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Hepatitis C virus (HCV) infections pose a growing challenge to health care systems. Although chronic HCV infection begins as an asymptomatic condition with few short-term effects, it can progress to cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC), and death. The rate of new HCV infections is decreasing, yet the number of infected people with complications of the disease is increasing. In the United States, people born between 1945 and 1964 (baby boomers) are developing more complications of infection. Men and African Americans have a higher prevalence of HCV infection. Progression of fibrosis can be accelerated by factors such as older age, duration of HCV infection, sex, and alcohol intake. Furthermore, insulin resistance can cause hepatic steatosis and is associated with fibrosis progression and inflammation. If more effective therapies are not adopted for HCV, more than 1 million patients could develop HCV-related cirrhosis, hepatic decompensation, or HCC by 2020, which will impact the US health care system. It is important to recognize the impact of HCV on liver disease progression and apply new therapeutic strategies.

Introduction

Approximately 180 million people worldwide are infected with hepatitis C virus (HCV) and are at risk of developing serious hepatic complications such as cirrhosis, hepatocellular carcinoma (HCC), or decompensation. In the United States, HCV-related end-stage liver disease is the most common indication for transplantation, and HCV markers are frequently found in cases of HCC. Although some data suggest that hepatitis C does not increase overall mortality, it has been postulated that HCV infection could result in an 8- to 12-year reduction in life expectancy. It is estimated that HCV caused more than 86,000 deaths in the European region in 2002. The prevalence of hepatitis C–related cirrhosis and its complications is expected to continue to increase through the next decade. In addition, demographic changes are expected to result in an increasing incidence of severe HCV-related liver disease as the population ages.

Various estimates of HCV prevalence in the US population place the number of infected individuals (as defined by anti-HCV antibody positivity) at between 4.1 and 5 million. Of these, 3.2–3.4 million are chronically infected. During the first 10–20 years of infection HCV-infected individuals generally experience asymptomatic or mild illness, which explains why an estimated 75% of infections remain undiagnosed in the United States. Despite a decline in the number of new US cases of HCV infection from a peak of an estimated 262,000/year in 1986 to 17,000/year in 2007, the prevalence of individuals infected with HCV for more than 20 years is expected to continue to increase until 2015. In the National Health and Nutrition Examination Survey (NHANES; 1999–2002), patients aged 40–49 years accounted for 66% of American HCVinfected patients, and the prevalence of HCV infection in the United States was 2.7 times higher among 40- to 49-year-olds than the general population. This "baby boomer" generation is particularly susceptible to blood-borne HCV transmission as a result of an increased lifetime risk of injection drug use (IDU), blood transfusion before 1992, or sexual activity with =20 partners, compared with older or younger patients. The prevalence of HCV infection varies by age, sex, and race/ethnicity, and early identification of at-risk individuals through routine questioning by clinicians is critical, because management options are limited in late-stage disease.

After 30 years of infection, an estimated 15%–35% of patients will develop cirrhosis (5-year survival, 75%–80%); after 40 years, up to 60% could have cirrhosis. Given the high prevalence of HCV infection among 40- to 49-year-olds and that Americans are now expected to live into their mid-70s or beyond, the incidence of complications of HCV infections can be expected to further increase in coming years. In fact, from 1995–2004, US HCV-related mortality already increased 123% from 1.09/100,000 to 2.44/100,000 persons, although this study has some limitations. Furthermore, the proportion of CHC patients in the United States with cirrhosis is projected to rise from 25% in 2010 to 45% in 2030. Projections also estimate that without effective treatment, the annual number of US patients with cirrhosis, hepatic decompensation, or HCC will roughly double by 2020, and liver-related deaths will almost triple.  Although not all data agree with these estimates, several studies have suggested that HCV infection could have a deleterious effect on population mortality rates and life expectancy. HCV increased the risk of death in several analyses, irrespective of comorbidities such as coinfection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV) and even after adjustment for alcohol consumption. Furthermore, numerous studies and a Cochrane review indicated that achievement of an SVR through effective antiviral therapy can significantly reduce mortality in patients with chronic HCV. If all HCV-infected patients were treated with currently available treatment in 2010, liver-related HCV-associated deaths could be reduced by 36% by 2020, whereas antiviral treatment rates are currently declining. Improvements in diagnosis and treatment are therefore necessary to reduce the associated public health burden.


Individuals with CHC are at increased risk of liverrelated morbidity and mortality. HCV infection was associated with 27% of all US liver transplants performed in 2007, and US-based studies demonstrated that up to 51%–55% of HCC patients have anti-HCV antibodies. There is also a link between steatosis and liver fibrosis in HCV-infected patients, as well as a potential association between HCV infection and HCC or, as described more recently, of intrahepatic cholangiocarcinoma (ICC). In some ethnic groups such as Latinos the course of HCV infection is more aggressive, with a higher risk of cirrhosis than other ethnic groups. Furthermore, disease progression is more rapid in patients who are coinfected with HCV and HIV. Coinfected patients have approximately double the risk of cirrhosis or decompensation than those infected with HCV alone.


Fibrosis and Cirrhosis

Progressive hepatic fibrosis leading to cirrhosis is the major complication of chronic HCV infection and accounts for almost all HCV-related morbidity and mortality. Early studies suggested little, if any, fibrosis progression during the first decade of infection, followed by a slow, regular progression during the next 15 years, increasing to an intermediate rate during the subsequent decade. In a German cohort study of 1833 women infected with HCV-contaminated immunoglobulin, 0.5% of patients developed cirrhosis after 25 years. Similarly, in a study of 376 HCV-infected women conducted by the Irish Hepatology Research Group, 51% of patients had fibrosis after 17 years, but only 2% had probable/definite cirrhosis. These estimates of cirrhosis rates are considerably lower than those from the US multicohort study and the widely cited US military study (approximately 35%). Fibrosis outcomes of 184 women from the same cohort were followed up for the subsequent 5 years; 49% showed no change in fibrosis, 24% showed regression, and 27% showed progression.

Recent data reinforce the potential for severe liver disease to develop in some patients. Among 485 plasma donors infected during the early 1970s, 34% had stage F3/F4 fibrosis (bridging fibrosis), cirrhosis, or HCC after 31 years; their 35-year cumulative survival was 84% versus 91%–95% for the general population. Similarly, a study of 300 black and white Americans with untreated HCV infection found that 29% of patients had stage F3/F4 fibrosis after 20 years, and 4.7% had confirmed cirrhosis. It should be noted, however, that these studies could have selected patients with severe disease.

The nonlinear progression of fibrosis was recently confirmed in a meta-analysis of 111 HCV studies. The mean annual stage-specific transition probabilities were 0.117 for stage F0 to F1, 0.085 for F1 to F2, 0.120 for F2 to F3, and 0.116 for F3 to F4. Although the estimated prevalence of cirrhosis was 16% after 20 years, there was wide variation between studies, suggesting that fibrosis is a highly unpredictable process.

Infection duration is a major risk factor for severe fibrosis, with the progression rate in a 50-year-old being almost 3 times that in a 20-year-old. Age at time of infection is also important. In a biopsy analysis of 247 treatment-naïve HCV patients, progression rates were 0.13, 0.14, 0.27, and 0.36 fibrosis units/year for patients aged =19, 20–24, 25–36, and >36 years at infection, respectively. Age >36 years (vs =36 years) at time of infection was independently associated with faster progression. Men infected before age 50 have been identified as comprising the majority of cases of cirrhosis today (73.6%), whereas men aged >50 years when infected have faster disease progression compared with other age groups.

Several other factors, including sex, baseline fibrosis, HCV genotype, HIV/HBV coinfection, and alcohol consumption, also influence fibrosis progression. Identifying these factors can be useful when determining prognosis and advising patients on minimizing liver damage. Indeed, a recent study suggested that HCV genotype 3 might pose a particularly high risk of progressive fibrosis. Insulin resistance has been linked with fibrosis, and several studies have reported that this relationship remains significant, irrespective of HCV genotype. In addition, serum aminotransferase level elevations and the degree of hepatocellular necrosis/inflammation on biopsy have been found to predict fibrosis progression. Genetic factors might also play a role in fibrosis progression. Recent data indicate that the cirrhosis risk score, which is based on the association of 7 host genes, might help to differentiate HCV patients at high versus low risk of progressing toward cirrhosis, including those with early or mild CHC. Steatosis has also been linked to fibrosis progression, as has regular cannabis use. There is evidence of an association between cigarette smoking and hepatitis fibrosis, but not all studies have verified such an association.


Hepatocellular Carcinoma

The greatest increase in US cancer deaths from 1995–2004 was in those caused by cancers of the liver and bile duct, of which HCC comprised about 76%. This might be attributed to the increasing incidence of HCV-related HCC because rates for HBVrelated and alcohol-related HCC have remained stable during recent years. The incidence of HCV-related HCC in the United States is projected to peak in 2019 at 14,000 cases/year. In a large US database, the proportion of HCV-related cases of HCC among HCC patients aged =65 years doubled from 11% in 1993–1996 to 21% in 1996–1999. During the past decade, the fastest increase in HCC incidence has affected Hispanics and whites. In multivariate analysis HCV infection was an independent predictor for the development of HCC. Furthermore, maintenance therapy with peginterferon did not reduce the 5-year incidence of HCC in the HALT-C cohort.

Comparisons of US and Japanese HCV strains suggest that the US HCV epidemic began about 2 to 3 decades after that in Japan. This has led to speculation that the burden of HCC in the United States might eventually equal that currently seen in Japan as HCV-infected individuals age and their infection duration increases. In Japan, HCV-related HCC accounts for 80% of all HCC cases, and the rate of HCC among HCV-infected men has risen from 17.4/100,000 in 1972–1976 (32,335 deaths) to 27.4/100,000 in 1992–1996 (109,365 deaths).

A recent Italian study of 214 HCV-infected patients with Child–Pugh class A cirrhosis showed that HCC developed at a rate of almost 4%/year. HCC was the first complication to occur in 55 (27%) patients; after 17 years, HCC had developed in 68 (32%) patients. In another cohort of 416 patients with uncomplicated Child–Pugh class A HCV-related cirrhosis, the incidence of HCC was 13.4% at 5 years, and the 5-year HCC death rate was 15.3%, with the hazard rate of HCC tending to increase over time.

Several factors influence the risk of HCC in patients with HCV-related cirrhosis. Generally, HCC risk is increased in patients aged >50 years or those infected when aged >50 years, patients with longer duration of infection, men, overweight or diabetic patients, and patients with advanced cirrhosis or elevated alpha-fetoprotein. Other possible risk factors include the presence of steatosis, HCV genotype 1b, Asian/African American race, and occult HBV infection. As for hepatic fibrosis, an association between cigarette smoking and HCV-related HCC has been suggested in some studies but not others.

Chronic HCV-related inflammation might increase HCC risk by shifting hepatocytic transforming growth factor– beta signaling from tumor suppression to fibrogenesis. HCC generally develops after cirrhosis is established, signifying the likely importance of long-standing necrosis and regeneration, an environment of extensive scarring, in its pathogenesis. HCV might influence hepatocarcinogenesis through the oncogenic effects of its core protein, which might augment oxidative stress. It might also alter the signaling cascade of mitogen-activated protein kinase and activating factor 1, thereby activating cellcycle control. Liver angiogenesis and the neovascular response, plus genomic changes that deregulate components of the Jak/STAT pathway in early carcinogenesis, might also promote HCV-related hepatocarcinogenesis. Additional mechanisms have also been proposed.


Cholangiocarcinoma

Various small studies have demonstrated a link between HCV and ICC. A recent large cohort study of >140,000 HCV-infected military veterans showed a >2-fold increase in ICC risk in HCV-infected patients versus noninfected controls. However, many of these hospital-based, case-control studies are limited by the potential for selection or ascertainment bias, and some studies have failed to observe any association between HCV and ICC.The association of HCV infection with susceptibility to ICC, and the pathogenetic basis for such an association, warrant further investigation. Chronic HCV infection was not a risk for extrahepatic cholangiocarcinoma (ECC).


Decompensation

Patients with HCV-associated cirrhosis are at high risk of developing hepatic decompensation, manifesting as hepatic synthetic dysfunction or complications of portal hypertension. Clinical signs of decompensation include ascites, encephalopathy, and upper gastrointestinal hemorrhage caused by variceal bleeding.

In an analysis of data from 1000 HCV patients with mild to advanced fibrosis, the incidence of decompensated cirrhosis after 5–7 years of follow-up was 43.5/10,000 person-years or about 1 in 230 patients/year. Similarly, a retrospective study reported the 5-year risk of decompensation to be 18% in 384 HCV patients with compensated cirrhosis (incidence, 3.9%/year), and a recent estimate suggests decompensation is currently present in 11.7% of CHC patients with cirrhosis. Decompensation has become more common since 1995, and because the proportion of CHC patients with cirrhosis is expected to increase through 2030, the incidence of decompensation can be expected to increase accordingly. It should be noted, however, that this model estimates that the majority of cirrhotic patients with chronic HCV infection will not develop decompensation during the first 3 decades of infection. Annual incidence rates for ascites (2.9%), jaundice (2.0%), upper gastrointestinal bleeding (0.7%), and encephalopathy (0.1%) were established in a later prospective study of 214 HCV-RNA seropositive patients after 114 months of follow-up.

Age at HCV acquisition is relevant, with decompensation risk as high as 133/10,000 person-years in patients infected after 39 years of age. In addition, the presence of the human leukocyte antigen DRB1*1201–3 allele might be associated with a higher rate of progression toward decompensated cirrhosis and HCC. The identification of reliable proteomic/genomic markers for risk of advanced HCV-related liver disease would aid prognostication and therapeutic decision-making.


Steatosis

Steatosis occurs to some degree in about half of all patients with chronic HCV infection. In a meta-analysis of data from >3000 patients, steatosis was independently associated with the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, overweight (body mass index >25), age =45 years, and genotype 3 infection. Among 101 HCV-infected patients with no factors predisposing to fatty liver, steatosis was found in 41% of patients, irrespective of sex, age, or infection route.

Two main mechanisms underlie the pathogenesis of steatosis in HCV-infected patients who abstain from alcohol, a direct viral effect and a metabolic mechanism. Viral steatosis is associated with genotype 3 HCV infection, where the severity of steatosis correlates with serum and intrahepatic viral load. This type of steatosis often resolves after viral eradication. It is believed that HCV genotype 3 has a direct effect on hepatocyte lipid metabolism, resulting in fat accumulation. Interactions involving the HCV genotype 3 core protein, such as enhanced fatty acid synthase promoter activation and increased lipid affinity, are being investigated in vitro.

Metabolic steatosis is seen primarily in patients infected with genotype non-3 HCV and is largely due to insulin resistance, characterized by hyperinsulinemia and free fatty acid overflow to organs and non-adipose tissues. These alterations give rise to triglyceride accumulation in hepatocytes, resulting in steatosis.

Steatosis might reduce the likelihood of achieving SVR with HCV treatment, even when other steatosis-inducing factors are accounted for. In one study, SVR rates were 18%–32% lower in people with steatosis versus those without steatosis after adjusting for other potentially confounding cofactors such as genotype, fibrosis score, and viral load.

About 85% of HCV-positive persons in the United States general population can be identified on the basis of 3 characteristics: IDU history, blood transfusion before 1992, or abnormal serum alanine transaminase levels. In selected populations, other characteristics might also be useful for screening. A retrospective study of 5400 US veterans found that the following factors predicted HCV infection: IDU, blood transfusion before 1992, service during the Vietnam war, tattoo, and a history of abnormal liver test results. However, HCV risk factor histories are rarely documented in clinical practice. Infected patients can thus remain undiagnosed until they present with hepatic complications.

The impact of HCV infection on the burden of liver disease is becoming evident as individuals unknowingly infected decades ago age and develop severe sequelae of advanced liver fibrosis. Up to 1 million Americans are predicted to develop HCV-related hepatic complications during the next 2 decades. Persons born between the 1940s and 1960s account for most infections, with the highest risk among those with a history of IDU or blood transfusions before 1992. Once chronic infection is established, disease progression is variable and dependent on several factors. Cirrhosis, liver failure, and HCC might occur at a faster rate and in more patients than previously believed.