Special Feature
Hepatitis C: Inescapable Issue in the Emergency Department
By Amy J. Behrman, MD
and Stephanie Abbuhl, MD
Hepatitis c (hcv) is the most common bloodborne pathogen in the United States. Emergency physicians encounter HCV as a clinical issue for their patients and as an occupational hazard for themselves and their staff on a daily basis. HCV also is the most recently characterized of all known bloodborne pathogens. This article reviews the current understanding of HCV epidemiology, pathophysiology, and treatment.
Epidemiology
Nearly 4 million people are infected with HCV in this country.1 An estimated 30,000 new HCV infections occur each year, although less than one-half are diagnosed. The acute infection rate has decreased by an order of magnitude over the past decade due to our ability to screen blood products, but new infections and chronic hepatitis from old infections remain a major public health problem. Most (80-85%) infected persons become chronic carriers of HCV and many develop chronic liver disease.2 The Centers for Disease Control and Prevention estimates that HCV causes 8000-10,000 deaths yearly in this country and is the most frequent cause of end-stage liver disease (ESLD) requiring liver transplantation.1 HCV disease costs more than $600 million annually in direct medical costs and lost productivity.1 The situation is no better worldwide, with an estimated 170 million chronic infections in developed and undeveloped countries.2
In the United States, the prevalence of HCV is highest among men ages 30-49 years. The incidence of acute infection is highest among men ages 20-39 years, and is approximately equal among African-American and Caucasian populations.1 Chronic infection is more prevalent in African-Americans, probably reflecting a reduced rate of viral clearance.2 Most infections acquired more than 10 years ago were due to blood product transfusion. Since 1994, the risk of transfusion-related HCV has fallen to near zero. The primary risk factor for new HCV infection now is injection drug use.1 HCV infection is also associated with intranasal cocaine use, possibly via sharing of microscopically-contaminated straws.3 HCV can be transmitted by sexual contact, particularly male-to-female.1 Sexual transmission is associated with high-risk practices including multiple partners and prior history of sexually transmitted diseases.3 Transmission in stable monogamous relationships appears much less common for HCV than for human immunodeficiency virus (HIV) and hepatitis B (HBV). Non-sexual household contacts of HCV patients may have a slightly increased risk of infection.1
It is not clear if health care workers (HCWs) have higher rates of chronic HCV infection than the general population, but percutaneous occupational exposure clearly can transmit HCV to HCWs, with an average seroconversion rate near 2%.1,4,5 Mucous membrane and skin-splash exposures appear to carry a lower risk, as is true for other bloodborne pathogens. Nosocomial transmission between patients has been documented in health care settings including dialysis units, hematology wards, and colonoscopy suites.6-8 Case reports of patient-to-patient transmission frequently implicate breaches in standard infection control practice such as inappropriate re-use and inadequate instrument sterilization. Provider-to-patient transmission has been rarely reported.9
Pathogenesis
After entering the bloodstream by percutaneous or mucous-membrane routes, this RNA virus infects hepatocytes, probably utilizing specific cell-surface proteins as receptors.10 The virus replicates in liver cells and may cause acute and/or chronic damage. Infected hosts mount humoral and cell-mediated responses against most viral proteins. Unfortunately, however, only 15-20% of those infected are able to clear the infection permanently.1,2,10 In the remaining 80-85% of immune-competent patients, HCV remains as a chronic infection. This is likely related to high intrinsic mutation rates in HCV, particularly in the hypervariable regions of the envelope proteins that are the primary targets of host antibodies.10 Co-infection with HIV is associated with an increased likelihood of developing chronic HCV, presumably by crippling an already ineffective cell-mediated response.2
Most people with acute HCV are asymptomatic.1 Approximately 25% may be jaundiced, and 10-20% have non-specific symptoms such as malaise, anorexia, and abdominal discomfort. Clinical illness, if present at all, is mild and otherwise similar to other types of acute hepatitis. The majority of patients are not diagnosed during their initial infection, and most will go on to develop chronic disease.
The natural history of chronic HCV is not yet fully defined. Most clinical studies are limited by relatively short follow-up periods and may be biased by selection for patients with co-morbid conditions. It is known that within one to three decades, persons with chronic HCV infection may develop a wide range of symptoms ranging from none to asymptomatic transaminitis to the classic manifestations of ESLD.1,2,10 Overall, 60-70% of those infected will have abnormal or fluctuating alanine aminotransferase (ALT) levels.1 Liver biopsy during the insidious progression of chronic HCV may show inflammation, fibrosis, or frank cirrhosis.10 Cirrhosis develops in 10-20% of cases within 20-30 years1,10 and hepatocellular carcinoma develops in 1-5%. Severe HCV liver disease appears more common in men, heavy drinkers, and persons infected after the age of 38. Extra-hepatic manifestations are probably immune-mediated and include cryoglobulinemia, glomerulonephritis, arthritis, and porphyria cutanea tarda.1,10
Diagnosis
None of the tests for HCV are immediately available, but all are relevant to long-term decision making and counseling HCWs who have sustained a body fluid exposure. Serum antibodies can be detected in 80% of cases within 15 weeks of exposure and in 97% of cases by six months after exposure.11 Importantly, since seroconversion does not occur for an average of 8-9 weeks after exposure, false negatives will be common in acute infections. The standard enzyme immunoassay (EIA) has poor positive predictive value in low-risk populations, so confirmation with a more specific test such as the recombinant immunoblot assay (RIBA) is recommended for all positive screening tests.1 Serologic testing cannot distinguish between acute, chronic, or resolved infections.
Gene amplification techniques for detecting HCV-specific nucleic acid sequences can be more valuable for diagnosing acute infections, distinguishing active from resolved infections, and following response to therapy. Polymerase chain reaction (PCR) testing for viral RNA is now widely available in quantitative and qualitative forms. This may allow diagnosis within days to weeks after exposure. Quantitative HCV PCR testing is accurate at higher viral loads and can be used to monitor disease progress. Quantitative PCR should not be used to rule out HCV diagnoses because of false-negative results at low copy levels.
HCV genotyping allows clinicians to distinguish between six genotypes and greater than 90 subtypes. Specific genotypes may have differential responses to antiviral therapy. The most common HCV strain in this country, genotype 1, also is the most resistant to current therapies.10
Finally, liver biopsy may be useful to confirm a diagnosis; define the extent of inflammation, fibrosis, and cirrhosis; and to exclude other diseases. Liver biopsy can be particularly useful in chronic HCV infection when clinical findings and transaminase levels may not reflect the severity of histologic changes. Liver biopsy, in addition to quantitative PCR testing, can be used to monitor treatment response in some cases.
Treatment
At this time there are no vaccines or immune globulin preparations active against HCV. Therapeutic options are currently limited to alpha-interferon and ribavirin,10 although clinical trials of additional agents will continue. Treatment is clearly indicated in adult patients with persistently abnormal ALT levels, measurable circulating HCV RNA, and liver biopsies showing chronic hepatitis with either fibrosis or moderate inflammation.1,10 Patients with HCV RNA who are clinically well with normal liver function and patients with severe decompensated cirrhosis should be treated only within clinical trials.
Interferon causes normalized ALT levels in 50% of patients and loss of detectable HCV RNA in 30% of patients after one year of therapy with 3 million units subcutaneously, three times weekly.1 Histologic improvement of fibrosis has also been demonstrated. However, half of those responding to interferon relapse with recrudescence of HCV RNA levels. Combination therapy with ribavirin and interferon for one year leads to significantly higher sustained response rates (i.e., undetectable HCV RNA more than 6 months after treatment cessation).10 ALT levels and biopsy results also show greatest improvement with combination therapy.
Sustained response rates are higher in younger patients, women, patients with lower levels of HCV RNA, and patients with milder degrees of fibrosis on liver biopsy.10 Response rates are also higher in patients with chronic HCV infection due to genotypes 2 and 3, as opposed to genotype 1.1,10 Patients with early, chronic HCV infection may respond better than patients with more established disease, and it is possible that patients with acute infection may also benefit from early treatment.1 Patients who do not respond after six months of combination treatment (i.e., remain positive for circulating HCV RNA) are unlikely to benefit from further therapy and should usually stop receiving it.10
Drug toxicity is common with combination therapy and can be severe. Interferon can cause incapacitating fatigue and depression as well as anorexia, myalgias, headaches, anxiety, cognitive deficits, insomnia, and bone marrow suppression.1,10 Ribavirin is associated with hemolysis, anemia, nausea, cough, pruritis, and dyspnea in some patients.10 Ribavirin is also teratogenic. Side effects may lead to patients requiring dose reductions or withdrawing from effective treatment. Patients on antiviral therapy should be followed by clinicians experienced with monitoring and treating HCV. Further understanding of HCV pathogenesis may lead to more effective and less toxic therapies as well as vaccine development.
Occupational Exposures
ED patients in some urban areas have been shown to have much higher rates of HCV infection (as well as other bloodborne pathogens) than the general population. In one study, the rate of HCV infection in ED patients was 18%.12 This, combined with the high frequency of emergent invasive procedures in ED settings, presents a challenge to emergency physicians. Exposures to high-risk patients may result from "needlestick" incidents, mucous membrane splashes during procedures, and even bites. Continuous efforts must be made to observe strict infection control standards during every patient encounter. Staff and students who are inexperienced in performing invasive procedures should be carefully monitored. Nosocomial transmission of HCV to patients has not yet been reported in the ED setting, but clearly could occur with inadequate sterilization of scopes or other re-usable equipment.
ED physicians should be familiar with post-exposure protocols and follow-up options within their institutions in order to provide optimal care to ED staff and other HCWs who present with potential HCV exposures. At this time, there are no recommended post-exposure prophylactic regimens for HCV. EDs can, however, play vital roles in documenting exposures, counseling exposed HCWs, and ensuring optimal follow-up. HCV antibody levels should be obtained immediately on all known source patients. Exposed HCWs should have baseline HCV antibody and ALT levels sent. The CDC recommends following serial HCV antibodies and liver function tests for six to nine months after exposure. HCWs who seroconvert should be referred immediately for further evaluation and possible treatment. PCR testing may demonstrate infection within two to four weeks after exposure, allowing even earlier detection and treatment of occupational HCV. (Dr. Behrman is Medical Director, Occupational Health Service, in the Emergency Medicine Department of the University of Pennsylvania Medical Center in Philadelphia.)
References
- Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Morb Mortal Wkly Rep 1998;47:1-39.
- Thomas DL, et al. The natural history of hepatitis C infection. JAMA 2000;284:450-456.
- Conry-Cantilena C, et al. Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C infection. N Engl J Med 1996;334:1691-1696.
- Moran GJ. Emergency department management of blood and body fluid exposures. Ann Emerg Med 2000;35:47-62.
- Hamid SS, et al. Risk of transmission and features of hepatitis C after needlestick injuries. Infect Control Hosp Epidemiol 1999;20:63-64.
- Allander T, et al. Hepatitis C transmission in a hemodialysis unit: Molecular evidence for spread of virus among patients not sharing equipment. J Med Virol 1994;43:415-419.
- Allander T, et al. Frequent patient-to-patient transmission of hepatitis C virus in a haematology ward. Lancet 1995;345:603-607.
- Bronowicki J, et al. Patient-to-patient transmission of hepatitis C during colonoscopy. N Engl J Med 1997;
337:237-240.
- Esteban JI, et al. Transmission of hepatitis C virus by a cardiac surgeon. N Engl J Med 1996;334:555-560.
- Liang TJ, et al. Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med 2000;132:296-305.
- Alter MJ, et al. The natural history of community acquired hepatitis C in the United States. N Engl J Med 1992;327:1899-1905.
- Kelen GD, et al. Hepatitis B and hepatitis C in emergency department patients. N Engl J Med 1992;326: 1399-1404.
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