Liver disease in pregnancy

This article briefly discusses gestational physiologic changes and thereafter reviews liver diseases during pregnancy, which are divided into 3 main categories. The first category includes conditions that are unique to pregnancy and generally resolve with the termination of pregnancy, the second category includes liver diseases that are not unique to the pregnant population but occur commonly or are severely affected by pregnancy, and the third category includes diseases that occur coincidentally with pregnancy and in patients with underlying chronic liver disease, with cirrhosis, or after liver transplant who become pregnant.     

Pregnancy-Associated Liver Disorders

Liver disorders associated with pregnancy include hyperemesis gravidarum (HG), intrahepatic cholestasis of pregnancy (ICP), preeclampsia, syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP), and acute fatty liver of pregnancy (AFLP). These conditions are relatively common and unique to pregnancy and are more likely to occur at certain terms of gestation specific to each condition. They can be associated with significant maternal and fetal morbidity and mortality. Although managing such patients may be very challenging, spontaneous resolution of the disease occurs shortly after termination of the pregnancy, usually without hepatic sequellae. Early diagnosis and timely treatment is a key to therapeutic success. This article explores the clinical features, pathophysiology, and management of these disorders.     

Liver abnormalities in pregnancy

Abnormalities of liver function (notably rise in alkaline phosphatase and fall in serum albumin) are common in normal pregnancy, whereas rise in serum bilirubin and aminotransferase suggest either exacerbation of underlying pre-existing liver disease, liver disease related to pregnancy or liver disease unrelated to pregnancy. Pregnant women appear to have a worse outcome when infected with Hepatitis E virus. Liver diseases associated with pregnancy include abnormalities associated hyperemesis gravidarum, acute fatty liver disease, pre-eclampsia, cholestasis of pregnancy and HELLP syndrome. Prompt investigation and diagnosis is important in ensuring a successful maternal and foetal outcome. In general, prompt delivery is the treatment of choice for acute fatty liver, pre-eclampsia and HELLP syndrome and ursodeoxycholic acid is used for cholestasis of pregnancy although it is not licenced for this indication.     

Advances in understanding and treating liver diseases during pregnancy:A review

Liver disease in pregnancy is rare but pregnancyrelated liver diseases may cause threat to fetal and maternal survival.It includes pre-eclampsia;eclampsia;haemolysis,elevated liver enzymes,and low platelets syndrome;acute fatty liver of pregnancy;hyperemesis gravidarum;and intrahepatic cholestasis of pregnancy.Recent basic researches have shown the various etiologies involved in this disease entity.With these advances,rapid diagnosis is essential for severe cases since the decision of immediate delivery is important for maternal and fetal survival.The other therapeutic options have also been shown in recent reports based on the clinical trials and cooperation and information sharing between hepatologist and gynecologist is important for timely therapeutic intervention.Therefore,correct understandings of diseases and differential diagnosis from the pre-existing and co-incidental liver diseases during the pregnancy will help to achieve better prognosis.Therefore,here we review and summarized recent advances in understanding the etiologies,clinical courses and management of liver disease in pregnancy.This information will contribute to physicians for diagnosis of disease and optimum management of patients.     

Liver diseases in pregnancy: Diseases unique to pregnancy

Pregnancy is a special clinical state with several normal physiological changes that influence body organs including the liver.Liver disease can cause significant morbidity and mortality in both pregnant women and their infants.This review summarizes liver diseases that are unique to pregnancy.We discuss clinical conditions that are seen only in pregnant women and involve the liver;from Hyperemesis Gravidarum that happens in 1out of 200 pregnancies and Intrahepatic Cholestasis of Pregnancy(0.5%-1.5%prevalence),to the more frequent condition of preeclampsia(10%prevalence)and its severe form;hemolysis,elevated liver enzymes,and a low platelet count syndrome(12%of pregnancies with preeclampsia),to the rare entity of Acute Fatty Liver of Pregnancy(incidence of 1 per 7270 to 13000deliveries).Although pathogeneses behind the development of these aliments are not fully understood,theories have been proposed.Some propose the special physiological changes that accompany pregnancy as a precipitant.Others suggest a constellation of factors including both the mother and her fetus that come together to trigger those unique conditions.Reaching a timely and accurate diagnosis of such conditions can be challenging.The timing of the condition in relation toward which trimester it starts at is a key.Accurate diagnosis can be made using specific clinical findings and blood tests.Some entities have well-defined criteria that help not only in making the diagnosis,but also in classifying the disease according to its severity.Management of these conditions range from simple medical remedies to measures such as immediate termination of the pregnancy.In specific conditions,it is prudent to have expert obstetric and medical specialists teaming up to help improve the outcomes.     

Liver disease in pregnancy

Development of liver diseases during pregnancy is not uncommon. They are caused by either a disorder that is unique to pregnancy or an acute or chronic liver disease that already exists or coincidentally develops as a comorbidity of pregnancy. Liver diseases unique to pregnancy include hyperemesis gravidarum; hypertensive disorders of pregnancy, such as pre‐eclampsia/eclampsia; hemolysis, elevated liver enzymes, and low platelet count syndrome; intrahepatic cholestasis of pregnancy; and acute fatty liver of pregnancy. Chronic liver diseases that affect pregnancy, or are affected by pregnancy, mainly include autoimmune liver diseases and non‐alcoholic fatty liver disease. Prompt diagnosis and management of liver diseases in pregnancy, while very challenging, is extremely important, as they might cause adverse maternal and fetal outcomes. Therefore, a multidisciplinary, collaborative approach involving both hepatologists and obstetricians is required. In this review article, the up‐to‐date epidemiology, etiology, clinical features, and outcomes of liver diseases in pregnancy are discussed, to promote a deeper understanding among physicians, and subsequently improved outcomes.     

Acute fatty liver of pregnancy： An update on pathogenesis and clinical implications

INTRODUCTION Acute fatty liver of pregnancy (AFLP) is a maternal liver disease unique to pregnancy. It was first described in 1934 as “yellow acute atrophy of the liver[1]” and was described as a specific clinical entity in 1940[2]. AFLP is a rare, buts…     

Liver diseases in pregnancy: Liver transplantation in pregnancy

Pregnancy in patients with advanced liver disease is uncommon as most women with decompensated cirrhosis are infertile and have high rate of anovulation.However,if gestation ensued;it is very challenging and carries high risks for both the mother and the baby such as higher rates of spontaneous abortion,prematurity,pulmonary hypertension,splenic artery aneurysm rupture,postpartum hemorrhage,and a potential for life-threatening variceal hemorrhage and hepatic decompensation.In contrary,with orthotopic liver transplantation,menstruation resumes and most women of childbearing age are able to conceive,give birth and lead a better quality of life.Women with orthotopic liver transplantation seeking pregnancy should be managed carefully by a team consultation with transplant hepatologist,maternal-fetal medicine specialist and other specialists.Pregnant liver transplant recipients need to stay on immunosuppression medication to prevent allograft rejection.Furthermore,these medications need to be monitored carefully and continued throughout pregnancy to avoid potential adverse effects to mother and baby.Thus delaying pregnancy 1 to 2 years after transplantation minimizes fetal exposure to high doses of immunosuppressants.Pregnant female liver transplant patients have a high rate of cesarean delivery likely due to the high rate of prematurity in this population.Recent reports suggest that with close monitoring and multidisciplinary team approach,most female liver transplant recipient of childbearing age will lead a successful pregnancy.     

Liver disease in pregnancy

Liver diseases in pregnancy may be categorized into liver disorders that occur only in the setting of pregnancy and liver diseases that occur coincidentally with pregnancy. Hyperemesis gravidarum, preeclampsia/eclampsia, syndrome of hemolysis, elevated liver tests and low platelets （HELLP）, acute fatty liver of pregnancy, and intrahepatic cholestasis of pregnancy are pregnancy-specific disorders that may cause elevations in liver tests and hepatic dysfunction. Chronic liver diseases, including cholestatic liver disease, autoimmune hepatitis, Wilson disease, and viral hepatitis may also be seen in pregnancy. Management of liver disease in pregnancy requires collaboration between obstetricians and gastroenterologists/hepatologists. Treatment of pregnancy-specific liver disorders usually involves delivery of the fetus and supportive care, whereas management of chronic liver disease in pregnancy is directed toward optimizing control of the liver disorder. Cirrhosis in the setting of pregnancy is less commonly observed but offers unique challenges for patients and practitioners. This article reviews the epidemiology, pathophysiology, diagnosis, and management of liver diseases seen in pregnancy.     

Liver stiffness reversibly increases during pregnancy and independently predicts preeclampsia

AIM To study liver stiffness(LS) during pregnancy and its association with complications during pregnancy.METHODS In this observational, diagnostic study, 537 pregnant women were prospectively enrolled at the Department of Obstetrics and Gynecology, University hospital Heidelberg and Salem Medical Center. LS was measured using the Fibroscan device(Echosens, Paris) in all women and in 41 cases 24 h after delivery. Clinical and morphological data were recorded and abdominal ultrasound and standard laboratory tests were performed. No complications were observed in 475 women(controls) while preeclampsia and intrahepatic cholestasis of pregnancy(ICP) developed in 22 and 40 women, respectively.RESULTS In controls, LS increased significantly from initially 4.5 ± 1.2 kPa in the second trimester to 6.0 ± 2.3 kPa(P 0.001) in the third trimester. In the third trimester, 41% of women had a LS higher than 6 kPa. Elevated LS in controls was significantly correlated with alkaline phosphatase, leukocytes, gestational age and an increase in body weight and body mass index(BMI). In women with pregnancy complications, LS was significantly higher as compared to controls(P 0.0001). Moreover, in multivariate analysis, LS was an independent predictor for preeclampsia with an odds ratio of 2.05(1.27-3.31) and a cut-off value of 7.6 kPa. In contrast, ICP could not be predicted by LS. Finally, LS rapidly decreased in all women within 24 h after delivery from 7.2 ± 3.3 kPa down to 4.9 ± 2.2 kPa(P 0.001).CONCLUSION During pregnancy, LS significantly and reversibly increases in the final trimester of pregnant women without complications. In women with preeclampsia, LS is significantly elevated and an independent noninvasive predictor.     

妊娠急性脂肪肝与麻醉——13例临床分析

目的探讨妊娠急性脂肪肝（AFLP）的临床特点、围术期处理、母亲及围产儿结局,以便早期诊断和及时治疗,改善预后。方法对近3年我院收治的13例AFLP患者的症状、实验室检查、临床过程、围术期处理以及母亲和围产儿结局进行回顾性分析。结果AFLP76．92％发生于初产妇,男性胎儿占69．23％,前驱症状为乏力、纳差、恶心、呕吐、黄疸,实验室检查示凝血病、肝功能异常、低血糖、低蛋白血症、尿胆红素阴性,产妇死亡2例,占15．4％,无围产儿死亡。麻醉方法采用椎管内麻醉（10例,76．9％）,全身麻醉（2例,15．4％）。结论妊娠急性脂肪肝是发生于妊娠晚期的一种严重并发症,早期诊断、尽快终止妊娠和围术期积极的对症支持治疗是提高母儿预后的关键。麻醉方法应个体化,有明显凝血病的患者以全身麻醉首选。     

Liver transplantation for nonalcoholic fatty liver disease:New challenges and new opportunities

Nonalcoholic fatty liver disease(NAFLD)is becoming rapidly one of the most common indications for orthotopic liver transplantation in the world.Development of graft steatosis is a significant problem during the posttransplant course,which may happen as a recurrence of pre-existing disease or de novo NAFLD.There are different risk factors that might play a role in development of graft steatosis including post-transplant metabolic syndrome,immune-suppressive medications,genetics and others.There are few studies that assessed the effects of NAFLD on graft and patient survival;most of them were limited by the duration of follow up or by the number of patients.With this review article we will try to shed light on post-liver transplantation NAFLD,significance of the disease,how it develops,risk factors,clinical course and treatment options.     

腺苷蛋氨酸和熊去氧胆酸治疗妊娠期肝内胆汁淤积症的回顾性分析

目的比较S-腺苷蛋氨酸（SAMe）、熊去氧胆酸（UDCA）以及二者联合用药对于妊娠期肝内胆汁淤积症（ICP）的治疗效果。方法根据药物治疗方案的不同,将138例ICP患者分成3组：A组43例,单用SAMe1g＋5%葡萄糖500mL,静脉滴注;B组56例,单用UDCA每日15mg/kg,口服;C组39例,联合使用SAMe1g和UDCA每日15mg/kg治疗。疗程均为2周,观察疗效。结果三组患者治疗后的瘙痒评分、总胆汁酸（TBA）、ALT和AST均较治疗前有所下降,差异均具有统计学意义（P〈0.01）,其中以C组下降最显著;而总胆红素（TBil）水平治疗前后差异无统计学意义（P〉0.05）。C组中直接胆红素（DBil）的下降较治疗前差异有统计学意义（P〈0.05）,但在A组和B组,DBil治疗前后的变化差异无统计学意义（P〉0.05）。在改善妊娠结局方面,三种治疗方法的效果差异无统计学意义（P〉0.05）。结论 SAMe和UDCA均是治疗ICP的有效药物,联合用药效果最佳。     

Acute fatty liver of pregnancy associated with severe acute pancreatitis: A case report

Acute fatty liver of pregnancy is a rare disease that affects women in the third trimester of pregnancy. Although infrequent, the disease can cause maternal mortality. The diagnosis is not always clear until the pregnancy is terminated, and significant complications, such as acute pancreatitis, can occur. Pancreatic involvement typically only occurs in severe cases after the development of hepatic and renal impairment. To date, little knowledge is available regarding how the disease causes pancreatitis. Treatment involves supportive measures and pregnancy interruption. In this report, we describe a case of a previously healthy 26-year-old woman at a gestational age of 27 wk and 6 d who was admitted with severe abdominal pain and vomiting. This case illustrates the clinical and laboratory overlap between acute fatty liver of pregnancy and pancreatitis, highlighting the difficulties in differentiating each disease. Furthermore, the hypothesis for this overlapping is presented, and the therapeutic options are discussed.     

Diabetes and liver disease: an ominous association

Diabetes mellitus and advanced liver disease are associated with each other more frequently than expected by chance, and such an association carries a significant risk of morbidity and mortality. A metabolic pathway leading to advanced liver disease via fatty liver and steatohepatitis has been demonstrated, further supporting the possibility that cirrhosis may be a late complication of diabetes. In addition, an interaction between hepatitis C virus (HCV) and insulin resistance increases the overall prevalence of associated diseases, through largely unidentified mechanisms. Extensive prospective monitoring of non-alcoholic fatty liver disease cases, analysis of insulin signaling in HCV-infected patients using molecular biology techniques, and intervention studies, will help to clarify the mechanisms of action of the possible clinical strategies, the predictive value of biochemical, histological, and clinical markers, and the effectiveness of treatments available.     

Early treatment efficacy of S-adenosylmethionine in patients with intrahepatic cholestasis: A systematic review

BACKGROUND S-adenosylmethionine(Ado Met) is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis(IHC) and chronic liver diseases. While the efficacy of Ado Met has been demonstrated previously, it has not been systematically investigated within the early weeks of treatment.AIM To systematically review the early treatment efficacy of Ado Met in adult patients with IHC.METHODS Studies reporting the efficacy of intravenous, intramuscular, or oral forms of Ado Met within 8 wk of treatment initiation were considered; three randomized and six non-randomized studies were eligible for inclusion(PROSPERO registration number CRD42018090936). Of the three randomized studies, two were double-blind and placebo-controlled, and one was comparator-controlled with unclear blinding and a relatively high risk of bias. Mean serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), alkaline phosphatase(ALP), and gamma-glutamyl transferase(_γGT) following Ado Met treatment vs placebo, comparator, or baseline were summarized to determine differences in liver enzymes. Changes in patient-reported clinical symptoms of cholestasis were also summarized.RESULTS Both placebo-controlled randomized studies reported significant reductions in serum ALT levels with Ado Met vs placebo within 2 wk. One of these also reported significant ALP reductions, and the other reported significant AST and _γGT reductions within 2 wk. The comparator-controlled randomized study,which had a number of notable limitations, reported significant reductions in serum ALT and AST levels with Ado Met vs potassium magnesium aspartate within 4 wk, but not within2 wk. All of the non-randomized studies(4/4) that investigated ALT, AST, ALP and/or _γGT reported significant reductions in at least two of these parameters within 2 wk. Of the five studies that evaluated fatigue, reductions were observed within 2 wk in one randomized and two nonrandomized studies. The remaining two non-randomized studies reported improvements in fatigue within 6 and 8 wk. Of the four studies reporting symptoms of depression, two non-randomized studies observed improvements within 2 wk and the other two observed improvements within 17 d and 8 wk.CONCLUSION Data from both randomized and non-randomized studies suggest that Ado Met improves some biochemical liver parameters and symptoms of cholestasis within2 wk, with further improvements observed in some studies after 4 and 8 wk of treatment.     

妊娠急性脂肪肝剖宫产术患者临床护理体会

目的探讨妊娠急性脂肪肝剖宫产术患者围手术期护理特点。方法选择1996年1月至2012年1月本院行剖宫产手术的AFLP患者剖宫产手术围手术期护理经验进行总结。结果共计19例患者纳入研究,平均年龄（27.9±3.5）岁,其中初产妇14例（73.7%）前驱症状为乏力、纳差、恶心、呕吐、黄疸。实验室检查示肝功能异常、凝血功能障碍、白细胞升高、肾功能损伤等。入院后密切进行胎儿监测、对围手术期孕产妇进行心理干预,在术后密切注意产后出血的观察和护理,同时加强产后护理,预防感染等护理措施干预后,产妇死亡2例（10.5%）,无围产儿死亡。结论对妊娠急性脂肪肝围手术期患者采取综合护理措施,对于改善预后起到积极的帮助。