Viral Hepatitis

The presentation of viral hepatitides ranges from mild, nonclinical illness to fulminant hepatic necrosis. Viral hepatitis is the most common cause of jaundice and most frequent reason for gastroenterology consultation during pregnancy. Six types—hepatitis A, B, C, D, E, and G—have been identified and are associated with specific viruses. Types A, B, and C are the most common. Infrequently, hepatitis can also be caused by herpes simplex virus (HSV), yellow fever virus, rubella virus, Epstein-Barr virus (EBV), or cytomegalovirus (CMV).

Hepatitis A (HAV) and hepatitis E (HEV) are viral infections of hepatocytes that typically spread by oral ingestion of food or water contaminated with feces from infected individuals. Although endemic in other countries, the current all-time low incidence of HAV of 0.4 per 100,000 in the United States is attributed to good sanitation. Despite its prevalence, it has been infrequently reported among pregnant women. In a study from Ireland, there was only one case of HAV in 13,181 consecutive deliveries. The incidence of HAV infection has also been reduced by vaccination for preexposure prophylaxis; immune globulin is available for postexposure prophylaxis to prevent or attenuate infection. Clinically, a preicteric phase typically occurs with nonspecific viral symptoms, followed by an icteric phase with jaundice and acholic stools. Acute treatment is supportive. Increased risk for preterm labor, premature rupture of membranes, and placental abruption have been associated with HAV during pregnancy, and vertical transmission to the fetus has been reported. Chronic HAV infection does not occur, but a prolonged or relapsing course occurs in up to 20% of patients, and an acute fulminant course occurs in less than 1% of patients.

HEV infection may be largely asymptomatic. In symptomatic patients, the disease is usually self-limited. Pregnant women and patients already infected with another hepatitis virus, however, have more severe presentations. A mortality rate of 27% has been reported in pregnant women with HEV, a consequence of fulminant hepatic failure. Pregnancy complications such as premature rupture of membranes, fetal growth restriction, placenta previa, retained placenta, and preterm delivery are also more common. Chronic HEV infection may occur in immunosuppressed patients, and vertical transmission can occur. Pegylated interferon and/or ribavirin treatment for chronic HEV infection has shown moderate success, and HEV vaccines are under development.

Hepatitis B (HBV) and hepatitis D (HDV) are usually transmitted via percutaneous or permucosal exposure to infected body fluids. In high-prevalence areas, HBV infection is most commonly acquired perinatally or in early childhood. In low-prevalence areas, infection is primarily acquired in adulthood through sexual contact or intravenous drug abuse. The incidence is decreasing after implementation of widespread vaccination and safety precautions in health care settings. Postexposure prophylaxis with HBV vaccination alone or a combination of vaccination with hepatitis B immune globulin (HBIG) is highly effective in preventing HBV transmission in adults as well as in infants of HBV-infected mothers and may prevent perinatal transmission in 90% of cases. The majority of acute infections are asymptomatic, with only 30% of adults developing typical symptoms of hepatitis, and less than 0.5% developing fulminant hepatitis. Most cases can be managed with supportive treatment, although nucleoside analogue therapy may improve prognosis in severe cases. Chronic HBV develops in less than 5% of adults but in more than 20% of children, and exacerbations of chronic HBV may occur in the postpartum period. The 5-year cumulative incidence of cirrhosis in those with chronic HBV may be as high as 20%, and once cirrhosis has developed the annual risk for hepatocellular carcinoma may be as high as 5%. Therefore, treatment of chronic HBV is aimed at clearance of virus to prevent the development of cirrhosis and cancer. Vertical transmission to the fetus from hepatitis Be antigen (HBeAg)-positive mothers can be as high as 90% without attempts to prevent transmission. For patients with active disease or high viral loads, oral antiviral therapies (lamivudine, telbivudine, or tenofovir) reduce transmission without apparent increased risk for adverse maternal or fetal outcomes, as does cesarean delivery. Interferon therapy has a finite course of treatment and an increased chance of viral clearance and significantly reduces the risk for cirrhosis and liver cancer; however, it has more side effects and is contraindicated during pregnancy. Current recommendations are to administer HBV vaccination to all neonates, and to administer HBIG to all offspring of infected mothers.

HDV is dependent on HBV co-infection to replicate. Acute co-infection with both viruses can be more severe than acute HBV infection alone and may result in acute liver failure. HDV superinfection in the setting of chronic HBV results in chronic HDV infection in most patients, and these patients have more rapid progression to cirrhosis.

Hepatitis C (HCV) transmission most commonly occurs from transfusion of infected blood products or injection of contaminated drugs (both illicit and iatrogenic). Maternal-fetal and sexual transmission are less common routes of transmission. Initial infection is generally asymptomatic, but up to 30% of patients develop acute hepatitis. In patients with acute HCV infection that has not cleared spontaneously within 12 weeks, treatment with pegylated interferon may be used to prevent chronic infection, with treatment success in up to 98% of patients. In most asymptomatic and untreated cases, infection persists for over 6 months and leads to chronic infection with progression to cirrhosis in up to 30% of patients within 30 years. Thus, HCV is the leading cause of chronic hepatitis, cirrhosis, and liver cancer (which develops in up to 3% of patients per year) and a primary indication for liver transplantation in the developed world. Depending on the severity of liver fibrosis, therapy may be warranted to prevent these complications. Combination treatment with pegylated interferon, ribavirin, and a protease inhibitor can result in a sustained virologic response in up to 80% of patients, but is contraindicated during pregnancy. Various second-generation antiviral drugs have been introduced for single-agent or combination regimens to clear HCV infection, but there are insufficient data to endorse their use during pregnancy.

Hepatitis G (HGV) is transmitted parenterally, sexually, or vertically. In the United States, nearly 20% of all blood preparations are infected with HGV. Although there have been reports of acute, fulminant, and chronic hepatitis and hepatic fibrosis, HGV replicates predominantly in the hematopoietic system rather than in hepatocytes. Clinical significance is mostly for those co-infected with HCV or human immunodeficiency virus (HIV) or for individuals with hematologic cancers.

Cholecystitis

Pregnancy may promote gallstone formation. Cholelithiasis is present in up to 3% of pregnant women, although acute cholecystitis occurs in only 0.1% of pregnancies. Patients may have right upper-quadrant pain, fever, and leukocytosis, and diagnosis is generally made by ultrasonography. Serious complications include cholangitis, pancreatitis, gangrenous cholecystitis, and perforation. To avoid surgery, conservative treatment may be considered in mild cases and includes intravenous hydration, antibiotics, opioid analgesia, bowel rest, and possibly percutaneous cholecystostomy. Although a conservative approach does not seem to be associated with poorer fetal outcomes, treatment failure or disease recurrence during pregnancy are common, so many conservatively managed patients ultimately require surgical treatment. Both open and laparoscopic cholecystectomy (preferably in the second trimester) can be considered, though laparoscopic techniques offer maternal recovery advantages similar to those in the nonpregnant patient and may have slightly lower fetal complication rates. With either technique, the incidence of miscarriage or preterm labor/delivery is over 25%.

Liver Abscess

Liver abscess can develop from infection by a range of organisms with various sites of entry. Organisms with a predilection for the liver include parasites such as Entamoeba, Echinococcus, Clonorchis, and Ascaris. Direct inoculation during medical instrumentation or hematogenous spread from intravenous drug abuse or endocarditis can occur. Appendicitis, diverticulitis, or other intra-abdominal infections may spread to the liver. Fungal infections are also possible in immunocompromised patients. Management of liver abscess includes antimicrobial agents, percutaneous or open drainage, and possibly surgical resection. The condition is rare during pregnancy, but treatment modalities are similar to those described for the nonpregnant patient.

Autoimmune Diseases

Autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis are conditions that may overlap and may also be associated with other extrahepatic autoimmune disorders. All may lead to end-stage liver disease, and treatment with corticosteroids, other immunosuppressants, and/or ursodeoxycholic acid is aimed at preventing this progression. For advanced and intractable disease, liver transplantation may be necessary. Pregnancy is associated with a 33% incidence of disease flares (mostly in the postpartum period), one-third of which result in maternal hepatic decompensation, liver transplantation, or death. Risks for preterm birth, gestational diabetes, and low birth weight are also significantly increased. Immunosuppressive therapy during pregnancy is reportedly safe and effective in reducing disease flares.

Vascular Syndromes

Budd-Chiari syndrome involves thrombosis of the hepatic vein or suprahepatic inferior vena cava and may be associated with pregnancy (comprising nearly one-half of all cases) or other hypercoagulable states. Hepatic venous congestion can also result from right-sided heart failure or other cardiopulmonary diseases that increase central venous pressure or from mechanical compression or compartment syndrome that impedes hepatic venous outflow. This congestive hepatopathy can ultimately lead to fibrosis, portal hypertension, and liver failure. Portal vein thrombosis may also occur and cause portal hypertension without cirrhosis. Initial therapy is anticoagulation with low-molecular-weight heparin, and endoscopic screening/treatment and beta-adrenergic receptor blockade (propranolol or nadolol) for prophylaxis of variceal bleeding are also recommended. Liver transplantation may ultimately be required in chronic cases. “ Shock liver ” syndrome can occur in the setting of perioperative hypotension, critical illness with septic shock or cardiac arrest, pulmonary embolus, heart failure, or heatstroke caused by disruption of hepatic arterial and/or portal venous inflow, resulting in acute ischemic/hypoxic hepatitis, especially in the setting of other co-existing liver disease.

Metabolic Diseases

Wilson disease is a condition of reduced copper excretion. Gradual copper accumulation in the liver can lead to cirrhosis, while rapid accumulation may result in acute liver failure. Patients may also develop neurologic, ophthalmologic, and renal dysfunction. Fertility is generally reduced in women, but treatment with copper-chelating agents during pregnancy can result in positive outcomes for both the mother and fetus. Hemochromatosis is a condition of iron accumulation that results in arthropathy, skin pigmentation, diabetes, hypopituitarism, hypogonadism, heart failure, and liver cirrhosis. Phlebotomy (with or without a chelating agent) to deplete iron stores markedly improves survival and prevents most of the complications. α ₁ -Antitrypsin deficiency results in uncontrolled tissue degradation, with effects predominantly in the lungs and liver. This leads to emphysematous changes in the lung as well as liver cirrhosis. Pregnancy can be complicated by fetal growth restriction, preterm labor, and pneumothorax or other respiratory decompensation.

Hepatotoxicity

Hepatotoxicity can result from a variety of exposures. Acetaminophen (paracetamol), involved in 20% of drug overdoses during pregnancy, is metabolized by the liver into highly reactive oxides. If their formation exceeds the binding capacity of glutathione, maternal and fetal hepatic injury occurs. Treatment with N- acetylcysteine within 16 hours of acetaminophen ingestion may bind toxic metabolites in both the mother and the fetus and improve outcomes. Alcoholic hepatitis can result from the acute ingestion of large amounts of alcohol, and chronic alcohol ingestion may lead to cirrhosis. Other agents that have potential to cause hepatotoxicity during pregnancy are antiretroviral drugs for HIV infection, propylthiouracil for hyperthyroidism, alpha-methyldopa and labetalol for hypertension, sevoflurane (given for status asthmaticus), isoniazid for tuberculosis, statins for antiphospholipid syndrome or hyperlipidemia, mushrooms and herbal supplements, and industrial agents. In one report, liver transplantation was successfully accomplished during pregnancy to treat acquired propylthiouracil-induced hepatotoxicity.