MEDICOLEGAL PITFALLS

Medicolegal pitfalls can be encountered in all stages in the management of patients with hepatitis C (HCV). This newsletter discusses some common errors in the care of these patients. Such errors can often be prevented with common sense, good communication, and adherence to established guidelines. This newsletter is not a comprehensive or exhaustive review of all medicolegal pitfalls but summarizes the clinical experience of a hepatologist and is supported by evidence-based literature.

Antibody Testing

Health care professionals should be aware that immunocompromised patients who have HCV may not produce antibodies against HCV; this may give rise to false-negative test results. Patients with acute HCV may also have a false-negative antibody test result, as a humoral response can take 6-8 weeks to mount. Under these circumstances, HCV diagnosis should be confirmed with a serum HCV RNA viral load. Diagnosis can be confirmed with either a qualitative test or a sensitive quantitative test such as TaqMan polymerase chain reaction, which has a sensitivity threshold of <50 IU/mL.¹

Conversely, false-positive test results also occur; they are more likely to occur when HCV testing is performed in groups in which disease prevalence and risk levels are low. Patients with autoimmune diseases may also be at higher risk of developing false-positive antibodies. Serum HCV RNA is, again, recommended to confirm or refute the diagnosis.

High-risk behavior

Patients with a history of blood transfusions before 1987 (when HIV screening was introduced) and high-risk sexual behavior should also be screened for HIV and chronic hepatitis B (HBV), as the presence of these diseases can influence the natural history and treatment of HCV.

Screening for other liver diseases

Given the prevalence of HCV, patients occasionally have coexisting diseases, such as alcoholic liver disease, nonalcoholic fatty liver disease, iron overload, or other viral hepatitis. Patients diagnosed with HCV should be screened for other causes of liver disease, as these diseases may impact HCV treatment.²

Normal liver function tests

Patients with chronic HCV can have normal liver function tests. So long as such treatment is not contraindicated, these patients should be offered treatment, as their sustained virologic response (SVR) is comparable to that of patients with HCV and elevated liver tests.³ If a liver biopsy shows mild disease and therapy is deferred, periodic laboratory and histological monitoring should be performed. No guidelines exist on the frequency of histologic monitoring.

Patients with extrahepatic manifestations of HCV, such as glomerulonephritis or vasculitis, often have normal liver function tests and are appropriate candidates for therapy that may need to be indefinite.

Imaging tests

Ultrasonography or CT scanning is recommended in the evaluation of all patients with HCV. Imaging studies may provide helpful information about liver size and hepatic morphology and, occasionally, provide information that changes management, such as radiological signs of cirrhosis (thus, possibly, obviating a liver biopsy) and the presence of an incidental hepatoma.

Liver biopsy

Frequently, little correlation exists between the severity of liver enzyme abnormalities and hepatic histology. Clinical and laboratory markers are also unable to accurately predict the degree of inflammation or stage of fibrosis in such patients.⁴ Liver biopsy is currently the criterion standard for determining histological grade and stage. Liver biopsy can provide prognostic information for future disease progression and detect the presence of steatosis or iron overload (which are negative predictors of response to therapy in patients with genotype 1). However, liver biopsies, although recommended for patients with genotype 1, are not mandatory. Many gastroenterologists and hepatologists forego biopsies in patients, particularly if screening test results do not reveal a coexisting liver disease that may impact treatment or contraindications to therapy. This remains a controversial issue and is best resolved by an earnest discussion between physician and patient, particularly because biopsies are invasive and associated with a small but not insignificant risk of complications.

Screening for comorbidities and pretreatment considerations

Pegylated interferon and ribavirin are associated with numerous adverse effects, the most common being weakness, flulike symptoms, depression, bone marrow suppression, and hypothyroidism. Prior to starting treatment for HCV, patients need to be screened for comorbidities to determine whether they are eligible for treatment. Common examples of pretreatment considerations include the following:

1. Patients with psychiatric diseases, particularly depression, should be evaluated by a psychiatrist before commencing treatment and during treatment.
2. Patients who cannot tolerate the onset of anemia, such as those with coronary artery disease or cerebrovascular disease, should not be treated with ribavirin.
3. Patients with a history of diabetic or hypertensive retinopathy need ophthalmological consultation because visual disorders such as retinal hemorrhages, although uncommon overall, are more likely in this subgroup.
4. Interferon and ribavirin are contraindicated in pregnancy (ribavirin is well known as an animal teratogen). Strict contraception and rigorous contraceptive practices in women of reproductive age and their partners are required immediately before, during, and for 6 months after treatment.

A thorough history and physical examination are required in all patients before HCV treatment is considered to screen for comorbidities or conditions that put them at significantly higher risk of developing complications from interferon and ribavirin therapy.⁵ Patients need to be informed that, of the adverse effects that have been attributed to interferon and ribavirin, the most common are weakness, depression, flulike symptoms, bone marrow suppression, and thyroid disease. These conditions are more likely to develop in the first few months of therapy, before symptoms stabilize.

Alcohol or drug users

Recovered drug users, including those on methadone therapy, should not be denied treatment. Active drug users should be evaluated on a case-by-case basis, especially those participating in drug treatment programs.⁶ Abstinence from alcohol is recommended for at least 6 months before commencing treatment, as a safe level of alcohol consumption has not been established. These individuals need to be informed that, in the presence of HCV, alcohol accelerates the progression to fibrosis and decompensated liver disease. If these patients are not candidates for interferon and ribavirin therapy, they should be informed that the complete discontinuation of alcohol would be the most effective intervention to decrease the progression of liver disease.⁷

Use of stimulating factors

Stimulating factors (SFs) such as erythropoietin and granulocyte colony-stimulating factor are frequently used to treat anemia and leucopenia from ribavirin and interferon, respectively. However, although studies show that the use of erythropoietin may improve quality of life and maintain higher doses of ribavirin, no data show that this translates into improved SVR.⁸ This information needs to be communicated to patients and their referring physicians, who are often under the impression that SFs should be routinely used to treat the adverse effects of antiviral therapy. To complicate matters further, both types of SFs are costly and associated with their own adverse effects, and their use should not be reflexive.

Vaccinations and preventive health care

Patients with chronic HCV should be tested or vaccinated (or both) for hepatitis A (HAV) and HBV. Studies have shown that HAV may account for acute hepatic decompensation in stable patients with chronic HCV; vaccination should be performed before patients decompensate.⁹ These patients should also be offered standard adult vaccinations and preventive health care services before they develop decompensated liver disease.

Screening for esophageal varices and hepatoma

People who have both cirrhosis and HCV are at risk of developing esophageal varices, gastric varices, or both. These patients should undergo at least one upper endoscopy to document the presence or absence of varices, which, if moderate or large, should be treated with prophylactic β antagonists. Patients with cirrhosis and HCV should also be screened for hepatocellular carcinoma with biannual α-fetoprotein tests and an imaging test, such as ultrasonography.¹⁰

References

1. Dienstag JL, McHutchinson JG. American Gastroenterological Association Technical Review on the Management of Hepatitis C. Gastroenterology 2006;130:231-64.

2. Sebastiani G, Varo A, Ferrari A , et al. Hepatic iron, liver steatosis and viral genotypes in patients with chronic hepatitis C. J Viral Hepat 2006;13:199-205.

3. Zeuzem S, Diago M, Gane E, et al. Peginterferon alfa-2a (40 kilodaltons) and ribavirin in patients with chronic hepatitis C and normal aminotransferase levels.
Gastroenterology 2004;127:1724-32.

4. National Institutes of Health. NIH Consensus Development Conference Statement. Management of Hepatitis C. Hepatology 2002;36:S3-20.

5. Russo MW, Fried MW. Side effects of therapy for chronic hepatitis C. Gastroenterology 2003;124:1711-9.

6. Edlin BR. Prevention and treatment of hepatitis C in injection drug users. Hepatology 2002;36:S210-9.

7. Peters MG, Terrault NA. Alcohol use and hepatitis C. Hepatology 2002;S220-5.

8. Curry MP, Afdhal NH. Use of growth factors with antiviral therapy for chronic hepatitis C. Clin Liver Dis 2005;9:439-51.

9. Keeffe EB. Acute hepatitis A and B in patients with chronic liver disease: prevention through vaccination. Am J Med 2005;118:21S-27S.

10. Sharma P, Rakela J. Management of pre-liver transplantation-part 1. Liver Transpl 2005;11:124-33.

SCREENING GUIDELINES

Approximately 4 million people in the United States are infected with HCV, and most of them have not been identified.¹ However, routine screening of all adults who are asymptomatic or at low risk is not recommended, as the prevalence of HCV in the general population is only 1.8-2%. For example, screening asymptomatic blood donors who have an HCV prevalence of <2% for HCV antibody (a test with 98-99% specificity) results in similar numbers of false-positive and true-positive test results.

In contrast, screening for HCV is recommended for high-risk groups who have a higher probability of true or active infection. These groups include people who underwent blood transfusions before 1992 (when donor screening was introduced), people with a past or recent history of injection drug use, people with hemophilia who received clotting factors before 1987 (when processing to inactivate viruses was introduced), people with frequent percutaneous exposures, people with clinical or biochemical evidence for chronic liver disease, immigrants from countries with a high prevalence of HCV infection, and spouses of patients with HCV. In these groups, the prevalence of HCV is much greater, and true-positive test results outweigh false-negative test results such that a positive test result is highly predictive of a true infection. Diagnostic testing is recommended for these groups, regardless of the presence of symptoms, by the US Public Health Service, expert panels, and professional medical societies such as the American Gastroenterological Association (AGA).^2,3,4

However, a recent article by the US Preventive Services Task Force stated that data to support HCV screening in these high-risk groups are insufficient.⁵ The authors reviewed controlled studies of screening and antiviral therapy, observational studies on other interventions, risk factors, accuracy of antibody testing, workup, harms of biopsy, and long-term outcomes. The task force stated that, although antiviral therapy can result in sustained viral eradication in 54-56% of patients, no trials have been performed in asymptomatic patients likely to be identified by screening. Few data were available to determine whether treatment in this group translated into long-term outcomes, and data did not demonstrate or estimate the benefit from counseling or immunizations. The task force stated that, although the risks of biopsy and treatment are small, only spare data are available on other adverse consequences of screening, such as anxiety, patient labeling, and damage to close relationships, and whether these factors can be mitigated by appropriate counseling. A further barrier to screening patients on the basis of risk factors is the difficulty in obtaining accurate histories, particularly for injection drug use and high-risk sexual behavior. Also, little is known about patient preferences for screening and no data are available to estimate risks and benefits of one-time screening versus other strategies.

Many professional societies, including the AGA, have taken issue with the conclusions of the US Preventive Services Task Force. Based on many factors (documented progression to cirrhosis, albeit slow in most cases; hepatic decompensation; hepatocellular carcinoma [HCC]; death; liver transplantation; benefits of curing HCV in approximately 50% of patients with antiviral therapy; slowing or even reversal of fibrosis in treated patients; possible reduction in incidence of HCC in patients who achieve sustained viral eradication), the AGA advocates that members of high-risk groups, whether symptomatic or not, should be screened for HCV. In turn, those with an established diagnosis of HCV should be counseled about the natural history of HCV, the benefits and risks of antiviral therapy, avoidance of alcohol, and the need for vaccinations for HAV and HBV.

References

1. Kim WR. The burden of hepatitis C in the United States. Hepatology 2002;36:S3-4.

2. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus infection (HCV) and HCV-related cirrhosis. MMWR Morb Mortal Wkly Rep 1998;47:1-39.

3. Dienstag JL, McHutchinson JG. American Gastroenterological Association Medical Position Statement on the Management of Hepatitis C. Gastroenterology 2006;130:225-30.

4. National Institutes of Health. NIH Consensus Development Conference Statement. Management of Hepatitis C. Hepatology 2002;36:S3-20.

5. US Preventive Services Task Force. Screening for hepatitis C virus infection in adults: recommendation statement. Ann Int Med 2004;140:462-4.