Inherited long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and a fetal-maternal interaction cause maternal liver disease and other pregnancy complications.

Fetal-maternal interactions are critical determinants of maternal health during pregnancy and perinatal outcome. This review explores the causative relationship of a fetal disorder of mitochondrial fatty acid oxidation, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, and the serious maternal liver diseases of pregnancy-preeclampsia, the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet counts), and acute fatty liver of pregnancy. Features of the metabolic adaptation necessitated during the fetal-neonatal transition; common phenotypes of pediatric fatty acid oxidation disorders, including neonatal hypoketotic, hypoglycemia and hepatic crisis; and clinical abnormalities of HELLP and acute fatty liver of pregnancy are presented. Evidence that a common mutation in the alpha-subunit (LCHAD) of trifunctional protein, E474Q, is always one of the mutant alleles in fetal isolated LCHAD deficiency associated with these disorders of pregnancy that cause high maternal, fetal, and newborn morbidity and mortality is reviewed. Recommendations for molecular testing for LCHAD deficiency in families with life-threatening maternal liver disease are given.     

Diagnóstico posparto de la enfermedad de Wilson en gestante con síndrome HELLP y coagulopatía

HELLP syndrome is a clinical-analytical entity defined by microangiopathic hemolytic anemia, elevated liver enzymes, and thrombocytopenia. Liver involvement in this syndrome is common to several liver diseases. Some of these liver diseases are inherent to pregnancy (acute fatty liver of pregnancy, gestational intrahepatic cholestasis), while others are related to intercurrent disease (acute viral hepatitis) or to previous chronic liver disease. We report a case of postpartum diagnosis of chronic liver disease secondary to Wilson disease, with onset in the third trimester of pregnancy and HELLP syndrome associated with acute liver failure and coagulopathy. We review the differential diagnosis and the scientific literature on the topic.     

Diagnosis and management of hemolysis, elevated liver enzymes, and low platelets syndrome

Pregnancies complicated by hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome require a well-formulated management plan. The development of this syndrome after 34 weeks' gestation or with documentation of maternal or fetal compromise is an indication for delivery. Acute fatty liver of pregnancy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura may present with signs, symptoms, and laboratory abnormalities that may be confused with HELLP syndrome. Thorough investigation is warranted because of the differences in proper management among these various complications of pregnancy. Expectant management in patients with HELLP syndrome remote from term and the use of corticosteroids to improve postpartum maternal outcome remain experimental.     

Pregnancy and inborn errors of metabolism

Increasing number of patients with inborn errors of metabolism (IEM) are now reaching adulthood and are in position to reproduce. Because of the rarity of individual disorders our knowledge of risks factors associated with pregnancy is limited. Obstetrics problems in IEM can be divided into two categories: pregnancy effects on maternal metabolic disorders and relation between mother and fetus related to who of them is affected. Detrimental effects upon the fetus may be directly caused by maternal disease, as it occurs in PKU, or indirectly by maternal supplementation with harmful substrate, as occurs in galactosemia. Less commonly, fetal inborn error of metabolism may affect the mother's health. Pregnancies in which the fetus had long-chain hydroxyacyl-CoA dehydrogenase deficiency have been complicated by life-threatening HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) or AFL (acute fatty liver of pregnancy) during third trimester. The management of labor and the postpartum period (for women and newborns) has to be carefully planned to avoid significant metabolic decompensation.     

Síndrome ELLP,un diagnóstico diferencial complicado

HELLP syndrome (Hemolysis, Elevated Liver enzymes, and Low Platelet count) is a thrombotic microangiopathy of pregnancy. This syndrome may be incomplete, with manifestations of only a few of its parameters: EL (elevated liver enzymes), ELLP (elevated liver enzymes and thrombocytopenia) and LP (thrombocytopenia alone). ELLP syndrome is a difficult differential diagnosis in which the main causes of thrombocytopenia in pregnancy and other diseases must be excluded. In current clinical practice, the management of ELLP is similar to that of complete HELLP syndrome. However, maternal and fetal morbidity is lower in ELLP syndrome, which may suggest the need to evaluate different protocols for these two variants of the same disease.     

Fetal fatty acid oxidation defects and maternal liver disease in pregnancy

OBJECTIVE: The objective was to evaluate the relationships between all types of fetal fatty acid oxidation defects and maternal liver disease, including acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. METHODS: This was a case-control study comparing fetal fatty acid oxidation defects to the outcome of maternal liver disease. Fifty case infants with fatty acid oxidation defects were identified, with 25 matched controls collected per case. This generated a total of 50 case infants and 1,250 control infants. Pregnancies were evaluated for the presence of maternal liver disease (comprised of acute fatty liver of pregnancy, HELLP syndrome, and preeclampsia evolving into HELLP syndrome) using a conditional logistic regression model. Subgroup analysis compared long chain to short and medium chain fatty acid defects. RESULTS: Maternal liver disease was noted in 16.00% of all fatty acid oxidation defect pregnancies compared with 0.88% in the general population (odds ratio 20.4, 95% confidence interval 7.82-53.2). These pregnancies demonstrated an 18.1-fold increase in maternal liver disease when compared with our matched population controls with unaffected fetuses. All classifications of fatty acid oxidation defects were at high risk of developing maternal liver disease. Long chain defects were 50 times more likely than controls to develop maternal liver disease and short and medium chain defects were 12 times more likely to develop maternal liver disease. CONCLUSION: Maternal liver disease is significantly higher across the entire spectrum of fatty acid oxidation defects pregnancies compared with the matched control population. Notably, there is significant risk to the pregnancies with fetuses affected with short and medium chain defects, not just those with fetal long chain fatty acid oxidation defects as previously reported. Future studies should examine the pathophysiology of all infant fatty acid oxidation defects and its implications for maternal liver disease for improved future health outcomes. LEVEL OF EVIDENCE: II-2.     

Lebererkrankungen in der Schwangerschaft

Liver diseases in pregnancy can result in maternal as well as fetal complications. Intrahepatic cholestasis in pregnancy may lead to a high fetal risk of IUD, meconium-stained amniotic fluid, premature delivery, asphyxia and arrhythmia. Concerning a good fetal outcome there is no evidence-based therapy. Pruritus and elevated cholic acid can be treated and controlled well by ursodeoxycholic acid. Since there is a higher risk of intrauterine death, most common at 37+ weeks of gestation, delivery is recommended starting at 36+ weeks, even earlier when excessively high cholic acid levels occur. Acute fatty liver of pregnancy is linked to higher maternal and fetal mortality. There are regular crossovers to the HELLP syndrome. Cholelithiasis causes 6% of all jaundice in pregnancy and thus has to be considered as another differential diagnosis particularly in multiparity. If operative treatment is required for cholecystolithiasis during pregnancy the best fetal outcome is achieved in the second trimester. It is likely that in the future chronic liver diseases such as Wilson??s disease and autoimmune hepatitis will be seen more often during pregnancy since there are increasingly better options for treatment. The same applies to pregnant women who have already undergone liver transplantation. An interdisciplinary approach with hepatologists in these high-risk pregnancies is mandatory.     

Imitators of severe preeclampsia

There are several obstetric, medical, and surgical disorders that share many of the clinical and laboratory findings of patients with severe preeclampsia-hemolysis, elevated liver enzymes, and low platelets syndrome. Imitators of severe preeclampsia-hemolysis, elevated liver enzymes, and low platelets syndrome are life-threatening emergencies that can develop during pregnancy or in the postpartum period. These conditions are associated with high maternal mortality, and survivors may face long-term sequelae. Perinatal mortality and morbidity also remain high in many of these conditions. The pathophysiologic abnormalities in many of these disorders include thrombotic microangiopathy, thrombocytopenia, and hemolytic anemia. Some of these disorders include acute fatty liver of pregnancy, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, and acute exacerbation of systemic lupus erythematosus. Because of the rarity of these conditions during pregnancy and postpartum, the available literature includes only case reports and case series describing these syndromes. Consequently, there are no systematic reviews or randomized trials on these subjects. Differential diagnosis may be difficult due to the overlap of several clinical and laboratory findings of these syndromes. It is important that the clinician make the accurate diagnosis when possible because the management and complications from these syndromes may be different. For example, severe preeclampsia and acute fatty liver of pregnancy are treated by delivery, whereas it is possible to continue pregnancy in those with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome and exacerbation of systemic lupus erythematosus. This review focuses on diagnosis, management, and counseling of women who develop these syndromes based on results of recent studies.     

妊娠期急性肾损伤的相关进展

妊娠期间肾脏损伤风险至少增加2倍,妊娠期急性肾损伤(acute kidney injury in pregnancy,P-AKI)是一种高风险产科疾病,严重威胁母亲和胎儿的健康。尽管P-AKI在过去30年中发病率下降,我国仍有较高的发病率及致死率。P-AKI是妊娠期严重的并发症,有起病急、进展快、病情重的临床特点,常伴有呼吸、心血管及消化等系统的症状。P-AKI的相关疾病,如子痫前期、妊娠期急性脂肪肝、HELLP综合征和血栓性微血管病等临床表现相似,容易出现诊断困难。现总结近年来国内外文献,从P-AKI病理生理变化、不同地区发病率及诱因、诊断标准、P-AKI的相关疾病及预防治疗措施等进行分析,并对P-AKI的透析指征进一步分析,旨在提高大家对疾病的了解、预防和诊治,降低发病率、病死率及致残率,改善母婴结局。     

Serious pregnancy complications in a patient with previously undiagnosed carnitine palmitoyltransferase 1 deficiency

Fetal defects in mitochondrial beta-oxidation have been linked with an increased risk for acute fatty liver of pregnancy and preeclampsia-related conditions. A woman with previously undiagnosed carnitine palmitoyltransferase 1 deficiency experienced hemolysis, elevated liver enzymes, low platelets-like syndrome late in her first pregnancy with an unaffected fetus. Carnitine palmitoyltransferase 1 deficiency should be considered as a potential cause of life-threatening complications of pregnancy.     

Current management of the HELLP syndrome

The HELLP syndrome as part of the microangiopathic syndromes requires special attention in terms of a rapid and accurate diagnostic and differential diagnostic workup because of its possibly rapid clinical deterioration. It is defined by the classical triad of hemolysis,elevated liver enzymes and low platelet counts which may lead to prognostically relevant problems in differentiating it from thrombotic-thrombocytopenic purpura and hemolytic-uremic syndrome and other pregnancy-related and unrelated liver diseases, i.e. mainly clinical and laboratory similarities to other liver diseases such as acute fatty liver or intrahepatic cholestasis in pregnancy or pregnancy-unrelated settings like viral hepatitides. The management in the different phases of pregnancy is described in detail. Therapeutic options to prolong pregnancy are discussed as are the possibilities of prophylaxis in subsequent pregnancies and aspects of the followup.     

Gastrointestinal disease

Gastrointestinal diseases in pregnancy can be divided into diseases specific to pregnancy, for example, hyperemesis gravidarum, obstetric cholestasis, HELLP syndrome and acute fatty liver of pregnancy, and diseases incidental to pregnancy, for example, inflammatory bowel disease, dyspepsia, peptic ulcer disease and viral hepatitis. Disorders in the second category may present for the first time in pregnancy. This chapter considers the drug management of each of these conditions, with the exception of HELLP syndrome and acute fatty liver. The preferred drug treatment and the known complications associated with their use in pregnancy are also described. Where possible, studies relating to the safety of different therapeutic options are discussed.     

Drugs in pregnancy. Gastrointestinal disease.

Gastrointestinal diseases in pregnancy can be divided into diseases specific to pregnancy, for example, hyperemesis gravidarum, obstetric cholestasis, HELLP syndrome and acute fatty liver of pregnancy, and diseases incidental to pregnancy, for example, inflammatory bowel disease, dyspepsia, peptic ulcer disease and viral hepatitis. Disorders in the second category may present for the first time in pregnancy. This chapter considers the drug management of each of these conditions, with the exception of HELLP syndrome and acute fatty liver. The preferred drug treatment and the known complications associated with their use in pregnancy are also described. Where possible, studies relating to the safety of different therapeutic options are discussed.     

Acute fatty liver of pregnancy: a rare pathology of the third trimester

Acute fatty liver of pregnancy is a rare clinical syndrome of pregnancy that occurs during the third trimester. Clinicians must have a high index of suspicion for this condition when a woman has nausea or vomiting during the last trimester. Early diagnosis and prompt delivery improve foetal and maternal prognosis. We report a case of a previously healthy 23-year-old woman who presented an acute fatty liver of pregnancy with intrauterine fetal death. Based on this experience as well as on medical literature, characteristics of this uncommon pathology are discussed.     

Preeclampsia: a microvesicular fat disease of the liver?

To study the interrelationship between preeclampsia, the syndrome of hemolysis, elevated liver enzymes, and low platelet count, and acute fatty liver of pregnancy, 41 liver specimens from 41 preeclamptic women with and without liver dysfunction were examined for the amount of fat deposited in hepatocytes. All 41 specimens stained with oil red O on frozen sections showed a significant amount of microvesicular fat droplets in varying degrees. In contrast, only 11 of the 41 stained conventionally (with hematoxylin-eosin) showed significant fatty infiltration. The density of hepatocellular fat correlated positively with plasma urate concentration and negatively with the platelet count. These findings suggest that preeclampsia may be one of several microvesicular fatty diseases of the liver and that acute fatty liver of pregnancy may be the most severe form.     

Fetal genotypes and pregnancy outcomes in 35 families with mitochondrial trifunctional protein mutations

OBJECTIVE: The purpose of this study was to evaluate the effects of fetal genotype on maternal and fetal outcomes in families with mitochondrial trifunctional protein mutations in the United States. Trifunctional protein has 3 enzymatic activities that include long-chain 3-hydroxyacyl-CoA dehydrogenase, which catalyzes long-chain fatty acid beta-oxidation. STUDY DESIGN: We analyzed pregnancy history and offspring genotypes in 35 families with heterogeneous mutations. The fetal genotype was determined in utero in 11 pregnancies and after birth in 50 pregnancies. RESULTS: Forty-nine percent of the women who carried affected fetuses had acute fatty liver of pregnancy. Another 11% of the women had the syndrome of hemolysis, elevated liver enzymes, and low platelets, or preeclampsia. All women who had the maternal illness carried fetuses with isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Sixty-eight percent and 43% of the affected pregnancies also were associated with premature delivery and intrauterine growth retardation, respectively. No maternal or fetal complications were associated with heterozygous or wild-type fetal genotypes. CONCLUSION: Fetal mitochondrial trifunctional protein defects should be considered a cause for maternal liver disease, preterm labor, and intrauterine growth retardation.     

重度子痫前期患者及其新生儿线粒体三功能蛋白酶α亚单位G1528C基因突变的研究

目的 探讨线粒体三功能蛋白酶（ MTP）α亚单位G1528C基因突变,在重度子痫前期及溶血、肝酶升高和低血小板计数（HELLP综合征）孕妇及其新生儿中的携带情况.方法 北京地区汉族重度子痫前期（子痫前期组）孕妇及其新生儿130例（其中合并肝损害18例）,HELLP综合征（HELLP组）孕妇及其新生儿10例,同期无妊娠期特发性肝损害等并发症及其他代谢性疾病的正常孕妇90例及新生儿560例作为对照组.应用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术分析3组孕妇外周血及其新生儿脐血中MTPα亚单位G1528C基因突变的携带情况.实验中阳性对照标准为西方白种人的G1528C杂合子标本.结果 3组孕妇外周血及其新生儿脐血中的MTPα亚单位G1528C基因电泳图中均无与阳性对照标本中相应分子质量的条带出现.结论 MTP的α亚单位G1528C基因突变可能不是北京汉族人种常见的突变位点; MTP缺陷在北京汉族人与西方白种人之间可能存在着种族差异.     

Acute fatty liver of pregnancy in 3 tertiary care centers

OBJECTIVE: The purpose of this study was to determine the demographics, clinical presentation, and maternal and neonatal outcomes in patients who were diagnosed with acute fatty liver of pregnancy over a 10-year period. STUDY DESIGN: This was a multicenter retrospective study of women with the diagnosis of acute fatty liver of pregnancy. Records were reviewed for symptoms, laboratory findings, clinical course, and maternal and perinatal outcomes. RESULTS: Sixteen cases of acute fatty liver of pregnancy were identified. Three of the 16 cases had multiple gestations (18%). Eleven of the 16 cases were diagnosed in the antepartum period, and 5 cases were diagnosed within 4 days after delivery. Nausea and vomiting were the most common symptoms (75%). There were 2 maternal deaths (12.5%) and 3 fetal deaths (15%). CONCLUSION: We recommend that patients with persistent nausea, vomiting, or epigastric pain in the third trimester receive evaluation of liver enzymes, renal function, and a complete blood count to rule out the diagnosis of acute fatty liver of pregnancy.     

The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing?

The question of whether the HELLP syndrome exists as a distinct entity or is part of a spectrum of pregnancy complications, which have in common hemolysis, elevated liver enzymes, and thrombocytopenia, has long been a source of speculation and debate among obstetricians and internists. A review of the literature indicates a definite need for a uniform definition, diagnosis, and management of this syndrome. Patients manifesting this syndrome usually are seen before term (less than 36 weeks' gestation) complaining of malaise (90%), epigastric or right upper-quadrant pain (90%), and nausea or vomiting (50%), and some will have nonspecific viral-syndrome-like symptoms. Hypertension and proteinuria may be absent or slight. Thus some of these patients may have a variety of signs and symptoms, none of which are diagnostic of classic preeclampsia. In consideration of the high maternal and perinatal mortality and morbidity reported with the presence of this syndrome, I recommend that all pregnant women having any of these symptoms should have a complete blood cell count with platelet and liver enzyme determinations irrespective of maternal blood pressure.     

Corticosteroids, pregnancy, and HELLP syndrome: a review

Corticosteroids are potent antiinflammatory and immunosuppressive drugs, which are used in the treatment of a wide range of medical disorders. During pregnancy, several corticosteroids are administered for maternal as well as fetal reasons. Prednisone and prednisolone show limited transplacental passage and are thus used for treatment of maternal disease. Dexamethasone and betamethasone, drugs that can easily cross the placenta, are more suitable for fetal indications. During the last decade, administration of corticosteroids was introduced in the treatment of hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome), a severe form of preeclampsia unique to human pregnancy. Several randomized, controlled trials as well as other prospective and retrospective studies have been performed to investigate this beneficial effect of corticosteroids on biochemical measures and clinical signs. This review discusses the characteristics of corticosteroids in humans and details the use of corticosteroids during pregnancy. A review of literature on the effect of corticosteroids on HELLP syndrome is given and possible mechanisms of action are discussed.