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 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.     

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.     

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。     

Clinical course and management of acute and chronic viral hepatitis during pregnancy

Pregnancy is a para‐physiologic condition, which usually evolves without any complications in the majority of women, even if in some circumstances moderate or severe clinical problems can also occur. Among complications occurring during the second and the third trimester very important are those considered as concurrent to pregnancy such as hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, HELLP syndrome and acute fatty liver of pregnancy. The liver diseases concurrent to pregnancy typically occur at specific times during the gestation and they may lead to significant maternal and foetal morbidity and mortality. Commonly, delivery of the foetus, even preterm, usually terminates the progression of these disorders. All chronic liver diseases, such as chronic viral hepatitis, autoimmune hepatitis, Wilson's disease, and cirrhosis of different aetiologies may cause liver damage, independently from pregnancy. In this review we will also comment the clinical implications of pregnancies occurring in women who received a orthotopic liver transplantation (OLT) Therefore, the management of immunosuppressive therapy before and after the delivery in women who received liver transplant is becoming a relevant clinical issue. Finally, we will focus on acute and chronic viral hepatitis occurring during pregnancy, on management of advanced liver disease and we will review the literature on the challenging issue regarding pregnancy and OLT.     

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.     

Pregnancy and liver transplantation

Since the first pregnancy in a transplant recipient in 1958, pregnancy in recipients of solid organ transplants has become increasingly common. Although previously considered a hazardous event, data collected over the last 50 years demonstrate that despite an increased risk of maternal and fetal complications, pregnancy in transplant recipients can have a successful outcome. As of 2006, there were over 3000 female liver transplant recipients of childbearing age in the USA. Two hundred and two pregnancies and 205 outcomes were reported in 121 liver transplant recipients in the National Transplantation Pregnancy Registry. Children born to female liver recipients have a greater risk of prematurity and low birth weight than the general population, but no malformation patterns have been observed. Mothers are more likely to experience pregnancy‐induced hypertension, pre‐eclampsia and caesarian section, but overall mortality is not worse. Rates of acute rejection and graft loss are similar to nonpregnant liver recipients. The optimal timing of conception post‐transplant is controversial, but current recommendations suggest waiting for at least 1 year after transplantation. Choice of contraception is also debatable, although barrier methods have traditionally been preferred. Many medications used for post‐transplant immunosuppression have potential effects during pregnancy and breast‐feeding. The risks and benefits of each medication should be reviewed with patients contemplating pregnancy, and regimens should be tailored accordingly.     

Liver disease in pregnancy: Medical aspects and their implications for mother and child

Liver disease during pregnancy is more common than expected and may require specialized intervention. It is important to determine if changes in liver physiology may develop into liver disease, to assure early diagnosis. For adequate surveillance of mother-fetus health outcome, liver disease during pregnancy might require intervention from a hepatologist. Liver diseases have a prevalence of at least 3% of all pregnancies in developed countries, and they are classified into two main categories: related to pregnancy; and those non- related that are present de novo or are preexisting chronic liver diseases. In this review we describe and discuss the main characteristics of those liver diseases associated with pregnancy and only some frequent pre-existing and co-incidental in pregnancy are considered.In addition to the literature review, we compiled the data of liver disease occurring during pregnancies attended at the National Institute of Perinatology in Mexico City in a three-year period.In our tertiary referral women hospital, liver disease was present in 11.24 % of all pregnancies. Associated liver disease was found in 10.8% of all pregnancies, mainly those related to pre-eclampsia (9.9% of pregnancies). Only 0.56% was due to liver disease that was co-incidental or preexisting; the acute or chronic hepatitis C virus was the most frequent in this group (0.12%).When managing pregnancy in referral hospitals in Latin America, it is important to discard liver alterations early for adequate follow up of the disease and to prevent adverse consequences for the mother and child.     

Acute fatty liver of pregnancy causes severe acute pancreatitis and stillborn fetus: A case report

Rationale:Acutefatty liver of pregnancy (AFLP) is a potentially fatal obstetric emergency characterized by acute hepatic failure secondary to fatty infiltration. The resultant effects include coagulopathy, electrolyte abnormalities, and multisystem organ dysfunction. Pancreatitis typically develops after the onset of renal and hepatic dysfunction. Pancreatitis has been suggested as a poor prognostic indicator because it is associated with more adverse outcomes.Patient concerns:A 29-year-old Chinese woman at 34.7 weeks pregnancy was admitted to hospital due to paroxysmal hypogastric pain and massive colporrhagia for 1 day.Diagnosis:Laboratory tests revealed hepatic and renal impairment, coagulopathy. Thoracoabdominal computed tomography (CT) scanning showed pleural and peritoneal effusion, fatty liver, and pancreatitis. She was diagnosed with AFLP, severe acute pancreatitis (SAP), multiple organ dysfunction syndrome (MODS), and intrauterine fetal death.Interventions:The patient was treated with blood component transfusions, plasma exchange combined with renal replacement therapy, antibiotic de-escalation, gastric and pancreatic secretion inhibitor, and enteral nutrition.Outcomes:After successful management, the patient was discharged without any complications on day 35 of admission. At 10 months follow-up, thoracoabdominal enhanced CT revealed was normal and laboratory tests revealed normal liver and kidney function.Lessons:Once AFLP is highly suspected or confirmed, the pregnancy should be terminated in time and active symptomatic management should be given.     

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.     

Lebererkrankungen in der Schwangerschaft

In pregnancy physiologically induced altered levels in liver function tests have to be distinguished from liver diseases. These can be divided into clearly pregnancy-associated and liver diseases coincidentally occurring with pregnancy, such as gall-stones, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson??s disease, hepatitis B and C infections and cirrhosis of the liver. Pregnancy-associated liver diseases include hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, preeclampsia/eclampsia, the hemolysis, elevated liver tests and low platelets (HELLP) syndrome and acute fatty liver of pregnancy. A close collaboration between obstetricians and hepatologists is recommended. In terms of pregnancy-related entities this often means prompt delivery of the neonate, whereas in pregnancy-independent liver diseases best supportive care including supervision of the embryo/fetus has priority.     

Pregnancy-related liver diseases

Liver diseases related to pregnancy may be associated with preeclampsia (liver dysfunction related to preeclampsia; hemolysis, elevated liver enzymes, and low platelets with or without preeclampsia [HELLP syndrome]; and acute fatty liver of pregnancy) or may not involve preeclampsia (hyperemesis gravidarum and intrahepatic cholestasis of pregnancy). Liver diseases associated with pregnancy have unique presentations, but it can be difficult differentiating these from liver diseases that occur coincidentally with pregnancy. Recently, advances have been made in the disease mechanism and intervention of pregnancy-related liver diseases. Early diagnosis and delivery remains the key element in managing the liver diseases associated with preeclampsia, but emerging data suggest that incorporating advance supportive management into current strategies can improve both maternal and fetal 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…     

Low Antithrombin III in Acute Hepatic Failure at Term

2 cases surviving acute fatty liver of pregnancy are reported. Both cases had signs of disseminated intravascular coagulation, and extremely low plasma concentration of antithrombin III. One of the women received antithrombin III concentrate. The rationale of this therapy is discussed.     

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。     

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.     

Gut microbiota in non‐alcoholic fatty liver disease and alcohol‐related liver disease: Current concepts and perspectives

The term, gut–liver axis, is used to highlight the close anatomical and functional relationship between the intestine and the liver. It has been increasingly recognized that the gut–liver axis plays an essential role in the development and progression of liver disease. In particular, in non‐alcoholic fatty liver disease and alcohol‐related liver disease, the two most common causes of chronic liver disease, a dysbiotic gut microbiota can influence intestinal permeability, allowing some pathogens or bacteria‐derived factors from the gut reaching the liver through the enterohepatic circulation contributing to liver injury, steatohepatitis, and fibrosis progression. Pathways involved are multiple, including changes in bile acid metabolism, intestinal ethanol production, generation of short‐chain fatty acids, and other by‐products. Bile acids act through dedicated bile acid receptors, farnesoid X receptor and TGR5, in both the ileum and the liver, influencing lipid metabolism, inflammation, and fibrogenesis. Currently, both non‐alcoholic fatty liver disease and alcohol‐related liver disease lack effective therapies, and therapeutic targeting of gut microbiota and bile acids enterohepatic circulation holds promise. In this review, we summarize current knowledge about the role of gut microbiota in the pathogenesis of non‐alcoholic fatty liver disease and alcohol‐related liver disease, as well as the relevance of microbiota or bile acid‐based approaches in the management of those liver diseases.     

Clinical differences between alcoholic liver disease and nonalcoholic fatty liver disease

Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple hepatic steatosis to steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. Although most subjects with excessive alcohol or food intake experience simple hepatic steatosis, a small percentage of individuals will develop progressive liver disease. Notably, both ALD and NAFLD are frequently accompanied by extrahepatic complications, including cardiovascular disease and malignancy. The survival of patients with ALD and NAFLD depends on various disease-associated conditions. This review delineates the clinical characteristics and outcomes of patients with ALD and NAFLD by comparing their epidemiology, the factors associated with disease susceptibility and progression, and the predictors and characteristics of outcomes. A comprehensive understanding of the characteristics and outcomes of ALD and NAFLD is imperative in the management of these chronic liver diseases.     

Metabolic syndrome and non‐alcoholic fatty liver disease after liver or kidney transplantation

Transplantation is a definitive treatment option for patients with end‐stage liver disease, and for some patients with acute liver failure, hepatocellular carcinoma or end‐stage renal disease. Long‐term post‐transplantation complications have become an important medical issue, and cardiovascular diseases (CVD) are now the leading cause of mortality in liver or kidney transplant recipients. The increased prevalence of metabolic syndrome (MS) likely plays a role in the high incidence of post‐transplantation CVD. MS and its hepatic manifestation, non‐alcoholic fatty liver disease (NAFLD), are prevalent among the general population and in pre‐ and post‐transplantation settings. MS components are associated with recurrent or de novo NAFLD in transplant recipients, potentially influencing post‐transplantation survival. Moreover, recent data reveal an important association between NAFLD and risk of incident of chronic kidney disease (CKD). Therefore, NAFLD identification could represent an additional clinical feature for improving the stratification of liver and kidney transplant recipients with regards to risks of CVD, CKD and renal allograft dysfunction. All MS components are potentially modifiable; therefore, it is crucial that hepatologists, nephrologists and primary care physicians become more engaged in managing post‐transplantation metabolic complications. The present review discusses the recent clinical evidence regarding the importance of MS and its components after liver and kidney transplantation, as well as the link between MS and NAFLD after liver and kidney transplantation.     

Acute fatty liver of pregnancy:Over six months follow-up study of twenty-five patients

AIM:To evaluate the prognosis of patients with acute fatty liver of pregnancy(AFLP)6 mo or longer after discharge.METHODS:The records of pregnant patients diagnosed with AFLP at Beijing Ditan Hospital over a 16-year period were reviewed in November 2012.Patients weremonitored using abdominal ultrasound,liver and kidney functions,and routine blood examination.RESULTS:A total of 42 patients were diagnosed with AFLP during the study period,and 25 were followed.The mean follow-up duration was 54.5 mo(range:6.5-181 mo).All patients were in good physical condition,but one patient had gestational diabetes.The renal and liver functions normalized in all patients after recovery,including in those with pre-existing liver or kidney failure.The ultrasound findings were normal in12 patients,an increasingly coarsened echo-pattern and increased echogenicity of the liver in 10 patients,and mild to moderate fatty liver infiltration in 3 patients.Cirrhosis or liver nodules were not observed in any patient.CONCLUSION:Acute liver failure and acute renal failure in AFLP patients is reversible.Patients do not require any specific long-term follow-up after recovery from AFLP if their liver function tests have normalized and they remain well.