What proportion of adult patients with active chronic hepatitis C virus infection, without hepatitis B or HIV co‑infection, advanced fibrosis or cirrhosis, and not taking hepatotoxic medications, have normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels?

Normal Liver Function Tests in Active Hepatitis C

Approximately 30-50% of patients with active chronic hepatitis C infection will have persistently normal ALT and AST levels, yet the majority of these patients still have histological liver disease and should never be considered "healthy carriers." 1, 2

Defining Normal ALT in HCV Context

• Persistently normal ALT is defined as ALT values <40 IU/mL on 2-3 occasions separated by at least one month over a 6-month period 1
• However, current evidence suggests the true upper limit of normal should be significantly lower: 30 IU/mL for men and 19 IU/mL for women, based on cohort studies of healthy blood donors 1
• Using traditional laboratory cutoffs of 40-45 IU/mL misses patients at risk for significant liver disease and progressive fibrosis 1

Prevalence and Clinical Significance

• Up to 60% of HCV-infected first-time blood donors and injection drug users have been reported to have normal aminotransferase values 1
• Approximately 50% of patients with chronic hepatitis C who are both anti-HCV and PCR positive will have completely normal transaminase values 2
• Among patients with persistently normal ALT (using traditional cutoffs), 5-30% still have advanced fibrosis and cirrhosis on liver biopsy 1
• One study found that 47% of HCV patients with repeatedly normal transaminases had significant liver pathology (chronic persistent hepatitis or chronic active hepatitis) on biopsy 3

Histological Findings Despite Normal LFTs

• Patients with persistently normal ALT generally have less severe portal inflammation, lobular inflammation, piecemeal necrosis, and fibrosis compared to those with elevated ALT 4
• The prevalence of cirrhosis is lower in the normal ALT group (approximately 1-10% versus higher rates in elevated ALT groups) 1, 4
• Fibrosis progression rate is slower in patients with normal ALT (0.058 fibrosis units/year versus 0.118 fibrosis units/year in elevated ALT patients) 5
• However, approximately 20-30% of patients with persistently normal ALT show significant progression of fibrosis over time, and hepatocellular carcinoma can develop despite persistent ALT normality 6

Virological Characteristics

• Mean HCV-RNA levels are significantly lower in patients with persistently normal ALT compared to those with abnormal ALT (12 × 10⁵ versus 33 × 10⁵ copies/mL) 4
• Lower viral load may partially explain the slower fibrosis progression rate in this population 4
• Despite lower viral loads and milder histology on average, these patients remain viremic and should not be dismissed as having benign disease 2

Critical Clinical Pitfalls to Avoid

• Never assume normal LFTs exclude hepatitis or significant liver disease—a patient with hepatitis C with normal ALT can progress to end-stage liver disease if undiagnosed 2
• Do not rely on routine liver tests to screen for chronic HCV infection, as about 50% of infected patients will have normal transaminases 2
• Normal ALT does not exclude NASH or significant liver disease; histological assessment or non-invasive fibrosis testing is needed for accurate staging 2, 7
• Liver biopsy is recommended for patients found to be viremic, whether or not liver function tests are abnormal, as routine liver tests correlate poorly with both necroinflammatory and fibrosis scores 2
• Test based on risk factors (people who inject drugs, migrants from high-prevalence areas, prisoners, those with country of origin or parental exposure risk factors), not LFT results 2

Treatment Implications

• The SVR rate in patients with normal ALT is similar to that in patients with abnormal ALT, so patients should not be excluded from therapy based on ALT levels alone 1, 8
• Treatment decisions should be based on degree of fibrosis on liver biopsy or non-invasive testing, HCV genotype, viral load, patient age and motivation, and comorbid conditions—not ALT levels 1, 8
• ALT levels fluctuate from normal to abnormal over time, limiting the value of monitoring transaminases alone 2