Viral liver disease remains a common and challenging problem for practicing physicians in many disciplines. The literature on this subject is vast and rapidly increasing, as new and promising therapies are available to patients. This chapter has been revised to reflect these advances, and incorporates much of the information from the American Association for the Study of Liver Disease Practice Guidelines.

Six viruses designated hepatitis A, B, C, D E, and G infect the liver and produce inflammation of the liver, or hepatitis, as their primary clinical manifestation. Other viruses, such as Epstein-Barr (EBV) and cytomegalovirus (CMV), may cause hepatitis as part of their clinical presentation but the liver is usually not the primary target organ.

This chapter covers hepatitis C. The other hepatitis viruses are discussed in separate chapters and can be viewed by clicking on the hyperlinks on the right-hand side of this page.

The discovery of the hepatitis C virus (HCV) in 1989 was a major breakthrough. Prior to that point, it had been clear that a major cause of acute hepatitis after a blood transfusion was neither related to hepatitis A nor to hepatitis B (hence the early name for this disease, non-A, non-B hepatitis). The virus was cloned using molecular biology techniques after extensive testing of serum from experimentally infected animals, and found to be an RNA virus that belongs the Flaviviridae family and genus Hepacivirus.¹ It is a double-shelled enveloped single-stranded RNA virus 50 to 60 nm in diameter. HCV replicates in the liver, and is detectable in serum during acute and chronic infection.

The HCV genome codes for the synthesis of a single large polyprotein of about 3000 amino acids that is then cut by specific enzymes into both structural and non-structural proteins. Based on differences in the sequence of specific proteins, hepatitis C can be divided into a number of different subtypes, known as genotypes. Because of the high rate of error in the production of viruses, patients typically harbor a heterogeneous group of viruses, with multiple mutations in specific proteins. This variability can be used to further divide the HCV virus infection in a given individual into subtypes and beyond that, into specific quasispecies.² This has considerable importance in determining the outcome of treatment, although probably does not affect the natural history of the disease. Although the virus is found throughout the world, the various genotypes of hepatitis C are distributed differently; for example, genotype 4 infection is very common in Egypt, but relatively rare in the United States (Figure 1).

A schematic of the hepatitis C viral structure is shown in Figure 2, along with the proteins that each section encodes.

In the past, a major route of infection was via blood transfusion; after implementing the use of polymerase chain reaction (PCR) assays to screen pooled blood, the risk of transfusion-associated HCV fell to less than 1/100000 units transfused. Although the incidence of new infection dropped dramatically, the prevalence of infection—the total population of patients still infected—continues to rise. The most common route of transmission is now thought to be related to recreational intravenous drug use, which is responsible for perhaps as many as 50% of new infections.⁴

Other potential avenues of infection include having multiple sexual partners, tattooing, body piercing and sharing straws during intranasal cocaine use - all of which are linked to an increased risk of infection. Maternal-fetal transmission occurs in approximately 10% of cases and is more likely with co-infection with HIV in the mother. The rate of infection after an HCV contaminated needle-stick injury ranges from 0% to 10% in various studies. Viral transmission to a sexual partner in a monogamous relationship is rare, with a less than 5% risk.⁵ The Centers for Disease Control and Prevention (CDC) does not advocate any change in sexual practice for partners engaging in a long-term, monogamous, sexual relationship.

Based on epidemiologic studies of transmission and prevalence rates, the Centers for Disease Control recommend screening patients with specific risk factors, including: patients who have previously used drugs, those with HIV, or hemophilia; patients on dialysis in the past, or those who received transplants or transfusions before 1992, health care workers after a needle stick injury, and possibly children of HCV infected mothers or sexual partners of HCV infected persons.⁶

Although HCV can be found in multiple sites throughout the body—including the liver, peripheral blood mononuclear cells, dendritic cells, epithelium, and even the central nervous system, HCV replicates in the hepatocytes. However, it is not directly hepatotoxic. Viral replication occurs through an RNA-dependent RNA polymerase process. Lymphocytes recognize infected cells and initiate an immune response to control the virus. Viral clearance is associated with the development and persistence of strong, virus-specific responses by cytotoxic T lymphocytes and T helper cells. Because of the rapid evolution of diverse quasispecies within an infected person, even a brisk B cell (eg, antibody) response to hepatitis C has been inadequate to clear the infection, as the virus represents a "moving target" to the immune system. For the same reason, the progress in development of a vaccine to protect patients from an initial infection has been slow.⁷

Damage to the liver parenchyma is mediated by inflammatory cytokines. Persistent inflammatory mediators activate stellate cells in the liver parenchyma and this results in various degrees of hepatic fibrosis. Why some patients develop progressive fibrosis and eventually cirrhosis and others do not is unknown, but some predictors of progression have been identified, and include male sex, age at onset of infection, and the use of alcohol.

Acute HCV infection is uncommonly recognized, as it is usually accompanied by very mild flu-like symptoms. Although the vast majority of patients with acute HCV infection are asymptomatic, weight loss, fatigue, muscle or joint pain, irritability, nausea, malaise, anorexia and jaundice have been reported to rarely occur in the 2 to 26 week incubation period. In chronic symptomatic HCV infection, fatigue is probably the most frequent complaint, the degree of which is unrelated to the severity of liver disease. Other complaints may include depression, nausea, anorexia, abdominal discomfort, and difficulty with concentration. Symptoms may first appear only with the onset of more advanced liver disease. Common extra-hepatic manifestations of HCV infection are mixed cryoglobulinemia and porphyria cutanea tarda. Membranoproliferative glomerulonephritis, leukocytoclastic vasculitis, focal lymphocytic sialadenitis and idiopathic pulmonary fibrosis may occur in rare instances and are believed to be secondary to immune complex deposition in association with intact virus or viral proteins. Many patients have no specific symptoms and the finding of abnormal hepatic transaminases on routine testing often prompts the evaluation for hepatitis C.⁸

Serologic assays for HCV are based on detecting HCV antibodies or HCV RNA. The most common serologic test for detecting antibodies to hepatitis C is the enzyme-linked immunosorbent assay (ELISA) (sensitivity 95%, specificity 95%). Some laboratories automatically confirm a positive ELISA test by a supplemental recombinant radio-immunoblot assay (RIBA) to increase the specificity of the test (eg, to decrease the number of false positives). In the 15% of infected individuals who clear the virus spontaneously, these antibody tests will remain positive and thus cannot be used for determining active infection. This also applies to treated patients who clear the virus, who will maintain a positive HCV Ab indefinitely. Furthermore, a very small percentage of patients infected with HCV are unable to mount an immune response to the viral protein and do not produce antibody. These false negatives occur in persons with HIV infections, renal failure, and HCV-associated mixed cryoglobulinemia. Confirmation of ongoing infection therefore requires the detection of HCV RNA in blood. HCV RNA is detected by polymerase chain reaction (PCR) using either a qualitative or quantitative assay. These assays may detect a viral count as low as 9.6 IU/L. A negative qualitative test supports the absence of viremia. The quantitative HCV-RNA test reflects the viral load. Viral load is an important variable to predict the outcome of anti-HCV therapy but not the likelihood of disease progression.⁶

Patients frequently come to medical attention based on elevated alanine aminotransferase (ALT) levels, which are indirect markers of liver cell necrosis. Although these measurements have been used to monitor HCV infection and the efficacy of therapy, the recognition that many infected patients may have normal ALT levels has limited their utility. Furthermore, the normalization of alanine aminotransferase levels with antiviral therapy is not proof of successful virus eradication. Viral quantification has replaced ALT levels, therefore, in monitoring treatment response.

In patients with documented HCV infection, a liver biopsy is often helpful in determining the need for therapy, although not considered mandatory before initiating treatment. It is useful in documenting the amount of ongoing destruction (grade) and degree of fibrosis (stage) of disease. Patients with more advanced fibrosis are at high risk of progressive liver disease, and therefore, should be considered strongly for therapy. Significant fibrosis may be present in patients with normal transaminase levels in up to 25% of patients. Conversely, patients with minimal fibrosis may choose to forego immediate therapy, in light of the side effect profile of current treatment as well as the likelihood of response.⁹

Viral load and viral genotype help predict the outcome of treatment, as response rates are directly linked to these two variables. In addition, they influence the length of therapy: patients with genotype 1, the most common form in North America, and a high viral load are more resistant to therapy, with response rates in the order of 40% even after a year of combination treatment. By comparison, patients with genotypes 2 or 3 may be expected to achieve sustained virologic response rates of nearly 80% after six months of treatment.⁶

Although acute HCV infection is uncommonly diagnosed, in natural history studies it has been shown to progress to chronic liver disease in up to 85% of patients. However, evidence suggests that interferon-based therapy given early in the course decreases the risk of progression to chronic infection.¹⁰ Health care workers, for example, who are accidentally exposed to HCV infected blood via a needlestick injury, should be followed carefully for evidence of infection and treated then, rather than be given routine post-exposure prophylaxis.

The more common situation facing clinicians is that of patients with chronic hepatitis C, for whom the goal of treatment is elimination of the virus. This is associated with stabilization or even improvement in liver histology and clinical course. Secondary aims are symptom control, improvement in liver function, and prevention of complications of progressive liver disease, including cirrhosis, decompensated liver disease, and hepatocellular carcinoma. Most interventions apart from interferon-based therapy have only marginal benefit.

Complete abstinence from alcohol is an extremely important behavioral modification, and has been shown to affect the likelihood of progression as well as impact the efficacy of therapy.¹¹ The utility of other therapies—including dietary supplements, herbs, and unconventional treatments—have not been rigorously studied, and the results are extremely varied.¹² Regardless of whether a patient elects to be treated or not, practice guidelines recommend that all patients with hepatitis C and no evidence for immunity be vaccinated for hepatitis A, and, if risk factors exist, for hepatitis B as well.

Treatment outcomes for patients treated with interferon are classified into nonresponse, relapse, and sustained virologic response. A sustained virologic response (SVR) is defined as undetectable virus in the serum 6 months after treatment completion, which correlates well with long-term absence of virus. Although any patient with hepatitis C infection can be considered for therapy, the decision must be individualized, based on the overall risks and benefits of therapy. Patients with detectable HCV RNA, elevated serum aminotransferase levels, evidence of chronic hepatitis on liver biopsy, absence of decompensation, and no contraindications, should be offered combination alpha interferon and ribavirin therapy. Specific contra-indications include severe concurrent disease, previous solid organ transplant, autoimmune hepatitis, hyperthyroidism, pregnancy, or uncontrolled depression. Previous contra-indications, such as HIV disease or otherwise immune compromised status, are no longer considered obstacles to treatment. Often, HIV positive patients are coinfected with hepatitis C, as the viruses may share a similar epidemiology. The most recent studies demonstrate response rates to therapy of 14-73% in these patients (depending on genotype), which are somewhat better than seen with previous treatments. These rates, however, are less than expected in HIV-negative patients.^13,14

A pre-treatment neuro-psychiatric assessment should be performed in all patients. If depression, anxiety, or other psychiatric illnesses are evident by history, a psychiatric consultation should be sought for evaluation, treatment, and follow-up during the interferon treatment period. Psychosis and homicidal or suicidal ideation are strong contra-indications to therapy.

Factors predicting a therapeutic response include low pretreatment HCV RNA level, genotypes 2 or 3, female gender, low body mass index (BMI) and low hepatic iron load. Patients with advanced liver disease or decompensated cirrhosis are also unlikely to respond, and frequently are unable to tolerate treatment.⁶

Treatment of hepatitis C infection has evolved over the last fifteen years. It remains based on interferon alfa, as an immune modulator. Response rates were modest when it was used as monotherapy (10% in genotype I and at best 30% in genotype 2 and 3). Side effects remain a significant problem, and are typically described as "flu-like symptoms", including fever, arthralgia, headache, depression, injection site inflammation and bone marrow suppression. The addition of ribavirin, a nucleoside analogue and an inhibitor of viral replication, improved the SVR rate to around 40% (20% in genotype 1 and 65% in genotypes 2 and 3) (Table 1). There is some evidence for a dose-response effect, with generally increased response rates in higher doses (typically 1000 to 1200 mg in divided doses). Ribavirin is cleared by the kidneys, and, therefore, is contraindicated in patients with significant renal dysfunction (a creatinine clearance <50 ml/min). It also has been shown to be teratogenic, and is therefore strictly contra-indicated in pregnancy. The commonest side effect is fatigue in about 15% of patients, resulting mainly from a hemolytic anemia that responds well to dose reduction.

The most recent innovation in treatment was the introduction of pegylated interferon, a form of interferon covalently bound to a large, inert polyethylene glycol molecule. The combination serves to reduce clearance rates, and thereby increase the duration of action. Enhanced response rates have been demonstrated for both commercially available pegylated interferons with the best response rate evident in combination therapy with ribavirin.^15,16 If patients are able to complete a full course of treatment at optimal doses (eg, not require dose adjustments for side effects or toxicity), sustained virologic response rates may range as high as 88% in genotype 2 and 3 patients, and up to 50% of those with genotype 1 (Table 1). Side effects such as injection site reaction and bone marrow suppression may be more pronounced with different formulations and doses.

Although the usual duration of treatment for patient with genotype 1 is 48 weeks, data from multiple studies suggest that it is possible to predict the outcome of therapy by twelve weeks of therapy. If a patient fails to either clear infection or have at least a two log decline in the viral load (measured with the same assay as used at baseline), it is unlikely that the patient will develop a sustained virologic response.¹⁷

Patients on therapy need to be monitored closely for complications or symptoms of the adverse reactions of combination therapy. This should include evaluation for depression, symptoms of irritability, sleep disturbance, visual disturbances, as well as evidence of hyper- or hypothyroidism, etc. Blood counts should be monitored frequently at the beginning of treatment and at least monthly afterward, if stable. An emerging literature suggests that support of the bone marrow with erythropoietin for anemia, and GCSF for neutropenia may allow continuation of therapy, even in patients with significantly affected counts. The cost-effectiveness of this approach, however, is uncertain.

Complications:

Chronic HCV infection is the most common indication for liver transplantation in the United States, and, as complications related to the epidemic continue, a significant impact on the US health care system is expected. It has been estimated that over the next twenty years, the proportion of infected patients with cirrhosis will increase from 16 to 32%, and other complications will also increase dramatically including hepatic decompensation (up 106%), hepatocellular carcinoma (up 81%), and liver-related deaths (up 180%).¹⁸

HCV infection typically progresses to chronic infection in more than 60% of patients, and may lead to cirrhosis in as many as 20% over a 20 year time period. Serum aminotransferase levels reflecting hepatocellular injury may fluctuate, as does the viral load.

As the disease evolves, hepatocytes are progressively destroyed, and replaced by fibrosis, insidiously leading to the development of bridging fibrosis and ultimately cirrhosis. The course of any individual patient is highly affected by a variety of factors, such as age at onset of infection, gender, co-infection with other viruses (HAV, HBV or HIV) or other medical conditions, as well as behaviors, such as alcohol consumption. Interferon-based treatment has a variable success rate in clearing the virus, as outlined above. Careful selection and monitoring of patients is essential in undertaking therapy. In patients without cirrhosis, hepatitis C-related mortality is only slightly increased. Severe complications usually occur only in persons with established cirrhosis. The risk of developing hepatocellular carcinoma (HCC) in chronic HCV patients with cirrhosis is as high as 4% per year. HCV infected individuals with cirrhosis should be screened at periodic intervals with ultrasound and alpha-fetoprotein. Some retrospective studies have shown that treatment with interferon has been associated with a lower rate of development of HCC even without a sustained virologic response. Although HCV remains a major global health problem, major advances in the understanding of the basic biology have allowed significant improvements in treatment over the last ten years. Treatment, while difficult, has been shown to prolong life,¹⁹ and the pace of discovery in this field gives hope that patients will be able to be treated even more effectively in the future.

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