Diagnosis and differential diagnosis


The Centers for Disease Control (CDC) recommends screening for exposure with HCV antibody (anti-HCV) and follow-up with HCV-RNA testing. About 70% to 86% of patients with positive results of anti-HCV testing are subsequently determined to be chronically infected with HCV.1

All adults born from 1945 through 1965 should be tested once regardless of risk factor status, and anti-HCV testing is also recommended for any patient with persistently high alanine aminotransferase levels or the recognized exposures/risk factors highlighted previously. Anti-HCV test results will be positive a few weeks following the exposing event; window periods may last up to 6 months. A positive anti-HCV test result does not distinguish patients who have cleared the virus from those with chronic infection. 


HCV recombinant immunoblot assay (RIBA) is an additional test that is highly specific for confirming the presence of anti-HCV antibodies. This test confirms exposure to HCV (positive RIBA) or a false-positive anti-HCV screen (negative RIBA). Polymerase chain reaction (PCR) is used to detect HCV-RNA; the result can be reported as a qualitative level (detects the presence of HCV), which can be used to distinguish someone with chronic HCV infection from a person who has cleared HCV either spontaneously or during treatment, or as a quantitative level (measures the viral load). Patients who have cleared the virus will continue to have positive results of the anti-HCV test and RIBA but will be negative for HCV-RNA. 


Additional laboratory investigations may be indicated based on clinical assessment to rule out various entities in the differential diagnosis (Table 4). Abdominal ultrasound may be used to assess the liver, gallbladder, and biliary tree and to screen for hepatocellular carcinoma or ascites, but a normal ultrasound result does not rule out cirrhosis. A triple-phase helical computed tomographic scan of the liver with contrast improves the detection of hepatomas smaller than 3 cm in diameter. 



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Liver biopsy is no longer required before treatment of HCV infection with pegylated interferon and ribavirin but does remain the definitive test for staging liver disease and is still important for assessing the prognosis and guiding therapy.10 Liver biopsies are evaluated in terms of grade and stage. As an alternative to liver biopsy, the HCV FibroSure test (FibroTest-ActiTest) has been validated for the initial diagnosis of fibrosis and for the monitoring of patients with HCV infection. This noninvasive biomarker test uses the results of 6 serum levels plus the age and gender of the patient to generate a score that correlates with the degree of liver damage and converts to a histological classification. 


Additional laboratory assessments before the initiation of treatment for HCV infection should include liver function tests: measurement of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total/direct bilirubin, and albumin. Complete blood cell count (CBC), international normalized ratio (INR), thyroid-stimulating hormone (TSH) level, and calculated glomerular filtration rate (GFR) should also be obtained.13 ALT levels may be normal despite progressive liver disease and are often normal in advanced cirrhosis. Patients with chronic HCV infection who have consistently normal ALT levels are at low risk for progression to cirrhosis. Albumin level is a strong prognostic measure; rates of progression to the complications of liver disease are higher with levels below 35 g/L.10

Case Study

A 47-year-old African-American man presents to the clinic for follow-up of elevated liver function test results. He was seen in the clinic 1 week earlier with persistent malaise, fatigue, and joint pain of 1 to 2 months’ duration.

On abdominal examination, he is found to have mild right upper quadrant tenderness, and the liver edge is palpable 1 cm below the right costophrenic margin. There is no splenomegaly, rash, or jaundice. The remainder of the examination is noncontributory. The patient reports some illicit intravenous drug use more than 20 years ago and states that he used to drink alcohol but stopped more than 15 years ago. He is taking no medications and has no other past medical or family history. The remainder of the review of symptoms is normal.

His laboratory values are as follows:

  • CBC and serum electrolytes: within normal limits
  • AST, ALT: 2.5 times the upper limit of normal
  • HCV-RNA: 5.8-log10 copies/mL (equivalent to 630,957 copies/mL)
  • HCV genotype 1a
  • Albumin: 4.2 g/dL
  • Total bilirubin: 1.1 mg/dL
  • Alpha fetoprotein: within normal limits
  • HIV antibody screen: negative

The result of an abdominal ultrasound is normal.

After consultation with a gastroenterologist, the patient is determined to be naïve to treatment, non-cirrhotic with an HCV PCR count of under 6 million, therefore the patient is managed on Harvoni (ledipasvir, 90 mg + sofosbuvir, 400 mg) for 8 weeks and achieves an SVR.