Hepatitis in Pregnancy

Updated: Mar 13, 2016
  • Author: Stephen A Contag, MD; Chief Editor: Christine Isaacs, MD  more...
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Acute viral hepatitis is the most common cause of jaundice in pregnancy. The course of most viral infections is not affected by pregnancy.

Jaundice is a characteristic feature of liver disease. The clinical signs and symptoms are indistinguishable between the various forms of viral hepatitis, thus, the differential diagnosis requires serologic testing for a virus-specific diagnosis, [1, 2] and the diagnosis is by biochemical assessment of liver function.

The differential diagnosis includes other forms of viral hepatitis including mononucleosis and Epstein-Barr virus (EBV) infections, autoimmune disease, and widespread systemic infection with liver failure. Patients presenting with jaundice during pregnancy often require a workup to differentiate obstructive gall bladder or bile duct disease, severe preeclampsia, HELLP (hemolysis, elevated liver enzyme levels, low platelet count), or acute fatty liver of pregnancy from viral hepatitis.

The most useful tests to diagnose hepatitis include laboratory evaluation of urine bilirubin and urobilinogen, total and direct serum bilirubin, alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), alkaline phosphatase (ALP), prothrombin time (PT), total protein, albumin, complete blood cell (CBC) count, and in severe cases, serum ammonia. [3, 4, 1, 5]

This article will review the hepatitides caused by the hepatitis viruses A, B, C, D, E, and G.

For patient education information, see Hepatitis A; Hepatitis B; Hepatitis C; Cirrhosis; Liver Cancer; and Immunization Schedule, Adults.

See also Liver Disease in Pregnancy, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, and Hepatitis E, and Viral Hepatitis.


Hepatitis A

Hepatitis A virus (HAV) infection is the second most common form of viral hepatitis in the United States. HAV is a small, nonenveloped, positive, single-stranded RNA virus that was first identified by electron microscopy in 1973 and classified within the genus Hepatovirus of the picornavirus family. [4] This virus is transmitted by the fecal-oral route, [3, 4, 1] and there is 1 worldwide serotype. [6]

Infections occur early in life in areas where sanitation is poor and living conditions are crowded. [7] The risk of hepatitis A infection is inversely proportional to the sanitation infrastructure available in a country. In countries with poor hygienic conditions, most children are affected before age 9 years, with ascertainment obscured by the asymptomatic nature of the disease. As sanitation increases, the age and proportion of symptomatic patients increases.

Vertical transmission of HAV during the pregnancy or puerperium is rare. [8, 9, 10, 11, 12] The incidence of acute HAV infection in pregnancy is approximately 1:1000 women. Pregnancy should not impact a physician's management of HAV infection or vice versa.

The following is a slide presentation on HAV from the Centers for Disease Control and Prevention (CDC).

Centers for Disease Control and Prevention (CDC) slide presentation on hepatitis A (HAV).

Pathophysiology and transmission

In hepatitis A disease, feces contain the highest concentration of HAV viral particles, and viral excretion is highest late in the incubation and early in the prodromal phase. [13] The duration of viremia is short with limited transmission in urine or other body fluids.

HAV replicates exclusively in the cytoplasm of the infected hepatocytes by a mechanism involving an RNA-dependent RNA polymerase. [13] The inflammation and necrosis observed during HAV infection does not appear to be a direct viral effect but rather an effect of the immune cell response induced by the viral infection. The resulting inflammatory response leads to hepatitis and necrosis and appears to be T-cell mediated. [3, 4, 1] In most patients, the process is reversible, with the damaged hepatic tissue restored within 8-12 weeks. [3]

Transfer of HAV infection occurs as a result of person-to-person transmission through the fecal-oral route. [2] Associated factors are poor hygiene, poor sanitation, and intimate personal or sexual contact. The virus can survive in the environment for extended periods, and epidemics usually result from exposure to contaminated food or water. [2] In areas with a high incidence, the disease is highly endemic among children, who are reservoirs for disease. In areas with a low endemicity, the disease rate is low, with the highest incidence among adults who travel to endemic areas, men who have sex with men (MSM), illicit drug users, and persons with chronic liver disease. [2]

Among pregnant women in the United States, transmission occurs after emigrating from or traveling to countries with a high incidence of hepatitis A disease. HAV infection induces lifelong protection against reinfection. [13] There is practically no maternal-fetal transmission of HAV, as anti-HAV immunoglobulin (Ig) G antibodies present during the initial stages of HAV infection cross the placenta and provide protection to the infant after delivery, [3] and it poses a minimal risk to the fetus and newborn. There is no evidence of congenital HAV infection. [14] Thus, no intervention is recommended.

Differential diagnosis and diagnostic studies

The differential diagnosis of hepatitis A disease includes other forms of viral hepatitis, and differentiating this condition from those other forms requires serologic testing for a virus-specific diagnosis. HAV is neutralized by both anti-HAV IgG and anti-HAV IgM. No serologic or hybridizing cross-reactivity exists between HAV and other viral hepatitis agents. [3, 1]

The specific diagnosis of acute hepatitis A is made by finding anti-HAV IgM in the serum of patients. An alternative is the detection of virus or antigen in the feces. [13, 2] The level of virus shedding does not correlate with the severity of liver disease. [13] The virus and antibody can be detected by commercially available radioimmunoassay (RIA), enzyme immunoassay (EIA), or enzyme-linked immunosorbent assay (ELISA) kits. These commercially available assays for anti-HAV IgM and total anti-HAV (IgM and IgG) for assessment of immunity to HAV are not influenced by the passive administration of immunoglobin, because the prophylactic doses are below detection level. [4] Patients previously vaccinated or exposed to HAV will have elevated IgG. [15, 16]

At the onset of disease, the presence of IgG anti-HAV is always accompanied by the presence of IgM anti-HAV. As IgG anti-HAV persists lifelong after acute infection, detection of IgG anti-HAV alone indicates past infection. If laboratory tests are not available, epidemiologic evidence can help in establishing a diagnosis. [3]

Clinical management

Antibiotics are of no value in the treatment of HAV infection, and antiviral agents, as well as corticosteroids, have no effect in the management of the acute disease. [3] The administration of immunoglobulins may improve the clinical manifestations of the disease if given within 2 weeks of infection, but this treatment is of no help in the acute phase of hepatitis A. [3]

Thus, medical therapy can only be supportive and is aimed at maintaining comfort and adequate nutritional balance. Complete recovery without therapy is generally the rule. [3] There are no specific dietary recommendations other than avoiding alcohol or any other hepatotoxic substances. [3, 1]

Hospitalization is reserved for patients with evidence of severe disease with coagulopathy, encephalopathy, or severe malaise and asthenia. Most patients can be managed outpatient with rest and avoidance of abdominal trauma. The degree of activity is usually limited by the severity of the asthenia and malaise.

Patients with fulminant hepatic necrosis may require liver transplantation. It is difficult to ascertain which patient will require a liver transplant, as many patients with advanced liver necrosis may recover completely from the disease. [1]


HAV infection does not lead to chronic or persistent hepatitis. [1, 13, 2] However, mortality increases with age at development of the disease: although most patients recover completely, mortality is 1 in 1000 at younger than 14 years and approximately 2% when the infection affects patients older than 40 years.

Mortality can result from massive necrosis of the liver, which usually occurs during the first 6-8 weeks of illness. This condition is characterized by high fever, marked abdominal pain, vomiting, jaundice, and the development of hepatic encephalopathy associated with coma and seizures. In this setting, there is 70-90% mortality. Infection superimposed on chronic hepatitis B or C or other underlying liver disease significantly increases the mortality.

Patient education and prevention

Patients traveling to endemic regions should be counseled regarding the risk for hepatitis A disease and receive preexposure prophylaxis as well as recommendations for improved and stricter sanitary precautions, such as use of bottled water. Hepatitis A does not have any known effects on the fetus, but immunization is recommended for patients at high risk of exposure. HAV infection is not a contraindication to breastfeeding. [17]

Prevention of HAV transmission and acquisition depends on preexposure vaccination, postexposure immunoglobulin, good hygiene, clean water systems, and avoidance of food contamination. HAV is resistant to thermal denaturation, acid treatment, 20% ether, chloroform, dichlorodifluoromethane, and trichlorotrifluoroethane, perchloracetic acid, detergent inactivation, and storage at -20°C for years. HAV is inactivated by heating to 85°C for 1 minute, autoclaving, ultraviolet radiation (UVR), formalin, potassium permanganate, iodine, and chlorine. Shellfish from contaminated areas should be heated to 90°C for 4 minutes or steamed for 90 seconds. [18]

Preexposure and postexposure prophylaxis

Current recommendations for preexposure prophylaxis primarily include the use of the inactivated HAV vaccine, which has been demonstrated to be safe for use in pregnancy. If a woman is allergic to any of the vaccine components, preexposure prophylaxis can be given with the immunoglobulin. The preexposure use of immunoglobulin provides temporary passive immunization that is effective for approximately 5 months in a nonpregnant population. [3, 4, 1]

Postexposure prevention with immunoglobulin should be given within 2 weeks of exposure to HAV. This has been shown to decrease both the risk of acquiring the disease and the severity of the disease. [19] Immunoglobulin has been shown to be safe for use in pregnancy. A single intramuscular dose of 0.02 mg/mL given within 2 weeks of exposure provides protection for 3 months in 80-90% of individuals. [20]

Some experts have recommended giving postexposure vaccination to prevent infection. [21] Newborns of mothers with HAV infection in the third trimester should be given passive immunoprophylaxis with immunoglobulin within 48 hours of birth. [18]


Hepatitis B

Globally, hepatitis B virus (HBV) infection is the most common form of chronic hepatitis around the world. Chronic carriers can continue to transmit the disease for many years before becoming symptomatic. [22] Infection occurs very often in early childhood when it is asymptomatic and then leads to the chronic carrier state. Chronic HBV infection leads to increased risk for chronic hepatic insufficiency, cirrhosis, and hepatocellular carcinoma (HCC).

Between 1990 and 2013 in the United States, the incidence of HBV infection declined from 8.5 cases to 1 case per 100,000 among all age groups, but the decline was most significant among children younger than 15 years. [23, 24] This has been due to increased awareness and identification of mothers who are hepatitis B surface antigen (HBsAg) positive as well as adequate prophylaxis among exposed newborns. [18] Approximately 0.5% of the US population is HbsAg positive, and 5% is hepatitis B core antibody (anti-HBc) positive. [25]

More than 2 billion people worldwide have been infected with HBV at some time, and approximately 350 million people remain chronically infected. [25] There are approximately 4 million new cases per year, of which approximately 25% become chronic carriers. [25, 18] The areas of highest incidence are Southeast Asia and the Pacific Basin (excluding Japan, Australia, and New Zealand), sub-Saharan Africa, the Amazon Basin, parts of the Middle East, the central Asian Republics, and some countries in Eastern Europe. [25] Low endemicity areas include North America, Western and Northern Europe, Australia, and parts of South America. The carrier rate is less than 2%, and up to 5% of the population is infected with HBV. [25, 26, 27]

The age group most likely to be affected around the world is the newborn population, particularly in areas with a high prevalence of disease and lack of identification of infected women whose infants are at risk for becoming chronic carriers. In regions with widespread perinatal screening and adequate newborn prophylaxis, horizontal transmission secondary to exposure to contaminated blood products, body fluids, or sexual contact become the primary modes of transmission of HBV in the young adult population. In adult-onset disease, males are more likely to go on to develop chronic disease, whereas females are more likely to develop anti-HBs antibodies. [25]

The following is a slide presentation on HBV from the Centers for Disease Control and Prevention (CDC).

Centers for Disease Control and Prevention (CDC) slide presentation on hepatitis B (HBV).

Pathophysiology and transmission

Hepatitis B disease is caused by HBV, an enveloped virus containing a partially double-stranded, circular DNA genome and classified within the family hepadnavirus. [22, 27] The nucleocapsid core measures 27 nm in diameter and is where the hepatitis B core antigen (HbcAg) is derived. The core is surrounded by a lipoprotein coat or envelope, which is the HbsAg. [22, 25, 26, 28, 29] The envelope lipoprotein is produced in excessive amounts and released into the circulation as HBsAg. [3]

HBV interferes with the functions of the liver while replicating in hepatocytes. The immune system is then activated to produce a specific reaction to combat and attempt to eradicate the virus. Intracellular HBV is not cytopathic [30] ; the inflammatory response develops as a result of the immune response.

HBV does not cross the placenta because of its size, and it cannot infect the fetus unless there have been breaks in the maternal-fetal barrier, such as those that occur during amniocentesis. Women who are infected can transmit HBV to the infant during delivery. Consequently, unless adequate prophylaxis is provided, the newborn is at high risk to develop a chronic HBV infection, with its known long-term complications. [26]

Perinatal transmission from the mother to her newborn baby is the most important mode of infection. If a pregnant woman is an HBV carrier and is also positive for hepatitis B "e" antigen (HBeAg), her newborn baby has a 90% likelihood of becoming infected. Approximately 25% of infected infants will become chronic carriers. Most HbsAg carriers are asymptomatic, potentially infectious, and a constant source of new infections. [28]

Less frequent, but important, modes of HBV transmission include transfer through percutaneous or parenteral contact with infected blood, body fluids, and by sexual intercourse. [22, 29] A break in the skin or mucosal barrier is required for transmission. [28]

HBV infection is transient in about 90% of adults and 10% of newborns and persistent in the remainder. [26] Approximately 5-10% of adults progress to become asymptomatic carriers and develop chronic hepatitis. This can lead to cirrhosis and hepatocellular carcinoma. [28]

Transfusion-related HBV infection occurs in approximately 1 in 200,000 transfusions. Some evidence shows that the rate may be lower; however, this is still higher than the human immunodeficiency virus (HIV)– and hepatitis C virus (HCV)–related risk of approximately 1 in 2,000,000. [31, 32, 33] Current rates for HBV are thought to be around 1 in 280,000 to 1 in 350,000, partially due to improved immunization and a decrease of infected products in the donor pool. [31]


HBV is able to remain on any surface it comes into contact with for about 1 week without losing infectivity, [27, 28] and an affected individual's blood is infective for weeks before the onset of any symptoms and throughout the acute phase of the disease. The infectivity of chronically infected individuals varies from highly infectious (HBeAg positive) to rarely infectious (hepatitis B "e" antibody [anti-HBe] positive). [25] HBeAg-positive specimens contain high concentrations of infectious virions and HBV DNA, in contrast to anti-HBe positive samples, in which the number of hepatitis B virions is substantially reduced. [25]

The concentration of HBV is highest in blood serum and wound exudates. A moderate concentration is found in semen, vaginal fluid, and saliva, and low or undetectable levels are found in urine, feces, sweat, tears, and breast milk. [27]

Hepatocellular carcinoma

More than 80% of hepatocellular carcinomas have integrated HBV sequences within the cell genome. Many copies can be found and these are usually rearranged with deletions, inversions, and sequence reiterations. These rearrangements are not transcriptionally active but rather interfere with normal cell cycle regulation. [22, 28, 34] The exact mechanism by which HBV infection predisposes to hepatocellular carcinoma is unknown. [34]

Differential diagnosis and diagnostic studies

All patients with hepatitis B should be tested for hepatitis D virus (HDV). Other conditions that can coexist and should be tested for are HCV and HIV infections.

The initial nonspecific diagnosis of hepatitis is made by the biochemical assessment of liver function. The initial laboratory evaluation should include total and direct bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), prothrombin time (PT), total protein, albumin, serum globulin, and complete blood cell (CBC) count. [27, 28] The hallmark is the elevation in ALT, which can range from 2- to 100-fold. However, the severity of the increase does not correlate with the prognosis.

Specific tests and evaluation

Specific testing for HBV requires evaluating for the presence of specific antigens and antibodies. HBV antigen and antibodies have been classified into 3 clinically useful groups: (1) surface antigen and antibodies (HBsAg and anti-HBs, respectively), (2) core antigen and antibodies (HBcAg and anti-HBc, respectively), and (3) "e" or precore antigen and antibodies (HBeAg and anti-HBe, respectively). Testing for entire viral particles or virions and HBV DNA are also available.

HBsAg can be detected in the serum from several weeks before the onset of symptoms and may persist for months in chronic infections. The presence of HBsAg indicates that the woman is potentially infectious. [26, 27, 28] HBcAg is not found in the blood stream. Other antigens present during the acute phase include virions, HBV DNA, HBV DNA polymerase, and HBeAg. The presence of HBeAg is indicative of infectivity and disease severity. [27, 28] The risk of maternal-fetal transmission can be as high as 90% among women positive for HBsAg who are also positive for HBeAg. [26, 27]

Anti-HBc is the first antibody to appear. This test may reliably diagnose acute HBV infection. Anti-HBc immunoglobulin (Ig) M appears early during the acute phase and usually disappears by 6 months; however, it can persist in some cases of chronic hepatitis. Anti-HBc IgG appears during convalescence and generally remains detectable for a lifetime. [27] HbsAg, HBeAg, and viral DNA are transiently present for approximately 6 months before clearing; then, they are replaced by anti-HBs and anti-HBe.

Anti-HBe appears after anti-HBc and reflects decreased infectivity. Anti-HBs appears during recovery from the acute phase and is evidence of resolution of the disease; this remains positive for the lifetime of the individual in more than 80% of patients. [27, 25] The chronic carrier state is more likely to develop among patients whose HBsAg consistently persists or in whom HBeAg remains positive for 2-3 months after the acute phase. This pattern is observed in more than 90% of adult-onset disease. Approximately 10% of adults and more than 90% of infants that are infected will go on to develop chronic disease. [26]

Chronic HBV and laboratory tests

Chronic disease develops in most neonates who are exposed and do not receive appropriate prophylaxis. Approximately 1,000,000 individuals are chronically infected with HBV in the United States. [25] Chronic HBV infection develops over many years, during which the disease goes through several phases. Some patients complain of fatigue, anorexia, and malaise, whereas others are completely asymptomatic.

By definition, chronic HBV infection lasts for more than 6 months, with persistently positive HbsAg and anti-HBc IgG with absence of an anti-HBs response. HBeAg is often present and correlates with elevated levels of HBV DNA. The inflammatory response varies but is always milder than in the acute disease. It is an ongoing inflammatory process that progresses to cirrhosis and increases the risk of hepatocellular carcinoma 100-fold. [27, 28]

Progression of disease is equated to viral replicative activity; this can be assayed by measuring serum ALT concentrations. An elevated ALT suggests active disease with progression. Once the liver becomes cirrhotic, ALT concentrations may decrease despite active inflammatory activity. In this phase, seroconversion is indicated by the presence of anti-HBe and a decrease in HBV DNA. The presence of HBV DNA determines the infectivity of an individual.

In addition to elevations in serum transaminases and bilirubin, patients with chronic HBV infection can develop antinuclear (ANA), antimitochondrial (AMA), and antismooth muscle antibodies (ASMA).

HCC and laboratory tests

Persistent HBV infection is sometimes associated with histologically normal liver and normal liver function, but about one third of chronic HBV infections are associated with cirrhosis and hepatocellular carcinoma. [28] This condition develops in 40-50% of chronically infected men and 15% of women. [25] Men who acquired HBV infection during childhood are the most likely to develop hepatocellular carcinoma. The average duration of HBV disease before the development of hepatocellular carcinoma is 35 years.

Serum HBV DNA is the strongest predictor of progression to cirrhosis, regardless of ALT and HBeAg status. [35] Tumors that are alpha-fetoprotein (AFP) positive with significant elevations above baseline are more aggressive and associated with a shorter survival. AFP cannot be monitored during pregnancy due to fetal production of AFP. Most women who are chronically infected with HBV complete childbearing before the onset of disease. [28]

Clinical management

Most individuals with HBV infection who acquire the disease during adulthood have self-limited disease and do not require treatment. During pregnancy, viral hepatitis is associated with the lowest risk of obstetric complications when compared with other potential hepatic complications, such as acute fatty liver of pregnancy, severe preeclampsia, and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets). In most cases, no special treatment is required during the acute phase. Bed rest is not mandatory.

Drug resistance mutations are one of the biggest concerns among individuals who are chronically infected with active HBV disease. Current therapeutic options use single or combined antivirals such as lamivudine, adefovir, and entecavir and less often include immunomodulatory drugs such as interferon (IFN).

Treatment with antivirals is recommended for patients with HBV DNA levels persistently greater than 10,000 copies/mL. [36, 37] Although antivirals are not labeled as teratogens, information is limited on human exposure during pregnancy. [38]

A systematic review and meta-analysis by Brown et al concluded that antiviral therapy improves hepatitis B virus suppression and reduces mother-to-child transmission in women with chronic hepatitis B virus infection with high viral load compared to the use of hepatitis B immunoglobulin and vaccination alone. The study also added that the use of telbivudine, lamivudine, and tenofovir appears to be safe in pregnancy with no increased adverse maternal or fetal outcome. [39]


The risk for chronic HBV disease is highest among individuals with perinatally acquired HBV infection. Most individuals who acquire the disease later in life will clear the infection. Prophylaxis of individuals at high risk and patient education are the most important measures to prevent disease.

Complications of chronic hepatitis B include cirrhosis and hepatocellular carcinoma. In addition, extrahepatic manifestations of HBV are seen in approximately 10-20% of patients. [26, 28, 30] These conditions develop as a result of immune complex deposition within various organ systems or within the vasculature. The various manifestations include a transient serum sickness–like syndrome, acute necrotizing vasculitis, membranous glomerulonephritis, and papular acrodermatitis of childhood. [26, 28, 30]


All women presenting for prenatal care should be routinely tested for HBsAg early in their pregnancy to identify those at risk for vertical transmission. In those cases in which prenatal information is not available or was not obtained, HBsAg status should be established at the time of admission. This will allow at-risk newborns to be appropriately immunized after birth. The routine vaccination of all infants at birth may be most cost effective in developing countries. [25] Pregnancy and lactation are not considered contraindications for HBV immunization. [26]

Preexposure prophylaxis

Preexposure immunization (hepatitis b vaccine) is recommended for high-risk individuals, of which the most important group to immunize is the newborn population. Furthermore, infants or adolescents not previously immunized should be vaccinated, because they are the next most important group at risk for exposure.

There are certain high-risk groups that also benefit from immunization, such as persons with occupational risk, students of healthcare professions, service providers in daycare programs caring for the developmentally disabled, patients on hemodialysis, patients receiving blood products or transfusions, intravenous (IV) drug users, individuals with multiple sexual partners regardless of sex, inmates at correctional facilities, household contacts of affected individuals, transplant candidates, and travelers to areas with a high incidence of disease. [27, 40]

Postexposure prophylaxis

Postexposure immunization with hepatitis B immunoglobulin (HBIG) should especially be considered for neonates born of mothers positive for HBsAg. Such infants often acquire chronic infection, especially when mothers are HBeAg positive, in whom the risk of becoming chronic carriers is extremely high (90%). When HBIG is given within the first hours, up to 24 hours after birth, the risk of HBV infection can be reduced to 20%. [27, 28]

Passive immunization with HBIG given immediately before or within 48 hours after exposure to HBV provides immediate but temporary protection for 3-6 months. HBIG is usually not used for preexposure prophylaxis because of cost, availability, and short-term effectiveness. [26] The vertical transmission rate is dramatically decreased when HBIG is given with the first dose of HBV vaccine. [26, 27]

HBIG plus HBV vaccine

When administered within 24 hours after birth, HBIG and vaccination are 85-95% effective in preventing HBV infection and the chronic carrier state. In contrast, administration of the HBV vaccine alone beginning within 24 hours after birth is 70-95% effective in preventing perinatal HBV infection. [26] With widespread vaccination, the number of susceptible individuals would theoretically decrease, rendering the need for prenatal HbsAg testing unnecessary. The problem is that vaccination programs do not provide 100% coverage, and there is a large immigrant population that has not received adequate immunization.

An anti-HBs titer greater than 10 IU/L after 2-3 months is regarded as being protective. Repeat exposure is associated with a rapid anamnestic response after reexposure. [26, 28] The vaccine-induced immunity has been demonstrated to last at least 15 years, if not longer. Booster doses are not recommended. [26, 27, 28]  The CDC has recommended shortening the interval for postvaccination serologic testing that assesses an infant's response to HepB vaccination from age 9-18 months to age 9-12 months.. [41]


Hepatitis C

Hepatitis C virus (HCV) was first identified in 1989. [42, 43] Infection with this virus is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) around the world. [44] HCV disease has a slow onset with symptoms in about 25% of patients. [45] Approximately 75% of patients are chronically infected and may not be aware of their infection, because they are not clinically ill. These individuals serve as a source of transmission to others and are at risk for chronic liver disease or other HCV-related chronic diseases. Approximately 40% of infected patients recover completely, and the remainder become chronic carriers; 20% of the carriers develop cirrhosis, and of those, up to 20% develop liver cancer. [46]

HCV-related end-stage liver disease (ESLD) is the most common chronic bloodborne infection and the leading reason for liver transplantation in the United States. Although new HCV infections decreased by more than 80% in the 1990s, [47] approximately, 17,000 new infections still occurred in 2007. [48] Approximately 60% of all new infections are believed to occur via intravenous/injection (IV) drug use, [49] 10-20% by sexual transmission, [50] less than 6% by blood transfusion, and the remainder includes occupational and unknown exposures. [51] The transmission risk from needlestick injury is approximately 3%. [51] Currently, there are an estimated 3.2 million cases of HCV disease, and 75-85% go on to become chronic infection. [48]

The World Health Organization (WHO) estimates that 3-4 million people annually are infected, with approximately 130-170 million people with chronic disease who may go on to develop cirrhosis and/or hepatocellular carcinoma. [46] The highest prevalence is in Egypt (22%). [46]

Acute HCV infection leads to symptomatic hepatitis in 20-30% of patients [48] ; 15% of acute liver disease in the United States is due to HCV. [52] HCV infection occurs among persons of all ages, but the highest incidence of acute HCV is found among persons aged 20-39 years. [40]

In the pregnant population, the prevalence of HCV is estimated to be about 1%, with the highest prevalence in the black population (6.1%) and the lowest in the Latino population (2.8%). [53, 54, 55] Only 25% of pregnant women report receiving blood products or using IV drugs when HCV infection is diagnosed. [56] Concurrent alcoholism, IV drug use (38%), and coexisting infection with human immunodeficiency virus (HIV) (33%) are important associated risk factors. [51, 57]

The decline observed in the incidence and prevalence of HCV is attributed to needle exchange programs among IV drug users and improved blood donor screening. [44] This has led to a relative increase in the importance of accidental needle sticks, and sexual and perinatal transmission in the incidence of HCV infections. [44]

The following is a slide presentation on HCV from the Centers for Disease Control and Prevention (CDC).

Centers for Disease Control and Prevention (CDC) slide presentation on hepatitis C (HCV).

Pathophysiology and transmission

HCV is a partially double-stranded RNA virus, one that mutates frequently secondary to changes in the structural proteins of the viral envelope. The development of antibodies against HCV does not produce immunity against the disease the way it does with most other organisms. [25]

Some data suggest that fewer than 10% of pregnant women develop chronic infection and that fewer than 5% develop cirrhosis. [51] Chronicity rates appear to depend on the mode of infection and the age at which patients acquire infection, with increased rates among transfusion or IV drug recipients. [44]

Humoral and cellular immune responses

After an individual is infected, HCV replicates with rates up to 1 trillion copies per day. It is constantly genetically mutating within the host, with the mutated forms frequently different enough from their predecessors that when the immune system is capable of identifying and eradicating one form, the mutant forms continue to cause ongoing disease and take over as the predominant strain. For this reason humoral immune responses have little effect on viral clearance, [58, 59] and no specific antibody response can predict the outcome of infection. [58]

However, cellular immune responses seem to have an important role in determining the outcome of acute HCV infection. The CD4 and CD8 cellular response mediated by a type 1 T helper cell (Th1) lymphocytic response is associated with a cytokine profile leading to viral clearance. [60, 61] Of the individuals chronically infected with HCV, 75-85% progress to chronic disease. The disease is an indolent and slowly progressive one; most infected individuals carry the virus and remain infective for life. [62] Spontaneous viral clearance is higher in symptomatic acute HCV infection. [44]

HCV genotypes

There are 11 major genotypes of HCV, with 15 different subtypes, which vary in prevalence in different regions of the world. [46, 62, 63] Each of these major genotypes can differ significantly in their biologic effects. The most important biologic differences are their replication rates, mutation rates, and the severity of damage they can cause. Most importantly, clinically, these different genotypes vary in their response to currently available therapies. [25, 64]

Maternal-fetal transmission

Transfer of HCV infection in pregnancy occurs as a result of vertical or horizontal transfer. The prevalence of HCV among pregnant women is approximately 1% (0.1-2.4%), and the rate of mother-to-infant transmission is 4-7% per pregnancy among women with detectable viremia. [55] Transfer of HCV infection to female infants may be twice as high as transfer to male infants. [65] Vertical or perinatal transfer could potentially occur before or during delivery.

Vertical perinatal transmission occurs in women who are HCV-RNA positive at the time of delivery and appears to be highly dependent on viral load and HIV status, which are independent of each other. [66] High HCV viral loads of more 100,000 copies/ mL are associated with an increased risk of vertical transmission.

The average rate of infection is approximately 4 of every 100 infants, although it is 2-3 times higher if a woman is coinfected with HIV, [46] probably due to a higher viral load. [44, 67, 68] Infection before delivery has been shown to occur in as many as 33% of patients. [69] The role of a viral titer is unclear, and there does not appear to be an association with method of delivery. [70] The infected infants tend to do well, and severe hepatitis is rare. [46]

Cesarean section vs vaginal delivery

Currently, no evidence is available upon which to base any practice recommendations regarding planned cesarean section versus vaginal delivery for preventing mother–to-infant hepatitis C virus transmission. [71] The role of cesarean section to prevent vertical transmission is questionable and results have been conflicting, particularly in patients with isolated HCV infection. [72, 65] Evidence from large multicenter trials does not support elective cesarean delivery for prevention of vertical HCV transmission, and cesarean delivery based on viral load is not advocated. [73]

HIV coinfection

An elective cesarean section has been suggested for pregnant patients coinfected with HIV, as transmission rates in this cohort appear to be higher. Elective surgery in these patients has been shown to reduce maternal-fetal transmission by up to 60%. [68, 74]

Transmission during breastfeeding also occurs more often in patients infected with HIV, [68] although breastfeeding alone does not appear to increase transmission. [68] Chronic HCV infection appears to be the exception among infected newborns.

The risk of HCV infection from accidental needle stick exposure is reported to be 0.2-0.4%, [75, 76] but HIV coinfection increases the risk of needle-stick transmission. Although the frequency of sexual transmission of HCV is much lower than that observed for HIV or hepatitis B virus (HBV), [77, 78] coinfection with other sexually transmitted diseases (STDs) and HIV does increase sexual transmission. [79] Barrier precautions do not impact viral transmission rates in stable monogamous couples.

Blood transfusions, improper use of medical supplies, unsafe procedures

Transfusion-related HCV infection occurs in approximately 1 in 2,000,000 transfusions, which is lower than HBV-related risk of approximately 1 in 200,000. [31, 32, 33] Blood transfusions in an unscreened population, reuse of disposable medical supplies, and unsafe therapeutic procedures are the major modes of transmission in the developing world. [44] The screening rates for HCV in blood bank donors in developing nations is lower than that for HIV, ranging from 6% to 23%. [80, 81] Unsafe medical procedures are responsible for a substantial number of cases of HCV worldwide, accounting for 2-3 million new cases of HCV infections per year. [82]

Most cases of such transmission occur from infected blood or infected needles. The infection may also occur after accidental exposure to infected blood.

Nonparenteral transmission

Nonparenteral transmission does not occur frequently. Sexual transmission has been documented in stable heterosexual couples at a rate of 1.5-3% [83] and between male homosexual exposures at a rate of 3%. The factors that facilitate transmission between partners are concurrent HIV infection, traumatic sexual practices, and concurrent sexually transmitted disease. [84]

Differential diagnosis and diagnostic studies

Acute exacerbations of chronic HCV infection, alcoholic hepatitis, and drug-induced hepatitis can be confused with acute HCV infection. Extrahepatic manifestations of hepatitis C have not been reported. [44]

No definitive test diagnoses acute HCV infection. [44] Most patients are identified by a known exposure, documented seroconversion, unexplained increases in liver enzymes, and exclusion of other causes of liver disease. [44] The only conclusive method to diagnose an acute or recent-onset HCV infection is to demonstrate seroconversion in a previously seronegative individual. This is most likely to occur after an acute event or when following a high-risk individual.

Attempting to establish infection based on the presence of antibodies is not a reliable way to confirm the diagnosis, as many individuals may continue to be antibody negative for 6-12 months. Therefore the absence of antibodies does not preclude infection in the acute setting. [44] Up to 30% of patients will have delayed seroconversion (especially those who are immunocompromised). [85]


HCV RNA can be very unreliable for up to 1 year after infection due to fluctuations and levels below a detectable concentration. This requires serial measurement of HCV RNA for at least 1 year after documented exposure or seroconversion. [86] Occasionally, the infection resolves, and HCV RNA either clears before seroconversion occurs [87, 88, 89] or up to 10% of individuals lose their serologic markers. [87] Among patients who do develop serologic markers, measuring immunoglobulin (Ig) M has not shown to be useful, as its concentrations remain stable in acute and chronic disease. [90]

Various methods are available to detect HCV RNA. The most sensitive are reverse transcriptase polymerase chain reaction (PCR), branched DNA assays, and transcription-mediated amplification (TMA). These techniques are reliable, with detection limits of 5 IU/mL and a sensitivity of more than 95%. However, despite their high sensitivity, these tests are not recommended for screening for chronic HCV infection because of their cost. [87, 91]

Postexposure testing

Clear postexposure testing guidelines are not available. The Centers for Disease Control and Prevention (CDC) recommend measuring HCV antibodies and serum transaminase concentration at baseline. Subsequent testing schedules have been proposed that include testing for HCV RNA at 0, 1, 2, and 3 months after exposure and for antibodies at 0, 3, and 6 months after exposure. [92] Monitoring the progression of liver disease every 6 months is recommended by checking blood counts and liver enzyme levels. In patients with more advanced liver disease, alpha-fetoprotein (AFP) measurement and ultrasonography should be added. [46]

Clinical management

The CDC does not recommend testing all pregnant women for HCV infection, only those who are at high risk, and care during pregnancy is not modified by HCV infection. [16] The objectives for treatment of chronic hepatitis are to reduce inflammation; prevent progression to fibrosis, cirrhosis, and hepatocellular carcinoma through the eradication of the virus; decrease infectivity; and control the spread of the disease. [46]

In August 2012, the Centers for Disease Control and Prevention (CDC) expanded their existing, risk-based testing guidelines to recommend a 1-time blood test for hepatitis C virus (HCV) infection in baby boomers—the generation born between 1945 and 1965, who account for approximately three fourths of all chronic HCV infections in the United States—without prior ascertainment of HCV risk (see Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965). [93] One-time HCV testing in this population could identify nearly 808,600 additional people with chronic infection. All individuals identified with HCV should be screened and/or managed for alcohol abuse, followed by referral to preventative and/or treatment services, as appropriate.

Spontaneous resolution occurs in one third of infected persons. [44] Medical treatment is unlikely to have a significant impact on disease, as most infected individuals remain undiagnosed and have limited resources and access to care. [44] Antibiotics are of no value in the treatment of the infection, and antiviral agents, as well as corticosteroids, have no effect in the management of the acute disease.

Currently the best indicator of effective treatment is a sustained viral suppression, defined by the absence of detectable HCV RNA in the serum as shown by a qualitative HCV RNA assay with lower limit of detection of 50 IU/mL or less by 24 weeks after the end of treatment. [45]

PEG-IFN and ribavirin, liver transplantation

The most widely used form of treatment is a combination of pegylated interferon (PEG-IFN) and ribavirin in cases of chronic HCV infection. The use of pegylated interferon leads to a suppression of viral replication in more than 50% of cases [94] ; however, its use in pregnancy is contraindicated owing to conflicting reports of decreased birth weight and increased fetal loss. [95, 96] The US Food and Drug Administration (FDA) labels ribavirin as category X, although reports exist of its use during pregnancy without adverse outcomes. [96]

Transplantation is an option for patients with cirrhosis and end-stage liver disease. Despite transplantation, the donor liver almost always becomes infected, and the risk of progression to cirrhosis reappears. [97]

Genotype and treatment

Genotype determinations influence treatment decisions, [48] and once identified, the genotype doesn't need retested again as it doesn't change during the course of infection. [48] Patients with genotype 2 or 3 have a 2- to 3-fold likelihood of responding to therapy with alpha-interferon or a combination of alpha-interferon and ribavirin [48] (treatment duration, 24 wk) relative to patients with genotype 1 (treatment duration 48 wk). [48, 98]


Patients with a sustained virologic response remain HCV RNA negative for at least 5 years after stopping therapy and experience a long-term biochemical and histologic outcome with a decrease in total inflammatory activity and a decrease in the reversible components of fibrosis. Nevertheless, sustained virologic responders have a highly reduced risk of disease progression. [99]

The WHO estimates that 60–70% of patients with HCV infection develop chronic liver disease, 5-20% develop cirrhosis, and 1–5% die from cirrhosis or hepatocellular carcinoma. [46]

Patient education and prevention

Educate patients that HCV is not spread by breastfeeding, sneezing, coughing, hugging, sharing eating utensils, or drinking from the same glass, other normal social contact, food, or water. [46]

Testing and counseling for HCV should be offered to women with known risk factors. Currently no preexposure prophylaxis, vaccine, or postexposure prophylaxis is available for HCV, [44, 14] and postexposure prophylaxis with immunoglobulin is not effective in preventing infection. [46]

Primary prevention activities to reduce the risk of contracting the infection and secondary prevention activities to reduce the risk of liver disease and other HCV-related chronic diseases among those infected with HCV are required to reduce the burden of HCV infection and HCV-related disease. [46]

The prevention of HCV transmission and acquisition depends on preventing exposure to infected blood or blood products as well as implementation of universal precautions. It also requires avoidance of high-risk sexual behavior.

The most common form of transmission in the United States is through IV drug use. Needle-exchange programs for injecting drug users may help to limit the spread of HCV infection as well as that of HIV and HBV. [45] Patients who are HIV positive also have a higher risk of acquiring the disease. Women with HCV infection should avoid alcohol consumption and be vaccinated against hepatitis A and B. [100]

The HCV is susceptible to heating at 60°C for 10 hours or 100°C for 2 minutes in aqueous solution, formaldehyde (1:2000) at 37°C for 72 hour, beta-propiolactone, and ultraviolet irradiation. In addition, HCV is relatively unstable when exposed to storage at room temperature and repeated freezing and thawing.

The National Institutes of Health (NIH) recommend follow-up testing for exposed infants on 2 different occasions between ages 2 and 6 months with HSV RNA testing or HCV antibody testing after age 15 months. [98]


Hepatitis D

The delta antigen was first identified in the nucleus of hepatocytes infected with hepatitis B virus (HBV). [101] Hepatitis D is caused by the hepatitis delta virus (HDV), a defective RNA virus that can only cause hepatitis in individuals who are infected with HBV. HDV is transmitted percutaneously or sexually through contact with infected blood or blood products. This virus uses hepatitis B surface antigen (HBsAg) as its envelope protein essential for viral transmission. [101, 102]

HDV infections can occur as a coinfection with HBV or as a superinfection on chronic HBV infection; thus, chronic HBV carriers are at risk for infection with HDV. Individuals who are not infected with HBV and have not been immunized against HBV are also at risk of infection with HBV with simultaneous or subsequent infection with HDV. Inoculation with HDV in the absence of HBV will not cause hepatitis D.

In the United States, most cases of HDV infection are found among intravenous/injection (IV) drug users and among immigrants from countries where blood product screening for HBV is not routinely performed and where there is risk of exposure to unsterilized injection needles. The prevalence ranges from 2% among homosexual men to 30% in individuals with HBV infection. [103, 104]

Of the approximately 350 million people worldwide who are chronically infected with HBV, [25] 15-20 million of them are coinfected or superinfected with HDV. [105] In Mediterranean countries where HDV is endemic, the main form of transmission is through close personal contact. The decreasing worldwide prevalence of acute and chronic HDV is attributed to a decline in the prevalence of chronic HBsAg carriers in the general population. [105]

Of the 6 reported HDV genotypes, [106, 107] the most common is type 1, which is distributed around the world, mostly in Europe, North America, the Middle East, and North Africa. Genotype 1 is associated with a broad spectrum of chronic disease, [108] both severe and mild. [109] Type 3 is observed almost exclusively in the northern part of South America, type 2 is seen in the Far East, and types 4-8 are seen predominantly in African women. [102]

The following is a slide presentation on HDV from the Centers for Disease Control and Prevention (CDC).

Centers for Disease Control and Prevention (CDC) slide presentation on hepatitis D (HDV).

Pathophysiology and transmission

The HDV is a 36-nm particle that contains a single-stranded circular HDV RNA surrounded by a capsid, which is the hepatitis delta antigen (HDAg). [102] The HDV genome is not related to the hepadnavirus genome, which includes HBV; rather, it is considered a natural subviral satellite of HBV [105] and is classified as a separate genus. [110] The pathologic changes observed during HDV infection are limited to the liver, which is where the virus has been shown to replicate. [111]

During the HDV replicative processes, there is temporary suspension of synthesis of HBV components. The infecting HDV is transported into the nucleus where genome replication occurs. The replication is carried out by cellular RNA polymerase II without a DNA intermediate or help from HBV. The transcribed RNA leads to formation of new RNA genomes as well as the nucleocapsid protein (HDAg), which is in the nucleus and not exposed on the outer surface of the viral particle. [110] These are then assembled in the cytoplasm of the infected cell with HBsAg from the endoplasmic reticulum. The intact particles are subsequently released from the cell.

HBsAg is essential for viral assembly and transmission. [112, 113] Blood is potentially infectious during all phases of active hepatitis D infection, especially just before the onset of acute disease. The intact virus particle is reactive with anti-HBs antibody but not with anti-HDAg antibody. [114] HDV replication is not cytopathic. Humoral and cellular immune mechanisms appear to be involved in the pathology of HDV infection. [105]

The transmission of HDV infection is similar to that known for HBV: bloodborne, sexual, percutaneous in illicit IV drug users and licit in those receiving replacement blood products, and, rarely, perinatal transmission. This disease is spread mostly through parenteral exposure. [115] The time of maximum transmissibility is soon after acquisition of the virus in superinfected hosts, at the peak of the acute infection. [116]

The population at highest risk for contracting HDV is IV drug users, individuals with multiple sex partners—although the risk for HDV is lower than that of HBV or HIV transmission—and persons exposed to unscreened blood products. [113]

Diagnostic studies

HDV should be considered in any person who is HBsAg positive or has evidence of recent HBV infection. [117] The diagnosis depends on documentation of anti-HDAg antibodies by commercially available tests. After diagnosing positive anti-HDAg antibodies, real-time–polymerase chain reaction (RT-PCR) assay of the infected serum should be obtained to confirm and document ongoing infection. [110, 108] Presence of anti-HDV antibodies is not evidence of active disease. HDV DNA can clear, indicating resolution of the disease, and in the long term, HDV antibodies can also clear after recovery from infection. No evidence shows that HDV RNA levels correlate with any clinical marker of activity or stage of liver disease. [117]

The early acute markers of HDV infection usually clear within a few months after recovery. During chronic disease, HDV RNA, HDAg, and HDAg antibodies persist. During chronic disease, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are elevated, although bilirubin, albumin, and prothrombin time (PT) are normal. During chronic HDV infection, HBV markers such as HBV DNA and HBeAg are suppressed. [113, 118] HBV viremia in coinfected patients is a marker of disease progression. [119]

Clinical management and prognosis

No antiviral therapy is effective against acute or chronic HDV infection. Long-term alpha-interferon (IFNa) and pegylated alpha-interferon (PEG-IFNa) have been shown to induce remission of the disease with decreased viral replication. Use of acyclovir, ribavirin, lamivudine and other nucleoside analogues are ineffective against the virus. Immunosuppressive agents are also ineffective. Among patients who underwent liver transplantation for end-stage liver disease, 5-year survival is more than 80%. [105, 113]

HDV depends on primary HBV infection for replication in the host; as a result, the prognosis for patients with chronic HBV is worse when superinfection with HDV occurs. In such cases, therapy depends on the response to treatment for HBV.


Secondary infection with the HDV can only occur in a patient who has an active HBV infection; the infection can occur simultaneously with HBV infection, or it can be superimposed. Cases of coinfection tend to resolve spontaneously, whereas superimposed infection frequently leads to chronic HDV infection and active disease. The routes of HDV infection are the same as for HBV.

Immunization against HBV prevents HDV infection, but this is only feasible among individuals who were previously HBV negative. In addition, immunoglobulin and HBV immunization in HBV carriers does not protect against infection.

Lamivudine is not effective against HDV infection. [26, 28, 18]


Hepatitis E

Hepatitis E is caused by the hepatitis E virus (HEV). Although most waterborne epidemics of hepatitis in developing countries were initially thought to be hepatitis A disease, it is now known they are due to hepatitis E infection. This condition is rare and sporadic in industrialized countries. [120] HEV is usually passed by fecal–oral transmission through a contaminated water supply. [121] The infection is typically mild and self-limited without chronicity or clinical sequelae.

In the United States, this infection is rare and is not routinely tested for in the evaluation of acute hepatitis, but HEV should be tested for when patients who have an acute hepatitis have recently traveled to an endemic area and have had hepatitis A, B, and C infection excluded by serologic tests. The prevalence of positive HEV antibodies in nonendemic regions like the United States is reported to be 1-3%. [122]

HEV has a restricted distribution in Central and Southeast Asia, North and West Africa, and Mexico. These are areas where fecal contamination of drinking water is encountered with a higher frequency than other regions [114] ; the prevalence ranges from 1% to 10%, with the highest rates found in Egypt, where the prevalence has been reported as high as 24%.

HEV infection is usually mild to moderate in severity, with a mortality of 0.4-4%. Pregnant patients have a more severe illness, with frequent fulminant hepatitis. [123] The mortality rate rises progressively with the term of pregnancy, with up to a 20% mortality from acute infection in the third trimester. Maternal infection is likewise associated with a high risk of fetal or neonatal mortality. [124] The cause of the increased severity of this hepatitis during pregnancy is unknown, but may relate to attenuated cellular immunity during pregnancy. Fulminant hepatitis may require liver transplantation.

The following is a slide presentation on HEV from the Centers for Disease Control and Prevention (CDC).

Centers for Disease Control and Prevention (CDC) slide presentation on hepatitis E (HEV).

Pathophysiology and transmission

HEV is a nonenveloped, spherical, positive-sense, and single-stranded RNA virus [114] that is 27-34 nm in diameter. It is composed of viral protein and RNA. HEV is transferred fecal-orally, [125] with the highest risk of acquisition in developing areas with poor sanitation. The highest risk for complications secondary to infection is for pregnant women traveling or residing in these areas. This is a water-borne disease, and it has been associated with outbreaks through contaminated food or water supplies. [121, 126]

HEV causes self-limited acute viral hepatitis in adults. Only those individuals who have never contracted HEV are at risk for infection. [114] No serologic or hybridizing cross-reactivity between HEV and other hepatitis viruses has been observed. [114]

HEV is excreted from the liver via the common bile duct into the duodenum of the small intestine, where it is relatively resistant to the acid and mild alkaline environment. [120] Peak viremia and viral shedding into the feces occurs during the incubation period and in the early acute phase.


The period of infectivity extends for up to 14 days after the onset of jaundice. During this phase, ongoing viral excretion in the stools has been documented. This is important, because the most common mode of transmission is the fecal-oral route. The rate of transmission is lower than that reported for HAV. [127] Most cases reported in the United States and other developed countries are among individuals returning from areas with a high prevalence of HEV. Occasionally, cases among individuals who have not traveled are attributed to an endemic source, such as a zoonosis with transfer from infected livestock, especially from porcine HEV. There is no evidence for sexual transmission or acquisition from transfusions. [128]

Diagnostic studies

HEV infection is clinically indistinguishable from other forms of viral hepatitis and relies on laboratory assessment. This disease is diagnosed by detection of the viral genome in blood or feces by polymerase chain reaction (PCR) or by detection of immunoglobulin (Ig) M antibodies to HEV. [129] These tests are available only in research laboratories in the United States. Previous infection is diagnosed by detection of IgG antibodies.

The specific diagnosis of HEV infection is by testing for the presence of IgM anti-HEV. HEV infection should be suspected during waterborne hepatitis outbreaks occurring in developing countries. It is most important to confirm the diagnosis in the pregnant population secondary to the reportedly increased mortality.

To confirm the results of initial enzyme-linked immunosorbent assay (ELISA) tests, Western blot assays are available to detect IgM or IgG antibodies in serum. The antibodies develop early in the prodromal phase, usually before the onset of jaundice. IgM titers decrease rapidly during convalescence, but IgG titers may remain elevated for years after the infection. This factor becomes most important among patients in whom hepatitis A has been excluded. HEV RNA can be detected in the blood and feces during the acute phase in approximately 50% of cases. [114]

Clinical management and prognosis

No hyperimmune hepatitis E immunoglobulin is available for preexposure or postexposure prophylaxis, and no known therapy is available to alter the course of the disease. Therapy is directed at providing supportive care.

The prognosis for HEV infection is similar to that reported for HAV infection. Most HEV infections are self-limited, and hospitalization is usually not required. The exceptions are for pregnant women, who have a reported increased mortality secondary to hypertensive and renal complications, and for individuals, especially younger children, with fulminant hepatitis. [114]


During pregnancy, the risk of fulminant HEV disease and maternal mortality occurs in 20% of patients when the disease presents during the third trimester. Premature deliveries with high infant mortality of up to 33% are also observed. [114] Although the mechanism underlying the increased mortality is unknown, the reported complications include gestational hypertension, preeclampsia, proteinuria, edema, and kidney disease. One possible mechanism of disease could be a direct or indirect effect on the kidneys, which may precipitate disease and increase the maternal mortality. [130]

Patient education and prevention

Patients traveling to endemic regions should be counseled regarding the risk for HEV infection and given recommendations for improved and stricter sanitary precautions, such as use of bottled water. In the United States, there is no vaccine available for hepatitis E, and immune globulin is not effective for prophylaxis.

The main concern with HEV infection is the increased risk for complications and severity of disease among pregnant women. HEV infection does not have any known effects on the fetus, and it is not a contraindication to breastfeeding. [17]

HEV infection is largely prevented by public health measures, such as a clean water supply. Pregnant women should avoid travel to endemic areas, and they should avoid drinking water from the municipal water supply and eating uncooked shellfish or uncooked fruits and vegetables in these areas. In recent years, a vaccine against hepatitis E has been developed that has shown great promise in preventing the infection in an endemic region. [131] The safety and efficacy of this vaccine in pregnant women is currently unstudied and unknown.


Hepatitis G

In 1966, the GB virus (GBV) was identified after isolating a viral agent that led to a 3-week period of jaundice. The exposure presumably occurred during surgery in a young male surgeon named G. Barker, which led to the abbreviation GBV. [132]

Subsequent development of new methods for viral identification allowed qualitative analysis of the virus with recognition of 3 related viral genomes: GBV-A, -B, and -C. GBV-C was the virus identified as the hepatitis G virus (HGV) and the only one capable of replicating in humans. The virus was subsequently detected in other individuals with parenteral hepatitis and was felt to be a new and separate hepatotropic entity. [132] Ongoing serologic screening has demonstrated that HGV is widespread; however, there is no evidence that the viremia is associated with development of hepatitis in all cases. [133]

HGV infection is common around the world; the average detection rate is 1.7% in all ethnic groups. [132] The prevalence of HGV RNA in certain blood donor populations can be higher, reaching levels as high as 10-11% among individuals coinfected with hepatitis C virus (HCV). [134] Antibodies to envelope protein E2 are detected several times more frequently than HGV RNA in blood donors. [132]

There are 5 different HGV genomes that have been described. These are distributed worldwide, with genotypes 2a and 2b the ones most frequently detected in North America and Europe. [135, 136]

Pathophysiology and transmission

The genome of the HGV is a single-stranded RNA chain with positive polarity, and its organization is similar to that of the HCV genome. [137] The RNA is surrounded by a protein nucleocapsid with an as-yet incompletely defined structure. [138] HGV-C codes for the 2 structural proteins E1 and E2, which are envelope proteins. These envelope proteins are used as antigens to identify the infection. [6] The virus appears to have a lipid envelope that may interfere with immune recognition. [132]

HGV has been detected in hepatocytes, peripheral blood lymphocytes and monocytes, vascular endothelial cells, and other tissues. [139, 140, 141] Viremia may persist for many years after infection. [132]

HGV replicates predominantly in the peripheral blood mononuclear cells, lymphocytes, and bone marrow. [142, 143] The mechanisms underlying the development of hepatitis are not clear and its hepatotropicity remains uncertain. [144]

Most cases of HGV infection are transferred through contaminated blood products. It is most commonly found among individuals infected with HCV or human immunodeficiency virus (HIV).

Perinatal transmission

Several factors appear to influence maternal-infant viral transmission. These include maternal viral count and coinfection with HCV or HIV. The rate of maternal-infant transmission is approximately 75-80%, which is in contrast to the transmission reported for HCV of 2-5%. [77] Most infants do not develop clinical or biochemical signs of liver disease despite 1-year HGV persistence. [145] The pool of perinatally infected individuals may account for the ongoing prevalence of disease.

Diagnostic studies

The basic marker for HGV diagnosis is RNA detectable by real-time–polymerase chain reaction (RT-PCR) amplification. Different tests using different primers for the RT-PCR report various degrees of sensitivity for the diagnosis. [146]

HGV infection leads to the development of antibodies against the E1 and E2 envelope proteins. [132] The antibody response is long lasting and may prevent reinfection, which is in contrast to the lack of protection conferred by HCV antibody formation in most cases. The antibodies can be detected by an enzyme immunoassay. The antigen most commonly used is the E2 protein.

Most individuals with anti-HGVE2–positive sera were HGV-RNA negative. This suggests that anti-HGVE2 is a marker of previous infection. [147] The presence of HGV RNA is a marker of ongoing infection. Production of HGVE2 antibodies and the cessation of viremia have been shown to occur spontaneously in 65-70% of immunocompetent patients. The highest prevalence of HGV antibodies is among individuals older than 50 years. [148]

Clinical management and prevention

Medical care for HGV is supportive in symptomatic patients. In general, most patients remain asymptomatic and do not require specific treatment. [149]

HGV is a parenterally transmitted infection. Cases of acute posttransfusion hepatitis have been documented with increased aminotransferase levels, positive HGV RNA, and absence of markers of viral hepatitis. Pooled blood products are a common source of infection. [132]

Evidence for sexual transmission is based on the high detection rates among prostitutes and individuals with multiple sex partners. [150]

The vertical transmission of HGV has been demonstrated in several different populations. [77, 151, 152, 153] Transmission may occur intrapartum or postnatally. Intrapartum transmission at the time of delivery appears to be substantiated by a significant decrease in risk of transmission when comparing cesarean to vaginal delivery. [153] Although perinatal transmission does occur, evidence suggests that it does not cause clinical disease in newborns.

Given the high transmission rate, lack of consistent clinical or pathologic changes associated with infection, and lack of specific therapy, screening for HGV infection in the pregnant population is not justified.



Management of hepatitis in pregnant women in conjunction with an internist or gastroenterologist is mandatory to follow up patients in cases of acute disease. Most patients seen in the obstetric setting are women who have become chronic disease carriers and are asymptomatic.

The emphasis of management is to prevent vertical transmission to the fetus. Occasionally, patients will have active chronic disease, in which case comanagement with a gastroenterologist may be required.