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Hepatitis C: A Review

Abstract

Hepatitis C virus is an RNA virus in the flavivirus family that was not identified until 1989. Since then blood donor screening has reduced the incidence of acute infection, but because this virus frequently leads to asymptomatic, chronic infection the prevalence of infection remains high. Chronic infection leads to increased risk of cirrhosis, hepatocellular carcinoma, and other extrahepatic manifestations. Guidelines for wide spread screening continue to evolve but with the advent of more effective treatment, early diagnosis is likely to become increasingly important. We discuss issues pertaining to routine screening by plastic and reconstructive surgeons for HCV infection and discuss issues pertaining to universal screening.

Overview

Hepatitis C virus (HCV) is a lipoprotein-enveloped agent containing a single stranded RNA genome. Approximately 3.9 million people in the U.S. are infected and many remain unaware of their chronic infection. Since 1992 universal screening of blood for HCV has dramatically reduced the number of newly infected individuals, but there exists a large pool of persons with chronic infection who remain asymptomatic throughout the course of their illness. Chronic HCV infection has become the leading cause of liver transplantation and is a major risk factor for hepatocellular carcinoma (HCC). Theoretically, universal precautions protect healthcare workers from the risk of exposure to HCV. However, absolute adherence to universal precautions is an ideal never realized in practice. A tremendaous reservoir of chronically infected people exist who are a potential source of transmission. Plastic and reconstructive surgeons are likely to encounter HCV infection and may play a role in early detection and referral.

Background

As early as 1967, investigators had described two distinct syndromes suggesting an infectious hepatitis and a serum hepatitis. After the viruses causing hepatitis A and B were identified, it became apparent that most post-transfusion hepatitis was not accounted for by either of these agents. The remaining infections were referred to as "non A, non B hepatitis". In 1989 the virus was identified, and between 1990 and 1992 blood screening for HCV was introduced. Since then six distinct genotypes and 80 different subtypes (quasi species) have been identified.

The 5' region of the hepatitis C genome encodes the core peptide is very highly conserved during replication. Likewise, the 3' region, or enzymatic region is highly conserved during transcription. While both the regions that encode the core peptide and the enzymatic region are conserved, this is not true for the E2 envelope protein. Mutations within this region give rise to variations in the peptides that are found on the surface of the mature virus. Many mutations may prove lethal, but enough viable mutations are produced to permit the virions to escape immune surveillance. This may account for the high proportion of infected individuals who go on to develop chronic infection (up to 85%). The course of HCV infection is influenced by viral, host, and environmental factors.

Viral Factors

The size of the inoculum (viral load) is directly related to the risk of infection, but may not exert any effect upon the progression of the disease., Therefore, the route of exposure (transfusion vs. needle stick) implies significant differences in risk of developing acute hepatitis but does not appear to imply anything about disease progression once infection has occurred.

Genotype, on the other hand, does correlate with the severity of acute infection and with response to treatment. The most common HCV genotypes in the United States are 1a and 1b (approximately 74%).4 While types II and III are less common in the United States, they exhibit a more sustained response to treatment. Elimination of detectable virus should be the goal of antiviral therapy and genotype has been identified as a useful predictor of response to interferon and combination therapies with ribavirin.

It has been suggested that co-infection with other viruses (HIV, hepatitis A, and hepatitis B) adversely affects disease progression. Vaccination for hepatitis A and B should therefore be considered for HCV positive individuals who do not already have co-infection.

Host Factors

Host factors can exert enormous influence over the risk of progression of the disease in HCV infection. In a study of 142 patients with a history of illicit drug use, those who were most likely to have cleared the virus without treatment had a history of jaundice (presumably associated with a more robust immune response), had lower viral titers, and were Caucasian. In another study of 883 patients with chronic HCV infection followed for a period of 50 months (± 27 months), decreased survival correlated with duration of disease, the presence of cirrhosis, a history of HIV, and excessive alcohol consumption. In the same study interferon therapy was associated with improved survival. A recent study looked at treatment of acute hepatitis C with interferon alhpa-2b and found that chronic infection could be prevented. The authors do not speculate about patients with normal serum alanine aminotransferase levels. However, one can extrapolate that if treatment during the acute infection can prevent chronic infection, earlier diagnosis and treatment of chronic infection might achieve an increase in sustained response. If this proves true the plastic and reconstructive surgeons role in early detection is potentially very important.

Environmental Factors

The presence of hepatitis B co-infection and excessive alcohol consumption have been shown to increase the risk of cirrhosis. Both factors also increase the risk of hepatocellular carcinoma (HCC). In patients with established cirrhosis, the 10 year rate of HCC with cirrhosis from alcohol alone is 19%, 57% with HCV alone, and 81% for patients with both HCV and alcohol consumption of more than 120 g per day (3.2 ounces).

Epidemiology

The incidence of acute hepatitis C infection in the United States has declined dramatically since 1989 when blood donor screening was introduced. The most significant routes of transmission had included transfusion and sharing contaminated needles, but presently the risk of post-transfusion HCV infection is approximately 0.001% per unit of transfused blood. An average transmission rate of 1.8%, following percutaneous injury, has been reported. The annual risks of infection for surgeons, assuming three percountaneous injuries in 12 months and without post-exposure prophylaxis after each ranged from 1 in 2,000,000 for urological/renal surgeons to 1 in 200,000 for those performing general surgery/ENT/gynecological procedures. In 1996, Esteben, et al, reported the detection of six cases of HCV infection following open heart surgery by an infected surgeon. However, at this time there are no recommendations regarding restrictions of health care workers with hepatitis C infection.


The overall prevalence of anti-HCV antibodies in the general population is 1.8% which corresponds to approximately 3.9 million people in the United States.4 HCV infection is the leading cause of liver transplant. There are an estimated 30,000 new infections each year of which only 25% to 30% are diagnosed. An expert panel, convened in March 2001 by the National Institutes of Health (NIH), estimates that 30,000 acute new infections occur each year in the United States. Twenty-five to 30 percent of those are diagnosed. Current data sources indicate that 8,000 to 10,000 Americans die from hepatitis C disease each year. Vertical transmission (maternal-fetal) occurs in approximately 5.1% of HIV negative mothers.

The prevalence among non-Hispanic blacks was significantly higher at 3.2% than the 1.8% prevalence in the general population and the highest prevalence (9.8%) was noted among black men between the ages of 40 and 49 years old. Zein, et al determined the frequency of genotypes as follows: 56.7% were 1a, 17% 1b, 3.5% were 2a, 11.4% were 2b, 7.4% were 3a, 0.9% were 4, and 3.2% were 6.7 In highly endemic areas of the world, like Egypt, the prevalence may range between 10% and 30 % of the population. Between 50% and 84% of infected individuals progress from acute to chronic infection and between 10% and 30% of those infected will develop cirrhosis. Risk factors for HCV infection include illicit drug use, high risk sexual behavior, poverty, and 12 years or less of education.

Societal Cost

The cost of treating an individual with end stage liver disease averages $100,000. The estimated annual cost of acute and chronic hepatitis C in 1992 was $600 million. A conservative estimate of Californians infected with the virus who will develop end stage liver disease, roughly 10 percent, puts the medical cost at $5 billion.

HCV complications and costs will rise in the United States over the next 20 years. Due to the current rates of chronic HCV infection and the long incubation period, the societal burden of this sleeping giant will be substantial. Costs are expected to be at least $83 billion annually between the years 2010 and 2019. Deaths are expected to increase to 19,000 annually during the same time period due to complications such as cirrhosis and hepatocellular carcinoma. Hepatocellular carcinoma occurs with a point risk of 15 to 20% per decade of infection.

Diagnosis

The incubation period for HCV infection is between two weeks and six months. Between 60 and 70 % of individuals with acute HCV infection will be asymptomatic. Approximately 20 to 30% develop jaundice and another 10 to 20% will have non-specific, flu-like complaints.

Most patients presenting with symptoms of acute infection have elevated bilirubin, alanine aminotransferase (ALT), greater than 600 Unit/L. Within one week of acute infection, viral replication can often be detected. ALT levels may return to normal after acute infection only to rise again, consistent with chronic infection. Patients found to have anti-HCV and normal ALT levels should undergo repeat measurements of ALT over the next six to twelve months. In circumstances where ALT's remain normal, chronic infection may be demonstrated by liver biopsy.

Making the Diagnosis

Enzyme immunoassay (EIA) detects the presence of antibodies to recombinant HCV antigens from the core and nonstructural regions of the polypeptide. A positive EIA can be confirmed with recombinant immunoblot assay (RIBA). When compared with EIA, the RIBA confers greater specificity, but a positive RIBA does not always indicate ongoing HCV infection. Because of this HCV RNA assay (polymerase chain reaction, PCR) is used to establish the presence of ongoing infection.

Several diagnostic algorithms have been developed. In positive anti-HCV patients presenting with chronic liver disease, 40% will be positive for HCV RNA. This fact has led some to suggest that RIBA confirmation is unnecessary and that polymerase chain reaction (PCR) assay should be utilized for confirmation.

Two approaches have been proposed for anti-HCV positive blood donors with normal ALT levels. One algorithm uses RIBA to confirm and is followed by PCR assay. Another algorithm involves testing all anti-HCV (by EIA) positive blood donors for HCV RNA using PCR assay since 60 to 70% will eventually be tested anyway. One drawback of this approach is that significant liver disease may be present in PCR assay negative donors and these individuals are likely to be positive on RIBA (positive RIBA could predict risk of liver disease in PCR negative patients). Immunocompromised patients have a weakened antibody response to HCV antigen. Therefore, anti-HCV negative patients with immune compromise should receive tests for HCV RNA.

As a rule, the presence of anti-HCV by EIA should lead to confirmatory tests that can include RIBA, HCV RNA (of two types: qualitative and quantitative). Chronic infection with HCV is established by the detecting the presence of HCV RNA. PCR is considered the gold standard among the tests for HCV RNA. Two types of PCR assays exist, qualitative and quantitative. Qualitative testing is more sensitive than quantitative tests but it does not offer information about the concentration of RNA. Quantitative assays that determine the concentration of viral RNA and this is one of the pretreatment predictors for response to interferon therapy. Full diagnostic evaluation will include genotype determination and liver biopsy to assess the degree of fibrosis and cirrhosis.

According to the CDC at risk groups that should be offered testing include:

CDC currently does not recommend routine HCV testing for the following groups:

Severity of Liver Disease

Liver biopsy is used to determine the extent of inflammatory changes and the extent of fibrosis and cirrhosis. It is the only means of detecting well-compensated cirrhosis. The staging obtained through biopsy provides useful information in assessing the risk of progression to cirrhosis. The extent of fibrosis and cirrhosis is another of the pretreatment factors that predict response to interferon therapy.

While serum HCV levels have not been shown to correlate to with ALT levels or liver histology, lower serum HCV RNA concentration (< 3million copies/ml) is one of the pretreatment factors that correlate with a better response to interferon. Anti-HCV positive patients with elevated ALT levels compared to those with persistently normal ALT levels are more likely to have a significant liver disease. The degree of ALT elevation however is not a reliable predictor of the severity of histolytic activity.

Extra-hepatic Manifestations

Various extra-hepatic manifestations have been described. These include: glomerulonephritis, various autoimmune disorders, and blood dyscrasias. In many instances, these manifestations are thought to be the result of deposition of immune complexes in various organs or the actual deposition of specific T lymphocytes in tissues. Of particular interest to the plastic and reconstructive surgeon are the dermatological manifestations, two of these are reviewed.

Porphyria Cutanea Tarda

Porphyria Cutanea Tarda is typically seen in middle aged people with major risk factors. Certain porphyrins are overproduced and leak into the plasma where they are then deposited in other tissues. When they are excreted in the urine they can cause dark red discoloration of the urine. With fluorescent spectra analysis of the plasma the specific type of porphyrins can be detected aiding in diagnosis. Chronic HCV infection is thought to increases the oxidative stress within hepatocytes and this may trigger the development of porphyria cutanea tarda. The Mayo Clinic Roshester reports that approximately 20% of their patients with sporadic porphyria cutanea tarda have HCV infection.

Typical skin manifestations include a with blisters, vesciles, or millia on the dorsal aspects of the hands. Other features include hypertrichosis, chloracne, changes in pigmentation, increased fragility of the skin, dystrophic calcifications accompanied by ulcerations, alopecia, onycholysis. Patients should be encouraged to avoid alcohol, estrogens, and other substances that can aggravate the disorder.

Mixed Cryogobulinemia

This disorder, characterized by systemic vasculitis, is associated with a classic triad of palpable purpura, arthralgias, and weakness. About 80% of mixed cryoglobulinemia is associated with HCV infection, and there are serum immunoglobulins present that precipitate in cold. Mixed cryoglobulinemias are thought to result from either low-grade malignant lymphoproliferation or the chronic stimulation of the immune system produced by various infections, including HCV. Treatment with anti-viral agents for patients with HCV will yield improvement in a majority of patients.

Treatment Elimination of Viral RNA

The ideal goal of treatment is the complete eradication of the virus. Various pre-treatment factors predict the likelihood of achieving this goal. Interferon has been used in trying to eliminate the virus. Interferons are a family of naturally occurring cytokine that modulate immune function and are able to induce antiviral and antitumor activity. They do not act directly upon viral antigens but stimulate effect or cells that subsequently transcribe genes that produce proteins that mediate the immune response. There are three broad categories of interferons denoted as a, ß, and ?. Alpha interferons are produced in response to tumor and viral antigens. In addition to the naturally occurring interferons, Amgen produced a "Consensus Interferon" by assigning the most commonly occurring amino acid in each position among the naturally occurring forms to generate a consensus form. Response rates with interferon vary according to dosage, duration of treatment, the form of interferon used, and the pretreatment features of the patients. In patients treated for 6 months, end of treatment response (ETR) range between 35% and 50%. Sustained response (SR) rates fall within a disappointingly low range of 8% to 21%.,,, Extending treatment for 12 months appears to confer some additional benefit in terms of SR for those with good pretreatment predictors.

Even the most recent treatment regimens employing combination therapy with peginterferon alpha-2a or 2b and ribavirin produce a sustained response in only 54 to 56 percent of chronically infected individuals.11, In a study of 44 patients with acute hepatitis C infection were treated with daily dosing of interferon alpha-2b for four weeks followed by 20 weeks of more standard three times per week dosing. Forty three of the 44 patients completed the study. Sixty one percent of the subjects were genotype 1. All 44 patients had undetectable levels of HCV RNA during treatment. At follow up (24 weeks) 42 of the 43 completing the study continued to have undetectable levels. Eighty percent had normal serum alanine aminotransferase levels at the end of 24 weeks of therapy, and the 42 patients with undetectable levels of HCV RNA at the end of 24 week follow-up also had normal serum alanine aminotransferase levels. Treatment of acute hepatitis C with interferon alpha-2b prevents chronic infection.15 Recently, pegylated interferon has been shown superior in achieving sustained response. Pegylated interferon is made by attaching polyethylene molecules to interferon resulting in slower clearance and longer half-life. It does not appear that pegylated interferon achieves lower relapse rates.

Transplantation

Cirrhosis due to chronic hepatitis C infection is the leading cause of liver transplantation. According to data from United Network for Organ Sharing (UNOS), of the more than 4000 liver transplantations performed annually in the United States from 1994 to 1998, 23% were for chronic hepatitis C, 16% for alcoholic cirrhosis, and 7% for both alcoholic cirrhosis and hepatitis C. Currently, about 50% of liver transplantation in the United States and Europe are related to HCV infection. According to one estimate of future morbidity and mortality the need for liver transplantation would be expected to rise until the year 2015.

Hepatocellular Carcinoma

The prevalence of anti-HCV among patients with HCC in the same geographical area may be related to ethnic mix and perhaps the prevalence of hepatitis B surface antigen. The core protein has some potential direct carcinogenic effects in vitro. Initial suggestions that there was an increased risk associated with genotype 1b has not been confirmed and genotype may not influence risk of HCC. It appears cirrhosis is the underlying precursor and therefore those risk factors, such as alcohol consumption, thought to accelerate progression of cirrhosis are also associated with increased risk of HCC.

Classical presentation includes weight loss and right upper quadrant abdominal pain. Patients with cirrhosis may present with decompression and worsening of liver functions. Patients undergoing evaluation for liver transplantation or those subjected to regular screening may be found to have an asymptomatic HCC. Numerous studies have estimated the rate of developing HCC among patients with cirrhosis to be between 1% and 7%. Serial serum alpha-fetoprotein determinations and ultrasound prove effective in early detection of HCC. The high cost of screening and the disappointing results on reducing mortality of early detection make prevention of HCV related cirrhosis critical.

Managing Risk Factors

Patients with chronic HCV infection should receive counseling. Several factors influence the rate of progression toward cirrhosis and end-stage liver disease. Some of these factors including age at exposure (higher risk with older age at time of infection), duration of illness route of transmission, genotype may not be altered. However, other factors including coexistence of alcohol abuse, concurrent hepatitis B or HIV infection, and exposure to hepatotoxic substances have all been shown to affect the rate of progression to end-stage liver disease. Patients should receive counseling since their own disease course and their risk of transmitting the infection can be influenced.

Implications for Plastic and Reconstructive Surgery

Universal screening is not currently recommended for asymptomatic patients with normal transaminases. Current understanding about HCV is rapidly changing and we continue to discover the extent of the impact that chronic infection has upon individuals and society. As more effective and more easily tolerated treatments become available the CDC guidelines regarding universal screening may need to be re-examined. For the practicing clinician it is hard to weigh the potential benefit to patients of earlier detection. Plastic and reconstructive surgeons are faced with some unique questions related to universal screening. At present no surgical specialty has advocated universal screening in defiance of the CDC's current guidelines. For plastic and reconstructive surgeons to unilaterally endorse universal screening in low risk groups may be considered premature by some.

One author, R.A.Y., compiled his results of pre-operative screening for 714 consecutive patients various elective procedures. Fifteen of those patients were found to be positive for antibodies to HCV. Not all patients offered testing accepted so the conclusions we can draw are limited. However, 2.1% of those patients who were screened were found to have HCV antibodies and were subsequently referred for further evaluation. Under the current guidelines these fifteen patients would not have been detected (none had elevated ALT or other indications for screening.) All fifteen patients now have the opportunity to manage their risk of developing end-stage liver disease. Their future mortality and morbidity may be affected by one surgeons decision to break with convention and offer screening. The matter of how the decision to screen low risk patients will impact upon societal costs is unclear.

Ethical arise if universal screening is adopted by a practioner. Do we have the resources to deal with the people who might be detected? Clear treatment protocols for persons with chronic HCV infection and normal transaminase levels awaits more conclusive studies. Given these circumstances, early detection may not alter morbidity and mortality sufficiently to warrant the cost. There is also the question of imposing universal screening upon patients without requiring similar testing of the healthcare worker. Detection of chronic HCV infection potentially affects insurability, lifestyle, long range planning in ways that are poorly understood at this time. Despite these ethical considerations we believe plastic and reconstructive surgeons, like all physicians, should increase their understanding of chronic HCV.

Plastic and reconstructive surgeons should be aware of the extraheaptic manifestation and to be familiar with this illness since they are likely to be treating patients who are infected. They must decide for themselves the best way to implement the current CDC guidelines. In an ever changing landscape, an ethical pandora's box may be opened whether the surgeon chooses to extend the current CDC guidelines or abide strictly by them.

Future Directions of Research

There is considerable interest in developing a vaccine that can prevent persistent HCV. The underlying cause of morbidity and mortality. The obstacles to development of an effective, low-cost vaccine include the absence of a small, affordable animal susceptible to HCV and the lack of a tissue culture that would support high-level HCV replication. This latter fact is also an impediment to developing a live, attenuated virus vaccine. Additionally, the risk of reversion to a wild-type that might cause chronic infection make human testing of a live, attenuated vaccine impractical.

A prototype vaccine tested in chimpanzees outlining envelope glycoproteins produced high titers of neutralizing antibodies Complete protection from infection occurred in 5 of 12 animals. In 5 animals who developed acute infection none went on to develop chronic infection. Novel approaches are being investigated using tobacco plant-derived vaccine.that reportedly induced antibody binding in mice.

Conclusions

Hepatitis C virus infection affects approximately 3.9 million people in the U.S. As many as 85% of those with acute infection will progress to chronic infection and 60% and 70% will remain asymptomatic until late in the course. Early diagnosis may afford infected individuals a chance to alter their host risk factors and make earlier decisions about treatment. Surgeons may wish to offer screening during routine pre-operative testing. If elevated serum transaminase levels are discovered the surgeon should include hepatitis C in the differential diagnosis. The authors believe that guidelines about universal screening may change as more effective treatments that are easier to tolerate are developed. Recent studies showing excellent cure rates for acute infection treated with interferon11 may soon be extended to treating chronically infected persons earlier in their course. If a higher rate of sustained response or if improved response in all genotypes is demonstrated for earlier treatment of chronically infected persons, the authors expect universal screening to be more readily accepted.

With greater understanding of HCV infection should come improved quality of care by surgeons and should lead to appropriate referral. Early detection and modification of other associated risk factors, such as alcohol consumption, can have profound impact upon the course of illness. The surgeon should be aware of current CDC guidelines even if they elect to screen more widely than currently recommended.

Reprint requests to:
Robert A. Yoho, M.D.
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