History Of Intrahepatic Cholestasis Of Pregnancy Research Articles

Is the Risk of Intrahepatic Cholestasis Increased with Supplemental Progesterone?

This study aimed to evaluate the relationship between supplemental progesterone use during pregnancy and the development of intrahepatic cholestasis of pregnancy (ICP). A retrospective, matched case-control study was conducted among a population of women who delivered at George Washington University Hospital (GW) between 2012 and 2022. Women diagnosed with ICP (cases) were identified using International Statistical Classification of Diseases (ICD) codes, and data were collected via chart abstraction. Descriptive data included patient demographics, pregnancy characteristics, and medical history. Laboratory values related to ICP were collected. Cases were matched on a 1:3 ratio by maternal age, body mass index, and gravidarum to women who delivered at GW during the same month and did not carry a diagnosis of ICP (controls). A univariate logistic regression model was created to assess the use of supplemental progesterone between groups, adjusting for the use of assisted reproductive technology in the current pregnancy, and a history of liver disease. One hundred and twenty women who delivered during the study period were confirmed to have a diagnosis of ICP. Cases were matched with 360 controls and measures compared between the two groups. Cases were significantly more likely to have a history of liver disease (5.9 vs. 1.7%, p = 0.0021), multiple gestation (10.0 vs. 3.3%, p < 0.0001), a history of ICP in a previous pregnancy (10.0 vs. 0%, p < 0.0001), and to have delivered at an earlier gestational age (mean 37.1 vs. 38.6 weeks, p < 0.0001) as compared with controls. No differences were seen in the odds of supplemental progesterone use in both unadjusted and adjusted models (OR = 1.14, 95% CI: 0.30-4.34; adjusted Odds Ratio [aOR] = 0.98 [0.24-3.94]). Contrary to recent evidence, no association was seen with the use of supplemental progesterone. It is possible that the associated risk with supplemental progesterone is dependent on medication formulation or route of administration. · Supplemental progesterone use in pregnancy may increase the risk of developing ICP.. · Previous investigations of progesterone and ICP have demonstrated mixed results.. · The association may be dependent on the route of administration and formulation of progesterone..

S3198 Was It Always in the Genes? ABCB4 and Its Variable Presentations

Introduction: Progressive familial intrahepatic cholestasis (PFIC), low phospholipid-associated cholestasis (LPAC), and autosomal dominant intrahepatic cholestasis of pregnancy (ICP) are rare genetic disorders that should be considered in patients with elevated alkaline phosphatase and unrevealing primary work ups. We present a case of a 36-year-old female with a history of ICP who presented with elevated ALP, eventually found to have a nonspecific variant in the ABCB4 gene, concerning for Type 3 PFIC. Case Description/Methods: A 36-year-old female with a history of ICP treated with Ursodiol, current oral contraceptive use (OCP), and remote cholecystectomy presented to a gastroenterologist for asymptomatic ALP elevation. Initial labs revealed ALP 279 U/L, bile acids 9.9 μmol/L, and gamma-glutamyl transferase (GGT) 283U/L. Magnetic resonance cholangiopancreatography (MRCP) was unrevealing. Given no signs of hepatic dysfunction, portal hypertension, or steatosis on fibroscan, liver biopsy was obtained, which was unremarkable. Due to persistent elevation in ALP without a clear etiology and history of ICP, genetic testing was pursued. Genetic testing revealed a heterozygous variant of uncertain significance in the ABCB4 gene that is associated with PFIC type 3. OCPs were discontinued due to an association of ICP and OCP induced cholestasis. Ursodiol was restarted given high rates of recurrent cholelithiasis in patients with PFIC. Discussion: Type 3 PFIC, LPAC, and ICP are rare genetic disorders linked to unique mutations in the ABCB4 gene responsible for ALP elevation. The ABCB4 gene may manifest later in life as cholestasis, jaundice, or pruritus. Mutations in the ABCB4 gene can cause a reduction in biliary phospholipid concentration, leading to sludge, cholesterol stones, and microlithiasis. Type 3 PFIC has a unique presentation associated with elevated GGT, unseen in type 1 or 2. LPAC should be considered in patients presenting with cholelithiasis before the age of 40, recurrent cholithialsis after cholecystectomy, ICP, and family history of cholelithiasis. The variant of uncertain significance in our patient’s ABCB4 gene appeared to be a unifying diagnostic factor given her history of ICP, cholelithaisis at age 18 years requiring cholecystectomy, and persistent new elevation in ALP. She ultimately met criteria for Type 3 PFIC, LPAC and ICP. Given the rapidly evolving nature of medical genetics, reclassification and evaluation of genetic mutations requires follow up.

Obstetric Cholestasis: A Review and Update

Obstetric cholestasis (OC) is a liver disorder that occurs in the late second and early third trimester of pregnancy characterized by pruritus with increased serum bile acids and other liver function tests. The pathophysiology of OC is still not completely understood. The symptoms and biochemical abnormality rapidly resolve after delivery. OC is associated with an increased risk of adverse obstetrical outcomes. The aetiology of obstetric cholestasis of pregnancy is poorly understood and is thought to be complicated and multifactorial. OC typically occurs in the late second trimester when the oestrogen levels are the highest in pregnancy. The most common complaint is generalized intense pruritus, which usually starts after the 30th week of pregnancy. Pruritus can be more common in the palms and soles and is typically worse at night. Other symptoms of cholestasis, such as nausea, anorexia, fatigue, right upper quadrant pain, dark urine, and pale stool, can be present. Clinical jaundice is rare but may present in 14% to 25% of patients after 1 to 4 weeks of the onset of pruritus. Some patients also complain of insomnia as a result of pruritus. Generally, physical examination is unremarkable except for scratch marks on the skin from pruritus. Pruritus is a cardinal symptom of intra-hepatic cholestasis of pregnancy (ICP) and may precede biochemical abnormalities. The diagnosis of intrahepatic cholestasis of pregnancy is via the presence of clinical symptoms pruritus in the third trimester with elevated maternal total serum bile acids and excluding other diagnoses, which can cause similar symptoms and lab abnormalities. Fasting blood samples should be used to check for the total bile salt acid level as it can become elevated in the postprandial state.&#x0D; Once the diagnosis of OC of pregnancy is confirmed, immediate treatment is necessary, and the primary goal of therapy is to decrease the risk of perinatal morbidity and mortality and to alleviate maternal symptoms. Maternal pruritus can be alleviated with use of moisturisers and oral antihistamines. Ursodeoxycholic acid (UDCA) is the drug of choice for the treatment of ICP.&#x0D; Many authors have advocated elective early delivery of women with intrahepatic cholestasis of pregnancy to reduce the risk of sudden foetal death. The Royal College of Obstetricians and Gynaecologists recommends induction of labour after 37+0 weeks of gestation. Obstetric cholestasis of pregnancy is not an indication for Caesarean delivery. Postpartum pruritus typically disappears in the first 2 to 3 days following delivery, and serum bile acid concentrations will normalize eventually. ICP is not a contraindication to breastfeeding, and mothers with a history of ICP in pregnancy can breastfeed their infants. Postpartum monitoring and follow up of bile acids and liver function tests should be done in 4-6 weeks to ensure resolution. Women with the persistent abnormality of liver function test after 6 to 8 weeks require investigation for other aetiologies.

Intrahepatic cholestasis of pregnancy and comorbidity: A 44-year follow-up study.

Intrahepatic cholestasis of pregnancy (ICP) is a reversible liver disorder occurring during pregnancy. It has a typical genetic background with known genetic mutations and can be considered an expression of this genetic predisposition. The objective of this study was to determine whether ICP is associated with specific long-term comorbidity. The study population comprised 571 women with ICP in at least one pregnancy who were compared with 1333 pregnant women without ICP during 1969-1988 at Tampere University Hospital, Finland. The cohort's follow-up time was 44years. All ICD-10 classification discharge diagnoses were examined for the women in the ICP group from 1998 to 2013 and ICD-10 diagnoses from outpatient care from 1969 to 2013. At least one disease of the digestive system had been diagnosed in 50.4% (288/571) of the ICP mothers compared with 34.4% (459/1333) of the reference group (P<0.001). In a more detailed analysis, women with a history of ICP had an increased risk for cholelithiasis and/or cholecystitis (odds ratio [OR] 2.88, 95% confidence interval [CI] 2.17 to 3.84), diseases of the pancreas (OR 2.26, 95% CI 1.20 to 4.27) and hypothyroidism (OR 2.38, 95% CI 1.27 to 4.46) compared with the reference group. Arterial diseases were less common in the ICP mothers than in the reference group (OR 0.38, 95% CI .15 to .99). Regarding other diseases, there were no statistically significant differences between the ICP mothers and reference group. Half of the women with a history of ICP were diagnosed with at least one disease of the digestive system compared with a third in the reference group. The risk of cholelithiasis, cholecystitis, diseases of the pancreas and hypothyroidism was increased compared with the reference group. These are important facts when counseling women after a pregnancy with ICP. Also, this is of importance for the general practitioners and other physicians who take care of these women.

Intrahepatic cholestasis of pregnancy and associated causes of death: a cohort study with follow-up of 27\u201346\xa0years

BackgroundThe aim of this study was to determine whether intrahepatic cholestasis of pregnancy (ICP) is associated with causes of death during on average 35 years follow-up after the delivery.MethodsThe study population comprised 571 women with ICP in at least one pregnancy seen at Tampere University Hospital, Finland, between 1969 and 1988. ICP was verified from patient records. The previous and following subjects in the maternity ward diary were taken as controls for each ICP case. In total, there were 1333 controls. All underlying causes of death were obtained from Statistics Finland in March 2017. The deaths occurred during 1971–2015 and the causes of death were classified according to ICD-10.ResultsAltogether, 39 of the mothers with ICP (6.8%) and 111 of the controls (8.3%) had died by the end of 2015 (p = 0.267). There were more underlying causes of death from gastrointestinal diseases (15%) in the ICP group than in the control group (4%) (p = 0.011). The number of underlying causes of death due to diseases of the circulatory system were lower in the ICP group (13%) than in the control group (26%), although the finding was not statistically significant (p = 0.088). Moreover, neoplasms were the underlying cause of death in 46% of cases among mothers with ICP and in 41% of cases among the controls (p = 0.609). Diseases of the other organ systems were rare in both groups.ConclusionWomen with a history of ICP do not have an increased overall mortality. However, deaths from gastrointestinal diseases are overrepresented among women with a history of ICP.

Impact of Prior History of Intrahepatic Cholestasis of Pregnancy on Current Pregnancy [33K

INTRODUCTION: The purpose of this study was to determine the impact of a prior history of intrahepatic cholestasis of pregnancy (ICP) on current pregnancy course and outcome in women with subsequent ICP. METHODS: This is a retrospective cohort study, comparing multiparous patients with ICP who had a history of ICP in a prior pregnancy to those patients without a prior history. Data was collected from a single hospital between 2005 and 2013. All patients with a diagnosis of ICP were identified. Data collected included maternal demographics, ICP management, delivery and neonatal outcomes. Logistic regression was used to evaluate the overall odds of an adverse neonatal outcome for those with and without a history of ICP. RESULTS: We identified 529 multiparous pregnancies with ICP during this time, 420 (79.5%) had no prior history of ICP and 109 (20.5%) had a prior history. There were no differences in demographics between the groups. Women with a history of ICP were diagnosed 6 days sooner and were more likely to be treated with ursodiol. There were lower birthweights, higher rates of RDS, and meconium in those with a history of ICP. When adjusting for maternal demographics, prior ICP, and gestational or other diabetes, a history of ICP was not significantly associated with any adverse neonatal outcomes. CONCLUSION: Patients with a history of ICP have earlier diagnosis. There is a significantly higher rate of meconium, lower birthweight and a higher rate of RDS. This may be driven by delivery timing which serves as valuable information when counseling patients on pregnancy expectations.

Evaluation of ventricular repolarization in pregnant women with intrahepatic cholestasis

BackgroundBile acids can induce arrhythmia by altering cardiomyocyte contractility or electrical conduction. The aim of this study was to investigate, by means of QT dispersion parameter detected by simple standard electrocardiogram (ECG), ventricular repolarization changes in pregnant women with and without intrahepatic cholestasis of pregnancy (ICP). MethodsIn this case–control study including 75 pregnant women with cholestasis and 35 healthy, uncomplicated pregnancy cases, electrocardiographic QT interval durations and QT dispersion (QT-disp) parameters, corrected for the patients' heart rate using the Hodges formula, were investigated. ResultsMaximum corrected QT interval values were significantly higher in the severe ICP group than in the control group (p<0.001) and significantly higher in the severe ICP group than in the mild ICP group (p=0.01). The values of the mild ICP and control groups were similar. Corrected QT-disp values were also significantly higher in both ICP groups than in the control group and significantly higher in the severe ICP group than in the mild ICP group. ConclusionCholestatic diseases predispose patients to cardiovascular complications. Our data clearly demonstrated that QT-disp values were significantly altered in pregnant women with cholestasis when compared to the normal ones. This simple ECG parameter can be used to screen high-risk women, in order to better target counseling regarding lifestyle modifications and to conduct closer follow up and management of women with a history of ICP.

Prediction of cardiovascular risk by electrocardiographic changes in women with intrahepatic cholestasis of pregnancy

Objective: We aimed to investigate P wave characteristics in pregnant women with and without intrahepatic cholestasis of pregnancy (ICP).Methods: In this case–control study, including 59 pregnant women with intrahepatic cholestasis and 28 with healthy uncomplicated pregnancies, electrocardiographic maximum (Pmax) and minimum (Pmin) P-wave durations and P-wave dispersion (Pd) parameters were investigated.Results: While Pmin and Pd values were significantly lower in women both with mild and severe ICP when compared to healthy pregnant women (p < 0.001), there was no significant difference between mild and severe disease groups.Conclusion: Intrahepatic cholestasis predisposes to cardiovascular complications. P-wave durations and Pd constitute a recent contribution to the field of noninvasive electrocardiology. Our data clearly demonstrated that these parameters were significantly altered in pregnant women with ICP when compared to the normal ones. This important association can be used to screen for women with an increased risk to better target counseling on lifestyle modifications and to closer follow-up and management of women with a history of ICP.

Variant adiponutrin confers genetic protection against cholestatic itch.

Lysophosphatidic acid (LPA) mediates cholestatic pruritus. Recently the enzyme PNPLA3, expressed in liver and skin, was demonstrated to metabolise LPA. Here we assess the association of the PNPLA3 variant p.Ile148Met, known to be associated with (non-)alcoholic fatty liver disease (NAFLD) in genome-wide association studies, with cholestatic itch in 187 patients with primary biliary cirrhosis (PBC) and 250 PBC-free controls as well as 201 women with intrahepatic cholestasis of pregnancy (ICP) and 198 female controls without a history of ICP. Our hypothesis was that the intensity of cholestatic itch differs in carriers of distinct PNPLA3 p.Ile148Met genotypes. Patients with PBC carrying the allele p.148Met that confers an increased NAFLD risk reported less itching than carriers of the p.148Ile allele (ANOVA P = 0.048). The PNPLA3 p.148Ile allele increased the odds of requiring plasmapheresis for refractory pruritus (OR = 3.94, 95% CI = 0.91–17.00, P = 0.048). In line with these findings, the PNPLA3 p.148Met allele was underrepresented in the ICP cohort (OR = 0.66, 95% CI = 0.47–0.92, P = 0.013). Notwithstanding the need for further replication of these findings, we conclude that the PNPLA3 allele p.148Met might confer protection against cholestatic pruritus, possibly due to increased LPA-acyltransferase activity in liver and/or skin.

Medically Refractaory Pruritis from Intrahepatic Cholestasis of Pregnancy Successfully Treated with Plasmapheresis: A Case Report

Purpose: Intrahepatic cholestasis of pregnancy (ICP) is a liver disease unique to pregnancy. Characterized by pruritus and elevated serum bile acids, Ursodeoxycholic acid has been shown to be an effective treatment. Here we present a case of ICP refractory to medical therapy treated with plasmapheresis beginning in the 23rd week of pregnancy. To our knowledge, this is the earliest reported use of plasmapheresis in the treatment of medically refractory ICP. Case Report 43 year old gravida 2, para 1 with a history of ICP in week 24 of her previous pregnancy reported the onset of pruritus approximately 19 weeks into the current pregnancy. Bile acids were 18 μmol/L, AST 26 IU/L, and ALT 43 IU/L. By week 23, the serum bile acids were 344 μmol/L. Pruritus was severe and unrelenting. She was treated with hydroxyzine, ursodeoxycholic acid, corticosteroids, and topical emollients with relief. Having exhausted medical therapy, the patient was referred for plasmapheresis. After a discussion of the risks and benefits, twice weekly plasmapheresis was initiated in the 23rd week of pregnancy. Sessions were increased to three times a week and serum bile acids were controlled to less than 25 μmol/L. Decrease in bile acids led to dramatic improvement in pruritus. Treatment continued until week 32 when the patient had a normal induced vaginal delivery of a 1.9 kg male. Apgar scores were 9 at both one and five minutes. Comment ICP complicates 1-14% of pregnancies; the prevalence varies with ethnic and geographic groups. While most cases produce mild pruritus, the disorder may result in jaundice, vitamin K deficiency, and associated coagulopathy. Risks to the infant include preterm delivery, meconium aspiration and fetal demise in up to 7%. Various therapies directed at resolving pruritus have been studied and ursodeoxycholic acid has been shown to be an effective treatment. Plasmapheresis removes from circulation the bile acids that are elevated by ICP. A Pubmed search reveals this as the second reported case of medically refractory ICP treated with plasmapheresis. In this case, plasmapheresis provided prompt relief of itching and was tolerated without adverse reaction. In cases of ICP refractory to medical therapy, plasmapheresis appears to be a safe and effective treatment for the potentially debilitating pruritus.

Health history after intrahepatic cholestasis of pregnancy

To establish whether intrahepatic cholestasis of pregnancy (ICP) is associated with other diseases during a woman's lifetime. Prospective controlled cohort study. University Hospital in Finland. A total of 575 women with ICP and 1374 control women, all having delivered in 1969-1988. Questionnaires were sent to 544 ICP patients and 1235 control women. Responses were received from 1178 (66.4%). Questionnaire survey in autumn 2010. Perceived health, symptoms and complaints, diseases diagnosed by a doctor and use of medicines. No statistically significant differences were detected in perceived health. Differences in recent symptoms and complaints were small. Diagnoses made by a doctor showed higher frequencies in the ICP group than in control women for other hepatobiliary diseases, breast cancer and hypothyreosis. Diagnosed hypertension and high cholesterol requiring medication as well as cardiac arrhythmia were less frequent in the ICP group. Women in this group used antacid medicines more often than control women. There were few differences between the ICP patients and control women except for a higher frequency of later hepatobiliary disease, breast cancer and hypothyreosis. Women with a history of ICP should be screened for hypothyreosis more readily than those without. The higher frequency of breast cancer warrants further research.

Fetal Outcomes in Pregnancies Complicated by Intrahepatic Cholestasis of Pregnancy in a Northern California Cohort

BackgroundIntrahepatic 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.MethodsOne 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).ResultsThe 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.ConclusionsMaternal clinical and laboratory features, including elevated TBA, did not appear to be substantial predictors of fetal complications in ICP.

Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder, thought to be specific for pregnancy and to spontaneously resolve after delivery. Increased rates of gallstone formation and hepatitis C have previously been associated with ICP. However, there are no longitudinal studies to determine its significance as an indicator of subsequent liver or biliary diseases. In this retrospective cohort study with cases and controls we assessed the risk of liver and biliary diseases in 21,008 women, 10,504 with a history of ICP during the years 1972-2000 (cases) and 10,504 with a normal pregnancy (controls). Cases and controls were matched for age, time of delivery, and place of delivery. The diagnoses of liver and biliary disease were traced from the Finnish Hospital Discharge Register with an almost 100% coverage. Several liver and biliary diseases were found to have a significantly higher incidence in patients with ICP than in controls. The rate ratio for hepatitis C was 3.5 (CI 1.6-7.6; P < .001), for nonalcoholic liver cirrhosis 8.2 (CI 1.9-35.5; P < .05), for gallstones and cholecystitis 3.7 (CI 3.2-4.2; P < .001) and for nonalcoholic pancreatitis 3.2 (CI 1.7-5.7; P < .001). In conclusion, there is an association of ICP with several liver and biliary diseases. Some patients with ICP are at risk of the subsequent development of cirrhosis and other severe chronic diseases. Contrary to what has been previously thought, follow-up may need to be considered for these patients.

Effects of Oral and Transdermal Estradiol Administration on Levels of Sex Hormone-Binding Globulin in Postmenopausal Women with and without a History of Intrahepatic Cholestasis of Pregnancy

SHBG, the most important transport protein for sex steroids, is produced in the liver under the control of estrogen action. In a randomized, double-blind, prospective crossover study we compared basal levels of serum SHBG and their responses to increasing doses of oral and transdermal estradiol (E2), followed by E2 plus oral progestin (medroxyprogesterone acetate [MPA]), in 40 postmenopausal women with or without a history of intrahepatic cholestasis of pregnancy (ICP), which could affect the synthesis of SHBG. Serum samples collected at baseline, on the last day of each E2 period, and on the last day of the E2 plus MPA combination were assayed for SHBG and E2. Basal levels of SHBG showed no difference between the study groups. Oral but not transdermal E2 increased SHBG concentrations by 67-171% in the control group, but the response was smaller (42-121%) in the ICP group. Addition of MPA decreased SHBG levels by 14-18% in both groups during both treatments. In conclusion, a history of ICP is associated with blunted responses of SHBG to oral estrogen.

Levels of Serum C-Reactive Protein during Oral and Transdermal Estradiol in Postmenopausal Women with and without a History of Intrahepatic Cholestasis of Pregnancy

Liver dysfunction may affect the production and release of C-reactive protein (CRP). We designed a double-blind prospective crossover study involving 40 postmenopausal women with or without a history of intrahepatic cholestasis of pregnancy (ICP), where we compared the basal levels of CRP and their responses to increasing doses of oral and transdermal estradiol (E2), followed by addition of oral medroxyprogesterone acetate (MPA). Serum samples collected at baseline, on the last day of each E2 period, and on the last day of the E2 + MPA combination were assayed for CRP, estrogens, and liver enzymes. There was no difference in basal CRP between the study groups. Both regimens (oral and transdermal E2) were accompanied by significant rises in estrone and E2 concentrations; the former were 16 times higher during the oral than during the transdermal regimen. Oral E2 elevated CRP dose dependently, and this response was unaffected by a history of ICP or the use of MPA. The activities of liver transaminases varied but were in normal ranges during E2 use, in women with and without a history of ICP. In conclusion, the synthesis of CRP is not affected by a history of ICP. It is readily and dose dependently stimulated by oral but not by transdermal E2 in as soon as 2 wk.

Postmenopausal estrogen therapy and serum estradiol fatty acid esters in women with and without previous intrahepatic cholestasis of pregnancy

BACKGROUND. Fatty acid esters of 17β‐estradiol (E2) are estrogen metabolites associated with lipoproteins in blood.AIM. To study the effects of estrogen therapy on concentrations of serum E2 fatty acid esters in postmenopausal women with a history of an estrogen‐related liver disorder, intrahepatic cholestasis of pregnancy (ICP), and in healthy women in a double‐blind, crossover fashion.METHOD. ICP (n = 10) and control women (n = 10) received increasing doses of E2 valerate orally 2–4 mg/day, or transdermal E2 50–100 μg/day for 6 weeks. After a 4‐week wash‐out period, the subjects crossed over to the alternate E2 treatment. Concentrations of serum E2 fatty acid esters were quantified after saponification by fluoroimmunoassay.RESULTS. Oral E2 administration increased median serum E2 fatty acid ester concentrations from 57 to 73 pmol/L in the ICP and from 56 to 74 pmol/L in the control group, in association with elevations in serum E2, estrone and sex hormone‐binding globulin levels. Transdermal E2 treatment did not increase serum E2 ester levels.CONCLUSIONS. The increase in serum E2 fatty acid esters during oral E2 administration may be attributed, at least partly, to the higher estrogen dose during oral compared with transdermal therapy. A history of ICP did not affect esterification of E2 during estrogen therapy.

Role of S-Adenosyl-L-Methionine in the Treatment of Intrahepatic Cholestasis

Recent studies have established the clinical efficacy of S-adenosyl-L-methionine (SAMe) in the treatment of cholestasis associated with hepatic diseases, pregnancy and the administration of estrogen-containing oral contraceptives. In 4 clinical trials involving a total of 639 patients with cholestasis due to acute or chronic liver disease, SAMe in an intravenous dose of 800 mg/day or an oral regimen of 1.6 g/day for 2 weeks was superior to placebo in relieving the symptom of pruritus and in restoring serum total bilirubin and serum alkaline phosphatase towards normal. The drug is also effective in intrahepatic cholestasis of pregnancy (ICP), with intravenous administration of 800 mg/day for 2 weeks producing a substantial reduction in pruritus and an improvement in abnormal liver function indices. Moreover, SAMe treatment decreases the incidence of premature labour. SAMe appears to be the first safe and effective approach to the treatment of this syndrome, and also protects against the adverse hepatic effects of small doses of estrogen in patients with a history of ICP by normalising liver biochemistry and the oversaturated biliary lipid composition of the gallbladder bile. In animal models, SAMe reverses the pathological liver changes induced by xenobiotics such as taurolithocholate and alpha-naphthyl-isothiocyanate (ANIT) and the antipsychotic chlorpromazine. Several cooperative mechanisms appear to underlie the anticholestatic action of SAMe, the most important being the restoration of normal hepatocyte membrane fluidity and Na+, K+ ATPase activity, through a reversal of the reduction in phospholipid methylation produced by hepatotoxic agents. In addition, SAMe may act by promoting trans-sulphuration pathway reactions and consequently improving the detoxifying capacity of this metabolic system.