~Hepatitis C, Part 2 - Diagnosis

  • Symptoms of CHC
  • Differential Diagnosis
  • Viral Genetics
  • Diagnostic Tests
  • Liver Function Tests
  • Virological Markers
  • Confirming a Diagnosis of HCV Infection
  • Hepatocellular Carcinoma Screening
Symptoms of CHC

Acute viral hepatitis is difficult to diagnose;50 symptoms can vary from a minor flu-like illness to liver failure. Most patients with acute HCV develop only a few mild, nonspecific symptoms and sustain minimal damage to liver tissue. Infection with HCV usually begins suddenly — this is called the prodromal phase. Symptoms vary in this phase; many people think they have the flu. Patients may experience low-grade fever, fatigue, loss of appetite, a distaste for cigarettes, nonspecific malaise, nausea and vomiting, and nondescript upper abdominal discomfort — or no symptoms at all. The liver is enlarged in half of infected individuals and about 20% of them also have an enlarged spleen. The icteric, or jaundice phase follows in 3 to 10 days. During this phase, the urine darkens and the skin may develop a yellow hue; other symptoms typically regress. During the 2- to 4-week recovery phase that follows, patients either clear the virus completely or develop a chronic infection. Because the course of the acute infection is mild, many people do not remember the original infection when they are diagnosed with CHC many years later.16

Symptoms of chronic viral hepatitis are variable; they might include fatigue, mild abdominal pain, nausea, poor appetite, muscle and joint pains, weight loss, and occasional bouts of jaundice.1 Severity of symptoms is not related to the seriousness of the disease. Approximately 15% of chronically infected adults develop cirrhosis within 20 years of the initial infection.3 Development of cirrhosis of the liver is often asymptomatic, and some patients are unaware of their HCV infection until they are diagnosed with advanced disease — notably, liver failure and hepatocellular carcinoma.51

Differential Diagnosis

Diagnosis of acute HCV infection is based on clinical symptoms and liver enzyme levels and antibodies to HCV in the blood. An antibody test can take 8 to 12 weeks following initial exposure;52 direct measurement of the genetic material of the virus (HCV RNA) in the blood is a more accurate test. Liver damage is reflected in elevations of the liver enzymes.6 One third of CHC patients have persistently normal enzyme levels; therefore a positive diagnosis relies on detection of anti-HCV antibodies or virus. A liver biopsy is used to grade the severity of liver disease, not for a diagnosis.53,54

Viral Genetics

HCV is a small single-stranded, RNA virus: 6 distinct HCV strains with distinct genetic characteristics (genotypes) have been identified, as well as 11 subtypes.1,55 The HCV genotype is an intrinsic viral characteristic—it does not change. The subtype can change its amino acid pattern over time and mutate over the course of the infection. This substantial immunogenic variability allows the virus to reproduce and mutate rapidly, and consequently, evade the immune response of the host.56,57 This creates a persistent infection that is difficult to cure (NIH 2002) and complicates vaccine development.16 Genotype and subtype have a direct influence on disease virulence, severity of fibrosis (formation of scar tissue), and development of cirrhosis or hepatocellular carcinoma.51,58 The genetic diversity of HCV creates a virus that has the ability to escape the immune system of its host. This leads to a high rate of chronic infections and lack of immunity to reinfection in repeatedly exposed individuals. Genotypes and their subtypes vary geographically. Some genotypes of HCV are geographically restricted; others are distributed worldwide. Genotype 1 is the most common in the U.S. and is responsible for greater than 70% of infections.1,19 It is associated with severe chronic liver disease and lower rates of response to treatment with antiviral drugs.55 Patients with HCV genotypes 2 or 3 have about a 25% greater chance of response to treatment than those with HCV genotype 1.59-62

The success of pharmaceutical treatment depends on the specific genotype. Although HCV genotype and viral load are the strongest predictors of response to treatment,63,64 most scientists think that one viral genotype is no more virulent than any other and that other factors are responsible for the variation seen in treatment outcomes.65

Diagnostic Tests

Diagnostic tests for hepatitis C are divided into two broad categories: tests to assess damage to the liver and tests to identify the type and amount of the hepatitis virus.66,67

Liver Function Tests

Serum ALT (SGPT) and AST (SGOT)

Serum alanine aminotransferase (ALT) (SGPT) and aspartate aminotransferase (AST) (SGOT) are enzymes produced in the liver. ALT and AST are used as rough indicators (or markers) of the degree of liver cell inflammation.51 In fact there is probably only a weak association between the ALT levels and inflammatory changes. Although elevations of these liver enzymes are frequently seen in both acute and chronic hepatic C,51 they are not related to severity or outcome of the disease68,69 or to inflammatory changes or degree of fibrosis.66,67 ALT can be normal even in those with liver damage, and ALT can be elevated in diseases other than CHC.70 AST can be very high in acute hepatitis and drop to normal or slightly elevated in chronic hepatitis.69 ALT is very useful for monitoring the effectiveness of antiviral drug treatment for CHC. The response to treatment is judged in terms of ALT normalization during and after treatment.69

Virological Markers

There are two types of virological tests—those that identify specific antibodies produced by immune cells in response to invading virus and those that test for the virus itself. Virologic tests have no prognostic value. They do not correlate with the severity of liver injury, and they cannot predict the natural course of the disease.

Anti-HCV Antibody Tests

Enzyme immunoassays (EIA) and enzyme-linked immunosorbent assays (ELISA). EIA and ELISA are used to detect antibodies to the virus in the blood, which indicated exposure to HCV. Enzyme assays cannot distinguish exposure to the virus from an active infection. It takes about 7 to 8 weeks from the time of infection until antibodies have formed in the blood. Eventually all infected individuals will have detectable anti-HCV antibodies. If an infection spontaneously resolves, the anti-HCV antibodies may persist or disappear after several years. All people with CHC will have antibodies—although they might become undetectable in severe immunodepression.1,71


The HCV RIBA test is used to detect false positive anti-HCV test, especially "weakly" positive results. It also detects antibodies to the virus.1,71

Quantitative HCV Tests

"Viral load" means the number of viral particles in the blood. Detection of HCV RNA, the genetic material of HCV, indicates an active infection. HCV RNA can usually be detected 1 or 2 weeks after infection. Then it rises to a peak, after which it either disappears when the infection resolves spontaneously or falls and stabilizes into a chronic hepatitis. There is no correlation between HCV RNA level and degree of liver damage, except in end-stage liver disease when HCV RNA levels low or undetectable.72 Qualitative HCV-RNA testing is also used to monitor the effectiveness of treatment.

HCV Viral Genotyping

Genotyping is used to determine the genetic makeup of the virus causing the infection and the length of treatment. Genotype 1 is less likely to respond to treatment than genotypes 2 or 3; for that reason, it usually requires longer treatment. The HCV genotype can also be determined by serotyping, i.e., testing for type-specific antibodies with an EIA. The assay can identify type but not subtype.73,74

Confirming a Diagnosis of HCV Infection

Acute HCV Infection

A diagnosis of an acute HCV infection is confirmed with anti-HCV and HCV RNA tests. Detection of HCV RNA without anti-HCV strongly indicates acute hepatitis C. Acute HCV infection is unlikely if HCV RNA is absent, but there are no anti-HCV antibodies.1

Chronic HCV Infection

The presence of both anti-HCV and HCV RNA is diagnostic of CHC. The exception would be the absence of anti-HCV antibodies and the presence of HCV RNA in a profoundly immunodepressed patient.1

Liver Biopsy

Liver biopsy is the gold standard for assessing the liver cell injury and determining the prognosis of a patient with CHC. There are several biopsy scoring systems used. All measure the same parameters: fibrosis, necrosis, and inflammation in the liver. A high score indicates a higher risk of rapid disease progression and cirrhosis and as such is used to decide if treatment should be started. Patients with cirrhosis have a high risk of developing hepatocellular carcinoma.75 Although there is some diagnostic information that only it can provide, a liver biopsy has several serous shortcomings. In some instances, it may be appropriate to forgo biopsy before initiating antiviral therapy—because of excessive risk to the patient, for example. There is a small but definite risk with a biopsy; the death rate is -0.12%, and 5% of those who undergo biopsies have complication.76,77

Hepatocellular Carcinoma Screening

Alpha-fetoprotein levels and ultrasound testing are used to screen for hepatocellular carcinoma. CT and MRI scans and hepatic angiography are used to confirm ultrasound findings in patients with cirrhosis.36,37 When a biopsy is used to test for hepatocellular carcinoma there is a small risk that the tumor will spread along the needle track.

Continued . . .

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