Natural History of Hepatitis C - Viral Hepatitis and Liver Disease
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Viral Hepatitis and Liver Disease


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Natural History of Hepatitis C

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Natural History - Hepatitis C


The natural history of hepatitis C virus (HCV) infection remains incompletely understood, in part due to differing research methods used to determine disease course across studies. There also seems to be variability in natural history between infected groups. For example, the risk of progression to cirrhosis after an estimated 20 years of HCV infection was approximately 22% in studies of patients from liver clinics, as compared with 4% in patients from cohort studies of transfusion of infected blood products.(1) In general, HCV infection is characterized by the following:

  • Frequent asymptomatic acute infection
  • Persistent infection following acute infection in 60-85% of those infected (2,3)
  • Persistently elevated or fluctuating ALT elevations*
    *Serum alanine aminotransferase (ALT) levels are elevated in approximately 60-70% of patients with chronic infection, indicating intrahepatic inflammation, but these levels are highly variable and may fluctuate over time. The remaining 30-40% of patients have persistently normal ALT values, with positive anti-HCV and HCV RNA results
  • Generally slow, but variable, disease progression

The average time from HCV exposure to seroconversion (detectability of anti-HCV antibody) is between 5 and 12 weeks.(2) HCV RNA is detectable within 1-2 weeks after exposure.

Diagnostic tools include(2,4)

  • tests for anti-HCV antibodies (serologic tests), including enzyme-linked immunoassay (ELISA) and recombinant immunoblot assay (RIBA)
  • tests for HCV itself (virologic tests), which include qualitative and quantitative polymerase chain reaction (qPCR) and branched DNA (bDNA) assay
    • In the veteran population, an ELISA test does not necessarily need to be followed with a confirmatory RIBA test unless the patient is in a low-risk category or has normal ALT levels. Instead, accurate confirmation of infection status is determined by qPCR, which, when positive, indicates viremia.
    • If a patient is ELISA positive but qPCR negative, a confirmatory RIBA may be used to determine whether the initial ELISA was a false positive or the patient has spontaneously cleared virus.
    • qPCR is also used to monitor patients on treatment, because the primary treatment endpoint is sustained virological response (SVR), defined as RNA negativity 6 months after interferon-based therapy has stopped.

Of patients exposed to HCV, 15-40% seem to clear the infection spontaneously, as evidenced by positive anti-HCV serology but negative HCV RNA and normal ALT levels.(2,3,5) Women and children may be more likely than men to clear the infection.(6,7,8) In recent years, acute HCV infection has been more readily identified due to increased screening in high-risk patients. In such cases, symptomatic patients seem to have rates of spontaneous clearance of 30-55%.(8,9,10) Genotype 3 infection may also be more readily cleared spontaneously than are other genotypes.(10)

Symptoms and Clinical Manifestations

Patients with chronic HCV may have nonspecific symptoms including fatigue and malaise. Disease course is slow, with the majority of patients showing few signs or symptoms during the first 20 years of infection.(3,5) Diagnosis of chronic HCV infection is often made when elevated ALT levels are detected during routine blood testing. HCV RNA is always detectable in any patient with chronic infection, but levels may also fluctuate, and may or may not be accompanied by ALT changes.(11) Additionally, serum HCV RNA can be present in patients with normal transaminases and minimal histological evidence of liver injury.

Extrahepatic Manifestations

Disease outside the liver due to HCV can be seen in some patients. Such HCV-associated conditions include:

  • diabetes mellitus
  • rheumatoid arthritis
  • keratoconjuctivitis sicca
  • mixed cryoglobulinemia
  • membranoproliferative glomerulonephritis
  • nephrotic syndrome
  • porphyria cutanea tarda

Although over a third of all HCV patients likely have detectable cryoglobulins, few develop clinical features of cryoglobulinemia.(12,13) Interferon-based therapies may be helpful in improving some forms of extrahepatic disease due to HCV, but their use needs to be individualized based on the individual condition.(14,15)

Factors Associated with Liver Disease Progression

Although the factors involved in the development and progression of chronic infection are incompletely understood, a number of studies have identified variables that contribute to progressive liver disease.

One frequently cited prospective study examined the relationship between fibrosis progression (defined as the ratio between the stage of fibrosis and the estimated duration of infection) and 9 possible contributory factors: gender, age at biopsy, infection duration, estimated age at infection, alcohol consumption, HCV genotype, level of HCV viremia, mode of acquisition, and histological activity score.(16) Of these potential contributory factors, 3 were independently associated with increased rates of fibrosis:

  • Age at infection >40 years
  • Male gender
  • Daily alcohol consumption >50 grams per day

Median time for progression to cirrhosis was 30 years. Among males over 40 years old who consumed more than 50 grams of alcohol per day, the mean time for progression to cirrhosis was 13 years. In contrast, among HCV-positive women less than 40 years old who consumed no alcohol, the mean time to cirrhosis was 42 years. Because of the variability in rates of progression, it has been suggested that there may be 3 outcome groups: rapid, intermediate, and slow fibrosers. Rapid fibrosers may progress to cirrhosis in 10-15 years, while slow fibrosers may not progress to cirrhosis despite many years of infection.(16) It is hypothesized that more severe liver injury among alcohol users is due to alcohol-induced enhancement of viral replication or increased susceptibility of cells to viral injury.(17)

Another factor that has become accepted as a contributor to fibrosis is fat within the liver (steatosis), which is felt to be either a marker of or a contributor to oxidative stress in the liver.(18,19) Steatosis is linked to obesity and type 2 diabetes mellitus, so control of these factors has also become accepted as having a role in limiting fibrosis in patients with HCV.

Hepatitis C Cirrhosis

Of concern is the presence of hepatic fibrosis that may progress to the development of cirrhosis. It is estimated that 20-30% of patients with chronic HCV infection will develop cirrhosis over the course of 20-30 years,(1,3,5,6) but that the majority will never progress to this stage. Cirrhosis is associated with portal hypertension and can also lead to the following complications:

  • Ascites
  • Encephalopathy
  • Variceal bleeding
  • Coagulopathy
  • Spontaneous bacterial peritonitis
  • Hepatocellular carcinoma (HCC)

Once patients have experienced one of these "decompensating events," their survival is impaired.

  • In one recent longitudinal study, 53% of a group of patients with hepatitis C-related cirrhosis decompensated during 6.5 years of follow-up. Once they decompensated, however, their subsequent 5-year survival without a liver transplant was only 28%.(20)
  • The 2 principal forms of decompensation in cirrhotic patients are the development of ascites and hepatocellular carcinoma, with rates of 2-5% and 1-4% per year, respectively, in patients with Child-Pugh class A cirrhosis.(21)
  • Estimating the outcomes of the nearly 4 million Americans with chronic HCV on the basis of current disease progression and Markov modeling, Davis and colleagues(22) project that the number of patients with cirrhosis will almost double between 2000 and 2030 (472,000 to 879,000), and liver-related deaths will more than triple during this time (13,000 to 39,875). They stress the importance of consideration of antiviral therapy in all patients and screening for hepatocellular carcinoma in cirrhotic patients as means to decrease these numbers.
  • Despite these findings, there is also evidence that, in some patients, cirrhosis may be present for decades with relatively few complications.(23)


Research continues to be performed to better understand the natural history of HCV infection and the variables that affect disease progression. Several features of the natural history of HCV infection can be incorporated into patient management. These include an understanding that:

  1. Rapid liver disease progression is not universal, and is affected by a variety of known and unknown factors.
  2. Uncertainty exists as to whether the disease progresses linearly in all patients.
  3. Predictive factors for disease progression include:
    • alcoholism
    • age greater than 40 years at infection
    • male gender
    • presence of fat (steatosis) within the liver
  4. HCV cirrhosis is common, and will become more of a problem over time, so aggressive attempts at HCV eradication and close follow-up of patients with cirrhosis are important management steps.


  1. Freeman AJ, Dore GL, Law MG, et al. Estimating progression to cirrhosis in chronic hepatitis C virus infectionLink will take you outside the VA website.. Hepatology 2001;34:809-816.
  2. Puoti M, Zonaro A, Ravaggi A, et al. Hepatitis C virus RNA and antibody response in the clinical course of acute hepatitis C virus infectionLink will take you outside the VA website.. Hepatology 1992;16:877-881.
  3. Centers for Disease Control and Prevention. Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCV-Related Chronic DiseaseLink will take you outside the VA website.. MMWR 1998;47 (No. RR-19):14.
  4. Pawlotsky JM. Use and interpretation of virological tests for hepatitis CLink will take you outside the VA website.. Hepatology 2002;36:S65-S73.
  5. Alter, MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994Link will take you outside the VA website.. N Engl J Med 1999;341: 556-562.
  6. Vogt M, Lant T, Frosner G, et al. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before implementation of blood-donor screeningLink will take you outside the VA website.. N Engl J Med 1999;341:866-870.
  7. Losasciulli A, Testa M, Pontisso P, et al. Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemiaLink will take you outside the VA website.. Blood 1997;11:4628-4633.
  8. Spada E, Mele A, Berton A, et al. Multispecific T cell response and negative HCV RNA tests during acute HCV infection are early prognostic factors of spontaneous clearanceLink will take you outside the VA website.. Gut 2004;53:1673-1681.
  9. Gerlach JT, Diepolder HM, Zachoval R, et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearanceLink will take you outside the VA website.. Gastroenterology 2003;125:80-88.
  10. Lehmann M, Meyer MF, Monazahian M, et al. High rate of spontaneous clearance of acute hepatitis C virus genotype 3 infectionLink will take you outside the VA website.. J Med Virol 2004;73:387-391.
  11. Nguyen TT, Sedghi-Vaziri A, Wilkes LB, et al. Fluctuations in viral load (HCV RNA) are relatively insignificant in untreated patients with chronic HCV infectionLink will take you outside the VA website.. J Viral Hepatitis 1996;3:75-78.
  12. Kayali Z, Buckwold VE, Zimmerman B, Schmidt WN. Hepatitis C infection, cryoglobulinemia, and cirrhosis: a meta-analysisLink will take you outside the VA website.. Hepatology 2002;36:978-985.
  13. Agnello V, DeRosa FG. Extrahepatic disease manifestations of HCV infection: some current issuesLink will take you outside the VA website.. J Hepatol 2004;40:341-352.
  14. Vassilopoulos D, Calabrese LH. Hepatitis C virus infection and vasculitis. Implications of antiviral and immunosuppressive therapiesLink will take you outside the VA website.. Arthritis Rheum 2002;46:585-597.
  15. Ramos-Casals M, Trejo O, Garcia-Carrasco M, Font J. Therapeutic management of extrahepatic manifestations in patients with chronic hepatitis C virus infectionLink will take you outside the VA website.. Rheumatology 2003;42:818-828.
  16. Poynard T, Bedossa P, Opolon P, for the OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Natural history of liver fibrosis progression in patients with chronic hepatitis CLink will take you outside the VA website.. Lancet 1997;349:825-32.
  17. Lieber CS. Hepatitis C and alcoholLink will take you outside the VA website.. J Clin Gastroenterol 2003;36:100-102.
  18. Hourigan LF, Macdonald GA, Purdie D, et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosisLink will take you outside the VA website.. Hepatology 1999;29:1215-1219.
  19. Monto A, Alonzo J, Watson JJ, et al. Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcoholLink will take you outside the VA website.. Hepatology 2002;36:729-736.
  20. Fattovich G, Pantalena M, Zagni I, et al. Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patientsLink will take you outside the VA website.. Am J Gastroenterol 2002;112:463-472.
  21. Bennett WG, Inoue Y, Beck JR, et al. Estimates of the cost-effectiveness of a single course of interferon-alpha 2b in patients with histologically mild chronic hepatitis CLink will take you outside the VA website.. Ann Intern Med 1997;127:855-865.
  22. Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic hepatitis C in the United StatesLink will take you outside the VA website.. Liver Transpl 2003;9:331-338.
  23. Niederau C, Lange S, Heintges T, et al. Prognosis of chronic hepatitis C: results of a large, prospective cohort studyLink will take you outside the VA website.. Hepatology 1998;28:1687-1695.