Etiology

 Hepatitis C, previously called non-A, non-B (NANB) hepatitis, was regarded as a diagnosis of exclusion because of the absence of specific serologic markers and unknown viral origin. HCV has now been identified, with immunologic assays developed for its detection. No homology exists among HAV, HBV, or HDV and HCV.

Viral Characteristics

 Hepatitis C virus is an enveloped flavivirus. It is a small, enveloped, single-stranded RNA virus. After binding to the cell sur face, 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.

T here 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 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.

Table1. Characteristics of Viral Hepatitis

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. 1). 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.

Fig1. Incidence of hepatitis C, by year, 1982-2009. (Courtesy National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA.)

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 expo sure 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.

Posttransfusion Hepatitis

After the introduction of serologic testing in the screening of blood donors, the rate of posttransfusion hepatitis C decreased from 33% to approximately 15%. Before laboratory screening, the transfusion of infected blood or blood components (e.g., factor VIII or IX) constituted a clear route of HCV transmission. The incidence of posttransfusion hepatitis C declined in the 1980s because of the effort to replace the pool of high-risk, paid donors. Also, dialysis patients now require fewer blood transfusions because recombinant erythropoietin (EPO) is used to stimulate the patient’s own bone marrow to produce red blood cells.

Parenteral and Occupational Exposure

In 2006, illegal IV drug use continued to be the most frequently identified risk factor for HCV infection. Accidental needle stick injuries also are a clearly documented route of hepatitis transmission (Fig. 2). 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.

Fig2. Hepatitis C infection after accidental needlestick  injury. (Adapted from Hernandez ME et al: Risk of needlestick injuries in the transmission of hepatitis C in hospital personnel, J Hepatol 16:56–58, 1992; and Mitsui T et al: Hepatitis C infection in medical personnel after needle stick accident, J Hepatol 16:1109–1114, 1992.)

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.

Sexual Transmission

 Sexual transmission is believed to occur, but is infrequent. Spouses of patients with HCV viremia and chronic liver dis ease have an increased risk of acquiring HCV proportional to the duration of the marriage.

Other Sources

 Mother to infant transmission has been documented. HCV is vertically transmitted from mother to infant and the risk of transmission is correlated with the level of HCV RNA in the mother. Personal contact is thought to be a route of infection but has not been conclusively demonstrated; the actual risk for such transmission is unknown.

Between 25% and 50% of sporadic community-acquired cases of hepatitis in the United States are of the HCV type and are unrelated to parenteral exposure. Some of these cases are believed to result from heterosexual transmission, but in approximately 40% the route of infection cannot be identified. Therefore, transmission can occur by inapparent and apparent parenteral routes; this form of hepatitis cannot be distinguished from other types of viral hepatitis solely by its epidemiologic characteristics.

In addition, liver disease can occur in the recipients of organs from donors with antibodies to HCV. Almost all the recipients of organs from anti-HCV–positive donors become infected with HCV. The current tests for anti-HCV antibodies may underestimate the incidence of transmission and the prevalence of HCV infection in immunosuppressed organ recipients. If the medical condition of the potential recipient is so serious that other options no longer exist, however, the use of an organ from an anti-HCV–seropositive donor should be considered.

Prognosis

Several strains of HCV exist. The genotype of HCV may influence the clinical course of HCV, as well as the response to IFN and newer treatments.

It is believed that about 50% of patients with acute hepatitis C will continue to have elevated serum liver enzyme levels more than 6 months after the onset of illness. These patients usually have persistent HCV RNA detected in their serum and evidence of chronic hepatitis on liver biopsy. Viremia, as detected by HCV RNA assay, may persist for months to years in patients in whom serum liver enzyme levels return to normal, and liver biopsy may reveal chronic hepatitis.

Chronic hepatitis C appears to be a slowly progressive, often silent disease. In addition, HCV may be associated with hepatocellular carcinoma predominantly, if not exclusively, in the setting of cirrhosis.

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:

1. Escape of immune response in more than 80% of infected patients

2. Production of monoclonal or polyclonal rheumatoid factor (RF) in 20% to 40% of infected patients

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. 3) 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.

Fig3. Hepatitis C virus testing algorithm. (From ARUP Laboratories: Hepatitis C virus testing algorithm, 2012 [http://www.arupconsult.com/ Algorithms/HCV.pdf].)

Western Blot

The Western blot or recombinant immunoblot assay (RIBA) can be used to confirm anti-HCV reactivity. Three successive generations of RIBAs have evolved since 1990, with each pro viding incrementally improved specificity. In this procedure, that antibodies are adhering to the proteins. An immunoblot test result is considered positive if two or more proteins react. The assay is considered indeterminate if only one positive band is detected. serum is incubated on nitrocellulose strips on which four recombinant viral proteins are blotted. Color changes indicate that antibodies are adhering to the proteins. An immunoblot test result is considered positive if two or more proteins react. The assay is considered indeterminate if only one positive band is detected.

Confirmatory testing by immunoblotting is helpful in some clinical situations (e.g., positive anti-HCV detected by EIA but negative for HCV RNA). The positive EIA anti-HCV reactivity could represent the following:

 • False-positive reaction

• Recovery from hepatitis C

• Viral infection with levels of virus too low to be detected

If the immunoblot test for anti-HCV is positive, the patient has most likely recovered from hepatitis C and has persistent antibody without virus. If the immunoblot test is negative, the EIA result was probably a false-positive.

Immunoblot tests are used routinely in blood banks when an anti-HCV–positive sample is found by EIA. Immunoblot assays are highly specific and valuable in verifying anti-HCV reactivity. Indeterminate tests require follow-up testing, including attempts to confirm the specificity by repeat testing for HCV RNA.

The current third-generation RIBA uses three recombinant antigens (c33c, c100-3, and NS5) and one synthetic peptide from the core region. Because the RIBA is based on the same recombinant antigens and synthetic peptides as the enzyme linked immunosorbent assay (ELISA), it is licensed as an additional, more specific test.

Polymerase Chain Reaction

 The PCR amplification technique can detect low levels of HCV RNA in serum. Testing for HCV RNA is a reliable way of demonstrating that hepatitis C infection is present and is the most specific test for infection.

Testing for HCV RNA by a PCR assay is particularly useful in the following situations:

• Transaminase levels are normal or only slightly elevated.

• Anti-HCV is not present.

• Several causes of liver disease are possible.

The best confirmatory assay to confirm a diagnosis of hepatitis C is to test for HCV RNA using a PCR assay. In addition, HCV RNA testing is of value when EIA tests for anti-HCV are unreliable (e.g., immunocompromised patients may not produce sufficiently high antibody titer for detection with EIA). Immunosuppressed or immunocompetent patients pose diagnostic problems because of their inability to produce anti HCV. HCV RNA testing may be required for the following:

 • Immunosuppressed patients (e.g., recipients of a solid-organ transplant)

• Patients undergoing dialysis because of chronic renal failure

• Patients taking corticosteroids

• Patients experiencing agammaglobulinemia

Patients exhibiting anti-HCV who have another form of liver disease (e.g., alcoholism, autoimmune disorder) can be difficult to diagnose. In these situations, the anti-HCV may represent a false-positive reaction, previous HCV infection, or mild hepatitis C occurring concurrently with another hepatic abnormality. In these cases, HCV RNA testing can help confirm that hepatitis C is contributing to the liver problem.

Hepatitis C RNA Titers in Serum

Several methods are available for measuring the titer or level of virus in serum, which is an indirect assessment of viral load. These methods include a quantitative PCR and a branched DNA test. Because these assays are not standardized, different laboratories may provide different results on the same specimen. In addition, serum levels of HCV RNA may vary spontaneously by threefold to tenfold over time. With these limitations in mind, however, carefully performed quantitative assays provide important insights into the nature of hepatitis C.

The usefulness of determining the viral load does not correlate with the severity of the hepatitis or with a poor prognosis, but viral load does correlate with the likelihood of a response to antiviral therapy. Monitoring viral load during the early phases of treatment may provide early information on the likelihood of a response. Rates of response to a course of interferon-α (IFN-α) and ribavirin are higher in patients with low levels of HCV RNA. The usual definition of a low level of HCV RNA is less than 2 million copies/mL.

The Heptimax assay (Quest Diagnostics, Madison, NJ) is an ultrasensitive quantitative test that detects levels of HCV based on transcription-mediated amplification technology. Because this technology can detect minute quantities of HCV, physicians can monitor HCV infection better, demonstrate posttreatment resolution, and detect relapses with greater sensitivity.

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مواضيع ذات صلة

DNA Tumor Viruses

Rhabdoviridae

Human T-cell Lymphotropic Viruses, Types 1 and 2

Treatment of HIV

Congenital Rubella Infection

Treatment of Hepatitis C

Acute and Chronic Hepatitis C

Pathogenesis and clinical significance of HIV

Transmission of HIV

HIV replication

Hepatitis D

Prevention and Treatment of hepatitis B