~Hepatitis C

~Hepatitis C
Reprinted with permission of Life Extension®.
Overview

Hepatitis C virus (HCV) is the cause of most cases of hepatitis in the United States, and the principal cause of chronic liver disease, cirrhosis (scarring of the liver), and liver cancer in the Western world. It was first recognized in 1975 and named non-A non-B hepatitis virus. After the virus genome was sequenced in 1989, it was renamed HCV. Chronic hepatitis C (CHC) can progress slowly and end in liver failure after decades. Today, there is no vaccine against HCV, and the only recognized treatment is far from satisfactory. Treatment is expensive, has debilitating side effects, and is successful only in a minority in the long-term.

EPIDEMIOLOGY AND GENETICS
  • Prevalence
  • Natural History
  • Genetic Profile and HCV
  • HCV and Alcohol
  • HCV and HIV
Prevalence

HCV infects approximately 170 million people worldwide. Nearly 4 million Americans have antibodies to HCV, indicating ongoing or previous infection with the virus. Chronic hepatitis C (CHC) is the most common chronic blood-borne infection in the U.S. and is the cause of approximately 40% of chronic liver disease. It is a condition that can progress to cirrhosis and hepatocellular carcinoma. Because of improved screening methods for blood products, the annual incidence of new infections decreased by more than 80% from 1989 to 1996. HCV is responsible for 8,000 to 10,000 deaths annually.1

In the past, hepatitis was spread primarily through infected blood and blood products.2 Today the most common mode of HCV transmission is injection drug use,3-5 occupational exposure (e.g., needle-stick accidents),1,6,7 sexual contact,8 and blood transfusion.1,9 Over the last 20 years, there has been an increase in HCV due to intravenous drug use and high-risk sexual behavior, but transfusion-related HCV has declined precipitously.1 Even with multiple sexual partners, the risk of sexual transmission of HCV is minimal.8 The risk is markedly increased by coinfection with HIV and hepatitis B virus10 and other sexually transmitted diseases. The risk of transmission of HCV from mother to baby is about 5%, but there is no evidence that breast-feeding is a risk factor.11 Homosexual contacts are not a risk factor for HCV transmission.12

Approximately one third of HIV-positive individuals in the U.S. are infected with HCV. This is, in part, explained by shared risk factors for both infections. However, for unknown reasons, HIV infection also increases the susceptibility to infection with HCV.1 HIV is much more likely to be transmitted than HCV.10 However, sexual transmission more likely in coinfected than in only HCV-infected individuals.13 Transmission from mother to baby is more likely by HCV-HIV coinfected mothers;12 the converse is also true, i.e., HIV transmission to the fetus is more likely in doubly infected mothers.

Natural History

The course and outcome of HCV infection is highly variable--from spontaneous resolution to end-stage liver disease.1,14,15 The time from the onset of the infection to the end-stages of disease may be decades.16 The course and prognosis for an HCV-infected patient varies with the individual. Genetic makeup and immunologic status alter the course and duration of the disease. Some people have mild symptoms; in others the symptoms are severe. Some people respond to treatment and recover completely--others remain chronically infected. The genetic character of both the virus and the infected individual contribute to these variations in outcome, disease susceptibility and progression, and success of treatment. In fact, the existence of numerous clinical syndromes associated with HCV points to the genetically linked character of the HCV infection. Researchers have already identified genes associated with the variability of the immune response in diseases such as malaria,17 tuberculosis, leprosy,18 AIDS and hepatitis B;19 consequently, the HCV research now underway focuses on the immunogenetics of HCV infection (www.clinicaltrials.gov).

The natural history of HCV infection also varies with geography, age, gender, characteristics of the virus, and type of treatment. Older age, cirrhosis, coinfection with hepatitis B or HIV, alcohol use, and male gender all predict a more severe disease course and a more severe long-term outcome.20

About 15% of those who are acutely infected clear the infection.21,22 The remaining 85% develop CHC, a disease that is benign and asymptomatic in many.21,22 Progression of the disease is exceptionally slow.20,23 Even asymptotic HCV-positive people are carriers of the virus and are at risk of developing chronic liver disease, cirrhosis, and hepatocellular carcinoma 20 or 30 years after the initial infection.24 Liver disease may progress to end-stage organ failure and result in ascites, esophageal varices, or encephalopathy.22

An analysis of a large group of HCV-positive people found no difference in the death rate between them and a control group 18 years after infection. Death due to liver disease was 3.2% for the HCV-positive enrollees and 1.5% for the controls. Of those in the group who died from liver disease, 71% were heavy drinkers. There were marked differences in morbidity, but it was confined largely to those with cirrhosis. Fewer than 8% had developed advanced liver disease over the 18-year period.20

Genetic Profile and HCV

Genetic differences create considerable disparity among racial and ethnic groups in the progression of CHC and in response to treatment.25 HCV infection has a different natural history in minority populations than in Caucasians. Effectiveness of antiviral drugs varies with race and ethnicity, as well.26

In the U.S., HCV infection is more common in minority populations (3.2%, African-Americans; 2.1%, Hispanics; and 1.5%, Caucasian);27 and they are disproportionately affected. African-Americans and Hispanics have more complications of liver disease more frequently and have a lower response to antiviral drugs.24,28 The viral load (amount of virus in the blood) is higher among ethnic minorities. African-Americans do not clear the virus as well as Caucasians29 which results in a higher rate of chronic infection.26,30

The rate of development of fibrosis and severe liver disease is higher for minorities24 and three times higher for Hispanics.26,31 This disparity may be due to the higher rate of metabolic syndrome, a genetically linked disease, in that population. Insulin resistance, a symptom that characterizes the metabolic syndrome,32 is a major risk factor for the development of non-alcoholic fatty liver disease. Approximately 15% of patients with this type of fatty liver disease develop fibrosis that leads to cirrhosis or hepatocellular carcinoma.33,34 African-Americans tend to have lower liver enzyme levels (a positive indicator for CHC) and less cirrhosis and liver damage--this advantageous profile is attributed to genetic differences.35 Although progression to cirrhosis is lower among African-Americans,30 the incidence of hepatocellular carcinoma is higher, however.36,37

HCV and Alcohol

About 25% of people with alcoholic liver disease are HCV-positive.38 Their viral loads of alcoholics are greater,39 and their time to development of cirrhosis and hepatocellular carcinoma is shorter.40,41 The risk for hepatocellular carcinoma in alcoholic cirrhotics is eight times higher with HCV infection.42 HCV causes more severe liver injury in alcoholics, especially those with cirrhosis.43 The reason for this association is unclear. Socioeconomic factors have been implicated, but there is a high prevalence of HCV among alcoholics with liver disease without a history of intravenous drug use.38,44 Factors such as the amount of alcohol consumed, age at the time of infection, and gender have greater influence on progression of the disease than the virus itself. Actively drinking alcoholics are more likely to have HCV in the blood than non-alcoholics with no other risk factors for hepatitis--suggesting that alcoholism is a predisposing factor for HCV infection.44

The question is, do alcohol and HCV act synergistically to cause liver injury? Alcohol may speed up viral replication--there is a correlation between HCV levels in the blood and the amount of alcohol consumed; or it may modify the ability of HCV to "turn on" the genes that cause hepatocellular carcinoma.45 Alcoholics with HCV infection have higher hepatic iron concentrations; this might increase HCV replication.46 Whatever the mechanism, even moderate alcohol drinking enhances the progression of liver disease appreciably.

HCV and HIV

HCV is a significant cause of liver disease in those who are HIV-positive.47 Cirrhosis due to HCV is probably as high as 22% at the time of death in HIV-HCV coinfected patients.48 Hepatocellular carcinoma appears at a younger age and after a shorter time in individuals in people with a combination of HCV and HIV infections.1 The encroachment of HCV infection into the HIV-positive population is so pervasive that is it now considered an opportunistic infection by many physicians.49

ANATOMY AND PHYSIOLOGY (STRUCTURE AND FUNCTION)

The liver is the largest and heaviest visceral organ in the body. The two lobes of the liver are made up of microscopic functional units called lobules that are bounded by portal triads and central veins. Each portal triad is the center of a microvascular unit called an acinus. Lobules contain enlarged capillaries (sinusoids), hepatocytes (liver cells), and a number of specialized cells. Most of the cells in the liver are hepatocytes. They are responsible for the liver's central role in metabolism and regulation of blood. Hepatocytes manufacturer bile, store absorbed vitamins and minerals, convert glucose to glycogen and glycogen to glucose, make plasma proteins from amino acids, detoxify chemicals, and destroy pathogens. Pit cells may be tissue lymphocytes that function similarly to natural killer cell functions. Ito cells store vitamin A, synthesize various proteins, and can transform into fibroblasts in response to injury. Kupffer's cells are macrophages that destroy microbes, foreign particles, and worn out blood cells, as well as remove endotoxins and modulate the immune response. The liver can also eliminate toxic substances, such as alcohol and drugs, by neutralizing them with the cytochrome P450 system. Cytochrome P450 enzymes contain iron and are specialized for oxidizing chemicals which makes them more water soluble and more easily eliminated by the kidneys. Overproduction of P450 enzymes is toxic to the liver. The liver can also detoxify harmful substances by attaching molecules to their side chains which changes their chemical composition and makes them inactive.

PATHOPHYSIOLOGY

The kinetics of acute HCV infection is uncertain. In the first stage of infection, there is no immune response and HCV replicates without injury to liver cells. In the second stage, viral replication slows, probably due to cytokines such as interferon-a. In the final stage, at about 12 weeks, there is a strong cytotoxic response in which T cells destroy infected cells; a rapid clearance of infected cells follows.60,61 Laboratory studies have shown that those who clear an acute infection have a more vigorous T-cell response to HCV and consequently developed fewer viral subtypes. Apparently an increase in the cellular immune response coupled with inhibition of viral replication with interferon-a can eradicate the virus.78

The overwhelming majority of those infected cannot clear the virus in the acute stage and consequently develop a chronic infection. The classic clinical picture of a CHC infection is a persistent low-grade inflammation and fibrotic changes of the hepatocytes that eventually progresses to cirrhosis.79

ETIOLOGY AND MECHANISMS OF ACTION

The factors that determine whether a HCV infection becomes chronic have not been completely elucidated. Research to date has focused on viral factors, such as genotype or viral load; however, the tendency to either clear the infection or develop a progressive disease appears to be influenced by the genetic makeup of the host coupled with the interaction of several of the defensive mechanism of the body.80 The effectiveness of an immune response determines the extent of inflammation and necrosis sustained by the liver -- e.g., a marginal immune response will cause fewer symptoms, but is less likely to eradicate the virus.

Cell-mediated immunity, especially natural killer cells and cytotoxic T-lymphocytes, play a role in chronic liver disease and the mechanisms of liver damage.81 The inflammatory response produces reactive oxygen species and cytokines.82,83 Cytokines combat viral infections, indirectly through the immune response and directly through inhibition of viral replication.84 Pro-inflammatory cytokines, such as interferon-a, tumor necrosis factor-a, and interleukins (ILs)-1 and -6, produce antiviral immune responses; anti-inflammatory or "permissive" cytokines, such as IL-4 and IL-10, downregulate the immune response. An inappropriate ratio of pro-inflammatory and anti-inflammatory cytokines may alter individual outcomes or the effect of antiviral drugs.80 Pro-inflammatory cytokine levels are elevated in CHC, hepatocellular carcinoma, and cirrhosis, but HCV may have some degree of resistance to inhibition by cytokines.84-87

Genetic factors are important determinants of inflammatory cytokine production and are closely linked to susceptibility to liver disease.88 In response to an immune stimulus, cytokines bind to cell membranes and signal the cell to alter its behavior through gene expression. Although the immune system plays a protective role in the body,89 the oxidant molecules produced as part of the inflammatory response may damage healthy tissue. The enhanced cytokine and reactive oxygen species production that follows bacterial infection, for example, is designed to combat bacteria; but during the battle, it can damage the body and accelerate disease. Some of the oxidative damage to the liver seen in CHC is due to excessive production of pro-inflammatory cytokines.90,91

The influence of cytokines IL-10 and -12 on liver disease has been the subject of dozens of studies. There is agreement among investigators that the capacity to produce IL-10 among individuals has a major genetic determinant, but there is little agreement on whether these cytokines are favorable or unfavorable prognostic indicators for the clinical outcome of CHC.80

Apoptosis, or programmed cell death, is an antiviral mechanisms employed by liver cells.92 It is thought that cytotoxic T-lymphocytes trigger apoptosis in infected cells; this interrupts viral replication and eliminates infected cells. However, many viruses escape from the immune system by encoding proteins that repress apoptosis. Inappropriate apoptosis is implicated in the pathogenesis of CHC; in fact, repeated cell damage caused by inappropriate apoptosis can induce HCC. Some researchers think that apoptosis is a mechanism for viral shedding rather than for viral elimination.93 HCV-infected hepatocytes can induce or inhibit apoptosis--inhibition of apoptosis results in a chronic infection. The antiviral effect of interferon-a may be mediated through induction of apoptosis. The degree of apoptosis in the liver of patients with CHC does not correlate with transaminase levels, viral load, or genotype; rather, it is directly proportional to the number T-lymphocytes.92

Continued . . .


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