What Is the Natural History of Hepatitis C?
By National Institutes of Health The hepatitis C virus is an RNA virus of the Flaviviridae family. Individual isolates consist of closely related yet heterogeneous populations of viral genomes (quasispecies). Probably as a consequence of this genetic diversity, HCV has the ability to escape the host’s immune surveillance, leading to a high rate of chronic infection. Comparing the genomic nucleotide sequences from different HCV isolates enables classification of viruses into several genotypes and many more subtypes. The extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, perhaps explaining variations in clinical course, difficulties in vaccine development, and lack of response to therapy. Clinical Course Data on the natural history of hepatitis C are limited, because the onset of infection is often unrecognized and the early course of the disease is indolent and protracted in many individuals. Prospective cohort studies are few, are typically small, include relatively few subjects whose date of infection can be well documented (e.g., blood transfusion recipients and victims of accidental needle sticks), and have relatively short followup. The natural history of this disease appears to differ according to geography, alcohol use, virus characteristics (e.g., genotype, viral load), coinfection with other viruses, and other unexplained factors. After initial exposure, HCV RNA can be detected in blood in 1-3 weeks. Within an average of 50 days (range: 15-150 days), virtually all patients develop liver cell injury, as shown by elevation of serum alanine aminotransferase (ALT). The majority of patients are asymptomatic and anicteric. Only 25-35 percent develop malaise, weakness, or anorexia, and some become icteric. Fulminant liver failure following HCV infection has been reported but is a rare occurrence. Antibodies to HCV (anti-HCV) almost invariably become detectable during the course of illness. Anti-HCV can be detected in 50-70 percent of patients at the onset of symptoms and in approximately 90 percent of patients 3 months after onset of infection. HCV infection is self-limited in only 15 percent of cases. Recovery is characterized by disappearance of HCV RNA from blood and return of liver enzymes to normal. Chronic Infection About 85 percent of HCV-infected individuals fail to clear the virus by 6 months and develop chronic hepatitis with persistent, although sometimes intermittent, viremia. This capacity to produce chronic hepatitis is one of the most striking features of HCV infection. The majority of patients with chronic infection have abnormalities in ALT levels that can fluctuate widely. About one-third of patients have persistently normal serum ALT levels. Antibodies to HCV or circulating viral RNA can be demonstrated in virtually all patients. Chronic hepatitis C is typically an insidious process, progressing, if at all, at a slow rate without symptoms or physical signs in the majority of patients during the first two decades after infection. A small proportion of patients with chronic hepatitis C—perhaps less than 20 percent—develop nonspecific symptoms, including mild intermittent fatigue and malaise. Symptoms first appear in many patients with chronic hepatitis C at the time of development of advanced liver disease. In chronic hepatitis, inflammatory cells infiltrate the portal tracts and may also collect in small clusters in the parenchyma. The latter instance is usually accompanied by focal liver cell necrosis. The margin of the parenchyma and portal tracts may become inflamed, with liver cell necrosis at this site (interface hepatitis). If and when the disease progresses, the inflammation and liver cell death may lead to fibrosis. Mild fibrosis is confined to the portal tracts and immediately adjacent parenchyma. More severe fibrosis leads to bridging between portal tracts and between portal tracts and hepatic veins. Such fibrosis can progress to cirrhosis, defined as a state of diffuse fibrosis in which fibrous septae separate clusters of liver cells into nodules. The extent of fibrosis determines the stage of disease and can be reliably assessed. Severe fibrosis and necroinflammatory changes predict progression to cirrhosis. Once cirrhosis is established, complications can ensue that are secondary to liver failure and/or to portal hypertension, such as jaundice, ascites, variceal hemorrhage, and encephalopathy. The development of any of these complications marks the transition from a compensated to a decompensated cirrhosis. The rate of progression is highly variable. Long-term studies suggest that most patients with progressive liver disease who develop cirrhosis have detectable ALT elevations; these can, however, be intermittent. The relationship is inconsistent between ALT levels and disease severity as judged histologically. Although patients with HCV infection and normal ALT levels have been referred to as “healthy” HCV carriers, liver biopsies can show histological evidence of chronic hepatitis in many of these patients. Cirrhosis of the Liver Chronic hepatitis C infection leads to cirrhosis in at least 20 percent of patients within 2 decades of the onset of infection. Cirrhosis and end-stage liver disease may occasionally develop rapidly, especially among patients with concomitant alcohol use.
Hepatocellular Carcinoma Chronic infection by HCV is associated with an increased risk of liver cancer. The prevailing concept is that hepatocellular carcinoma (HCC) occurs against a background of inflammation and regeneration associated with chronic hepatitis over the course of approximately 3 or more decades. Most cases of HCV-related HCC occur in the presence of cirrhosis. The risk that a person with chronic hepatitis C will develop HCC appears to be 1–5 percent after 20 years, with striking variations in rates in different geographic areas of the world. Once cirrhosis is established, the rate of development of HCC increases to 1–4 percent per year. Among patients with cirrhosis due to hepatitis C, HCC develops more commonly in men than in women and in older than in younger patients.
Extrahepatic Manifestations of HCV Patients with chronic hepatitis C occasionally present with extrahepatic manifestations or syndromes considered to be of immunologic origin, including arthritis, keratoconjunctivitis sicca, lichen planus, glomerulonephritis, and essential mixed cryoglobulinemia. Cryoglobulins may be detected in the serum of about one-third of patients with HCV, but the clinical features of essential mixed cryoglobulinemia develop in only about 1–2 percent of patients. Chronic hepatitis C may be a major underlying cause of porphyria cutanea tarda. Mortality After an average followup of 18 years, a prospective study of patients who received blood transfusions showed no difference in overall mortality between HCV-infected cases and noninfected controls. Liver-related mortality, although rare, was twice as high in the cases (3.2 percent vs. 1.5 percent). A recent European study showed that survival among hepatitis C patients with compensated cirrhosis was 91 percent after 5 years and 79 percent after 10 years. Among patients developing decompensated cirrhosis, however, 5-year survival was only 50 percent. Source: National Institutes of Health Consensus Development Statement: MANAGEMENT OF HEPATITIS C
Natural History of HCV Hepatitis C is often asymptomatic. Most symptoms begin only when irreversible liver damage (cirrhosis) is established. The best outcomes for HCV patients depend upon early recognition of the infection. Any person with risk factors should be screened for HCV. Multiple studies have shown that earlier treatment of patients who have chronic liver disease associated with hepatitis C results in improved outcomes. Chronic infection with HCV is an epidemic within the United States. A majority of patients who acquire hepatitis C will progress to some form of chronic liver disease. Recent evidence published in the New England Journal of Medicine indicates some patients may have a long course in which the disease does not causes significant damage to the liver. However, it is difficult to identify those patients since their clinical characteristics are unknown. There are no blood or radiologic tests which identify this group of HCV patients. Most patients who acquire HCV infection are not aware that they have become infected. Acute infection with HCV is usually associated with flu like symptoms and not jaundice (turning yellow). As a result, patients may have the infection for years before being identified. Most patients are identified during routine physical exam or blood donations. Abnormal liver function tests are identified during these evaluations. When abnormal liver function tests or a history of risk factors are identified, further testing is recommended. Once the infection has been established, the liver experiences inflammation which over 20 years may result in cirrhosis. It is thought that 85 % patients infected with HCV will develop some form of chronic inflammation of the liver. Of these patients, about 20 % will develop cirrhosis of the liver after about 20 years of infection. Some patient populations seem to tolerate the infection better than others. These patients are under investigation to identify the means by which this is accomplished. The primary goal for patients with HCV is early institution of therapy to prevent the development of cirrhosis. Once cirrhosis is present, the response rates for treatment decrease significantly. In addition, the possibilities of developing complications from cirrhosis (such as hepatocellular carcinoma and portal hypertension) increase rapidly. Patients with Hepatitis C infection may have normal, fluctuating or persistently elevated ALT levels. It is important that these liver function test abnormalities be present for at least 6 months. However, if an individual has recently had been identified as having elevated liver function test, and has one or more of the above risk factors, an immediate test for the Hepatitis C antibody test (EIA) is appropriate. Hepatitis C is a heterogeneous infection. Its interrelationship with the human immune system is variable and difficult to correlate. However, some trends have been identified. In some patients serious liver disease may occur within the first several years. However, in most patients chronic liver disease requires infection for 20 to 30 years. When acquired in older age, the disease may progress more rapidly. Ingestion of alcohol has been clearly associated with an increased rate of hepatic inflammation. HCV patients who drink often have an acceleration of their disease. Associated Diseases Hepatitis C is thought to be associate with multiple other diseases:
The most common presentation of hepatitis C is a patient with no complaints. Many patients, especially when questioned closely, report a history of fatigue and malaise. Intermittent right upper quadrant abdominal pain may also be present. However, the typical patient with hepatitis C will be asymptomatic and have normal, intermittently elevated, or persistently elevated liver function test. The primary problem for patients with HCV and their physicians is communication regarding possible risk factors for acquisition of the HCV virus. If you have a history of any of the risk factors, please contact your physician. Diagnosis of Hepatitis C The initial test for hepatitis C is the enzyme-linked immunoassay. This is also known as the enzyme immunoassay (EIA). This test looks for the antibody to HCV in the blood. Over the past 10 years three generations of EIA antibody tests for hepatitis C has been developed. The most commonly used today, EIA 3, is 95 percent specific and sensitive for hepatitis C. However, this test, even when positive, needs to be confirmed with a polymerase chain reaction (PCR) to evaluate the presence of HCV virus. If the PCR is positive, further blood testing for the viral load (amount of virus in one milliliter of serum) and the genotype (type of HCV present) can be performed. http://www.gastromd.com/education/hepatitisc2.html
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