Diagnostic difficulties in prajmaline-induced intrahepatic cholestasis

A case of prajmalium-induced intrahepatic cholestasis is presented. A proper diagnosis was delayed because differential diagnosis did not include toxic liver damage. Pathogenetic considerations included immunological background of the disease which improved completely within one year. No clinical and biochemical complications were seen.     

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

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

Low activity of gamma-glutamyl transpeptidase in serum of acute intrahepatic cholestasis.

Low gamma-glutamyl transpeptidase (gamma-GTP) activity in serum was observed in 11 patients with acute intrahepatic cholestasis (cholestatic hepatitis and fulminant hepatitis), despite a marked increase in bilirubin levels. Inhibitors of gamma-GTP were not detected in sera of these patients. Their gamma-GTP levels in the liver were significantly higher than those in chronic liver diseases. An electrophoretic study of liver gamma-GTP in acute intrahepatic cholestasis showed the same mobility as in chronic liver diseases. These results suggest that the low serum gamma-GTP activity in acute intrahepatic cholestasis is due to factors inhibiting the release of the enzyme from the liver.     

Metabolomic profiling of maternal hair suggests rapid development of intrahepatic cholestasis of pregnancy

Introduction

Intrahepatic cholestasis of pregnancy (ICP) is a common maternal liver disease; development can result in devastating consequences, including sudden fetal death and stillbirth. Currently, recognition of ICP only occurs following onset of clinical symptoms.

Objective

Investigate the maternal hair metabolome for predictive biomarkers of ICP.

Methods

The maternal hair metabolome (gestational age of sampling between 17 and 41 weeks) of 38 Chinese women with ICP and 46 pregnant controls was analysed using gas chromatography–mass spectrometry.

Results

Of 105 metabolites detected in hair, none were significantly associated with ICP.

Conclusion

Hair samples represent accumulative environmental exposure over time. Samples collected at the onset of ICP did not reveal any metabolic shifts, suggesting rapid development of the disease.

     

Pathogenesis of lithocholate-induced intrahepatic cholestasis: role of glucuronidation and hydroxylation of lithocholate.

It has been shown that lithocholic glucuronide is more cholestatic than lithocholic acid (LCA), as well as its taurine and glycine conjugates. Furthermore, LCA hydroxylation is thought to be a major detoxifying mechanism. Therefore, the role of LCA glucuronidation and hydroxylation was investigated during the development of LCA-induced cholestasis and recovery from it. Male rats received a bolus intravenous injection of [14C]LCA (12 mumol/100 g body weight) and bile samples were collected every 30 min for 5 h. Bile flow (BF) was reduced immediately after LCA injection, dropping to 40% of basal BF at 60 min. It then started to increase, reaching normal bile flow values at 3.5 h. Morphologically, canalicular lesions were dominant at 60 min and virtually absent at 2 h. At 60 min (maximal cholestasis), 30% of the LCA injected was secreted in bile, 20% was found in plasma while the other 50% was recovered in the liver and distributed mainly in plasma membranes, microsomes and cytosol. At the end of the experiment (normal BF), 20% of the LCA injected was still in the liver but was present mainly in the cytosol. In bile, within 30 min after injection, 46% of the LCA secreted was lithocholic glucuronide, 24% was conjugated with taurine and glycine, and 21% was in the form of hydroxylated bile acids. During the recovery period, lithocholic glucuronide secretion decreased to 18-25%. Taurine and glycine conjugate secretion increased to a maximum of 43% at 60 min, after which it was reduced to 21-28%. In contrast, hydroxylated metabolites were elevated during the recovery periods, reaching a maximum (45%) at 120 min and remaining constant thereafter. These results suggest that: (i) LCA binding to plasma membranes and microsomes appeared to correlate with the development of cholestasis; (ii) LCA glucuronidation may initiate and/or contribute to LCA-induced cholestasis; and (iii) hydroxylation predominates during recovery from cholestasis.     

Lipopolysaccharide alters ecto-ATP-diphosphohydrolase and causes relocation of its reaction product in experimental intrahepatic cholestasis

Lipopolysaccharide (LPS), a bacterial endotoxin, exerts profound inflammatory actions toward various tissues and cells. We induced intrahepatic cholestasis in rats by administration of LPS and followed ecto-ATP-diphosphohydrolase (ecto-apyrase) activity in the liver. The activity of the enzyme had decreased to 77% 2 h after injection compared with the activity in control animals. The maximum decrease was detected 24 h after administration. The activity was found to have partially recovered 1 week after injection, but had yet to reach control levels. In contrast to the decrease in ecto-apyrase activity, there were increases in alkaline phosphatase activity and bilirubin concentration, markers of cholestasis. In response to LPS, the reaction product of ecto-apyrase was found to relocate from the canalicular domain of the plasma membrane of hepatocytes, its predominant localization in the liver of intact animals, to the basolateral and sinusoidal domains. The pattern of histochemical reaction indicated modulation of the enzyme activity and changes in trafficking of intracellular proteins. Taken together, our findings showed that LPS administration alters ecto-apyrase and causes relocation of its reaction product from the canalicular domain of the plasma membrane of hepatocytes in the rat. It is suggested that relocation of the reaction product may be a protective mechanism to enable the hepatocytes to withstand the cytokine-induced metabolic perturbations.     

Low serum selenium concentration and glutathione peroxidase activity in intrahepatic cholestasis of pregnancy.

Serum selenium concentrations were found to be significantly lower in women with intrahepatic cholestasis of pregnancy than in women with normal pregnancies during the last trimester of pregnancy and post partum. The activity of the selenoenzyme glutathione peroxidase had a significant positive correlation with selenium concentration and it was also significantly lower in women with the disease. These findings suggest that selenium deficiency and reduced glutathione peroxidase activity are associated with the aetiopathogenesis of intrahepatic cholestasis of pregnancy.     

A novel ABCB11 mutation in an Iranian girl with progressive familial intrahepatic cholestasis

Progressive familial intrahepatic cholestasis is an autosomal recessive liver disorder caused by (biallelic) mutations in the ATP8B1 of ABCB11 gene. A nine-year-old girl with cholestasis was referred for genetic counseling. She had a family history of cholestasis in two previous expired siblings. Genetic analysis of the ABCB11 gene led to the identification of a novel homozygous mutation in exon 25. The mutation 3593- A > G lead to a missense mutation at the amino acid level (His1198Arg). This mutation caused PFIC2 due to abnormal function in the bile salt export pump protein (BSEP).     

妊娠肝内胆汁淤积症胎儿猝死发病机制的研究进展

妊娠肝内胆汁淤积症（ICP）妊娠晚期胎儿猝死,难以预料和准确监测,具有高风险性。目前其机制不明。孕妇和胎儿高胆汁酸水平对胎盘功能的影响和对胎儿的损伤是当前研究的主要方向。特别是一系列胆汁酸对心肌细胞毒性作用的实验,提示胆汁酸对胎儿心脏的毒性作用可能是引起胎儿猝死的重要原因。     

Fetal outcomes in pregnancies complicated by intrahepatic cholestasis of pregnancy in a Northern California cohort

Background

Intrahepatic cholestasis of pregnancy (ICP) has important fetal implications. There is increased risk for poor fetal outcomes, including preterm delivery, meconium staining of amniotic fluid, respiratory distress, fetal distress and demise.

Methods

One hundred and one women diagnosed with ICP between January 2005 and March 2009 at San Francisco General Hospital were included in this study. Single predictor logistic regression models were used to assess the associations of maternal clinical and biochemical predictors with fetal complications. Clinical predictors analyzed included age, race/ethnicity, gravidity, parity, history of liver or biliary disease, history of ICP in previous pregnancies, and induction. Biochemical predictors analyzed included serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin, albumin, total protein, and total bile acids (TBA).

Results

The prevalence of ICP was 1.9%. Most were Latina (90%). Labor was induced in the majority (87%) and most were delivered by normal spontaneous vaginal delivery (84%). Fetal complications occurred in 33% of the deliveries, with respiratory distress accounting for the majority of complications. There were no statistically significant clinical or biochemical predictors associated with an increased risk of fetal complications. Elevated TBA had little association with fetal complications until reaching greater than 100 µmoL/L, with 3 out of 5 having reported complications. ICP in previous pregnancies was associated with decreased risk of fetal complications (OR 0.21, p = 0.046). There were no cases of late term fetal demise.

Conclusions

Maternal clinical and laboratory features, including elevated TBA, did not appear to be substantial predictors of fetal complications in ICP.