Intrahepatic cholestasis of pregnancy is of unknown cause, characterized by hepatic dysfunction and pruritus, which resolve postpartum.1–3 The identification of women with intrahepatic cholestasis of pregnancy is important because it is a significant cause of maternal and perinatal morbidity and mortality.1–4 However, the differential diagnosis includes benign pregnancy-related pruritus (pruritus gravidarum), which is not associated with cholestasis and is difficult to distinguish from intrahepatic cholestasis of pregnancy early in pregnancy when liver function is apparently normal.5,6
Intrahepatic cholestasis of pregnancy is associated with an increased prevalence of cholelithiasis,7,8 and cross-sectional studies have reported an association of intrahepatic cholestasis of pregnancy with deranged lipid profiles.9–12 However, it is unclear whether dyslipidemia is a primary causative process in intrahepatic cholestasis of pregnancy or secondary to established hepatocellular dysfunction. A primary role for altered lipid metabolism in the pathophysiology of pregnancies affected by intrahepatic cholestasis of pregnancy is plausible, because lipoproteins and constituent lipids contribute to oxidative stress and influence cell membrane fluidity, permeability of canalicular epithelium, and the function of hepatobiliary transporters and receptors and promote synthesis of cholestatic metabolites of placental steroid hormones.13–16
The aim of this study was to evaluate plasma lipids in a prospectively recruited cohort of women with intrahepatic cholestasis of pregnancy, pruritus gravidarum, and gestation matched healthy pregnancies. The effect of ursodeoxycholic acid on the lipid parameters was also investigated,17 because it is known to decrease plasma total and low-density lipoprotein (LDL) cholesterol in hypercholesterolemic patients.18
MATERIALS AND METHODS
This study used blood samples from women recruited prospectively from the antenatal clinics of 3 London hospitals (Whipp's Cross, West Middlesex, and Guy's and St Thomas' NHS Foundation Trust) for an investigation of pruritus in pregnancy from August 1999 to April 2001 (Kenyon AP, Girling J, Nelson-Piercy C, Williamson C, Seed PT, Poston L, et al. Pruritus in pregnancy and the identification of those at risk of obstetric cholestasis: A prospective prevalence study of 6531 women [abstract]. J Soc Gynecol Investig 2002;9:671A). Informed consent was obtained from each patient and the study had local ethical committee approval at each site. Sixty-three women with intrahepatic cholestasis of pregnancy (54 recruited at the time of diagnosis and 9 recruited before diagnosis of intrahepatic cholestasis of pregnancy) and pruritus gravidarum (n = 43, pruritus with no evidence of liver dysfunction) were identified and recruited. A further 26 age-matched healthy pregnant women (controls) were also recruited during the same period. The clinical details of this cohort of women are as described previously.19
Intrahepatic cholestasis of pregnancy was defined as persistent pruritus in combination with abnormal liver biochemistry that resolved postnatally in the absence of any other known liver or skin pathology. Abnormal liver biochemistry was defined as 1 or more abnormalities in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, or total bile acids (≥14 μM).19 The clinical diagnosis of intrahepatic cholestasis of pregnancy was confirmed using values of 80% of the normal upper reference limit for each local laboratory.20 On detection of abnormal liver function, possible alternative causes of liver disease were sought by testing for anti–smooth muscle antibodies, antimitochondrial antibodies, Epstein Barr virus, cytomegalovirus, hepatitis A, hepatitis B, and hepatitis C serology and by performing liver ultrasonography. In the intrahepatic cholestasis of pregnancy group, 2 women had essential hypertension, 1 had polycystic ovarian disease, and 1 subject had Sjogren's syndrome with positive anti-Ro antibodies. Seventeen women in the intrahepatic cholestasis of pregnancy group received ursodeoxycholic acid (maximal dose 2 g/d) and 4 women with intrahepatic cholestasis of pregnancy received dexamethasone for symptomatic relief.
Women with pruritus and normal liver biochemistry, but without pregnancy-specific dermatosis or hepatic pathology, were defined as having pruritus gravidarum. In the pruritus gravidarum group, 1 woman had essential hypertension. Women with a history of pruritus, cholestasis during pregnancy, jaundice or pruritus by oral contraceptives, hepatitis, or any other disease affecting hepatobiliary function were excluded from the control group.
Nonfasted blood samples were obtained at 4 weekly intervals during pregnancy and 4 to 6 weeks postpartum together with information regarding the nature and severity of any symptoms. Sampling was less frequent in some women, but an average of 3 samples was obtained from each woman (Table 1), and all available blood samples were analyzed in the present study. Post hoc power calculations were not performed.21 Only blood samples before ursodeoxycholic acid and dexamethasone treatment were included in the longitudinal assessment of plasma lipid concentrations in the intrahepatic cholestasis of pregnancy group. The last longitudinal sample before administration of ursodeoxycholic acid and the sample at which maximal ursodeoxycholic acid serum concentrations were recorded were used to determine the effect of ursodeoxycholic acid on lipid measurements. Liver function data for this cohort of patients during pregnancy and 4–6 weeks postpartum are published.19
Plasma was stored at −80°C before analysis. Plasma total cholesterol was assayed by an enzymatic colorimetric test, LDL cholesterol by a selective inhibition colorimetric assay using direct double precipitation method (ABX Diagnostics, Montpellier, France), and high-density lipoprotein (HDL) cholesterol by an immunoinhibition method (Wako Chemicals, Neuss, Germany) on an automated Cobas Mira analyser (Roche, Lewes, Sussex, UK). Apolipoprotein A-I (apo A-I) and apolipoprotein B-100 (apo B) were measured using an International Federation of Clinical Chemistry standardized nephelometric method on a Behring BN 2 analyzer (Dade Behring, Marburg, Germany) using reagents and protocols supplied by the manufacturer. For ethical reasons pregnant participants could not be asked to fast before blood was drawn; consequently, triglycerides were not assessed. Coefficients of variations were less than 5% for all assays. Very-low-density lipoprotein (VLDL) cholesterol was calculated by the formula VLDL cholesterol equals total cholesterol minus LDL cholesterol minus HDL cholesterol. Calculated values less than 0.1 mM for VLDL cholesterol were censored due to being likely to be caused by the effects of primary assay variance. The cardiovascular risk predictor indices, total and HDL cholesterol, apo B and apo A-I, and LDL and HDL cholesterol were also calculated for each measurement. Ursodeoxycholic acid concentrations were determined in serum after solid phase extraction using high-performance liquid chromatography and mass spectrometry.
Stata 8.0 (StataCorp, College Station, TX) was used for data analysis. Distributions were investigated using Box-Cox transformation tests and normal distribution plots.22 For LDL cholesterol, apo B, total cholesterol, VLDL cholesterol, and all ratios, the data were closer to a log-normal distribution than a normal distribution and accordingly underwent log transformation. Results are expressed as ratios (or percentages) with 95% confidence intervals (CIs) for statistical analysis and geometric means with standard errors of the mean (SEM) for graphical display (Figs. 1 and 2). For HDL cholesterol and apo A-I, results are expressed as differences between groups and arithmetic means. Graphs were plotted using Sigma Plot 6.0 (SPSS Inc, Chicago, IL). Tobit regression was used to allow for values censored at the limit of detection for a test by the maximum likelihood approach.23 To compare subject groups, regression using generalized estimating equations was used (command -xtgee- in Stata).24 Gestational age, in 4-week categories, was included in the model as a main effect. Standard errors, CI, and P values were adjusted to allow for multiple measurements on the same subject using Huber's method.25 Interaction tests were performed to determine whether the effect of gestation on lipid measurements differed between the groups. Exact P values are given, small P values in the range .05 to .001 are taken as increasing evidence against the null hypothesis, but the totality of evidence is regarded as more important than any single test.26
In the intrahepatic cholestasis of pregnancy group, the mean maternal age (± standard deviation) was 31 ± 5 years, with the median gestation at diagnosis being 33 + 4 weeks (range 12 + 0 to 40 + 5) weeks and the onset of pruritus occurred at 30 (range 4–39) weeks, as recalled by women at the time of recruitment. Liver biochemistry normalized and pruritus resolved postnatally in all intrahepatic cholestasis of pregnancy cases. In the healthy pregnant control and pruritus gravidarum groups, the mean maternal age (± standard deviation) was 31 ± 5 years and 31 ± 4 years, respectively. Gestational age at delivery was 37 + 4 ± 1 + 2, 39 + 4 ± 1 + 5, and 39 + 6 ± 1 + 3 weeks for the intrahepatic cholestasis of pregnancy, pruritus gravidarum, and control groups, respectively.
Total cholesterol concentrations were significantly elevated in intrahepatic cholestasis of pregnancy women (Fig. 1A), compared with controls (19%, P = .001) and pruritus gravidarum groups (32%, P < .001) during the gestational period investigated (Table 2). Significant elevations in total cholesterol in the intrahepatic cholestasis of pregnancy women, compared with control and pruritus gravidarum groups, were first detected at 28 weeks (P = .02) and 16 weeks (P = .008), respectively. Total cholesterol was also higher in postnatal (Table 3) samples in women with intrahepatic cholestasis of pregnancy compared with controls (18%, P = .003) or pruritus gravidarum (20%, P = .002). Plasma total cholesterol concentrations were slightly lower in the pruritus gravidarum group compared with controls across gestation (P = .019), but this difference was not apparent postnatally. Total cholesterol changed significantly with gestation (P ≤ .001) and followed a similar temporal pattern throughout pregnancy in all groups (Fig. 1A). Maximal total cholesterol concentrations exceeded 5.2 mM (200 mg/dL) in 96% of the controls (n = 25), 81% of pruritus gravidarum (n = 35), and 95% of intrahepatic cholestasis of pregnancy (n = 60) cases. There was no significant difference in VLDL cholesterol concentrations (Fig. 1B) overall during the gestational period investigated (except a slight difference between pruritus gravidarum and controls [−28%, P = .041], Table 2) or postpartum (Table 3) in all groups. Very-low-density lipoprotein cholesterol concentrations did not change significantly with gestation in any of the groups (Fig. 1B).
Plasma LDL cholesterol was consistently elevated from 16 weeks (P < .001) and throughout the gestational period investigated in the intrahepatic cholestasis of pregnancy group (Fig. 1C) compared with control (56%, P < .001) and pruritus gravidarum (57%, P < .001) women (Table 2). Data from 16 weeks (n = 3/4), 20 weeks (n = 6/6) and 24 weeks (n = 4/6) predominantly originates from the subgroup of women who provided plasma samples before diagnosis of intrahepatic cholestasis of pregnancy. Postpartum, higher LDL cholesterol was observed in the intrahepatic cholestasis of pregnancy group compared with control (64%, P < .001) and pruritus gravidarum (55%, P < .001) cases (Table 3). Low-density lipoprotein cholesterol significantly increased across gestation (P < .001) in all 3 groups of women, with a tendency to peak before 40 weeks. Low-density lipoprotein cholesterol was similar in control and pruritus gravidarum women (Tables 2 and 3) throughout pregnancy (P = .931) and postpartum (P = .707). Maximal LDL cholesterol exceeded 3.4 mM (120 mg/dL) in 42% (n = 11) of controls, 42% (n = 18) of pruritus gravidarum, and 92% (n = 58) of intrahepatic cholestasis of pregnancy cases.
Plasma HDL cholesterol was lower (Fig. 1D) in women with intrahepatic cholestasis of pregnancy than controls (−0.4 mM, P < .001) or pruritus gravidarum (−0.2 mM, P < .001) across gestation (Table 2). HDL cholesterol was slightly lower in the intrahepatic cholestasis of pregnancy group compared with control and pruritus gravidarum groups from week 20 (P < .02) and week 28 (P < .001) respectively. No significant differences in HDL cholesterol were detected postnatally between the groups (Table 3). Pruritus gravidarum pregnancies had significantly lower HDL cholesterol (-0.2 mmol/L, P < .01) than controls (Table 2) during the pregnancy period investigated. Plasma HDL cholesterol did not change with gestation in control (P = .549) or pruritus gravidarum cases (P = .120). However, the temporal pattern of HDL cholesterol was significantly different in the intrahepatic cholestasis of pregnancy group. High-density lipoprotein fell with advancing gestation in women with intrahepatic cholestasis of pregnancy compared with those in pruritus gravidarum and control groups (group-time interaction test, P = .008). Minimal HDL cholesterol levels fell below 1.2 mM (60 mg/dL) in 23% of control (n = 7), 35% (n = 15) of pruritus gravidarum pregnancies, and 65% (n = 41) of women with intrahepatic cholestasis of pregnancy.
In women with intrahepatic cholestasis of pregnancy, apo B was elevated over the study (Fig. 1E) compared with controls (13%, P = .05) and pruritus gravidarum (23%, P < .001) cases, with no difference (P = .166) between the pruritus gravidarum or control groups (Table 2). However, apo B was only significantly raised in the intrahepatic cholestasis of pregnancy group compared with pruritus gravidarum cases from 24 weeks (P = .01) onwards. Apo B concentrations increased with gestation in all women (Fig. 1E, P < .001). Apo B levels were similar in all postpartum groups (Table 3). Apo A-I concentrations were similar in all 3 groups (Table 2, Fig. 1F) throughout the pregnancy period investigated. There is a suggestion that apo A-I concentrations fall in the intrahepatic cholestasis of pregnancy group toward the end of pregnancy compared with a rise in controls and pruritus gravidarum groups (gestation by group interaction test, P = .004), but no consistent difference between the groups was detected at individual time points. In postnatal samples, there was a slight reduction in apo A-I plasma concentrations in the intrahepatic cholestasis of pregnancy group compared with pruritus gravidarum cases (P = .004, Table 3).
The differences in cardiovascular risk indices LDL/HDL cholesterol and total/HDL cholesterol in the 3 groups mirrored the temporal patterns of individual lipids. Low-density lipoprotein/HDL cholesterol and total/HDL cholesterol were consistently higher in the gestational period studied (from 16 weeks onwards, Table 2, Fig. 2, P ≤ .002) and in postnatal (Table 3) samples in the intrahepatic cholestasis of pregnancy group compared with controls and pruritus gravidarum cases. Apo B/Apo A-I was only raised in intrahepatic cholestasis of pregnancy group compared with pruritus gravidarum across gestation (P < .01), and this difference remained post partum. Ursodeoxycholic acid treatment was reflected by substantial elevations in serum concentrations of ursodeoxycholic acid, but this was not related to any significant change in lipid, lipoprotein, or apolipoprotein concentrations (Table 4) during treatment.
The mechanisms responsible for the development of intrahepatic cholestasis of pregnancy in otherwise healthy pregnancies are unknown. A defect centered on hepatobiliary transport proteins is likely;2 however, the findings of this study suggest that lipid metabolism may also be involved. This study has shown that lipids, lipoproteins, and apolipoproteins undergo both quantitative and gestation-related alterations in healthy pregnancy.27 These differences in the lipid profile were exaggerated, or even reversed, in women with intrahepatic cholestasis of pregnancy. This corroborates and expands upon earlier cross-sectional studies reporting lipid alterations in this condition.28,29 Moreover, we have clearly demonstrated that intrahepatic cholestasis of pregnancy is associated with raised abnormal plasma LDL cholesterol concentration throughout gestation, which clearly distinguishes women with intrahepatic cholestasis of pregnancy from those with pruritus gravidarum.
LDL cholesterol was measured in this study, unlike previously,29 by a direct method. This has 2 advantages: 1) the Friedwald equation for calculating LDL cholesterol has never been validated in pregnancy and 2) fasting plasma samples, essential for the Friedwald equation that are ethically difficult to obtain from pregnant women, are no longer required. Using this method, LDL cholesterol was shown to be elevated in the intrahepatic cholestasis of pregnancy group from 16 weeks of gestation and throughout pregnancy, several weeks earlier than the mean gestation for diagnosis as assessed by conventional markers (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and total bile acids)19 in plasma samples taken at the same time points. Because the majority of plasma samples taken before 24 weeks of gestation originated from women who were recruited before diagnosis, we propose that direct measurement of LDL cholesterol in women presenting with pruritus may be a useful single test for distinguishing between intrahepatic cholestasis of pregnancy and pruritus gravidarum.
Alterations in plasma LDL cholesterol concentrations are often reflected in apo B concentrations because particles in the endogenous lipid pathway contain 1 apo B/ lipoprotein particle, but this was not obviously apparent in the intrahepatic cholestasis of pregnancy women. Although there was an overall increase in the apo B concentrations in the intrahepatic cholestasis of pregnancy group compared with pruritus gravidarum cases (not controls) this was only detectable later in gestation (from 24 weeks'). This may imply that the increase in LDL cholesterol relates to an increase in particle size (ie, an increase in the amount of cholesterol carried per apo B particle) as opposed to particle number.
The lower plasma concentrations of HDL cholesterol in the intrahepatic cholestasis of pregnancy group compared with pruritus gravidarum and controls may have several important consequences, because HDL cholesterol is considered to have a beneficial role in pregnancy.11 Lower HDL cholesterol in the pruritus gravidarum group conflicts with a previous study reporting no difference with pregnant controls;29 this may in part be due to the small numbers in the earlier study, the different criteria used in the characterization of pruritus gravidarum, or indeed a different assay method for HDL cholesterol.
Interestingly, the concentration of apo A-I, the major heterogenic protein in HDL, was similar among the 3 groups of women despite a decrease in HDL cholesterol in the intrahepatic cholestasis of pregnancy group. This implies a depletion or redistribution of cholesterol from HDL particles in women with intrahepatic cholestasis of pregnancy rather than an overall increase in HDL turnover. This may account for the observation that the plasma LDL cholesterol concentration in pregnant women with intrahepatic cholestasis is increased across gestation without a concomitant increase in apo B.
The literature reporting total cholesterol in women with intrahepatic cholestasis of pregnancy presents a conflicting picture.10,29,30 Our study suggests that total cholesterol concentrations are raised throughout gestation (from 16–24 weeks) in comparison with both controls and women with pruritus gravidarum and that the gestational profile of plasma total cholesterol is similar to that of LDL cholesterol. Interestingly there were no consistent changes in VLDL cholesterol in the intrahepatic cholestasis of pregnancy group.
The lipid changes associated with intrahepatic cholestasis of pregnancy could be the consequence of the modulation of lipid metabolism by bile acids.31–34 However, in the current cohort bile acids were only raised from 28 weeks gestation,19 so while bile acids may be responsible for the changes in HDL cholesterol in the intrahepatic cholestasis of pregnancy group, they are unlikely to influence LDL cholesterol, which was altered several weeks before elevations in bile acids (as are other liver function markers).19 The abnormal LDL cholesterol profile may, therefore, be fundamental to the development of intrahepatic cholestasis of pregnancy, rather than a consequence of the disease process.
Two lipid indices were significantly increased in women with intrahepatic cholestasis of pregnancy throughout gestation compared with pregnant controls. The ratio of LDL to HDL cholesterol seemed to be particularly useful in the identification of intrahepatic cholestasis of pregnancy from pruritus gravidarum and controls. Two atherogenic predictor indices calculated in this study were significantly higher in postnatal samples, as were LDL cholesterol and total cholesterol, with lower HDL cholesterol concentrations observed in women with intrahepatic cholestasis of pregnancy. This raises the possibility that the dyslipidemia observed in pregnancies complicated by intrahepatic cholestasis of pregnancy reveals an underlying lipoprotein disorder. The evaluation of plasma lipids several months or years postpartum in women who have had intrahepatic cholestasis of pregnancy is therefore indicated.
Ursodeoxycholic acid is increasingly used to treat patients with intrahepatic cholestasis to alleviate the symptoms of intrahepatic cholestasis of pregnancy.17,35 However, in this study ursodeoxycholic acid had no significant effect on lipid, lipoprotein, or apolipoprotein concentrations in 17 women with intrahepatic cholestasis of pregnancy in this study, despite a substantial elevation of serum ursodeoxycholic acid concentrations after treatment.
The data presented here provide an integrated description of the temporal pattern of changes in lipid, lipoprotein, and apolipoprotein levels during pregnancy and postpartum in women with intrahepatic cholestasis of pregnancy and pruritus gravidarum. Major alterations occur in hepatic lipid homeostasis during intrahepatic cholestasis of pregnancy, and in particular, LDL cholesterol may prove to be useful for the early recognition of the disease.
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