Liver diseases in pregnancy: Diseases not 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.Few challenges arise in reaching an accurate diagnosis in light of such physiological changes.Laboratory test results should be carefully interpreted and the knowledge of what normal changes to expect is prudent to avoid clinical misjudgment.Other challenges entail the methods of treatment and their safety for both the mother and the baby.This review summarizes liver diseases that are not unique to pregnancy.We focus on viral hepatitis and its mode of transmission,diagnosis,effect on the pregnancy,the mother,the infant,treatment,and breast-feeding.Autoimmune hepatitis,primary biliary cirrhosis,primary sclerosing cholangitis,Wilson’s disease,Budd Chiari and portal vein thrombosis in pregnancy are also discussed.Pregnancy is rare in patients with cirrhosis because of the metabolic and hormonal changes associated with cirrhosis.Variceal bleeding can happen in up to 38%of cirrhotic pregnant women.Management of portal hypertension during pregnancy is discussed.Pregnancy increases the pathogenicity leading to an increase in the rate of gallstones.We discuss some of the interventions for gallstones in pregnancy if symptoms arise.Finally,we provide an overview of some of the options in managing hepatic adenomas and hepatocellular carcinoma during pregnancy.     

Liver diseases unique to pregnancy

Liver injury and dysfunction in a pregnant woman may be caused by intrinsic features of the pregnancy itself, disorders that are coincidental with pregnancy or pre-existing liver disease that is exacerbated by pregnancy. The clinical setting, gestational age and standard liver biochemistry testing are useful tools in helping to establish a diagnosis. Prompt recognition of the signs of liver disease in pregnant patients leads to timely management and may save the life of both mother and baby. This review summarises the incidence, risk factors, pathogenesis, clinical presentation, diagnosis, treatment and outcome of those liver diseases unique to pregnancy.     

Liver disease in pregnancy

Changes in the liver biochemical profile are normal in pregnancy. However, up to 3% to 5% of all pregnancies are complicated by liver dysfunction. It is important that liver disease during pregnancy is recognized because early diagnosis may improve maternal and fetal outcomes, with resultant decreased morbidity and mortality. Liver diseases that occur in pregnancy can be divided into 3 different groups: liver diseases that are unique to pregnancy, liver diseases that are not unique to pregnancy but can be revealed or exacerbated by pregnancy, and liver diseases that are unrelated to but occur coincidentally during pregnancy.     

Effect of pregnancy on pre-existing liver disease physiological changes during pregnancy

The pregnant woman experiences physiological changes to support fetal growth and development. Particularly the physiological changes of the liver are the results of the increment of estrogens and progesterone during the pregnancy, and also the hemodynamics changes. (hemodilution). Telangiectasia may appear in up to 60% of normal pregnancies. Liver function test (LFT) abnormalities occurs in 3% of the pregnancies, and the Preeclampsia is the most frequent cause. Most of the articles agree that in normal pregnancy the LFT are either normal or slightly increase o decrease but within normal range. Thus, an increase in serum ALT, AST and GGT activities and serum bilirubin and total bile acid concentration during pregnancy may be pathologic and should prompt further evaluation. In the same way the serum albumin levels is significantly low and the serum alkaline phosphatase concentrations are considerably higher and are a normal component of the pregnancy , and if they are within normal range, do not usually indicate the presence of liver disease. The prothrombine time and the partial prothrombine time remain unchanged during pregnancy and serum fibrinogen increase in late pregnancy. Most of the articles related to plasma lipids in pregnancy agree that cholesterol. Triglyceride and lipoprotein increase during pregnancy. Use of gestational age of the pregnancy are the best guide to the differential diagnosis of liver disease in the pregnancy.     

Liver disease in pregnancy

Abnormal liver tests occur in 3%-5% of pregnancies, with many potential causes, including coincidental liver disease (most commonly viral hepatitis or gallstones) and underlying chronic liver disease. However, most liver dysfunction in pregnancy is pregnancy-related and caused by 1 of the 5 liver diseases unique to the pregnant state: these fall into 2 main categories depending on their association with or without preeclampsia. The preeclampsia-associated liver diseases are preeclampsia itself, the hemolysis (H), elevated liver tests (EL), and low platelet count (LP) (HELLP) syndrome, and acute fatty liver of pregnancy. Hyperemesis gravidarum and intrahepatic cholestasis of pregnancy have no relationship to preeclampsia. Although still enigmatic, there have been recent interesting advances in understanding of these unique pregnancy-related liver diseases. Hyperemesis gravidarum is intractable, dehydrating vomiting in the first trimester of pregnancy; 50% of patients with this condition have liver dysfunction. Intrahepatic cholestasis of pregnancy is pruritus and elevated bile acids in the second half of pregnancy, accompanied by high levels of aminotransferases and mild jaundice. Maternal management is symptomatic with ursodeoxycholic acid; for the fetus, however, this is a high-risk pregnancy requiring close fetal monitoring and early delivery. Severe preeclampsia itself is the commonest cause of hepatic tenderness and liver dysfunction in pregnancy, and 2%-12% of cases are further complicated by hemolysis (H), elevated liver tests (EL), and low platelet count (LP)-the HELLP syndrome. Immediate delivery is the only definitive therapy, but many maternal complications can occur, including abruptio placentae, renal failure, subcapsular hematomas, and hepatic rupture. Acute fatty liver of pregnancy is a sudden catastrophic illness occurring almost exclusively in the third trimester; microvesicular fatty infiltration of hepatocytes causes acute liver failure with coagulopathy and encephalopathy. Early diagnosis and immediate delivery are essential for maternal and fetal survival.     

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.     

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.     

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.     

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.     

Thrombocytopenia and disorders of platelet function in pregnancy

Pregnancy is associated with physiological and pathological changes in platelet numbers and function, which can be of clinical concern because of risks for maternal and fetal or neonatal bleeding. Thrombocytopenia in pregnancy is frequently encountered and may be due to increased platelet turnover and plasma dilution, immune-mediated mechanisms, or a complication of a more severe underlying pregnancy-related disorder such as preeclampsia. Inherited defects in platelet function and number may also manifest during pregnancy with the risk of bleeding dependent on the underlying problem. In some women, the diagnosis of thrombocytopenia will precede pregnancy but in others, the problem is first identified when routine pregnancy blood tests are performed. An accurate diagnosis and risk assessment in the antenatal period are essential for developing specific plans for any antenatal interventions and for management of delivery and the postpartum periods, and the neonate. Management of pregnant women with platelet disorders requires a multidisciplinary approach and close collaboration between the obstetric and hematology teams.     

An overview on systemic lupus erythematosus pregnancy

A systemic lupus erythematosus (SLE) pregnancy is no longer regarded as unacceptable, with an early diagnosis, a mild disease condition, and good interdisciplinary collaboration ensuring intense surveillance of pregnant SLE patients. The key point is a sufficiently long period of disease quiescence before conception. A low dose of prednisone is preferable during pregnancy. Nevertheless, 20% of disease flare-up still happens interpartum or postpartum, even in such well-planned pregnancies, although usually with only mild severity. Pregnancy during an active disease stage, especially active nephritis, should always be avoided. Substantial renal function damage may occur, and there is a relatively high prevalence of preeclampsia, which may further compromise the mother as well as the fetus. It is well documented that antiphospholipid syndrome and antiphospholipid antibodies are strongly associated with fetal wastage. Low-dose aspirin or heparin is indicated for a favorable fetal outcome. Women with positive anti-SSA and/or anti-SSB should be aware of the danger of congenital heart block in their infants. Cytotoxic drugs applied in the early stage of pregnancy are dangerous to the fetus. A rather long-term follow-up is required to make a precise evaluation of the maternal SLE influence on the offspring.     

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.     

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.     

Gene profiling of maternal hepatic adaptations to pregnancy

Background: Maternal metabolic demands change dramatically during the course of gestation and must be co‐ordinated with the needs of the developing placenta and fetus. The liver is critically involved in metabolism and other important functions. However, maternal hepatic adjustments to pregnancy are poorly understood. Aim: The aim of the study was to evaluate the influences of pregnancy on the maternal liver growth and gene expression profile. Methods: Holtzman Sprague–Dawley rats were mated and sacrificed at various stages of gestation and post‐partum. The maternal livers were analysed in gravimetric response, DNA content by PicoGreen dsDNA quantitation reagent, hepatocyte ploidy by flow cytometry and hepatocyte proliferation by ki‐67 immunostaining. Gene expression profiling of non‐pregnant and gestation d18.5 maternal hepatic tissue was analysed using a DNA microarray approach and partially verified by northern blot or quantitative real‐time PCR analysis. Results: During pregnancy, the liver exhibited approximately an 80% increase in size, proportional to the increase in body weight of the pregnant animals. The pregnancy‐induced hepatomegaly was a physiological event of liver growth manifested by increases in maternal hepatic DNA content and hepatocyte proliferation. Pregnancy did not affect hepatocyte polyploidization. Pregnancy‐dependent changes in hepatic expression were noted for a number of genes, including those associated with cell proliferation, cytokine signalling, liver regeneration and metabolism. Conclusions: The metabolic demands of pregnancy cause marked adjustments in maternal liver physiology. Central to these adjustments are an expansion in hepatic capacity and changes in hepatic gene expression. Our findings provide insights into pregnancy‐dependent hepatic adaptations.     

Blood pressure patterns in normal pregnancy, gestational hypertension, and preeclampsia

With the aim to describe the daily pattern of blood pressure during the trimesters of pregnancy in clinically healthy women as well as in pregnant women who developed gestational hypertension or preeclampsia, we analyzed 1494 blood pressure series systematically sampled by ambulatory monitoring for 48 hours every 4 weeks after the first obstetric visit in 124 women with uncomplicated pregnancies, 55 with gestational hypertension, and 23 with a final diagnosis of preeclampsia. The circadian pattern of blood pressure variation for each group and trimester of gestation was established by population multiple-component analysis. A highly statistically significant circadian pattern represented by a linear model that includes components with periods of 24 and 12 hours is demonstrated for systolic and diastolic blood pressure for all groups of pregnant women in all trimesters (P:<0.001 in all cases). The differences in circadian rhythm-adjusted mean between complicated and uncomplicated pregnancies are highly statistically significant in all trimesters (always P:<0.001). There is also a statistically significant difference in circadian amplitude (extent of daily change) of blood pressure between healthy and complicated pregnancies in all trimesters (always P:<0.004). Results further indicate similar circadian characteristics between women who later developed gestational hypertension or preeclampsia in the first trimester of pregnancy. The difference between these 2 groups in circadian mean is statistically significant in the second trimester for systolic (P:=0.022) but not for diastolic blood pressure (P:=0.986). In the third trimester, the difference in circadian mean is highly statistically significant for both variables (P:<0.001). The differences in blood pressure between healthy and complicated pregnancies can be observed as early as in the first trimester of pregnancy. Those highly significant differences are found when both systolic and diastolic blood pressure for women with a later diagnosis of gestational hypertension or preeclampsia are well within the accepted normal physiological range of blood pressure variability. These differing changes in the circadian pattern of blood pressure with advancing gestational age between healthy and complicated pregnancies offer new end points that may lead to an early identification of hypertensive complications in pregnancy as well as to the establishment of prophylactic intervention.     

Acute renal failure in pregnancy

Acute renal failure is a most challenging clinical problem when it occurs in pregnancy. It requires an understanding of the normal physiology of the kidney in pregnancy and the natural history of different underlying renal diseases when pregnancy occurs. Because patients with chronic renal disease may present with worsening proteinuria, hypertension, and renal function, these disorders must be excluded from those conditions that cause acute deterioration of renal failure in otherwise normal women during pregnancy. As in all patients who develop acute renal failure, prerenal and obstructive causes must be excluded. Particularly important causes of prerenal azotemia in pregnancy include hyperemesis gravidarum and uterine hemorrhage, especially if it is unsuspected as in abruptio placentae. Infectious causes of acute renal failure in the pregnant woman include acute pyelonephritis and septic abortion. The clinical presentation of both these conditions should be apparent, and appropriate diagnosis and treatment can then be promptly instituted. Renal cortical necrosis is another cause of renal failure that occurs more frequently in pregnancy, and it must be differentiated from the many causes of acute tubular necrosis that may be associated with pregnancy. Those conditions that cause renal failure unique to pregnancy must always be considered when renal function deteriorates in the last trimester or the postpartum period. Severe preeclampsia, acute fatty liver of pregnancy, and idiopathic postpartum acute renal failure may all present similar complications, but the approach to each of these clinical disorders must be individualized. By understanding the causes of renal functional deterioration in pregnancy, a logical differential diagnosis can be established, allowing appropriate therapeutic decisions to preserve both maternal and fetal well-being.     

Asthma in pregnancy.

Asthma, one of the most common serious medical problems to complicate pregnancy, affects 3-8% of pregnancies in the United States. The goals of therapy in the pregnant asthmatic patient do not differ from those in non-pregnant patients. Inhaled corticosteroids (ICS) are preferred in the management of all levels of persistent asthma in pregnant patients, because these agents have been shown to reduce asthma exacerbations during pregnancy. Asthma in pregnancy is often undertreated due to physician and patient concerns over the effects of asthma medications on the fetus. However, undertreatment leads to loss of asthma control and increases in maternal morbidity, perinatal mortality, preeclampsia, preterm birth, and low birth weight infants. Recent prospective clinical cohort studies with active asthma management by NAEPP guidelines show no evidence of increased maternal or fetal morbidity or mortality. Therefore, it is critical for the mother to understand that failure to control asthma during pregnancy may lead to poor outcomes. A case study follows to highlight clinical pearls and pitfalls in the management of asthma in the pregnant patient.     

Ischaemic heart disease in pregnancy

Ischaemic heart disease (IHD) in pregnancy, particularly myocardial infarction (MI), is a rare yet potentially fatal condition for the mother and the foetus. With delays in the age of conception, the changes in some social habits among females including cigarette and shisha smoking in addition to an increased prevalence of diabetes mellitus, IHD may represent a real hazard among pregnant women in the near future. The difficulty in the diagnosis emerges from the similarity of the signs and symptoms of ischaemia and infarct to some of the physiological adaptations that occur in a normal pregnancy. The physiological changes that are normal in pregnancy may aggravate pre-existing disease and may unmask some underlying unrecognized coronary vascular changes; therefore, the diagnosis requires a high index of suspicion and careful assessment of the underlying risk factors. The management of IHD always requires a multidisciplinary team approach. The management of each patient should be individualized according to the clinical condition, the risk factors, and the availability of the necessary support. Pregnancy after MI may be an acceptable and reasonably safe option provided the cited criteria are met. A systematic PubMed search was performed to identify all published data including cases reports, small series and systematic reviews in the existing literature. These publications were comprised of both retrospective and cross sectional population studies to maximize the number of cases considered in order to reach conclusions and make recommendations based on the best available evidence considering the rare occurrence of this event. The epidemiology, diagnosis, medical and surgical treatment, and prognosis of IHD in pregnancy are the subjects of the present review.     

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.     

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.