The spectrum and treatment of gastrointestinal disorders during pregnancy

Gastrointestinal symptoms are extremely common during pregnancy. Increased levels of female sex hormones cause or contribute to symptoms such as heartburn, nausea, vomiting and constipation. If these symptoms do not respond adequately to lifestyle and dietary changes, drug therapy is often warranted to improve quality of life and to prevent complications. Physicians, therefore, need to be familiar with the low-risk treatment options available. Treatment of chronic conditions such as IBD or chronic liver disease during pregnancy can be demanding. In women with IBD, maintenance of adequate disease control during pregnancy is crucial. Most IBD drugs can be used during pregnancy, but the benefits and risks of specific drugs should be discussed with the patient. Liver diseases can be coincidental or pregnancy-specific. Pregnancy-specific liver diseases include not only benign disorders such as intrahepatic cholestasis of pregnancy, but also pre-eclampsia, eclampsia and HELLP syndrome (hemolytic anemia, elevated liver enzymes and low platelet count). Accordingly, the spectrum of therapeutic measures ranges from expectant management to urgent induction of delivery. During pregnancy, lamuvidine therapy for chronic hepatitis B can be continued; however, interferon and ribavirin therapy for chronic hepatitis C is contraindicated. This Review provides an overview of the spectrum and therapy of motility disturbances that occur during pregnancy, and discusses pregnancy-specific aspects of IBD and liver diseases.     

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.     

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.     

Effect of liver disease on maternal and fetal outcome--a prospective study.

BACKGROUND: Liver disease in pregnancy can have serious consequences. Its prevalence, profile and effect on outcome of pregnancy have not been documented systematically in India. We prospectively determined the frequency, causes and outcome of liver disease in pregnant women. SETTING: Tertiary-care teaching hospital. METHODS: Consecutive pregnant women with liver disease attending the inpatient or outpatient services of the Departments of Gastro-enterology and Obstetrics and Gynecology between December 2002 and October 2004 were evaluated and followed up till 2 weeks postpartum or death. RESULTS: Liver disease was found in 107 (0.9%) of 12,061 pregnancies. Of these, fifty six (52.3%) had pregnancy-specific liver disorders (pregnancy-induced hypertension [PIH]-associated liver dysfunction 36--including HELLP syndrome 22 and pre-eclamptic liver dysfunction 14; intrahepatic cholestasis of pregnancy 10; hyperemesis gravidarum 7; acute fatty liver of pregnancy 3). Liver disorders not specific to pregnancy included hepatitis E (16), hepatitis B, non A-E hepatitis and chronic liver disease (5 each) and others (14); in 6 patients no cause could be found. Ninety-six patients completed follow up. Overall maternal and perinatal mortality rates were 19.7% and 35.4%, respectively. CONCLUSIONS: PIH-associated liver dysfunction was the most common cause of liver disease in pregnancy. This is associated with significant maternal and perinatal morbidity and mortality.     

Jaundice in pregnancy

The occurrence of hepatobiliary disease with or without jaundice during pregnancy provides both the hepatologist and obstetrician with an interesting and urgent diagnostic challenge. Advances in our understanding and management of liver disorders unique to pregnancy and hepatobiliary disease in general have resulted in a significant improvement in the outcome for both mother and fetus. Certain disorders such as acute fatty liver of pregnancy and hepatic haemorrhage associated with toxaemia should be considered medical emergencies and delay in diagnosis of these conditions will probably adversely affect maternal and fetal outcome. A careful clinical history, physical examination, appropriate laboratory tests and radiological investigations should allow a diagnosis within 24-48 hours of presentation. Liver biopsy is rarely required. A careful history may provide important information. Does the patient have pre-existent liver disease? Has there been contact with hepatitis, intravenous drug abuse or any other factor predisposing to acute viral hepatitis? Does the patient have a family history of pruritus and/or jaundice to suggest intrahepatic cholestasis of pregnancy? Is the patient's alcohol consumption excessive? Has the patient received any hepatotoxic medications? Has there been abdominal pain and/or fever to suggest gallstones, hepatic bleeding or acute fatty liver of pregnancy? Laboratory investigations may give valuable diagnostic clues. Marked aminotransferase elevation would suggest acute viral or 'ischaemic' hepatitis. Haematological features of microangiopathic haemolysis would point towards toxaemia or AFLP. Hepatitis A and B serological tests may be helpful in viral liver disease. Radiological investigations may be indicated depending on the clinical context. Abdominal ultrasonography may be useful in the diagnosis of gallstones, biliary obstruction, liver tumours or intrahepatic bleeding. Fatty infiltration of the liver may be diagnosed by ultrasonography but computed tomography (CT) of the abdomen is probably more reliable for a diagnosis of acute fatty liver of pregnancy as it allows measurement of liver density which is typically reduced by fatty infiltration. CT scanning is also probably more valuable than ultrasound in assessing the extent of capsular rupture and haemorrhage into the liver and peritoneal cavity.     

Hepatic manifestations of inflammatory bowel diseases

Inflammatory bowel diseases are associated with various hepatobiliary disorders, reported both in Crohn's disease and ulcerative colitis. They may occur at any moment in the natural course of the disease. The prevalence of liver dysfunction rises from 3% to 50% accordingly to definitions used in different studies. Fatty liver is considered as the most common hepatobiliary complication in inflammatory bowel diseases while primary sclerosing cholangitis is the most specific one. Less frequently, inflammatory bowel diseases‐associated hepatobiliary disorders include: autoimmune hepatitis/ primary sclerosing cholangitis overlap syndrome, IgG4‐associated cholangiopathy, primary biliary cholangitis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis and liver abscess. The spectrum of these manifestations varies according to the type of inflammatory bowel diseases. Treatments of inflammatory bowel diseases may cause liver toxicity, although incidence of serious complications remains low. However, early diagnosis of drug‐induced liver injury is of major importance as it affects future clinical management. When facing abnormal liver tests, clinicians should undertake a full diagnostic work‐up in order to determine whether the hepatic abnormalities are related to the inflammatory bowel diseases or not. Management of hepatic manifestations in inflammatory bowel diseases usually involves both hepatologists and gastroenterologists because of the complexity of some situations.     

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.     

Optimal Management of the Hepatitis B Patient Who Desires Pregnancy or Is Pregnant

Women of childbearing age with recognized hepatitis B infection should have their liver disease assessed before pregnancy occurs since the management of hepatitis B virus (HBV) infection in this setting is complex. Initiation of treatment in a woman of child-bearing age will depend on when she intends on conceiving, as well as the severity of her liver disease. During pregnancy, all decisions about initiating, continuing or stopping HBV therapy must include an analysis of the risks and benefits for both mother and fetus. The trimester of the pregnancy and the stage of the mother's liver disease are important factors. Treatment in the third trimester may be considered to aid in prevention of perinatal transmission, which appears to be most pronounced in mothers with high viral loads. Consideration of initiation of third trimester treatment should occur after a high viral load is documented in the latter part of the second trimester, to allow adequate time for initiation of antiviral therapy with significant viral suppression before delivery. This discussion should include the topic of breastfeeding, since it is generally not recommended while on antiviral therapy. Until recently lamivudine and tenofovir appeared to be the therapeutic options with the most reasonable safety data in pregnancy. There are emerging data that telbivudine may also be considered in this setting.     

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.     

妊娠特有肝病诊治进展

妊娠期肝脏存在正常的生理变化。尽管如此,妊娠期仍有3%的孕妇出现肝功能异常。妊娠特有肝病是妊娠期肝功能异常的常见原因,在死亡的妊娠期妇女中,约0%～25%孕妇死于妊娠特有性肝病。提高对妊娠特有肝病的认知度和诊治水平尤为重要。本文回顾了近几年有关妊娠特有肝病的研究文献,总结了部分妊娠特有肝病的诊断和治疗进展,供临床医师参考。     

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.     

Evaluation of abnormal liver-enzyme results in asymptomatic patients

Abnormal liver enzymes may be present in the absence of symptoms and signs of liver disease. A good clinical history and physical examination are mandatory. If a systematic approach is adopted, based on additional non-invasive serological tests and imaging procedures covering the most frequent liver diseases, the cause is often apparent. The clinician should be aware of nonhepatic diseases that can cause abnormal liver enzymes, such as thyroid disorders and occult celiac disease. In those patients in which no explanation can be found at the time of the initial evaluation for these abnormal liver enzymes, there is a high probability of non-alcoholic fatty liver disease. The risks and benefits of a liver biopsy in this setting should be carefully considered, as it only seldom alters management.     

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.     

Heart diseases affecting the liver and liver diseases affecting the heart

BACKGROUND: The association of cardiac and liver disorders has not been extensively outlined in the literature. METHODS: A survey of the MEDLINE database was performed to assess the current status of research regarding the association between cardiac and liver disorders. RESULTS: Combined cardiac and hepatic disorders occur in 3 different settings: heart diseases affecting the liver, liver diseases affecting the heart, and cardiac and hepatic disorders with joint etiology. The spectrum of heart diseases affecting the liver includes mild alterations of liver function tests in heart failure, cardiogenic ischemic hepatitis, congestive liver fibrosis, and cardiac cirrhosis. The liver diseases affecting the heart include complications of cirrhosis such as hepatopulmonary syndrome, portopulmonary hypertension, pericardial effusion, and cirrhotic cardiomyopathy as well as noncirrhotic cardiac disorders such as high-output failure caused by intrahepatic arteriovenous fistulae. Cardiac and hepatic disorders with joint etiology include infectious, metabolic, immune, vasculitic, and toxic disorders. We propose a practical approach to a diagnostic workup of combined cardiac and hepatic disorders based on recognizing the sequence of appearance of the cardiac and liver disease, presence of features of a multisystem disease, and presence of pathognomonic features. The evaluation of combined cardiac and hepatic disorders takes into consideration the expected benefit of treatment and the risks related to invasive procedures. Accordingly, investigations can be limited to ancillary tests for patients with congested liver and mild alterations of liver function tests, in cardiogenic ischemic hepatitis, patients with cardiac cirrhosis who are proposed for conservative treatment, and multisystem disease involving the heart and the liver. Conversely, comprehensive investigations are recommended when invasive therapeutic interventions are considered for the treatment of hepatopulmonary syndrome, portopulmonary hypertension, or arteriovenous fistulae. CONCLUSION: Classification of a patient to any of the 3 categories-heart diseases affecting the liver, liver diseases affecting the heart, and cardiac and hepatic disorders with joint etiology-permits the physician to narrow the span of the possible diagnoses and allows for a more simple workup.     

Pregnancy and liver disease

Liver disease has an impact on women's health during pregnancy because of the complex interactions between the physiologic changes induced by pregnancy and the pathophysiologic changes of liver disease. In particular, liver diseases that predominantly afflict females, such as primary biliary cirrhosis and autoimmune hepatitis, pose a special problem for conception and management of pregnancy. Pregnancy, moreover, specifically is associated with several potentially life-threatening liver diseases. This article reviews comprehensively the impact of liver diseases on pregnancy and of pregnancy on liver function and liver disease.     

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.     

Herpes simplex virus hepatitis in pregnancy. Two patients successfully treated with acyclovir

Two cases of herpes simplex virus hepatitis in pregnancy are presented. Each case was characterized by extremely high serum aminotransferase levels with minimal bilirubin elevation. In both cases, liver biopsy was instrumental in arriving at the diagnosis. In addition, computed tomography showed a radiographic appearance of the liver not characteristically seen in other hepatic disorders of pregnancy. A high index of suspicion in the second case led to early recognition and treatment. Despite the presence of fulminant liver failure and evidence of herpes encephalitis in the other case, institution of therapy with acyclovir was associated with complete recovery in both patients. The present cases are compared and contrasted with the literature. The incidence of two cases within a 6-month period suggests that herpes simplex virus hepatitis in pregnancy may occur more frequently than previously reported.     

Liver-side of inflammatory bowel diseases: Hepatobiliary and drug-induced disorders

Hepatobiliary disorders are among the most common extraintestinal manifestations in inflammatory bowel diseases (IBD), both in Crohn’s disease and ulcerative colitis (UC), and therefore represent a diagnostic challenge. Immune-mediated conditions include primary sclerosing cholangitis (PSC) as the main form, variant forms of PSC (namely small-duct PSC, PSC-autoimmune hepatitis overlap syndrome and IgG4-related sclerosing cholangitis) and granulomatous hepatitis. PSC is by far the most common, presenting in up to 8% of IBD patients, more frequently in UC. Several genetic foci have been identified, but environmental factors are preponderant on disease pathogenesis. The course of the two diseases is typically independent. PSC diagnosis is based mostly on typical radiological findings and exclusion of secondary cholangiopathies. Risk of cholangiocarcinoma is significantly increased in PSC, as well as the risk of colorectal cancer in patients with PSC and IBD-related colitis. No disease-modifying drugs are approved to date. Thus, PSC management is directed against symptoms and complications and includes medical therapies for pruritus, endoscopic treatment of biliary stenosis and liver transplant for end-stage liver disease. Other non-immune-mediated hepatobiliary disorders are gallstone disease, whose incidence is higher in IBD and reported in up to one third of IBD patients, non-alcoholic fatty liver disease, pyogenic liver abscess and portal vein thrombosis. Drug-induced liver injury (DILI) is an important issue in IBD, since most IBD therapies may cause liver toxicity; however, the incidence of serious adverse events is low. Thiopurines and methotrexate are the most associated with DILI, while the risk related to anti-tumor necrosis factor-α and anti-integrins is low. Data on hepatotoxicity of newer drugs approved for IBD, like anti-interleukin 12/23 and tofacitinib, are still scarce, but the evidence from other rheumatic diseases is reassuring. Hepatitis B reactivation during immunosuppressive therapy is a major concern in IBD, and adequate screening and vaccination is warranted. On the other hand, hepatitis C reactivation does not seem to be a real risk, and hepatitis C antiviral treatment does not influence IBD natural history. The approach to an IBD patient with abnormal liver function tests is complex due to the wide range of differential diagnosis, but it is of paramount importance to make a quick and accurate diagnosis, as it may influence the therapeutic management.     

Liver abnormalities in the immunosuppressed

The immunosuppressed state may arise due to medical illness or drug therapy, which can result in a diverse array of liver derangements. This article discusses the commonly-encountered immunosuppressed conditions and the associated specific liver diseases. Due to the frequency of blood-borne viral disease globally, viral hepatitis (hepatitis B and C) during chemotherapy, transplantation and the increasingly utilised biological therapies for autoimmune disorders is discussed. An overview of human immunodeficiency virus co-infection with hepatitis B and C is provided. This article aims to highlight the variety of liver diseases which can occur in clinically relevant, particularly iatrogenic, immunosuppressed conditions, and summarise learning and practice points for clinicians. Recognition and prevention of viral liver disease is crucial and early involvement of experts prior to administration of immunosuppressive therapy is advised.     

Connective tissue diseases and the liver

Connective tissue diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, Sj?gren's syndrome, and scleroderma are systemic disorders that may have an autoimmune basis. The system manifestations vary, and there is frequent overlap among the syndromes. Liver involvement in patients with connective tissue diseases has been well documented but is generally considered rare. Although advanced liver disease with cirrhosis and liver failure is rare in patients with connective tissue diseases, clinical and biochemical evidence of associated liver abnormalities is common. Previous treatment with potentially hepatotoxic drugs or coincident viral hepatitis has usually been implicated as the main causes of liver disease in patients with connective tissue diseases. However, even after careful exclusion of these etiologies, the question remains whether to classify the patient as having a primary liver disease with associated autoimmune, clinical, and laboratory features or as having liver disease as a manifestation of generalized connective tissue disease. The main example of this pathogenetic dilemma is autoimmune hepatitis and SLE-associated hepatitis, which have been regarded as two different entities, although they have features in common of autoimmune syndromes. Several clinical and histopathologic features have been used to discriminate autoimmune hepatitis from SLE, a relevant diagnostic exercise because complications and therapy are quite different. Although hepatic steatosis and abnormal results on biochemical liver function tests are the most common hepatic abnormalities associated with connective tissue diseases, other less frequent abnormalities have been noted, such as nodular regenerative hyperplasia, portal vein obliteration and portal hypertension, features of primary biliary cirrhosis, and rarely portal fibrosis with abnormal lobular architecture. Vascular disorders of the liver also have been described, such as Budd-Chiari syndrome. Histologic assessment may reveal a variety of subclinical liver diseases. The aim of this contribution is to review the current published data regarding liver involvement in connective tissue diseases.