Recurrent Intrahepatic Cholestasis Of Pregnancy Research Articles

Familial clustering of intrahepatic cholestasis of pregnancy: a nationwide population-based study in Denmark.

Genetics plays a role in the pathogenesis of intrahepatic cholestasis of pregnancy (ICP); however, empirical evidence on familial clustering of ICP is scarce. We aimed to assess the extent of familial recurrence of ICP. This population-based cohort study included all 668,461 primiparous women who gave birth between 1995 and 2018 in Denmark. Women diagnosed with ICP were included to the index cohort. Kinship with index women was determined with the Danish Civil Registration System. Log-binomial regression was used to calculate the relative recurrence risk (RRR) of ICP in relatives of index women. A total of 6722 (1.0%) primiparous women were diagnosed with ICP. In co-twins (n=57), first-degree (n=2279), second-degree (n=1373), and third-degree (n=1758) relatives of the index women, the incidence of ICP reached 5.3%, 2.6%, 0.7%, and 1.4%, respectively, corresponding to adjusted RRRs of 4.82 (95% CI, 1.60-14.48), 2.54 (1.98-3.26), 0.81 (0.44-1.51), and 1.15 (0.77-1.71), respectively. The first-degree relatives of women who had recurrent ICP or first-trimester ICP seemed to be at higher risks [RRR, 4.30 (2.85-6.48), 3.04 (1.93-4.77), respectively]. A minor increased risk was observed in nonbiological relatives [RRR, 1.35 (1.05-1.73); n=4274, including women's full-brothers' partner and women's husbands' full sisters]. Co-twins and first-degree relatives of ICP patients were at ~5- and ~2.5-fold increased risk of ICP, respectively. No increased risk was observed in second-degree and third-degree relatives. Recurrent ICP and first-trimester ICP might indicate a higher degree of family clustering. Further investigation is needed to investigate the increased risk of ICP in nonbiological relatives.

2251 An Atypical Case of Recurrent Intrahepatic Cholestasis of Pregnancy

INTRODUCTION: Intrahepatic cholestasis of pregnancy (ICP) usually manifests in the second to third trimester with pruritus, jaundice and abnormal liver tests. It can increase risks of preterm birth, respiratory distress syndrome, and stillbirth. Timely diagnosis and planned delivery are crucial. We hereby describe an atypical case of recurrent ICP. CASE DESCRIPTION/METHODS: Patient is a 31-year-old Chinese female who presented to hepatology clinic at week-13 of her second pregnancy. During her first pregnancy 4 years ago, she experienced pruritus associated with significant elevation of bile acids and serum aminotransferases at about 20-week gestation. Diagnosis of ICP was made and she was promptly started on ursodeoxycholic acid (URSO) [Figure 1]. Bile acids improved and pruritus resolved but she had a preterm delivery at 30-week gestation. URSO was discontinued after delivery and bile acids were completely normal by 6 weeks postpartum. The ALT levels, however, increased to >200 U/L and remained abnormal for 10 months post-partum [Figure 1]. Other common causes of liver diseases such as viral hepatitis, autoimmune and drug-related liver diseases were ruled out. Her liver biopsy reported only non-specific resolving inflammation. For her second pregnancy, bile acids were checked at 14-week gestation and were mildly elevated at 14.7umol/L; they increased to 20.8 umol/L by 26 weeks. At that time, she experienced mild pruritus. URSO was initiated at 28-week gestation for recurrent ICP. Despite being on URSO for 3 weeks, ALT normalized but bile acid increased further to 53.5 umol/L without worsening of pruritus. Induced labor was planned at week-37 and the delivery was uneventful.URSO was subsequently discontinued. At week-3 postpartum, URSO was reinitiated for her ALT significantly elevated at 259 U/L even though bile acids continued to decrease. About 1 week after starting URSO, ALT decreased to 62 U/L and bile acids completely normalized. DISCUSSION: ICP usually resolves after delivery and URSO can be discontinued. Our case was atypical for her serum aminotransferases actually markedly increased during early postpartum in both pregnancies despite improvement of the bile acid levels. URSO was promptly reinitiated postpartum that resulted in reduction of ALT. For patients with elevated liver tests associated with ICP, physicians need to be vigilant in monitoring the patient closely during postpartum period and consider continuing URSO therapy until both serum aminotransferases and bile acids return to normal range.

Recurrent intrahepatic cholestasis of pregnancy: Case report

Recurrent intrahepatic cholestasis of pregnancy: Case report

Prenatal Molecular Diagnosis of Inherited Cholestatic Diseases

Progressive familial intrahepatic cholestasis (PFIC) and to a lesser extent, Alagille syndrome, often lead to end-stage liver disease during childhood. We report our experience of DNA-based prenatal diagnosis of PFIC1-3 and Alagille syndrome. Four molecular antenatal diagnoses were performed in 3 PFIC families and 17 in 11 Alagille syndrome families. DNA was isolated from chorionic villus or cultured amniocyte samples from women, without pregnancy complications. All four foetuses with a family history of PFIC1, 2, or 3 were heterozygous for an ATP8B1, ABCB11, or ABCB4 mutation and pregnancies were continued. Three of the infants were healthy after birth, and 1 premature infant, who had an ABCB4 mutation, experienced transient neonatal cholestasis. Among the families with a history of de novo JAG1 mutation, none of the foetuses was mutated, versus 40% of those with a history of familial mutation. Of 4 pregnant women with a JAG1-mutated foetus, 3 cut short their pregnancy and 1 gave birth to a child with overt Alagille syndrome. Molecular antenatal diagnosis of PFIC1-3 and Alagille syndrome is reliable because clinical outcome after birth corresponded to molecular foetal data.

A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis

We describe a 47-year-old patient who developed cholelithiasis in adolescence, followed by recurrent intrahepatic cholestasis of pregnancy, and finally biliary cirrhosis in adulthood. In our patient, the consecutive presentation of the 3 mentioned disorders raised the suspicion of a defect of MDR3, the canalicular protein involved in the transport of phospatidylcholine to bile. Mutational analysis in our patient showed a heterozygous missense mutation of the MDR3 gene that has not been described previously, which occurs in exon 14 at codon 535, and results in the substitution of glycine for aspartic acid. Further analysis of 7 members of the family showed the same mutation in her daughter who, on follow-up, developed cholestasis of pregnancy and persisting high serum levels of γ-glutamyl transpeptidase and alkaline phosphatase after delivery. Although biliary cirrhosis associated with MDR3 deficiency typically appears before the age of 25 years, in our case, the relatively mild MDR3 dysfunction allowed for a slower progression of the disease with established, well-advanced cirrhosis in the fifth decade of life. The present case, which accumulates the 3 clinical disorders assocaited with MDR3 deficiency, shows that this condition should be suspected not only in children or young people with high γ-glutamyl transpeptidase cholestasis but also in middle-aged or older patients with chronic idiopathic cholestasis, especially when there is a previous history of cholestasis of pregnancy or juvenile cholelithiasis.

Exploring the genetic role of the HLA-DPB1 locus in Chileans with intrahepatic cholestasis of pregnancy

Background/Aims: Intrahepatic cholestasis of pregnancy is a rare disease of unknown etiology, with a strikingly higher prevalence in Chile than in most other countries. Although several studies suggest that a genetic predisposition is involved in the pathogenesis, no genetic disease-marker has so far been identified. Using a recently developed HLA-genotyping technique, we performed an association study with a highly polymorphic HLA class II gene in patients with recurrent intrahepatic cholestasis of pregnancy and normal control patients. Methods: Genomic DNA was extracted from 26 unrelated patients with recurrent ICP and 30 unrelated multiparous women without a personal or family history of this disease among a Chilean population. The polymorphic second exon of the HLA-DPB1 gene was amplified by the polymerase chain reaction and hybridized with 25 sequence-specific oligonucleotide probes to assign the HLA-DPB1 alleles on the basis of known sequence variations. Results: Out of more than 50 HLA-DPB1 alleles presently known, 13 were represented in the analyzed groups. Patients with ICP had a higher frequency of the allele DPB1 *0402 when compared to controls (69% vs 43%). This difference failed to reach statistical significance (χ 2=2.81, corrected p > 0.5). No significant differences were observed between the frequencies of other detected HLA-DPB1 alleles in the analyzed groups. Conclusion: In this study, we observed a high frequency of the allele HLA-DPB1 *0402 among Chilean patients with recurrent ICP, but no association of the disease with HLA-DPB1 alleles. Therefore, HLA-DPB1 alleles do not play a major role in determining susceptibility or resistance to intrahepatic cholestasis of pregnancy.

Familial Recurrent Intrahepatic Cholestasis of Pregnancy: A Genetic Study Providing Evidence for Transmission of a Sex-Limited, Dominant Trait

Three generations of a kindred comprising 50 individuals are described in which recurrent intrahepatic cholestasis of pregnancy has occurred with high frequency. A uniform expression and complete penetrance of the trait in the women of a limited "affected" portion of the kindred (6 affected of 10 women), along with the direct parent-to-child inheritance mode, supports the conclusion that the inheritance mode is Mendelian dominant in type. Male expression of the phenotype seems to be inhibited. This is derived from observations that unmasking of carriers in the kindred by normal challenge provided useful information only in women, and was unhelpful when applied to a male obligate carrier. A linkage analysis is presented that explores the possibility of a relationship between the syndrome and homologous leukocyte antibody histocompatibility antigens. On the basis of present data, no conclusion can presently be reached regarding this possibility.

Radioimmunoassay of serum bile acids in normal pregnancy and in recurrent cholestasis of pregnancy.

Radioimmunoassay has been used to quantitate the conjugates of cholic and chenodeoxycholic acid in venous blood from women in different stages of normal pregnancy and in patients with recurrent intrahepatic cholestasis of pregnancy (RCP). The levels of cholic and chenodeoxycholic acid were shown to be within normal limits throughout uncomplicated pregnancy, and elevated in RCP. Because of RIAs simplicity and reliability, it is suggested that this method can be used to detect and follow the course of RCP and to assess the possible influence of treatment, e.g. diet.

Urinary bile acids in late pregnancy and in recurrent cholestasis of pregnancy.

The metabolic profiles of urinary bile acids in pregnant women in the last trimester and patients with recurrent intrahepatic cholestasis of pregnancy (RCP) were studied. Following separation according to mode of conjugation, about thirty different bile acids were quantitatively analysed by gas chromatography-mass spectrometry. In all patients the sulphate fraction comprised 50--90% of the total bile acids. In RCP a shift from glycine to taurine conjugation was noted to together with a slight relative increase in sulphation. A ten- to hundred-fold increase in cholic and chenodeoxycholic acids was seen in RCP, the increase being mainly in the sulphate fraction. Tetrahydroxylated bile acids, tentatively regarded as 1- and 6-hydroxylated products of cholic acid, were quantitatively important in patients with RCP. The relative amounts of the secondary bile acids, deoxycholic and lithocholic acids, decreased with increasing cholestasis. Metabolites hydroxylated at C-6 were common, and the excretion of hydroxylated at C-6 were common, and the excretion of hyocholic acid was positively correlated to that of chenodeoxycholic acid. An increase in the excretion of 5 alpha-configurated bile acids in RCP was noted. A positive correlation between the excretion of 3 beta-hydroxy-5-cholenoic acid and 3 beta,12 alpha-dihydroxy-5-cholenoic acid indicates a metabolic relationship between the two compounds. Because of the relatively small amounts of lithocholic and 3 beta-hydroxy-5-cholenoic acids in patients with RCP, these compounds do not seem to be of pathogenetic importance in this type of cholestasis.

Urinary excretion of estriol and 15α-hydroxyestriol in complicated pregnancies

Urinary excretion of estriol and 15α-hydroxyestriol (estetrol) was determined in 89 women whose pregnancies were complicated by toxemia, diabetes mellitus, Rh isoimmunization, intrauterine fetal death, or recurrent intrahepatic cholestasis of pregnancy. More than 300 urine samples were analyzed by a highly specific gas chromatographic method and the results were compared with values during normal pregnancies. The 2 estrogens usually gave the same correct information on the fetal state. In some cases of toxemia, the amount of estetrol was more reliable for monitoring the intrauterine fetal condition than that of estriol. In pregnancies complicated by Rh isoimmunization, the urinary excretion of estetrol bore a linear correlation to the cord blood hemoglobin concentration. The amount of estriol in the same maternal urine samples showed no correlation with the cord hemoglobin.

Oral contraceptives and liver function

Oral contraceptives can cause liver damage and jaundice but this is very rare in women in the United Kingdom. The drugs are contraindicated where there is a history of recurrent intrahepatic cholestasis of pregnancy and acute or chronic disturbance of liver function which can be congenital or acquired. It is not yet known whether the oestrogenic or progestogenic components of oral contraceptives cause the hepatic abnormalities. The available data suggest that neither oestrogens nor progestogens in low doses impair hepatic excretory processes. The full implications of the continued administration of oestrogens and progestogens for many years on liver proteins are not yet known.

RECURRENT INTRAHEPATIC CHOLESTASIS OF PREGNANCY: OBSERVATIONS ON PATHOGENESIS.

RECURRENT idiopathic jaundice is an unusual but benign complication of pregnancy. It is characterized by intense, generalized pruritus, often associated with an obstructive form of icterus, occurring without known cause in the latter half of gestation. Recovery occurs rapidly after delivery. The condition formerly known as pruritus gravidarum with subclinical elevations of levels of both serum bilirubin1and alkaline phosphatase2,3and sulfobromophthalein (BSP) retention4is considered to be a part of the same syndrome. Recurrence of either form of the syndrome can be expected in at least 50 %2,5of cases. Although there is a tendency to premature labor,2neither mother nor child is exposed to special risks. The condition often goes undiagnosed because the icteric state is usually mild and is often late in onset or detection. Liver biopsy obtained in the presence of this complication has consistently revealed only a transient intrahepatic cholestasis.6