Etiology

Viral hepatitis is the most common liver disease worldwide. The viral agents of acute hepatitis can be divided into two major groups, as follows:

Incidence

Primary hepatitis viruses account for approximately 95% of the cases of hepatitis. These viruses are classified as primary hepatitis viruses because they attack primarily the liver and have little direct effect on other organ systems. The secondary viruses involve the liver secondarily in the course of systemic infection of another body system. The viruses for hepatitis types A, B, C, D, E, and GB virus C, as well as secondary viruses (e.g., EBV, CMV), have been isolated and identified (Table 23-1).

Signs and Symptoms

As a clinical disease, hepatitis can occur in acute or chronic forms. The signs and symptoms of hepatitis are extremely variable. It can be mild, transient, and completely asymptomatic or it can be severe, prolonged, and ultimately fatal. Many fatalities are attributed to hepatocellular carcinoma in which hepatitis viruses B and C are the primary causes. The course of viral hepatitis can take one of four forms—acute, fulminant acute, subclinical without jaundice, and chronic (Table 23-2).

Epidemiology

Hepatitis A virus was formerly called infectious hepatitis or short-incubation hepatitis. In developing countries, hepatitis A is primarily a disease of young children; the prevalence of infection, as measured by the presence of antibody (immunoglobulin G [IgG] anti-HAV), approaches 100% at or shortly after 5 years of age. The national rate of hepatitis A has declined steadily since the last peak in 1995 (Fig. 23-2). After asymptomatic infection and underreporting were taken into account, an estimated 21,000 new infections occurred in 2009 (the last year for which statistics were available at the time of publication).

The incidence of hepatitis A varies by age. Historically, the highest rates were observed among children and young adults. Effective vaccines have been available since 1995. Since the issuance in 1999 of recommendations for routine childhood vaccination, rates of hepatitis A have declined. In 2005, the licensing of hepatitis A vaccines was revised to allow vaccination of children aged 12 to 23 months. Nationwide, hepatitis A vaccination of children is likely to result in lower overall rates of infection.

Susceptibility to infection is independent of gender and race. Crowded unsanitary conditions are a definite risk factor. HAV is transmitted almost exclusively by a fecal-oral route during the early phase of acute illness; the virus is shed in feces for up to 4 weeks after infection. Large outbreaks are usually traceable to a common source, such as an infected food handler, contaminated water supply, or consumption of raw shellfish. Institutions and day care centers are known to be favorable sources for transmission as well.

Hepatitis A infection is noted for occurring in isolated outbreaks or as an epidemic, but it also may occur sporadically. Although rarely a transfusion-acquired hepatitis because of its transient nature, an outbreak of HAV infection that occurred in 52 patients with hemophilia in Italy was documented to have been acquired through infusion of contaminated factor VIII concentrate. This concentrate had been treated by a virucidal method (solvent detergent) that ineffectively inactivates nonenveloped viruses.

Improvements in socioeconomic and sanitary conditions and declining family size may be responsible for a decreasing frequency of infection. The incidence of HAV infection is not increasing among health care workers or in dialysis patients. Maternal-neonatal transmission of HAV is not recognized as an epidemiologic entity. Person to person contact, usually among children and young adults, remains the major route of HAV infection.

The most frequently identified risk factor for hepatitis A has been international travel, reported at 15% of patients overall. Most travel-related cases have been associated with travel to Mexico and Central or South America (70%). As HAV transmission in the United States has decreased, cases among travelers to countries where hepatitis is endemic have accounted for an increased proportion of all cases.

Sexual and household contact with another person with hepatitis A have been among the most frequently identified risk factors, reported for 10% of cases in 2006. In 2006, the proportion of HAV-infected persons who reported injection of street drugs was 2.1%.

Signs and Symptoms

Nonimmune adult patients infected with HAV can develop clinical symptoms within 2 to 6 weeks after exposure (average, ≈4 weeks). However, hepatitis A is often a subclinical disease, with many patients being anicteric. Clinically apparent cases show elevated serum liver function enzyme and bilirubin levels, with jaundice developing several days later. Viremia and fecal shedding of virus disappear at the onset of jaundice. Atypical presentations include prolonged intrahepatic cholestasis, relapsing course, and extrahepatic immune complex deposition, all of which resolve spontaneously.

Complete clinical recovery is anticipated in almost all patients. Hepatitis A rarely causes fulminant hepatitis and does not progress to chronic liver disease. Unusual clinical variants of hepatitis A include cholestatic, relapsing, and protracted hepatitis. In cholestatic hepatitis, serum bilirubin levels may be dramatically elevated (>20 mg/dL) and jaundice persists for weeks to months before resolution. In relapsing hepatitis and protracted hepatitis, complete resolution is anticipated.

A chronic carrier state (persistent infection) and chronic hepatitis (chronic liver disease) do not occur as long-term sequelae of hepatitis A. Rarely, injection with HAV may cause fulminant hepatitis, with about 0.1% mortality. Fulminant hepatitis is the most likely complication of coinfection with other hepatitis viruses.

Immunologic Manifestations

Shortly after the onset of fecal shedding, an IgM antibody is detectable in serum, followed within a few days by the appearance of an IgG antibody. IgM anti-HA is almost always detectable in patients with acute HAV. IgG anti-HAV, a manifestation of immunity, peaks after the acute illness and remains detectable indefinitely, perhaps lifelong.

The finding of IgM anti-HAV in a patient with acute viral hepatitis is highly diagnostic of acute HAV. Demonstration of IgG anti-HAV indicates previous infection. The presence of IgG anti-HAV protects against subsequent infection with HAV but is not protective against hepatitis B or other viruses.

Diagnostic Evaluation

Testing methods for HAV include the following:

The short period of viremia makes detection difficult. Specific IgM antibody usually appears about 4 weeks after infection and may persist for up to 4 months after onset of clinical symptoms. The presence of IgG or total (IgM and IgG) antibody indicates past infection or immunization and associated immunity. The total assay detects IgM and IgG antibodies but does not differentiate between them. The hepatitis A antibody IgM assay is appropriate when acute HAV infection is suspected. Specific IgG antibody apparently protects an individual from symptomatic infection, but specific IgM may increase with reinfection. In the acute phase of HAV, liver function levels (e.g., serum liver enzyme levels) will be elevated and may aid in establishing the diagnosis.

Prevention and Treatment

The first effective control measures to prevent enterically transmitted viral hepatitis resulted from World War II research. In 1945, the following were demonstrated: (1) infectious virus could be transmitted by contaminated drinking water; (2) treatment of the water by filtration and chlorination made it safe to drink; and (3) gamma globulin derived from convalescent-phase serum from patients with hepatitis could protect adults from clinical hepatitis. For 50 years, refining food and water preparation and establishing standards for immune globulin constituted the methods of HAV prevention. An individual who has had close contact with an HAV-infected person should receive passive immunization with immune globulin intramuscularly.

A safe, highly immunogenic, formalin-inactivated, single-dose vaccine is available to prevent HAV infection (Box 23-1). HAV vaccine should be targeted at high-risk groups (e.g., staff in child care centers; food handlers; international travelers, including military personnel; homosexual men; institutionalized patients).

Universal childhood vaccination may prove to be the most cost-effective method of protecting large populations, both nationally and globally. Routine childhood hepatitis A vaccination is recommended.

In May 2001, the U.S. Food and Drug Administration (FDA) approved a new combination vaccine that protects individuals 18 years of age and older against diseases caused by HAV and HBV. The vaccine, called Twinrix (GlaxoSmithKline Beecham, Philadelphia), combines two already approved vaccines, Havrix (hepatitis A vaccine, inactivated) and Engerix-B (hepatitis B vaccine, recombinant) so that those at high risk for exposure to both viruses can be immunized against both at the same time. Areas with a high rate of both HAV and HBV include Africa, parts of South America, most of the Middle East, and South and Southeast Asia. Clinical trials of Twinrix, given in a three-dose series at ages 0, 1, and 6 months, have shown that the combination vaccine is as safe and effective as the already licensed, separate HAV and HBV vaccines.

Epidemiology

Hepatitis B infection has been referred to as long-incubation hepatitis. In 2009 (the last year for which statistics were available at the time of publication), a total of 3371 acute symptomatic cases and 38,000 estimated total new infections of hepatitis B were reported in the United States. The overall incidence was the lowest ever recorded and represents a decline of 81% since 1990 (Fig. 23-4).

About 1.25 million people in the United States have chronic HBV infection, 20% to 30% of whom acquired the infection in childhood. Each year, about 3000 to 5000 people die from cirrhosis or liver cancer caused by HBV. The highest rate of disease occurs in those ages 20 to 49 years. The greatest decline has occurred in children and adolescents as a result of routine hepatitis B vaccination.

The incidence of HBV infection caused by blood transfusion is increasingly rare in developed countries. Transfusion-acquired HBV has been severely reduced because high-risk donor groups (e.g., paid donors, prison inmates, military recruits) have been eliminated as major sources of donated blood and because specific serologic screening procedures have been instituted. This shift to an all-volunteer donor supply probably accounts for a 50% to 60% reduction of transfusion-related hepatitis. The overall incidence of HBV is high among patients who have received multiple transfusions or blood components prepared from multiple-donor plasma pools, hemodialysis patients, drug addicts, and medical personnel (see Table 23-1).

Persons at risk of exposure to HBV, including those mentioned earlier, include members of the following groups:

Hepatitis B virus does not seem capable of penetrating the skin or mucous membranes; therefore, some break in these barriers is required for disease transmission. Transmission of HBV occurs via percutaneous or permucosal routes and infective blood or body fluids can be introduced at birth, through sexual contact, or by contaminated needles. Infection can also occur in settings of continuous close personal contact. About 50% of patients with acute type B hepatitis have a history of parenteral exposure. Inapparent parenteral exposure involves intimate or sexual contact with an infectious individual. Transmission between siblings and other household contacts readily occurs via transmission from skin lesions such as eczema or impetigo, sharing of potentially blood-contaminated objects such as toothbrushes and razor blades, and occasionally through bites. HBV has been found in saliva, semen, breast milk, tears, sweat, and other biological fluids of HBV carriers. Urine and wound exudate are capable of harboring HBV. Stool is not considered to be infectious.

Signs and Symptoms

Infection with HBV causes a broad spectrum of liver disease, ranging from subclinical infection to acute, self-limited hepatitis and fatal fulminant hepatitis. Exposure to HBV, particularly when it occurs early in life, may also cause an asymptomatic carrier state that can progress to chronic active hepatitis, cirrhosis of the liver, and eventually hepatocellular carcinoma.

A number of factors, including the dose of the agent and an individual’s immunologic host response ability, influence the clinical course of HBV infection. Extrahepatic manifestations, reflecting an immune complex–mediated, serum sickness–like syndrome, are seen in fewer than 10% of patients with acute hepatitis B and include rash, glomerulonephritis, vasculitis, arthritis, and angioneurotic edema. Manifestations such as vasculitis, glomerulonephritis, arthritis, and dermatitis are mediated by circulating immune complex deposition (HBV antigen-antibody) in blood vessels.

The progression of liver disease in HBV infection is fostered by active virus replication, manifested by the presence of an HBV DNA level above a threshold of approximately 1000 to 10,000 IU/mL. Patients with lower levels and normal liver enzyme levels are considered to be inactive carriers, with a low risk of clinical progression. Rarely, reactivation in these patients can occur spontaneously or with immunosuppression. Perinatal infection can result in high HBV level replication without substantial liver injury in the early decades of life; however, the risk of progression to cirrhosis and hepatocellular carcinoma is proportional to the level of HBV DNA maintained persistently over time.

Persistent infection is the usual consequence of HBV infection acquired at an early age, signaled by the prolonged presence of HBsAg. Some individuals with chronic HBV infection are asymptomatic carriers, whereas others have clinical, laboratory, and histologic evidence of chronic hepatitis that may be associated with the development of postnecrotic cirrhosis. Persistent HBV infection is believed to be a precursor of primary hepatocellular carcinoma. In about 5% to 10% of individuals with HBV, especially patients with immunodeficiencies (e.g., AIDS), the disease will progress to a chronic state.

Laboratory Assays

Laboratory diagnosis (Fig. 23-5) and monitoring of acute and chronic HBV infections involve the use of several of the following tests (Tables 23-3 and 23-4):

Serum testing procedures may be performed by qualitative chemiluminescent immunoassay, qualitative EIA, quantitative real-time PCR, quantitative real-time PCR–nucleic acid sequencing, or real-time PCR with reflex to genotype. Immunohistochemistry may be used to detect HBsAg in liver tissue samples.

Hepatitis B Surface Antigen

Serum HBsAg is a marker of HBV infection. Antibodies against HBsAg signify recovery. The initial detectable marker found in serum during the incubation period of HBV infection is HBsAg. HBsAg usually becomes detectable 2 weeks to 2 months before clinical symptoms and as soon as 2 weeks after infection. This marker is usually present for 2 to 3 months. This procedure screens for the presence of the major coat-protein of the virus (HBsAg) in serum and is considered to be the most reliable method of choice for preventing the transmission of HBV via blood. The presence of HBsAg indicates active HBV infection, acute or chronic.

The titer of HBsAg rises and generally peaks at or shortly after the onset of elevated liver serum enzyme levels (e.g., ALT, SGPT). Clinical improvement of the patient’s condition and a decrease in serum enzyme concentrations are paralleled by a fall in the titer of HBsAg, which subsequently disappears. There is variability in the duration of HBsAg positivity and in the relationship between clinical recovery and the disappearance of HBsAg (Fig. 23-6). About 5% of positive HBsAg values are false-positive results.

Among persons infected with HBV with detectable HBsAg in their serum, not all the HBsAg represents complete Dane particles. HBsAg-positive serum also contains two other virus-like structures, which are incomplete spherical and tubular forms consisting entirely of HBsAg and devoid of HBcAg, DNA, or DNA polymerase. The incomplete HBsAg particles can be present in serum in extremely high concentrations and form the bulk of the circulating HBsAg.

Diagnostic Evaluation

Appropriate diagnostic procedures should be ordered, depending on clinical factors such as patient history, signs and symptoms being evaluated, and cases involving donated blood. The various components of HBV infection can be measured by a laboratory assay.

In an HBsAg-positive individual, the differential diagnosis should include acute hepatitis B, reactivation of chronic HBV infection, HBeAg seroconversion to anti-HBe flare, superinfection by other hepatitis viruses, and liver injury resulting from other causes (e.g., drug-induced, alcoholic, or ischemic hepatitis). Accurate diagnosis requires testing for serologic markers and sequential studies.

The first antibody to appear during an acute HBV infection is antibody to hepatitis B core antigen (anti-HBc). Anti-HBc becomes measurable shortly after HBsAg is detected and reaches peak levels within several weeks of onset of infection. It persists long after the disappearance of HBsAg. Initially, the predominant immunoglobulin class of anti-HBc is IgM. Early after the development of serologic tests for HBV markers, when tests for anti-HBs were less sensitive than current assays, a window period between the loss of HBsAg and the appearance of anti-HBs was recognized. During this infrequently encountered window, or when levels of HBsAg do not reach detection thresholds, the detection of IgM anti-HBc is the sole marker of acute HBV infection. Over several weeks to months, the titer of IgM anti-HBc falls, tending to become undetectable after 6 months. Total anti-HBc reactivity declines at a considerably slower rate; the predominant immunoglobulin form of anti-HBc during the late recovery phase is IgG. This IgG anti-HBc persists in slowly declining titers for many years to decades after acute infection.

Within a few days to 1 or 2 weeks of the appearance of HBsAg, hepatitis Be antigen (HBeAg) also becomes detectable in the circulation of acutely infected individuals. HBeAg, a nonstructural nucleocapsid protein, is a marker of HBV replication; its presence is correlated with the presence of complete HBV particles and HBV DNA in the circulation. In acute HBV infection, patients are most infectious during the period in which HBeAg can be detected. In self-limited HBV infection, HBeAg disappears before HBsAg disappears. With the disappearance of HBeAg, its corresponding antibody, anti-HBe, becomes detectable and persists for a prolonged period.

HBV DNA, and possibly HBV virions, may persist in circulating immune complexes. The viral genome can remain in an active form in peripheral blood mononuclear cells for more than 5 years after complete clinical and serologic recovery from acute viral hepatitis B.

Prevention and Treatment

Routine hepatitis B vaccination of U.S. children began in 1991. Since then, the reported incidence of acute hepatitis B among children and adolescents (<15 years) has decreased by more than 98% and by 93% in those aged 15 to 24 years. Although not as large as the declines in younger age groups, substantial decreases also have occurred among older persons. The rates are a decrease of 78% in adults aged 25 to 44 years and 61% in adults 45 years of age or older.

The most important factors in preventing transfusion-acquired HBV are donor interviewing, screening of donor blood, use of hepatitis-free products when possible, and appropriate use of blood and blood components. In addition, the avoidance of high-risk blood components such as untreated factor VIII prepared from multiple-donor pools reduces the incidence of HBV.

Elimination of high-risk donors has accounted for at least a 50% reduction in the incidence of hepatitis; routine testing of donated blood for HBsAg has further reduced the incidence by another 20% to 30%. Testing for anti-HBc will detect almost 100% of HBsAg-positive persons, the rare asymptomatic donor in the core window, and the large number of donors who have had subclinical hepatitis B infections and are now immune.

The use of recombinant vaccine against hepatitis B, licensed in 1982, is warranted for high-risk persons, including medical personnel (Box 23-1). HBV vaccine is administered in three doses over 7 months and is about 80% to 95% effective. The vaccine is now included in the childhood vaccination schedule. Hepatitis B vaccine is also a vaccine against cancer (hepatocellular carcinoma). Vaccination offers a new approach to preventing transfusion-acquired HBV and the dependent hepatitis D virus (HDV) in patients who are likely to need ongoing transfusion therapy, such as nonimmune patients with hemophilia, sickle cell anemia, or aplastic anemia.

In cases of accidental needlestick exposure or exposure of mucous membranes or open cuts to HBsAg-positive blood, hepatitis B immune globulin (HBIG) should be administered within 24 hours of exposure and again 25 to 30 days later to nonimmunized patients. Infants born to mothers with acute hepatitis B in the third trimester, or with HBsAg at delivery, should be given HBIG as soon as possible and no later than 24 hours after birth. Persons who are HBsAg-positive or who have anti-HBs need not be given HBIG unless the HBV titer is shown to be low or unknown.

Seven drugs have been licensed in the United States for the treatment of HBV infection. Treatment for about 1 year usually results in the reduction of serum HBV DNA levels and a serum level of HBV DNA that is undetectable by PCR assay.

Liver transplantation is also used for some severe cases of liver disease caused by HBV, although the new organ usually becomes infected with HBV.

Epidemiology

Hepatitis D was originally described in Italy and appears to be most common in southern European countries. It also appears to be endemic among Indian tribes living in the Amazon basin. In the United States, Northern Europe, and Asia, infection is uncommon. In the United States, hepatitis D is seen predominantly in intravenous (IV) drug users and their sexual partners, but it has been reported in homosexual men and men with hemophilia. According to the Centers for Disease Control and Prevention (CDC), there are approximately 70,000 people with chronic HDV infection in the United States.

Hepatitis D is a severe and rapidly progressive liver disease for which no therapy has proven effective. Patients with this form of hepatitis are significantly more likely to have cirrhosis and liver failure and to require liver transplantation than patients with HBV infection alone. Chronic HDV infection is responsible for more than 1000 deaths/year in the United States. The mortality rate can be up to 20% of infected patients.

Hepatitis D virus is spread chiefly by direct contact of HBsAg carriers with HDV- or HBV-infected individuals. Family members and intimate contacts of infected individuals are at greatest risk. IV drug users and individuals with multiple sex partners are two other high-risk groups. Maternal-neonatal transmission is uncommon.

Hepatitis D can be acquired either as a co–primary infection (coinfection) with HBV (e.g., after inoculation with blood or secretions containing both agents) or as a superinfection in patients with established HBV infection (HBsAg carriers or patients with chronic hepatitis B). A superinfection can make an HBV infection worse by transforming a mild infection into a persistent infection in 80% of patients. In contrast, coinfection rarely leads to a chronic condition. Although HDV is dependent on HBV for its expression and pathogenicity, replication of HDV appears to be independent of the presence of its associated hepadnavirus.

Signs and Symptoms

Hepatitis D infection may be benign and brief, but fulminant hepatitis and chronic hepatitis have been attributed with increasing frequency to HDV. Chronic HDV infection is associated with increased hepatic damage and a more severe clinical course than is expected from chronic HBV infection alone. The occurrence of sequential attacks of HBV in the same patient is probably attributable in most cases to HDV infection superimposed on a previous acute HBV infection.

Infection with HDV agent can occur in several conditions; the symptoms would be typical of acute or chronic hepatitis, as follows:

Immunologic Manifestations

The HDV probably partially suppresses HBV replication. Hepatitis D infection is diagnosed by the appearance of HDV antigen in serum or the development of IgM or IgG HDV antibodies that appear sequentially in a time frame similar to that described for hepatitis A or B antibodies. HBsAg will also be present.

Diagnostic Evaluation

The HDV appears in the circulating blood as a particle with a core of delta antigen and a surface component of HBsAg. A person with hepatitis D will have detectable antigen in the liver and antibody in the serum. Test methodologies for HDV use the qualitative EIA (Fig. 23-7)

In addition, HDV antigen can be demonstrated in liver biopsies by double immunodiffusion (DIF) and immunoperoxidase and in serum by cloned DNA (cDNA). The importance of the detection of antibodies to HDV is largely prognostic. Detection of IgG anti-HDV in the presence of IgM anti-HBc antibody strongly suggests simultaneous infection (coinfection). Detection of IgM anti-HDV in a patient with chronic HBV infection is evidence of HDV superinfection.

Screening for total HDV antibodies in serum is important in the identification of a subpopulation of apparently healthy HBsAg carriers whose risk of serious liver damage is fourfold higher than that of anti-HDV–negative carriers. The combined presence of total anti-HDV antibody and abnormal liver function test results in a symptom-free carrier suggests parenchymal damage and is considered an indication for liver biopsy. Hepatic lesions in anti-HDV–positive carriers often consist of chronic active hepatitis or advanced cirrhosis. A positive test result for IgM anti-HDV increases the likelihood of occult active HBV infection.

Viral Characteristics

Hepatitis C virus is an enveloped flavivirus. It is a small, enveloped, single-stranded RNA virus. After binding to the cell surface, HCV particles enter the cell by receptor-mediated endocytosis. Because the virus mutates rapidly, changes in the envelope protein may help it evade the immune system.

There are at least six major HCV genotypes and more than 50 subtypes of HCV. The different genotypes have different geographic distributions. Genotype 1 represents most infection in North and South America, and Europe. Genotypes la and lb are the most common genotypes in the United States. The HCV genotype does not appear to play a role in the severity of disease. Knowing the genotype-specific antibodies of HCV is useful to physicians when making recommendations and counseling patients regarding therapy. Patients with genotypes 2 and 3 have a more favorable prognosis and are more likely to respond to treatment.

Epidemiology

Worldwide, an estimated 180 million people are infected with HCV. In the period 2004 to 2009 (the last year for which statistics were available at the time of publication), 2.7 to 3.9 million persons in the United States were living with chronic infection caused by hepatitis C. Annually, 12,000 patients die in the United States as the result of chronic liver disease associated with HCV. HCV infection is a leading cause of chronic hepatitis, cirrhosis, and liver cancer and is a primary indication for liver transplantation in Western countries.

In the past, hepatitis C was considered a disease limited to transfusion recipients. HCV is now recognized in many other epidemiologic settings (see Table 23-1) and as a major cause of chronic hepatitis worldwide. The number of cases reported to the National Notifiable Disease Surveillance System are considered unreliable because of the following: (1) the lack of a serologic marker for acute infection; and (2) the inability of most health departments to determine whether a positive laboratory result for HCV represents acute infection, chronic infection, repeated testing of a person previously reported, or a false-positive result.

In 2009, the total number of reported cases of acute hepatitis was 2600. The estimated total number of new cases of hepatitis C in the United States was 16,000 in 2009 (the last year for which statistics were available at the time of publication). Since the mid-1990s, hepatitis C rates have declined in all age groups, almost reaching a plateau since 2003 (Fig. 23-8). The greatest decline has occurred among persons 25 to 39 years old, the age group traditionally with the highest rates of disease, in whom incidence has declined by 58% since 2000.

Viral Transmission

HCV is spread primarily by percutaneous contact with infected blood or blood products. Currently, injectable drug abuse is the most common risk factor. Workers with needlestick injuries, infants born to HCV-infected mothers, those with multiple sexual partners, and recipients of unscreened donor blood are also at risk for contracting HCV.

Although most hepatitis C patients are injectable drug abusers, many patients acquire HCV without any known exposure to blood or drug use. Sporadic or community-acquired infections without a known source occur in about 10% of acute hepatitis C cases and 30% of chronic cases.

Parenteral and Occupational Exposure

In 2006, illegal IV drug use continued to be the most frequently identified risk factor for HCV infection. Accidental needlestick injuries also are a clearly documented route of hepatitis transmission (Fig. 23-9). The Occupational Safety and Health Administration (OSHA) has estimated that the general risk to health care workers of occupational transmission of HCV is 20 to 40 times higher than the risk of contracting HIV. The CDC has more conservatively estimated that the average risk of HCV transmission after a needlestick injury is six times greater than the risk of HIV transmission. Because of these grim statistics, occupationally acquired HCV infection is a growing concern for health care providers.

A person with a high level of circulating HCV may be capable of transmitting the virus by exposing others percutaneously or mucosally to small amounts of blood or other body fluids. A person with a low level of circulating HCV may be capable of transmitting the virus only by exposing others percutaneously to a large volume of blood. The threshold concentration of virus needed to transmit or cause infection is uncertain.

Signs and Symptoms

Although the clinical characteristics of the acute disease of both types of hepatitis C are basically indistinguishable, the chronic consequences are very different. The signs and symptoms of hepatitis C are extremely variable. It can be mild, transient, and completely asymptomatic, or it can be severe, prolonged, and ultimately fatal.

Hepatitis C more closely resembles HBV than HAV in regard to its transmission and clinical features. Hepatitis C, as with HBV, can be acute and ranges from mild anicteric illness to fulminant disease. A fulminant course with a rapidly fatal outcome is rare. Usually, the patient is only mildly symptomatic and nonicteric; less than 25% of patients develop jaundice. Transfusion-associated hepatitis C can be divided into short- and long-incubation types. Incubation periods for the short-duration type range from 1 or 2 to 5 weeks; the longer duration type ranges from 7 to 12 weeks to 6 months or longer.

Hepatitis C is characterized by serum liver enzyme levels in the range of 200 to 800 U/L and marked fluctuations, with intervening periods of normalcy. Mean serum liver enzyme and bilirubin levels of patients with hepatitis C, however, are significantly lower than those of patients with HBV; the extensive overlap of the ranges of elevation precludes the identification of the type of viral hepatitis by the use of these assays.

The diagnosis of hepatitis C has a guarded prognosis. Although hepatitis C was initially thought to be a relatively benign disease, there is increasing evidence of progression to cirrhosis in about 20% of patients, liver failure, and even hepatoma. The hepatic damage is caused by the cytopathic effect of the virus and the inflammatory changes secondary to immune activation. Up to 60% of patients with posttransfusion hepatitis C develop chronic liver disease, based on biopsy analysis, and up to 20% of these patients develop cirrhosis.

Posttransfusion hepatitis C affects men and women equally, but a reported 75% of patients developing chronic hepatitis were men. Patients with parenterally acquired (nontransfusion) hepatitis C, including those who have no identifiable source, have the same clinical characteristics and develop chronic liver disease with the same frequency.

Extrahepatic immunologic abnormalities have been shown to occur frequently in patients with chronic HCV infection. HCV infection has been linked to a number of extrahepatic conditions, including Sjögren’s syndrome, cryoglobulinemia, urticaria, erythema nodosum, vasculitis, glomerulonephritis, and peripheral neuropathy. HCV apparently causes the cases of mixed cryoglobulinemia previously mentioned.

Laboratory Assays

HCV infection is characterized by two major immunologic fingerprints:

Immunologic failure results in chronic infection, persistent stimulation of the immune system, and subsequent production of circulating immune complexes, of which almost one third become insoluble when exposed to low temperatures and are associated with the clinical picture of cryoglobulinemia. Many epidemiologic studies have demonstrated an association between HCV infection and an increased incidence of B cell, non-Hodgkin’s lymphoma (NHL), ranging from 20% to 30% to almost twice that of HCV-negative control subjects.

Traditional Hepatitis C Virus Testing

Traditional testing methods (Fig. 23-10) include a qualitative chemiluminescent immunoassay and qualitative EIA, qualitative recombinant immunoblot assay, quantitative real-time PCR assay, qualitative PCR assay, quantitative branched chain DNA test, polymerase chain reaction–nucleic acid sequencing. interleukin 28 B (IL-28B)–associated variants test, and two single-nucleotide polymorphisms (SNPs) method—qualitative PCR–qualitative fluorescence monitoring.

The coordinated activities of CD4+ T cells and cytotoxic CD8+ T cells, primed in the context of human leukocyte antigen (HLA) class II and I alleles, respectively, on antigen-present cells are critically important for the control of acute HCV infections. The signs and symptoms of acute hepatitis C infection usually include jaundice, fatigue, and nausea. Laboratory manifestations include a significant increase in serum liver enzyme levels (usually >10-fold) and the presence or de novo development of anti-HCV.

Demonstration of HCV antibodies can be problematic because anti-HCV is not always present in the patient with symptoms. In 30% to 40% of patients, anti-HCV is not detected until 2 to 8 weeks after the onset of symptoms. Acute hepatitis C can also be diagnosed by testing for HCV RNA, apparently the earliest detectable marker of acute HCV infection, preceding the appearance of anti-HCV by several weeks. The current ELISA for antibodies to recombinant HCV antigens becomes positive earlier and is more sensitive than preceding ELISAs. Another approach is to repeat the anti-HCV testing 1 month after the onset of illness.

Hepatitis C viremia may persist despite the normalization of serum ALT levels. Intracytoplasmic HCV antigen has been found in the hepatocytes of acutely infected chimpanzees and, by analogy, is presumed to be present in acute hepatitis C in human beings. HCV antigens were not detected in hepatocyte nuclei, Kupffer or sinusoidal lining cells, bile duct epithelium, or blood vessels.

Treatment

The standard of care for HCV treatment since the early 1990s has been interferon, which aimed to boost the immune system rather than attacking the HCV directly. Two new protease inhibitors, boceprevir and telaprevir, approved by the FDA in May 2011, have the potential to transform the management of HCV. The main goal of treatment of chronic hepatitis C is to eliminate detectable viral RNA from the blood. Lack of detectable HCV RNA from blood 6 months after completing therapy is known as a sustained response and has a very favorable prognosis that may be equivalent to a cure. Other, more subtle benefits of treatment may include slowing the progression of fibrosis in patients who do not achieve a sustained response.

All current treatment protocols for hepatitis C are based on the use of various preparations of IFN-α, a naturally occurring glycoprotein secreted by cells in response to viral infections. It exerts its effects by binding to a membrane receptor, which initiates a series of intracellular signaling events that ultimately lead to enhanced expression of certain genes. This leads to enhancement and induction of certain cellular activities, including augmentation of target cell killing by lymphocytes and inhibition of virus replication in infected cells.

Interferon alfa-2a (Roferon-A; Hoffmann-La Roche, Basel, Switzerland), IFN-alfa-2b (Intron-A; Merck/Schering-Plough Pharmaceuticals, North Wales, Pa), and IFN-alfacon-1 (Infergen; Intermune, Kadmon, New York, NY) are all approved in the United States as single agents for the treatment of adults with chronic hepatitis C. Treatment is administered for 6 months to 2 years. Treatment with IFN alone leads to a sustained response in less than 15% of subjects. Because of this low response rate, these IFNs alone are rarely used for the treatment of patients with chronic hepatitis C.

More recently, peginterferon alpha, sometimes called pegylated IFN, has become available for the treatment of chronic hepatitis C. There are two preparations—peginterferon alfa-2b (Peg-Intron; Schering-Plough) and peginterferon alfa-2a (Pegasys; Hoffmann-La Roche). With peginterferon alfa-2a alone, approximately 30% to 40% of patients achieve a sustained response to treatment for 24 to 48 weeks. The addition of ribavirin to IFN-α is superior to IFN-α alone in the treatment of chronic hepatitis C.

Ribavirin is a synthetic nucleoside that has activity against a broad spectrum of viruses. The FDA did not approve ribavirin alone for hepatitis C, but the FDA did approve IFN-alfa-2b plus ribavirin (1998) for the treatment of individuals with chronic hepatitis C who relapsed after previous IFN-α therapy. Relapsers were defined as patients who had normal liver serum enzymes ALT activity at the end of up to 18 months of IFN-α therapy, with abnormal liver serum enzyme activity within 1 year after the end of the most recent course of therapy. The FDA has approved the combination of peginterferon alpha plus ribavirin for the treatment of chronic hepatitis C. For eligible patients with chronic hepatitis C, peginterferon alpha plus ribavirin is likely to be the best treatment option. Clinical trials have shown that a sustained response rate is seen in approximately 50% of patients given this combination for 24 to 48 weeks.

Most studies have indicated that genotypes 1a and 1b are more resistant to treatment with any IFN-α–based therapy than non–type 1 genotypes. Thus, some physicians may prescribe longer a duration of treatment for patients infected with viral genotype 1a or 1b. The best available current treatment for chronic hepatitis C, peginterferon alpha plus ribavirin, leads to an overall sustained response rate in more than 50% of all patients. The sustained response rates are even better for individuals infected with non–type 1 genotypes of the hepatitis C virus.

Several drugs, known as immune modifiers or immunomodulators, that alter the immune response have been tested (some with IFN-α) in clinical trials for chronic hepatitis C. These drugs alter the inflammatory response against liver cells infected with the virus; however, their mechanisms of action are poorly understood. Compounds tested in human beings include thymosin alpha-1 (Zadaxin; SciClone Pharmaceuticals, San Mateo, Calif) and histamine dihydrochloride (Ceplene; EpiCept Tarrytown, NY).

New medications and approaches to treatment are needed for HCV infection. Most promising for the immediate future are newer forms of long-acting IFNs. In addition, promising molecular therapies consist of using ribozymes, enzymes that break down specific viral RNA molecules, and antisense oligonucleotides, small complementary segments of DNA that bind to viral RNA and inhibit viral replication.

Therapeutic vaccines are also being developed to enhance the immune response against the HCV. In contrast to a preventive vaccine (likely a distant development for hepatitis C), a therapeutic vaccine is administered to already infected individuals to stimulate the immune system to fight the infection. Several therapeutic vaccines are in preclinical development for hepatitis C. The most promising of these are DNA vaccines involving the injection of DNA copies of the HCV RNA genome, which are taken up by certain immune system cells. Theoretically, these cells then express viral proteins, stimulating an immune response against the virus.

Prevention

Preventive practices among health care workers to avoid needlestick injuries should be promoted. Investigations have shown that removal of blood from donors with anti-HBcAg from the blood supply and use of third-generation anti-HCV testing can reduce the incidence of posttransfusion hepatitis C.

Vaccines and immunoglobulin products do not exist for the prevention or treatment of hepatitis C. Development of preventive strategies appears unlikely in the near future because these products would require antibodies to all the genotypes and variants of hepatitis C; however, some type of vaccine may eventually be developed.

Epidemiology

Only a few cases of hepatitis E have been reported, with none originating in the United States. All have been seen in travelers returning from the Indian subcontinent, northern Africa, the Far East, portions of Russia (the former Soviet Union), and Mexico.

Hepatitis E virus (HEV) is transmitted by the fecal-oral route. Infection is usually the result of poor sanitation conditions. HEV is responsible for large, water-borne outbreaks of hepatitis in the developing world and is the most common cause of sporadic hepatitis in young adults in developing nations. Clinically apparent disease frequently is found in patients 15 to 40 years old.

The HEV infection rate among household contacts of infected patients appears to be low. The seroprevalence of HEV in blood donors is approximately 2%.

Virus-like particles have been observed in the stool from patients with HEV infection. In addition, serologic tests (IgM and IgG anti-HEV) have been developed now that the HEV genome has been cloned and sequenced.

Signs and Symptoms

The incubation period of HEV ranges from 2 to 9 weeks, with an average of 6 weeks. The symptoms of HEV infection are similar to those of other forms of viral hepatitis. HEV particles may appear in feces, inconstantly, during prodromal symptoms of hepatitis E. Fecal HEV shedding occurs predominantly during the first week after the onset of jaundice and has not been identified in stool samples obtained at 8 to 15 days. Viremia may occur during the period of fecal HEV shedding.

No form of chronic liver disease has been attributable to infection by HEV. Although most acute infections are self-limited and mild, 10% to 20% of HEV infections in pregnant women about result in fulminant hepatitis, especially in the third trimester of pregnancy.

Immunologic Manifestations

A short-lived, IgM anti-HEV has been found in acute-phase sera. IgG anti-HEV appears and replaces IgM anti-HEV about 2 to 4 weeks after symptoms subside. The duration of detectable IgG anti-HEV remains uncertain.

Diagnostic Evaluation

Specific serologic tests for IgM and IgG anti-HEV are available. HEV can be diagnosed by performing immunoelectron microscopy on a stool specimen. Liver serum enzymelevels, if elevated, are indicative of the acute phase of the infection.

Prevention and Treatment

Standard gamma globulin preparations have not been shown to be effective in the prevention of viral E hepatitis. No effective vaccine has been developed. Treatment of HEV is usually supportive care.

Epidemiology

Hepatitis G virus is a bloodborne agent (Table 23-5). Transfusion recipients and IV drug abusers are at risk of infection. HGV infection frequently occurs as a coinfection with HCV. Prevalence patterns of GBV-C/HGV suggest that the virus is transmitted sexually.

GB virus C infection is common; 1% to 2% of U.S. blood donors have HGV RNA detectable in their serum. HGV is estimated to produce 900 to 2000 infections/year, most of which may be asymptomatic. Chronic infection develops in 90% to 100% of infected persons. Chronic disease is rare or may not occur at all.

Signs and Symptoms

Chronic HGV infection does not appear to be a common cause of important liver disease and does not alter the course of chronic HCV infection. The vast majority of patients with acute, non–A-E hepatitis have no evidence of HGV infection. The role of HGV (GBV-C) in human hepatitis remains unclear.

GB virus C may not be a significant cause of acute or chronic liver disease. In all, 15% of children with chronic hepatitis C or hepatitis B are infected with HGV. In these cases, HGV coinfection does not appear to cause more severe liver disease.

The HGV has not been proven to cause fulminant hepatitis. Studies have suggested that the virus may not even replicate in the liver. The role of HGV in acute and chronic hepatitis remains to be defined fully.

Diagnostic Evaluation

A cDNA expression library was constructed from the plasma of a patient with chronic hepatitis C. Immunoscreening of the expression library with the patient’s serum identified several unique HCV and other sequences, from which an anchored PCR method (Table 23-6) was used to amplify overlapping clones for the entire viral genome. The virus was termed the GB virus C virus.

Prevention

Confirmation of disease association, establishment of routes of transmission, and development of serologic screening assays are necessary before preventive measures can be considered.

Epidemiology

The TTV has been associated with posttransfusion hepatitis of unknown etiology (non–A-G). The prevalence in the global population, particularly the United States, United Kingdom, Japan, Germany, and Thailand, can reach 100% in healthy people.

There is evidence that TTV may be transmitted not only by parenteral exposure to blood, but also by the fecal-oral route and from mother to child.

Signs and Symptoms

Although similar to HGV, TTV may be an example of a human virus with no clear disease association. This hypothesis is supported by the fact that the high prevalence of active TTV infection in the general population, both in the United Kingdom and Japan, is not comparable to the rate of significant liver damage.

As with HGV, the pathogenicity of TTV has not been proven.

Principle

This test uses an indirect lateral flow immunoassay method to detect antibodies to structural and nonstructural HCV proteins. The device uses synthetic peptides and recombinant antigens from the core, NS3, and NS4 regions of the HCV genome that are immobilized as a single test line on the assay strip.

See the website for the procedural protocol.

Results

Antibodies reacting with these peptides and antigens are visualized by colloidal gold labeled with protein A, generating a visible line in the test zone for a reactive sample. The presence of antibodies to HCV indicates that the individual may be currently infected and capable of transmitting the virus.

In conjunction with other laboratory results and clinical information, the OraQuick HCV Rapid Antibody Test results may be used to provide presumptive evidence of infection with HCV (state of infection or associated disease not determined) in persons with signs or symptoms of hepatitis and in persons at risk for hepatitis C infection.

Limitations

The test is for individuals 15 years or older who are symptomatic or at high risk for hepatitis C infection. The assay is not for use in screening whole blood, plasma, or tissue donors. Performance characteristics have not been established for testing a pediatric population younger than 15 years or for pregnant women.