Natural History of Hepatitis C


Hepatitis C is a major cause of chronic liver disease worldwide and remains the leading indication for liver transplantation in the United States and western Europe. The epidemiological characteristics of chronic hepatitis C infection are evolving and leading to more advanced liver disease; this has significant implications for liver transplantation. Recent trends reveal an increasing prevalence of cirrhosis and hepatocellular carcinoma associated with hepatitis C. This chapter provides an overview of the hepatitis C virus (HCV), the natural history of chronic infection, and key issues related to liver transplantation.

Hepatitis C Virus

Although a virus was long suspected as the cause of a form of hepatitis not associated with either hepatitis A or hepatitis B, its identity was elusive and the hepatitis C virus was not identified until 1989. Nonetheless, the agent responsible for non-A, non-B hepatitis was well characterized before this time by careful observation of infectious isolates in humans and chimpanzees. The agent was known to be lipid encapsidated and approximately 40 nm to 70 nm in size. These characteristics were suggestive of an RNA virus, most likely of the Flaviviridae family. Eventually, blind cloning methods were able to identify a portion of the virus and assemble the complete 9.6-kb RNA genome, later named hepatitis C.

Several characteristics of HCV affect the natural history of the virus and our ability to treat it. The virus is a single-stranded RNA virus without the ability to proofread and correct errors during replication. It replicates entirely within the hepatocyte cytoplasm; there is no nuclear replication or viral genomic integration into host DNA. HCV replicates at an extremely high rate, producing up to 10 12 virions per day. As a result, considerable genomic heterogeneity occurs. It is mathematically estimated that every nucleic acid in the genome should mutate each day. Although most of these variants are not viable, the resulting viral heterogeneity likely contributes to escape from immune surveillance, survival of the virus within the host, and as discussed later, failure to respond to some antiviral therapies. Over time this heterogeneity has resulted in distinct populations of HCV known as genotypes, which may vary by up to 35% in nucleotide sequence. Currently there are six genotypes and over 100 subtypes. HCV genotypes differ not only in genetic composition but also in geographical distribution. Genotype 1 is the most prevalent in North America, South America, and western Europe. The distribution of other genotypes includes genotype 2, more commonly found in the Mediterranean and Asia; genotype 3 in Southeast Asia and India; genotype 4 in Africa and the Middle East; genotype 5 in South Africa; and genotype 6 in Southeast Asia and eastern Asia.

Pathogenesis

Early activation and mobilization of the cellular immune response directed toward HCV is pivotal in the early host response to acute infection and most likely in the rate of progression of the disease if chronic infection evolves. The CD4 + helper T cells appear to play a critical role in viral clearance following acute infection, in which a vigorous, multispecific, and durable CD4 + response is associated with a stronger likelihood of achieving spontaneous viral eradication. This appears to be at least partly related to polymorphisms near the IL28B gene locus because these correlate well with spontaneous clearance of acute infection. Although CD8 + cytotoxic T cells also contribute to viral clearance in the acute setting, their role is more significant after chronic infection is established, and they appear to be responsible for hepatocyte injury. In the setting of antiviral therapy, patients with higher levels of virus-specific cellular immunity may also be more sensitive to the antiviral effects of IFN-α. In immunocompromised patients, particularly those with exogenous immune suppression after transplantation, HCV replicates without cellular immune restraint and may become directly cytopathic to infected hepatocytes in some individuals. In these patients, virus levels are typically extremely high and immunochemical stains demonstrate large amounts of intracellular virus, resulting in a clinical picture of fibrosing cholestatic hepatitis.

Although the majority of acutely infected persons mount an antibody response to HCV within weeks of exposure, the presence of antibody does not appear to influence the outcome of infection and in fact persists in both chronic infection and after clearance of virus with antiviral therapy. The genomic heterogeneity associated with HCV may have a major role in allowing viral escape from the humoral immune response. Other proposed mechanisms of HCV immune evasion include dysfunctional homing of activated T cells to the liver, increased activity of regulatory T cells, impaired antigen presentation, viral mutational escape, or perhaps most importantly, inhibitory effects of the virus on the host innate immune response.

Incidence and Prevalence

Acute infection with HCV is usually asymptomatic and typically occurs unrecognized by the host. The incubation period ranges from 5 to 12 weeks ( Table 10-1 ). In the setting of acute infection, antibody to HCV may be undetectable during the initial period of infection in many patients, and assessment of serum HCV RNA should be performed to confirm the diagnosis. In cohorts acutely exposed to HCV, spontaneous recovery has been reported in 15% to 45% of cases and appears to be related to younger age, female sex, Asian ethnicity, and a favorable IL28B genotype. In contrast, the risk for chronicity in older adults and those with unfavorable IL28B genotypes may be as high as 80% to 85%. Spontaneous recovery should be assumed only if serum aminotransferase levels and HCV RNA remain normal and undetectable for at least 6 months after acute infection. It is important to recognize that serum alanine aminotransferase may return to the normal range and HCV RNA may transiently become undetectable in some patients who nonetheless go on to develop chronic infection.

TABLE 10-1
Characteristics of Hepatitis C Viral Infection
Acute Infection
Incidence (U.S.) 16,000 cases/yr
Incubation period 5-12 wk
Diagnosis HCV RNA by amplification
Spontaneous resolution 15%-45%
Chronic Infection
Prevalence United States: 3-4 million (1.8%)
Worldwide: 170 million (3%)
Diagnosis Anti-HCV, confirmatory HCV RNA by amplification
Risk for cirrhosis 20%-30% after 10-20 yr of infection
HCV , Hepatitis C virus.

Because progression to chronic infection may occur in the majority of adults following acute exposure, chronic HCV has emerged as a major cause of chronic liver disease. The worldwide prevalence of chronic infection is estimated to be at least 170 million persons (approximately 3%), although the prevalence varies greatly based on geography. In some regions such as West Africa, greater than 10% of the population may be chronically infected with HCV, likely as a result of iatrogenic spread associated with cultural and medical practices. In the United States about 4 million individuals (approximately 1.8%) have chronic hepatitis C.

The greatest prevalence of chronic HCV infection in western countries occurs within specific populations at risk. The incidence of acute HCV infection before the mid-1980s was extremely high, largely because of intravenous drug use and a high risk for transfusion-associated transmission. It has been estimated that 200,000 to 300,000 cases of acute hepatitis C occurred per year during the 1960s, mostly attributable to blood products, in which the incidence of acute hepatitis C following transfusion was as high as 33%. The overall incidence of transfusion-associated hepatitis decreased in the 1970s once a volunteer blood donor system was introduced in the United States and serological testing for hepatitis A and B viruses became available. However, transfusions continued to account for approximately 50% of reported cases of acute non-A, non-B hepatitis until more intensive screening of donor risk factors was introduced. The practice of heat inactivation of coagulation factors in 1987 and the widespread introduction of specific antibody screening for HCV in potential blood donors in 1992 virtually eliminated the risk for acquiring HCV infection through blood products. Now that third-generation antibody tests are required in blood donation centers, the risk for transfusion-associated HCV infection may be as low as 1 per 280,000 (0.00036%) units transfused in the United States. Nucleic acid testing in some blood banks has reduced the risk for hepatitis C to nearly zero.

Although the incidence of acute hepatitis C has fallen to approximately 16,000 cases per year, HCV remains the most common chronic blood-borne infection in the United States and accounts for up to two thirds of newly diagnosed cases of chronic liver disease. Injection drug use remains the most frequent means of HCV transmission in the United States; the seroprevalence of antibody to HCV in this group may rise to over 70% within 3 to 5 years of habitual exposure. More than two thirds of acute infections with HCV involve easily identifiable risk factors ( Table 10-2 ). Other groups known to be at risk for exposure to HCV include hemodialysis patients, hemophiliacs, and individuals infected with human immunodeficiency virus (HIV). Current recommendations for identifying individuals who would benefit from hepatitis C screening include these groups ( Table 10-3 ) ; however, it is estimated that 50% to 75% of persons with chronic infection in the United States are not aware they are infected. In light of these emerging data and the availability of more effective antiviral therapy, screening strategies have evolved to more adequately identify individuals who have yet to be diagnosed with chronic HCV, most of whom were born between 1945 and 1965. Based on these data, the Centers for Disease Control and Prevention (CDC) has proposed widespread screening of individuals included in this baby boomer birth cohort.

TABLE 10-2
Exposures Associated with Acute Hepatitis C in the United States (1994-2006)
Risk Factor Reported Frequency (%)
Injection drug use
HCV-positive sex partner
Health care worker and blood exposure
Multiple sex partners
Blood transfusion
HCV-positive household contact
Aggregate risk category
No risk factor identified
46.7
10.7

3.3
3.3
1.9
1.5
3.7
29.3

Based on report from national surveillance program assessing risk factors for exposure within 6 months of acute HCV presentation (n = 2075).
HCV , Hepatitis C virus.

Includes both known and suspected HCV positivity.

Circumstances in which the individual acknowledged an exposure risk but would not specify the category.

TABLE 10-3
Persons Recommended for Hepatitis C Virus Screening
Data from references .
Persons with elevated liver enzyme levels
Injection drug users or persons with history of injection drug use
Persons with HIV infection
Persons with hemophilia
Hemodialysis patients
Recipients of clotting factors or other blood products before 1987
Recipients of solid organ transplants before 1992
Recipients of blood transfusions before 1992
Children born to HCV-positive mothers
Sexual partners of HCV-infected individuals
Persons with any known potential exposure via HCV-positive blood donor, organ donor, or occupational exposure
Persons born between the years 1945 and 1965
HCV , Hepatitis C virus; HIV , human immunodeficiency virus.

As proposed by the Centers for Disease Control and Prevention: Proposed recommendations for the identification of HCV chronic infection among persons born during 1945 through 1965 , reviewed and updated May 18, 2012. http://www.cdc.gov/hepatitis/HCV/BirthCohortTesting.htm . Accessed June 10, 2012.

Progression to Cirrhosis

It has been estimated that 20% to 30% of individuals with chronic HCV develop cirrhosis after 10 to 20 years of infection ( Fig. 10-1 ). The duration of infection with HCV is perhaps the most important factor associated with progression to cirrhosis ( Table 10-4 ). Most patients who develop cirrhosis have had infection for more than 20 years. In the year 2000 approximately 30% of patients with chronic hepatitis C had a history of infection for at least this long. It is now estimated that more than half of patients have had infection for more than 2 decades, a proportion expected to increase as the cohort with chronic infection ages. This has obvious and significant implications for the prevalence of cirrhosis in the infected population. Mathematical models estimate that the proportion of infected patients with cirrhosis will approach 50% by 2030 ( Table 10-5 ), and the prevalence of complications of cirrhosis such as liver failure and hepatocellular carcinoma will also increase. In the decade from 2000 to 2010, the prevalence of cirrhosis and decompensation associated with HCV doubled and hepatocellular carcinoma increased 20-fold. As a consequence, annual liver-related deaths attributed to chronic HCV (liver-related death and carcinoma) could more than nearly triple between 2000 and 2020 ( Table 10-6 ). Indeed, the mortality rate attributed to hepatitis C based on death certificate data in the United States doubled over the decade from1995 at 1.09 deaths per 100,000 persons to 2.44 deaths per 100,000 in 2004.

FIGURE 10-1, Natural history of hepatitis C virus infection.

TABLE 10-4
Risk Factors for Fibrosis Progression in Chronic Hepatitis C
Duration of infection
Degree of hepatic inflammation
Presence of hepatic fibrosis
Heavy alcohol intake
Age greater than 40 years
Male sex
Obesity
Hepatic steatosis
Coinfection with HIV; CD4 + T cell counts < 500 cells/μL
Coinfection with hepatitis B virus
HIV , Human immunodeficiency virus.

TABLE 10-5
Projected Prevalence of Cirrhosis Among Persons with Chronic Hepatitis C
From Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology . 2010;138:513-521.
Year Prevalence (%)
1989
1998
2006
2010
2020
2030
5
10
20
24.8
37.2
44.9

TABLE 10-6
Projected Impact of Chronic Hepatitis C Based on Complications and Associated Mortality
Projections from Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology . 2010;138:513-521; numbers rounded to closest 100.
Year
2000 2010 2020 2030
Prevalence
Chronic hepatitis C 3,560,800 3,385,700 2,805,500 1,826,000
Cirrhosis, all 413,200 838,200 1,043,300 819,100
Decompensated cirrhosis 44,900 99,700 143,800 124,100
Annual Incidence
Hepatocellular carcinoma 6,200 11,700 13,700 9,900
Liver-related deaths 10,000 21,000 29,200 24,500

The rate of progression to cirrhosis is highly variable and is influenced by several factors in addition to duration of HCV infection (see Table 10-4 ). These include heavy alcohol intake, fatty liver disease, obesity, male sex, age greater than 40 years, hepatitis B coinfection, and HIV coinfection with low CD4 + T-cell counts. Alcohol consumption is an important risk factor associated with a more rapid progression of hepatic fibrosis and is entirely preventable. The relative risk for cirrhosis increases at least threefold among regular alcohol consumers with chronic HCV. The presence of fibrosis on liver biopsy is also a risk factor because patients with periportal or bridging fibrosis demonstrate a more rapid progression to cirrhosis compared to those with minimal or only portal fibrosis. Viral factors such as serum HCV RNA level or HCV genotype do not appear to contribute to disease progression.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here