Emergency Medicine

Hepatitis C

The authors provide an update on transmission, diagnosis, prognostic considerations, and treatment for an insidious form of liver disease that continues to challenge clinicians 15 years after its discovery.

By Marc S. Itskowitz, MD, and Michael M. Babich, MD

What is hepatitis C?

Hepatitis C virus (HCV) was identified in 1989 when the genome of the virus was cloned. It is a single-stranded RNA virus that belongs to the Flaviviridae family. Like many RNA viruses, HCV has an inherently high mutational rate that results in considerable genomic heterogeneity. Six distinct but related HCV genotypes and molecular subtypes have been identified. In the United States and Western Europe, genotypes 1a and 1b are most common (75% of cases), followed by genotypes 2 and 3. Genotype 4 is found in Egypt, genotype 5 in South Africa, and genotype 6 in southeastern Asia. Knowledge of the genotype is important because it has predictive value in terms of the response to antiviral therapy. In general, antiviral therapy response is better in genotypes 2 and 3 than with genotype 1.

What is the incidence and prevalence of HCV infection?

Infection with HCV is the most common cause of chronic viral hepatitis in the Western world and ranks only slightly below chronic alcoholism as a cause of cirrhosis, end-stage liver disease, and hepatocellular carcinoma in the United States. The worldwide seroprevalence of HCV infection is estimated to be 1% (170 million people). However, marked geographic variation exists, from 1.8% in North America to 9.6% to 13.6% in North Africa. The actual number infected with HCV may be underestimated because high-risk groups (incarcerated, institutionalized, and homeless persons) are not included in most prevalence studies.

After the introduction of anti-HCV screening of blood donors in 1991, transfusion-related cases of HCV declined significantly. The prevalence of HCV infection in injection drug users remains high (48% to 90%), and this population is an important reservoir of the disease. According to the Centers for Disease Control and the National Health and Nutrition Examination Survey, it is estimated that 3 million people in the United States have chronic HCV infection, with about 36,000 new cases per year. These data likely underestimate the actual incidence of HCV infection because most patients are asymptomatic and have not sought medical attention. Since most patients with chronic HCV infection have yet to be diagnosed but are likely to seek medical attention in the next decade, a fourfold increase in the number of adults diagnosed with chronic HCV infection is projected from 1990 to 2015. The frequency of patients presenting with complications associated with HCV infection is expected to triple within the next 20 years, bringing with it a 61% increase in cirrhosis, a 279% increase in decompensated liver disease, and a 528% increase in the demand for liver transplantation.

How is the hepatitis C virus transmitted?

The modes of transmission of HCV infection can be divided into percutaneous, including blood transfusion and needlestick inoculation, and nonpercutaneous, including sexual contact and perinatal exposure. The majority of patients currently infected with HCV in the United States and Europe acquired the disease through intravenous drug use or blood transfusion. Until recently, blood transfusion posed the major risk of HCV infection in developed countries. Screening blood donors with the use of highly sensitive assays has reduced the risk of transfusion-related hepatitis to less than 0.5% per patient. Currently, more than 60% of newly acquired infections occur in patients who have injected illegal drugs during the six months prior to disease onset. Infection has also been associated with a history of intranasal cocaine use, presumably due to blood on shared straws.

Needlestick injuries in the health care setting continue to result in nosocomial transmission of the virus. Seroconversion rates of about 2% have been documented in longitudinal studies of health care workers with needlestick exposures to HCV-positive patients. The size of the inoculum, the size of the needle, and the depth of inoculation likely influence the actual risk.

Nonpercutaneous transmission of HCV occurs less frequently. Most seroepidemiologic studies have demonstrated anti-HCV in only a small number of sexual contacts. Overall, sexual partners of patients with HCV infection have infection rates of approximately 1% annually, with a lifetime risk thought to be less than 5% in monogamous couples. Sexual transmission of the virus appears to be inefficient, perhaps due to the low levels of the virus found in genital fluids and tissues. Perinatal transmission of HCV also appears to be uncommon, occurring in less than 5% of cases. Further studies are needed to determine the time of perinatal transmission, the role of breast feeding in neonatal transmission, and the natural history of perinatally acquired HCV infection. All children born to women who are infected with HCV should be screened for the virus.

Chronic hemodialysis is also associated with HCV infection. The prevalence in this population is a relatively high 5% to 10%, due to the frequency of risk factors in this population (prior blood transfusion and prior injection drug use) and to nosocomial spread within dialysis units.

In approximately 25% of patients with HCV infection, there are no identifiable risk factors. Sporadic HCV infection may result from a prevalent nonpercutaneous route yet to be determined.

What are the clinical manifestations of HCV infection?

HCV infection is infrequently diagnosed during the acute phase of infection because most patients experience mild or no symptoms. Symptoms suggesting acute viral hepatitis include anorexia, nausea, malaise, right upper quadrant discomfort, and, uncommonly, jaundice. In patients who experience acute symptoms, the illness typically lasts for 2 to 12 weeks. The overwhelming complaint of patients with chronic infection is fatigue. Other nonspecific symptoms include myalgia, arthralgia, and depression. If patients develop cirrhosis, they are at risk for the complications of portal hypertension, including ascites, gastrointestinal bleeding, and encephalopathy.

In addition to hepatic disease, there are important extrahepatic manifestations of HCV infection, including cryoglobulinemia. Cryoglobulins are immunoglobulins that precipitate in the cold and dissolve on rewarming. The cryoglobulin contains both a polyclonal IgG (which may either act as an antigen or be directed against an antigen) and a monoclonal IgM rheumatoid factor directed against the IgG. Mixed cryoglobulinemia is a lymphoproliferative disorder that can lead to deposition of circulating immune complexes in small- to medium-sized blood vessels. It usually presents with the clinical triad of palpable purpura, arthralgias, and weakness, but can also involve the kidneys, peripheral nerves, and brain. Treatment of patients with cryoglobulinemia due to HCV should be based upon the presence of cryoglobulinemia symptoms rather than the usual criteria used in patients with chronic hepatitis alone. Similarly, the response should be assessed by symptomatic improvement of cryoglobulinemia, a reduction in cryocrit, and an increase in serum complement levels. Complete responses may be more common in patients with low pretreatment levels of viremia and with high-dose interferon regimens.

Hepatitis C virus infection is also associated with membranoproliferative glomerulonephritis, porphyria cutanea tarda, leukocytoclastic vasculitis, sicca syndrome, and lichen planus. Higher rates of non-Hodgkin's lymphoma, thyroiditis, and diabetes mellitus have also been observed in patients with HCV infection. Hepatitis C-associated osteosclerosis is a rare disorder characterized by a marked increase in bone mass during adult life. In addition, psychological disorders including depression have been associated with HCV infection in up to 30% of cases. Treatment of HCV infection has resulted in improvement in many of these extrahepatic conditions.

What is the natural history of HCV infection?

The natural history of chronic hepatitis C has been difficult to clearly define because of the long course of the disease. A growing number of studies have provided estimates of the proportion of patients with chronic infection who develop cirrhosis within 20 years. Estimates have been higher from retrospective studies than prospective studies, possibly reflecting referral bias in the retrospective studies. A consensus statement issued by the National Institutes of Health suggests that the actual risk is closer to that derived from the prospective studies.

In most people who become infected with HCV, viremia persists and is accompanied by variable degrees of hepatic inflammation and fibrosis. Disease progression is largely silent, with patients often identified only on routine biochemical screening or during the course of blood donation. It is estimated that 60% to 80% of patients infected with HCV will have persistent viremia and chronic hepatitis. As a rule, spontaneous clearance of HCV viremia will occur within 20 weeks or not at all. Higher rates of spontaneous HCV RNA clearance have been described in children, in those infected after Rh immunization, and in other subgroups. There is also some evidence that the risk of developing chronic infection may be somewhat lower in patients presenting with symptomatic acute HCV infection.

The mechanism responsible for the high prevalence of chronic infection is not known. It may be related to the genetic diversity of the virus and its tendency toward rapid mutation, allowing HCV to constantly escape immune recognition. Available data suggest that chronic HCV infection leads to cirrhosis in about 5% to 20% of patients within 20 years of initially contracting the virus. Once cirrhosis is established, the risk of hepatocellular carcinoma (HCC) is approximately 1% to 4% per year, with the incidence rising most dramatically after 30 years of viremia. It is common practice in the United States to screen patients for HCC with a right upper quadrant ultrasound and serum alfa fetoprotein level every six months. A number of studies have demonstrated that a sustained virologic response to interferon treatment is associated with a reduced risk of developing HCC.

Fulminant hepatic failure due to acute HCV infection is very rare, but may be more common in patients with underlying chronic hepatitis B virus (HBV) infection. Chronic HCV infection accounts for at least 10,000 deaths each year in the United States, largely due to the development of cirrhosis and its complications. Once decompensated cirrhosis occurs, liver transplantation is the only effective therapy proven to prolong survival.

The factors that contribute to histologic progression of liver disease are poorly understood. Factors that appear to accelerate clinical progression include alcohol intake, coinfection with HIV or HBV, male sex, and older age at infection. High viral load is also associated with disease progression.

Several recent studies provide evidence that HCV infection may not be progressive in all patients. In a large French series, the mean time to cirrhosis was 30 years. It was estimated that 31% of patients would show no evidence of cirrhosis for at least 50 years. Another study focused on a cohort of 917 women who developed acute HCV after exposure to contaminated anti-D immune globulin used to prevent Rh isoimmunization. During 20 years of follow-up, 85% tested positive for HCV antibodies while 55% were positive for HCV RNA. Only four patients (0.4%) had overt signs of cirrhosis. Liver biopsies obtained in 44% of the viremic women showed minimal to moderate hepatitis (96%) and portal fibrosis (47%).

Who should be tested for HCV infection?

The Centers for Disease Control and Prevention recommend that testing for HCV should be routine in patients with any history of injecting illegal drugs, receiving clotting factors made before 1987, receiving blood or organs before 1992, undergoing chronic hemodialysis, or exhibiting evidence of liver disease. Testing should also be performed on health care workers after needlestick or mucosal exposure to HCV-positive blood and on children born to HCV-positive women. Testing should be considered in recipients of transplanted tissue, users of intranasal cocaine, and patients with a history of sexually transmitted disease, multiple sex partners, or a long-term partner who is HCV-positive.

What diagnostic tests are available for HCV infection?

Diagnostic tests for HCV infection include both serologic assays for antibodies and molecular tests for viral particles. The actual sequence of diagnostic testing in an individual patient depends on the clinical setting. The primary serologic screening assay for HCV infection is the enzyme immunoassay (EIA) for the HCV antibody. The EIA test has many advantages including ease of use, wide availability, low variability, and relatively low expense. The second-generation version of the test, EIA-2, is highly sensitive and specific, and can detect antibodies within 4 to 10 weeks after infection. In a high prevalence population, EIA-2 has a sensitivity of 95% and a positive predictive value of 90%. False negative tests occur in patients with immune compromise, renal failure, and HCV-associated cryoglobulinemia. False positive tests are also seen, especially in patients without risk factors, and therefore other tests must be used to confirm the diagnosis. A third version of the screening test, EIA-3, has been approved for screening blood products in the United States. EIA-3 appears to have increased sensitivity and slightly better specificity in the blood donor population.

The recombinant immunoblot assay (RIBA) has been used to confirm positive EIAs, particularly in low-prevalence situations where there are no evident risk factors for HCV. The RIBA test is not more sensitive than EIA-2, but it does confer increased specificity. RIBA testing is most appropriate in low-risk populations, such as prospective blood donors with a positive anti-HCV screen. However, a positive RIBA is not always indicative of ongoing infection since patients who have recovered from HCV infection may remain positive for many years. With the greater availability of other tests including polymerase-chain reaction (PCR), RIBA testing is now utilized less frequently.

Since viral culture of HCV is currently not available, viral detection is accomplished by amplification methods such as PCR. Quantification of viral RNA may be useful in assessing the effectiveness of antiviral therapy and in evaluating the course of clinical disease, while the qualitative assay is useful in confirming ongoing viremia. A positive EIA should be followed by a PCR assay to confirm the diagnosis of HCV infection. Other uses of HCV RNA are in diagnosis during early stages of acute infection (before antibody production), in immunocompromised patients (in whom antibody production is impaired), and in blood donors with indeterminate serology results. A PCR-based method called target amplification involves extraction of nucleic acid from the virus. The nucleic acid is then hybridized to short nucleotide primers, which are complementary to the virus sequence and amplified through controlled replication of the hybridized sequence until a quantity of DNA sufficient for detection is reached.

A high spontaneous mutational rate has resulted in considerable heterogeneity throughout the HCV genome. Viral genotyping helps predict the outcome and duration of therapy. Currently, the only clinically relevant distinction is between genotypes 1 and 4, which are more resistant to therapy, and genotypes 2 and 3, which are much more responsive.

An important nonspecific laboratory test in HCV-infected patients is measurement of the alanine aminotransferase (ALT) level. It is an inexpensive and readily available means of screening for HCV infection. However, in patients with HCV infection, ALT levels often fluctuate and a single normal value does not rule out active infection, progressive liver disease, or even cirrhosis. In fact, up to one-third of patients with chronic HCV infection have consistently normal serum ALT levels. Furthermore, serum ALT levels do not correlate well with histologic staging, genotype, or likelihood of response to therapy, and the normalization of ALT levels with antiviral treatment is not predictive of sustained virologic response.

Although a liver biopsy is not necessary for the diagnosis of HCV infection, histologic evaluation remains the gold standard for determining the activity of HCV-related liver disease. Histologic staging is also the most reliable predictor of prognosis and disease progression. Therefore, liver biopsy is usually recommended for the initial assessment of patients with chronic HCV infection. Some trials have also assessed histologic response to medical therapy, but in clinical practice there is little indication for post-treatment biopsy.

Identification of patients with acute HCV infection is uncommon since most patients are asymptomatic. Following a needlestick exposure, patients should undergo testing for HCV by both ELISA and PCR, since the development of HCV antibodies may be delayed up to eight weeks following infection. EIA-2 is positive in only 50% of patients with acute HCV infection at the time of presentation. Testing for HCV RNA by PCR allows for an earlier diagnosis, which may be important since early interferon therapy can decrease the incidence of chronic infection.

Which patients with HCV infection should be treated and what are the options?

The goal of therapy is to prevent progression of disease and to eradicate infection. Only a subgroup of patients with chronic HCV infection has a clear indication for therapy. Optimal candidates for therapy are those patients with detectable levels of HCV RNA who have a liver biopsy showing increased fibrosis or at least moderate necrosis and inflammation. These patients have a high risk of disease progression and treatment is recommended in the absence of contraindications. Although treatment recommendations vary among physicians, many hepatologists consider the amount of liver fibrosis to be a critical factor in starting therapy. Patients with no histologic evidence of necrotic and inflammatory changes have an excellent prognosis without therapy. Patients with persistently normal ALT levels often have minor histologic changes on liver biopsy, but nearly one-third will have more advanced disease and treatment should be considered.

Further studies of the effect of therapy on the quality of life are necessary before treatment for nonspecific symptoms alone can be recommended. Patients with compensated cirrhosis are less likely to have a sustained response to monotherapy, but combination therapy increases the rate of response and should be considered in view of the substantial benefits associated with viral eradication. There is a higher rate of side effects, especially neutropenia and thrombocytopenia, in patients with cirrhosis who are treated for HCV infection. Patients with decompensated cirrhosis have a poor response to therapy and their condition may worsen with treatment.

In 1989, the first cases of successful treatment of HCV infection with interferon alpha were reported. Interferon became the first agent approved for the treatment of chronic HCV infection in the United States. A complete or partial biochemical response is seen in 20% to 40% of patients treated with interferon. However, the rate of sustained, long-term response to a standard regimen of interferon is only 10% to 20%. The attachment of polyethylene glycol to interferon extends the duration of therapeutic activity and permits once-a-week dosing. Pegylated interferon therapy results in improved biochemical and histologic response rates over standard interferon and has been better tolerated by patients. Contraindications to interferon are psychosis or depression; neutropenia or thrombocytopenia; decompensated cirrhosis; autoimmune hepatitis; uncontrolled seizures; or poorly controlled diabetes. Common adverse effects are headache, fever, fatigue, myalgias, and cytopenias. Administration of interferon at night with prophylactic acetaminophen prior to injection may alleviate many of these flu-like symptoms.

Ribavirin is an antiviral agent with activity against DNA and RNA viruses. Large prospective trials have demonstrated that the combination of interferon and ribavirin significantly increases the percentage of patients who have a sustained virologic response (about 30% to 40%). Combination therapy is effective both as initial treatment of HCV infection and in patients who relapse following treatment with interferon alone. Ribavirin is generally well tolerated. Common side effects are nausea, insomnia, rash, pruritus, and hemolysis. Anemia requiring dose reduction occurs in 10% to 15% of patients; the hemolysis is reversible after discontinuing the medication. There has been increasing experience using recombinant human erythropoietin to help support the hemoglobin concentration. Contraindications to ribavirin are pregnancy, renal failure (creatinine clearance below 50 mL/min), anemia, and severe heart disease (which may be worsened by drug-induced anemia). Co-administration of antacids containing magnesium, aluminum, and simethicone may decrease the absorption of ribavirin, although the clinical significance of this effect is unknown. No clinically significant food interactions have been reported.

Based on consensus guidelines from 2002, combination therapy with both pegylated interferon and ribavirin is recommended for the initial treatment of HCV infection. A prolonged course of a higher dose of interferon is another option, mainly in patients with contraindications to ribavirin therapy. Virologic response should be assessed at week 12. The loss of HCV RNA and the normalization of serum ALT levels have been used as treatment endpoints. If there is a less than 2-log reduction in quantitative HCV PCR at week 12, the likelihood of achieving a sustained viral response with further therapy is only 1% and physicians may consider stopping treatment. Those patients infected with HCV genotype 2 or 3 who have a negative PCR assay at week 24 can usually stop therapy at this time. Patients with genotype 1 should be treated for a total of 48 weeks. Patients with a sustained response have a high probability (>95%) of having a durable biochemical, virologic, and histologic response. Pegylated interferon-ribavirin combination therapy provides a lower likelihood of sustained response in patients who have previously failed to achieve a response or who have relapsed after therapy.

Optimal treatment for patients who do not respond to combination therapy is uncertain. Options include observation, enrollment in a clinical trial, or treatment with maintenance pegylated interferon, which is currently under clinical investigation. The rationale for maintenance therapy is based on the observation that interferon may have a beneficial effect on liver histology even in patients who do not respond virologically. The safety and efficacy of these approaches are currently under investigation in large multicenter trials.

Liver transplantation is the only available treatment option for patients with decompensated HCV-related cirrhosis. In fact, chronic HCV infection is now the most common indication for liver transplantation in the United States, with HCV infection present in more than 25% of patients undergoing liver transplantation. Recurrence of HCV after liver transplantation is nearly universal because most patients are viremic at the time of transplantation. Levels of HCV RNA can increase 15-fold after transplantation, and high levels have been associated with early acute hepatitis of the graft. Despite these drawbacks, the survival of HCV-infected patients who undergo liver transplantation is similar to that of patients with other common indications for liver transplantation, and it clearly exceeds survival rates in similar patients without transplantation. There are no controlled trials to guide treatment of HCV after liver transplantation. Most transplant centers attempt to reduce immunosuppressive therapy and treat rejection episodes cautiously. Recurrent HCV is generally treated only if it is associated with significant histologic liver injury.

What experimental and alternative medicines have been used to treat HCV infection?

The search for new therapies for chronic HCV infection is ongoing. Investigational therapies include protease inhibitors, antisense DNA oligonucleotides, interleukins, ribozyme therapy, vitamin E, hepatitis C immunoglobulin, and iron reduction. Early studies suggested that HCV-infected patients with elevated concentrations of iron in the blood and liver are less likely to respond to interferon, and that the response could be enhanced with iron reduction. Subsequent controlled trials have demonstrated no difference in the sustained virologic response in patients randomized to iron reduction plus interferon versus iron reduction alone. These data suggest that iron reduction does not augment treatment with interferon monotherapy. It has not been well studied in the setting of combination therapy with interferon plus ribavirin.

Silybum marianum (milk thistle), given alone or in combination with traditional therapy, has limited scientifically proven value, although it is commonly used and probably safe. A systematic review of 10 controlled trials of various Chinese herbal treatments of HCV found no firm evidence of efficacy. Some herbal therapies for HCV have been associated with serious adverse and even fatal effects.

Should acute HCV infection be treated?

There is a strong theoretical rationale for treating patients with acute HCV infection because the majority develop persistent infection and chronic liver disease. Higher rates of disease remission have been observed in patients treated with interferon at an early stage. Early therapy is therefore recommended, but the optimal therapeutic regimen and the best point at which to intervene have not been well defined. It is also not known whether prophylaxis after needlestick injury is effective.

What factors predict response to treatment of HCV infection?

There are several clinical and serologic features that predict a high likelihood of a long-term response to interferon. The most important factors are age less than 45 years, duration of disease less than 5 years, absence of cirrhosis, low levels of serum HCV RNA before treatment, and presence of HCV genotype 2 or 3. In large trials, the two most important predictors of a good response to therapy are serum HCV RNA level and the viral genotype. On the other hand, patients with severe inflammatory changes or cirrhosis on initial liver biopsy have a lower likelihood of a sustained response. Because of the limited efficacy of interferon in the early clinical trials, several strategies have been explored to increase the rate of sustained response, including optimization of the dose and duration of interferon and the combination of interferon with other therapeutic agents. Future studies should clarify the predictive value of such factors and therefore allow for more individualized approaches to therapy. In the meantime, HCV infection remains a major clinical challenge and will continue to have a global impact.

What precautions are necessary to prevent spread and comorbid complications of HCV infection?

Patients with HCV should refrain from donating blood, organs, tissue, or semen. Among household contacts, toothbrushes and razors should not be shared. Safe sexual practices, including the use of latex condoms, are encouraged for individuals with multiple sexual partners or other high-risk sexual practices. Direct contact with blood or fresh wounds should be avoided, and all health care workers should practice universal precautions. No passive immunization with immune globulin is currently available or recommended. There is currently no effective vaccine for preventing HCV infection. Superinfection with hepatitis A virus (HAV) in individuals who are infected with HCV can result in severe acute or even fulminant hepatitis. Vaccination of patients with HCV infection against HAV is both safe and effective. Patients should also be vaccinated against HBV. Pneumococcal vaccine and yearly influenza vaccination should be considered in patients who have developed cirrhosis.