Written by Linda McInnes
The natural history of hepatitis C virus infection begins with a generally unrecognized acute phase occurring during the initial 6 months following exposure to the virus. Acute infection may resolve spontaneously during that time, but the majority of cases progress to chronic infection. The key features of acute and chronic hepatitis C virus infection are reviewed in this section.
Primary Infection and Acute Hepatitis C
Primary infection with hepatitis C virus (HCV) is mostly asymptomatic, rendering its timely diagnosis difficult. Furthermore, some patients may be reluctant to seek medical consultation because this may involve admitting habits leading to infection, such as illicit drug use. As a result, the true incidence rate is underestimated.[Armstrong 2000; CDC 2007] Because there are no specific markers of primary HCV infection, it is diagnosed via a documented seroconversion to anti-HCV in a person who was previously anti-HCV negative, with or without an increase in alanine aminotransferase (ALT) levels. In most Western countries, when underreporting and asymptomatic cases are factored in, incidence rates may reach 15 per 100,000 per year.[Armstrong 2000] Incidence has declined during the past 20 years owing to generalized screening of blood donors and prevention measures among injection drug users. Currently, in the West, injection drug use is by far the most important factor associated with HCV transmission, although sexual transmission has recently emerged as a strong risk factor among HIV-infected men who have sex with men.[van de Laar 2010] In resource-limited countries, a high proportion of infections occur following invasive procedures or injection-based therapies with contaminated instruments.[Hauri 2004]
For more information from in Practice on transmission of HCV, click here.
Following HCV exposure, HCV RNA cannot be detected in serum until after a 1- to 3-week window (Table 8).[Santantonio 2008] The most common symptoms, when present, are fatigue, jaundice, flulike symptoms, dyspepsia, and abdominal pain, and may occur 2-12 weeks after exposure. Because most symptoms are mild and not specific, patients often do not report to their physicians. The first sign of liver injury may be evident 4-12 weeks after infection in the form of an elevated ALT level. Wide fluctuations of serum ALT are common, but severe liver damage is infrequent, and in general ALT peaks below 1000 IU/L. A fulminant course is very rare. Seroconversion may take place 4-10 weeks following HCV exposure.
Table 8. Most Common Signs and Symptoms of Acute Hepatitis C (If Present)
|Time Frame, Wks from exposure||Symptoms|
Acute hepatitis C has a high propensity to progress to chronicity. Chronic infection with HCV is defined by viremia persisting more than 6 months. The risk of chronicity ranges between 55% and 85%.[McHutchison 2004; Seeff 2002] However, this risk has been assessed in prospective studies in which symptomatic cases were prevalent; because a symptomatic course may be associated with increased likelihood of spontaneous resolution,[Gerlach 2003] when asymptomatic primary infections are considered, the progression to chronicity is likely to occur in the vast majority of cases. Spontaneous remission following the establishment of chronic HCV infection rarely occurs among adults,[Yoshikawa 2001] but has been reported to occur in 8% to 45% of children.[Fujisawa 1997; Iorio 2005; Vogt 1999] Table 9 lists chronicity rates by subgroup from several studies.
Spontaneous resolution most often occurs during the first 3 months of infection.[Santantonio 2006] Apart from the presence of symptoms, other factors favoring spontaneous eradication of HCV infection are host genes (IL28B polymorphisms)[Thomas 2009] and the vigor of the cellular immune response.[Santantonio 2008] Coinfection with HIV seems to hinder resolution.[Schnuriger 2009; Danta 2008] The role of the type of exposure, size of inoculum, age, sex, and previous exposure to HCV with subsequent recovery is controversial. An important aspect is that eradication, either spontaneous or treatment induced, does not confer protection, and patients (especially those with high-risk behavior) should be advised that HCV reinfection may occur.
Table 9. HCV Chronicity Rates by Subgroup
|Study and Subgroup||HCV Chronicity Rate, %|
|Gerlach et al[Gerlach 2003]|
|Danta et al[Danta 2008]|
|Thomas et al[Thomas 2009]|
Chronic Hepatitis C
Chronic hepatitis C is a progressive disease, taking decades to reach the final stage of cirrhosis. The latter then may evolve toward liver failure or hepatocellular carcinoma (HCC) (~ 2% to 4% yearly) (Figure 5). The variability of progression is remarkable and influenced by several cofactors; it is indeed the combination of these factors that accounts for the extreme diversity of liver disease progression observed in chronic hepatitis C.[Poynard 1997] For example, females infected with hepatitis C virus (HCV) at a young age who did not drink alcohol developed cirrhosis in a very small proportion of cases (2%) 25 years after infection.[Wiese 2005] By contrast, 17% of males who acquired HCV via blood transfusion later in life developed cirrhosis after a comparable follow-up.[Seeff 2001]
A review of factors involved in liver disease progression among patients with chronic hepatitis C are outlined in Table 10.
The most important factor influencing liver disease progression is the extent of intrahepatic inflammation elicited by HCV.[Leandro 2006] In keeping with this finding, patients with persistently normal alanine aminotransferase (ALT) present a slow liver disease progression,[Mathurin 1998] although a small minority of them may have advanced liver disease.
Serum HCV RNA level is not associated with prognosis, at variance with other viral infections.[Bochud 2009] However, there is some evidence that genotype 3 is associated with accelerated fibrogenesis.[Bochud 2009] The risk of developing HCC was reported to be higher in HCV genotype 1b infection relative to other genotypes in a meta-analysis.[Raimondi 2009] However, other studies have not supported this association.[Yotsuyanagi 1995; Yamada 1994; Benvegnù 1997; Han 1997]
Host factors are much more relevant in determining the progression of HCV-related liver disease. Male sex is associated with accelerated fibrogenesis and HCC incidence.[Bochud 2009; Chiba 1996] However, with the onset of menopause, the rate of fibrosis progression increases substantially in women.[Di Martino 2004] Estrogen replacement therapy and the number of pregnancies may protect women from liver fibrosis progression.[Di Martino 2004] The contribution of host genes is debated and has not been clarified with the advent of powerful methods of analysis such as genomewide association studies, underscoring the multifactorial nature of liver fibrogenesis. Candidate gene–based studies have proposed single nucleotide polymorphisms or their combinations to identify patients at higher risk of progression.[Marcolongo 2009] However, the contribution of such genetic signatures seems small and overshadowed by more important cofactors. Whether race affects fibrosis progression rate is also a matter of debate. A study assessing the fibrosis progression rate in black vs white Americans failed to show a significant difference.[Terrault 2008] Age at infection affects prognosis,[Poynard 1997; Minola 2002] as persons infected with HCV at a young age, including children[Rerksuppaphol 2004] and young females,[Wiese 2005] have a reduced risk of progressing to cirrhosis, at least for the first 1-2 decades. For subsequent time points, one must keep in mind that the rate of progression is not linear and that stage-specific rates should be applied in formulating prognosis.[Poynard 2001; Thein 2008a]
Environmental factors play a major role in liver disease progression among patients infected with HCV. The most important is excessive alcohol consumption, which impacts both fibrosis progression and risk of HCC.[Poynard 1997; Tagger 1999] Tobacco smoking has been shown to be associated with increased intrahepatic inflammation (histologic activity score), which in turn was associated with increased fibrosis score.[Hézode 2003] In chronic hepatitis C, this effect seems relevant, especially for cannabis smoking.[Hézode 2005] On the other hand, several studies have shown the protective effect of coffee on both fibrosis[Freedman 2009] and HCC.[Ohishi 2008]
A worrying synergism exists between hepatitis C and the metabolic syndrome, considering the evolving epidemiology of both diseases.[Kanwal 2011] Steatosis,[Leandro 2006; Pekow 2007] insulin resistance,[Hui 2003; Hung 2010] and type 2 diabetes[Hu 2009; Veldt 2008] increase liver fibrosis progression and risk of HCC. Among metabolic disturbances, iron overload is also associated with advanced fibrosis.[Bonkovsky 2003] Coinfections are relevant due to their prevalence and synergistic effects on HCV-related morbidity. Although the effect of coinfection with the hepatitis B virus (HBV) on fibrosis is unclear, the risk of HCC in patients coinfected with HCV and HBV is significantly increased.[Tagger 1999] Large meta-analyses have confirmed that liver fibrosis progression is accelerated in patients coinfected with HIV.[Thein 2008b; Deng 2009] Control of HIV replication and immune restoration by highly active antiretroviral therapy does not seem to completely reverse this effect.[Thein 2008b]
Liver disease progression is accelerated after liver transplantation relative to nontransplant patients; a variety of diverse factors may be associated with accelerated posttransplantation fibrogenesis.[Meriden 2010]
Figure 5. Natural history of HCV infection.
[McHutchison 2004; Seef 2002; Liang 2000; Fattovich 1997]
Table 10. Relationship Between Patient Factors and Liver Disease Progression
|Factor||Impact on Liver Disease Progression|
|Intrahepatic inflammation||Greater inflammation equates to greater disease progression; persistently normal ALT levels represent slower disease progression in most, but not all, cases|
|HCV RNA level||Not associated with disease progression*|
|HCV genotype||Genotype 3 appears to be associated with accelerated fibrogenesis;|
risk of HCC development highest with genotype 1b
|Patient sex||Male sex associated with accelerated fibrogenesis and HCC incidence|
After onset of menopause, rate of fibrosis progression increases in women
|Alcohol consumption||Increased risk of progression and HCC development|
|Tobacco smoking||Associated with increased intrahepatic inflammation and in turn with increased fibrosis|
|Coffee consumption||Protective against fibrosis progression and HCC|
|Metabolic syndrome||Steatosis, insulin resistance, and type 2 diabetes increase liver fibrosis progression and HCC risk|
|Iron overload||Increased fibrosis progression|
|HBV coinfection||Increased risk of HCC development|
|HIV coinfection||Increased fibrosis progression|
|Liver transplantation||Increased disease progression|
*HCV RNA level was associated with spontaneous remission of chronic HCV infection among children in 1 study.[Fujisawa 1997]