Hepatitis C

What is hepatitis C?

Hepatitis C virus (HCV) was identified in 1989 when the genome of the virus was cloned. It is a single-stranded RNA virus that belongs to the Flaviviridae family. Like many RNA viruses, HCV has an inherently high mutational rate that results in considerable genomic heterogeneity. Six distinct but related HCV genotypes and molecular subtypes have been identified. In the United States and Western Europe, genotypes 1a and 1b are most common (75% of cases), followed by genotypes 2 and 3. Genotype 4 is found in Egypt, genotype 5 in South Africa, and genotype 6 in southeastern Asia. Knowledge of the genotype is important because it has predictive value in terms of the response to antiviral therapy. In general, antiviral therapy response is better in genotypes 2 and 3 than with genotype.
What is the incidence and prevalence of HCV infection?

Infection with HCV is the most common cause of chronic viral hepatitis in the Western world and ranks only slightly below chronic alcoholism as a cause of cirrhosis, end-stage liver disease, and hepatocellular carcinoma in the United States. The worldwide seroprevalence of HCV infection is estimated to be 1% (170 million people). However, marked geographic variation exists, from 1.8% in North America to 9.6% to 13.6% in North Africa. The actual number infected with HCV may be underestimated because high-risk groups (incarcerated, institutionalized, and homeless persons) are not included in most prevalence studies.

After the introduction of anti-HCV screening of blood donors in 1991, transfusion-related cases of HCV declined significantly. The prevalence of HCV infection in injection drug users remains high (48% to 90%), and this population is an important reservoir of the disease. According to the Centers for Disease Control and the National Health and Nutrition Examination Survey, it is estimated that 3 million people in the United States have chronic HCV infection, with about 36,000 new cases per year. These data likely underestimate the actual incidence of HCV infection because most patients are asymptomatic and have not sought medical attention. Since most patients with chronic HCV infection have yet to be diagnosed but are likely to seek medical attention in the next decade, a fourfold increase in the number of adults diagnosed with chronic HCV infection is projected from 1990 to 2015. The frequency of patients presenting with complications associated with HCV infection is expected to triple within the next 20 years, bringing with it a 61% increase in cirrhosis, a 279% increase in decompensated liver disease, and a 528% increase in the demand for liver transplantation.
How is the hepatitis C virus transmitted?

The modes of transmission of HCV infection can be divided into percutaneous, including blood transfusion and needlestick inoculation, and nonpercutaneous, including sexual contact and perinatal exposure. The majority of patients currently infected with HCV in the United States and Europe acquired the disease through intravenous drug use or blood transfusion. Until recently, blood transfusion posed the major risk of HCV infection in developed countries. Screening blood donors with the use of highly sensitive assays has reduced the risk of transfusion-related hepatitis to less than 0.5% per patient.

Currently, more than 60% of newly acquired infections occur in patients who have injected illegal drugs during the six months prior to disease onset. Infection has also been associated with a history of intranasal cocaine use, presumably due to blood on shared straws.

Needlestick injuries in the health care setting continue to result in nosocomial transmission of the virus. Seroconversion rates of about 2% have been documented in longitudinal studies of health care workers with needlestick exposures to HCV-positive patients. The size of the inoculum, the size of the needle, and the depth of inoculation likely influence the actual risk.
Nonpercutaneous transmission of HCV occurs less frequently. Most seroepidemiologic studies have demonstrated anti-HCV in only a small number of sexual contacts.

Overall, sexual partners of patients with HCV infection have infection rates of approximately 1% annually, with a lifetime risk thought to be less than 5% in monogamous couples. Sexual transmission of the virus appears to be inefficient, perhaps due to the low levels of the virus found in genital fluids and tissues. Perinatal transmission of HCV also appears to be uncommon, occurring in less than 5% of cases. Further studies are needed to determine the time of perinatal transmission, the role of breast feeding in neonatal transmission, and the natural history of perinatally acquired HCV infection. All children born to women who are infected with HCV should be screened for the virus.

Chronic hemodialysis is also associated with HCV infection. The prevalence in this population is a relatively high 5% to 10%, due to the frequency of risk factors in this population (prior blood transfusion and prior injection drug use) and to nosocomial spread within dialysis units.

In approximately 25% of patients with HCV infection, there are no identifiable risk factors. Sporadic HCV infection may result from a prevalent nonpercutaneous route yet to be determined.

What are the clinical manifestations of HCV infection?

HCV infection is infrequently diagnosed during the acute phase of infection because most patients experience mild or no symptoms. Symptoms suggesting acute viral hepatitis include anorexia, nausea, malaise, right upper quadrant discomfort, and, uncommonly, jaundice. In patients who experience acute symptoms, the illness typically lasts for 2 to 12 weeks. The overwhelming complaint of patients with chronic infection is fatigue. Other nonspecific symptoms include myalgia, arthralgia, and depression. If patients develop cirrhosis, they are at risk for the complications of portal hypertension, including ascites, gastrointestinal bleeding, and encephalopathy.

In addition to hepatic disease, there are important extrahepatic manifestations of HCV infection, including cryoglobulinemia. Cryoglobulins are immunoglobulins that precipitate in the cold and dissolve on rewarming. The cryoglobulin contains both a polyclonal IgG (which may either act as an antigen or be directed against an antigen) and a monoclonal IgM rheumatoid factor directed against the IgG. Mixed cryoglobulinemia is a

lymphoproliferative disorder that can lead to deposition of circulating immune complexes in small- to medium-sized blood vessels. It usually presents with the clinical triad of palpable purpura, arthralgias, and weakness, but can also involve the kidneys, peripheral nerves, and brain. Treatment of patients with cryoglobulinemia due to HCV should be based upon the presence of cryoglobulinemia symptoms rather than the usual criteria used in patients with chronic hepatitis alone. Similarly, the response should be assessed by symptomatic improvement of cryoglobulinemia, a reduction in cryocrit, and an increase in serum complement levels. Complete responses may be more common in patients with low pretreatment levels of viremia and with high-dose interferon regimens.

Hepatitis C virus infection is also associated with membranoproliferative glomerulonephritis, porphyria cutanea tarda, leukocytoclastic vasculitis, sicca syndrome, and lichen planus. Higher rates of non-Hodgkin's lymphoma, thyroiditis, and diabetes mellitus have also been observed in patients with HCV infection. Hepatitis C-associated osteosclerosis is a rare disorder characterized by a marked increase in bone mass during adult life. In addition, psychological disorders including depression have been associated with HCV infection in up to 30% of cases. Treatment of HCV infection has resulted in improvement in many of these extrahepatic conditions.
What is the natural history of HCV infection?

The natural history of chronic hepatitis C has been difficult to clearly define because of the long course of the disease. A growing number of studies have provided estimates of the proportion of patients with chronic infection who develop cirrhosis within 20 years. Estimates have been higher from retrospective studies than prospective studies, possibly reflecting referral bias in the retrospective studies. A consensus statement issued by the National Institutes of Health suggests that the actual risk is closer to that derived from the prospective studies.

In most people who become infected with HCV, viremia persists and is accompanied by variable degrees of hepatic inflammation and fibrosis. Disease progression is largely silent, with patients often identified only on routine biochemical screening or during the course of blood donation. It is estimated that 60% to 80% of patients infected with HCV will have persistent viremia and chronic hepatitis. As a rule, spontaneous clearance of HCV viremia will occur within 20 weeks or not at all. Higher rates of spontaneous HCV RNA clearance have been described in children, in those infected after Rh immunization, and in other subgroups. There is also some evidence that the risk of developing chronic infection may be somewhat lower in patients presenting with symptomatic acute HCV infection.

The mechanism responsible for the high prevalence of chronic infection is not known. It may be related to the genetic diversity of the virus and its tendency toward rapid mutation, allowing HCV to constantly escape immune recognition. Available data suggest that chronic HCV infection leads to cirrhosis in about 5% to 20% of patients within 20 years of initially contracting the virus. Once cirrhosis is established, the risk of hepatocellular carcinoma (HCC) is approximately 1% to 4% per year, with the incidence rising most dramatically after 30 years of viremia. It is common practice in the United States to screen patients for HCC with a right upper quadrant ultrasound and serum alfa fetoprotein level every six months. A number of studies have demonstrated that a sustained virologic response to interferon treatment is associated with a reduced risk of developing HCC.

Fulminant hepatic failure due to acute HCV infection is very rare, but may be more common in patients with underlying chronic hepatitis B virus (HBV) infection. Chronic HCV infection accounts for at least 10,000 deaths each year in the United States, largely due to the development of cirrhosis and its complications. Once decompensated cirrhosis occurs, liver transplantation is the only effective therapy proven to prolong survival.

The factors that contribute to histologic progression of liver disease are poorly understood. Factors that appear to accelerate clinical progression include alcohol intake, coinfection with HIV or HBV, male sex, and older age at infection. High viral load is also associated with disease progression.
Several recent studies provide evidence that HCV infection may not be progressive in all patients. In a large French series, the mean time to cirrhosis was 30 years. It was estimated that 31% of patients would show no evidence of cirrhosis for at least 50 years.

Another study focused on a cohort of 917 women who developed acute HCV after exposure to contaminated anti-D immune globulin used to prevent Rh isoimmunization. During 20 years of follow-up, 85% tested positive for HCV antibodies while 55% were positive for HCV RNA. Only four patients (0.4%) had overt signs of cirrhosis. Liver biopsies obtained in 44% of the viremic women showed minimal to moderate hepatitis (96%) and portal fibrosis (47%).

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