnancy compared with pruritus gravidarum and controls, and LDL-cholesterol was raised before clinical diagnosis. High-density lipoprotein cholesterol was lower in women with intrahepatic cholestasis of pregnancy compared with the pruritus gravidarum group. Ursodeoxycholic acid did not alter plasma lipid concentrations. CONCLUSION: Intrahepatic cholestasis is associated with dyslipidemia, which may contribute to the pathogenesis of the disease. The elevation of LDL cholesterol and reduction of high-density lipoprotein cholesterol before clinical diagnosis may prove to be a useful biomarker for the early identification of intrahepatic cholestasis of pregnancy and differentiation from pruritus gravidarum. LEVEL OF EVIDENCE: II-2.

Adult↗
PubMed1997

Benign recurrent intrahepatic cholestasis.

Benign recurrent intrahepatic cholestasis is a rare disorder of unknown etiology and has not yet been reported in Taiwan. We report a case with a typical clinical course. A 17-year-old Taiwanese boy had three episodes of pruritus and jaundice from February 1993 to July 1995, each lasting 3 to 4 months. Jaundice spontaneously subsided and he was symptom-free during periods of remission. A fourth episode of pruritus began in July 1995, with jaundice developing later and lasting for 3 months. Laboratory tests revealed direct hyperbilirubinemia. Endoscopic retrograde cholangiopancreatography showed normal intra- and extrahepatic biliary trees. Light microscopy of a liver biopsy sample revealed hepatocellular and canalicular cholestasis with bile retention in the Kupffer cells. Benign recurrent intrahepatic cholestasis was diagnosed after exclusion of other possible causes of jaundice. The patient made an uneventful recovery.

Adolescent↗
PubMed2004

Benign recurrent intrahepatic cholestasis.

Benign recurrent intrahepatic cholestasis is a rare autosomal recessive disorder characterized by repeated episodes of intense pruritus, profound elevations in serum alkaline phosphatase and bilirubin, with normal or nearly normal values for serum gamma-glutamyl transferase. Attack lasts from several weeks to months and resolve spontaneously. Between attacks patients remain asymptomatic for months to years. The disorder does not lead to progressive liver injury and is not fatal. Genetic studies have demonstrated that the disorder is the result of a mutation in ATP8BI, a gene that codes for the FIC1 (familial intrahepatic cholestasis) protein, which is also affected in other forms of familial intrahepatic cholestasis. It is believed this protein plays a role in bile acid secretion, in aminophospholid transport, and in maintaining fluidity of the cell membrane. Therapy is supportive and aimed at relieving pruritus and other complications of severe cholestasis until the episode resolves spontaneously.

Cholestasis↗
PubMed2005

ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) affects approximately 0.7% of pregnancies in the UK and is associated with prematurity, fetal distress, and intrauterine death. Homozygous mutations in the ATP8B1 gene cause cholestasis with a normal serum gamma-glutamyl transpeptidase (gamma-GT), and have been reported in two forms of cholestasis: progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis (BRIC). AIMS: To establish whether mutations in ATP8B1 are associated with ICP in British cases PATIENTS: Sixteen well phenotyped women with ICP without raised gamma-GT were selected for sequence analysis. Subsequently, 182 patients and 120 controls were examined for the presence of the variants detected. METHODS: All coding exons were sequenced in 16 cases. Eight ICP cases, including two women carrying a mutation, were investigated using in vivo hepatic (31)P magnetic resonance spectroscopy (MRS) RESULTS: Two heterozygous ATP8B1 transitions (208G>A and 2599C>T) that resulted in amino acid substitutions were identified; 208G>A was identified in three cases. MRS revealed an increased phosphodiester signal (Mann-Whitney U test, p = 0.03) and a decreased phosphomonoester/phosphodiester ratio (p = 0.04) in ICP cases compared with controls. CONCLUSIONS: We were able to demonstrate ATP8B1 mutations in ICP. MRS studies suggest that susceptibility to ICP is associated with a relative rise in biliary phospholipid. These data also suggest that MRS may be used for non-invasive assessment of the liver and biliary constituents in cholestasis.

Adenosine Triphosphatases↗
PubMed2002

Progressive familial intrahepatic cholestasis.

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive childhood cholestasis of hepatocellular origin. PFIC 1, also known as Byler disease, was first described in Amish kindred. It is characterized by cholestasis often arising in the neonatal period and it leads to death due to liver failure. PFIC 1, like Benign Recurrent Intrahepatic Cholestasis (BRIC) which is the benign form of the same disease, recognizes mutations in the ATP8B1 gene. PFIC 2 disease is clinically similar to PFIC 1 but it has a different gene mutation causing a defect in the Bile Salt Export Pump (BSEP), exclusively expressed in the liver and involved in the canalicular secretion of bile acids. PFIC 3 usually appears later in life and it has a higher risk of portal hypertension, gastrointestinal bleeding and liver failure. This particular form of disease (the only one with high serum values of g-glutamil transpeptidase), is associated to a genetic defect in the class III multidrug resistance protein (MDR). External biliary diversion and ursodeoxycholic acid therapy, should be considered as the initial therapy in these patients, even if liver transplantation still seems to be the only solution for most patients.

Cholestasis, Intrahepatic↗