Host Factors

Age and Duration of Infection

Separating the role of age, per se, from length or duration of infection is often difficult, when examining relationships to disease progression. One study (55), of 838 patients referred to an outpatient hepatology clinic for management of CHC, examined patients for factors associated with disease progression. Most of the patients had established liver disease, 16.8% had cirrhosis on entry, and 7.4% died during a mean follow-up of 26.9 mo. Death resulting from complications of liver disease, including liver failure and HCC, occurred only in cirrhotics and accounted for half of the total deaths. Risk of death was increased in patients with cirrhosis, long duration of disease, alcohol consumption, injection drug use, and older age. Acquisition of infection at a young age was associated with higher risk of dying from liver disease. Risk of death was decreased by use of interferon.

The Niederau study (55) also suggested that young age at acquisition of infection was associated with higher risk of liver disease. In contrast, other studies (47) have suggested that the rate of disease progression is more rapid, the older the age at the time of infection. This discrepancy may result from the unique characteristics of the study populations, and simply reflect the most important variable, duration of disease, which can be related to age.

Prevalence studies, which examine a cross-section of a population at a given point in time, indicate that more severe histology changes are found in older patients with high levels of HCV RNA, genotype 1 or 1B, and more extensive quasispecies diversity (56-61). Cohorts followed for a short period of time after acute infection tend to be younger and have relatively benign outcomes; but cohorts followed later, after development of established hepatitis, tend to be older, and to have higher risk of morbidity and mortality related to liver disease (62).

Mode of Transmission

Several pieces of evidence suggest that transfusion-acquired hepatitis C is more rapidly progressive than community-acquired hepatitis C. First, posttransfusion acute hepatitis C is histologically worse that sporadic acute hepatitis C (63). Second, histology tends to be worse in patients with CHC acquired by transfusion (64,65). Third, the link of PTH to more aggressive disease was convincingly demonstrated in a large sample of 6664 patients, studied at 30 French health centers (66). The cases were representative of patients with established disease, who would be referred to a treatment center. The average length of time between estimated time of exposure and referral was 11 yr, and most patients exhibited biochemical evidence of hepatitis for 2 yr prior to establishment of the diagnosis of hepatitis C.

As expected from the above discussion, these cases represented later-stage disease with 20% of patients who underwent liver biopsy demonstrating cirrhosis. Cirrhosis was more common in patients who acquired hepatitis C via blood transfusion, had longer duration of disease, were heavy users of alcohol, and had co-infection with hepatitis B. HCC was only observed in patients with cirrhosis. Fourth, Gordon et al. studied 627 patients at one U.S. medical center, and confirmed the link of PTH to more aggressive disease. Logistic regression analysis revealed that the risk of liver failure was predicted primarily by acquisition of infection through transfusion (67). Those authors also found that serum albumin, prothrombin time, and platelet count predicted risk of future hepatic decompensation, and that the risk of developing HCC in cirrhotics was 1.2%/yr. The finding that acquisition by transfusion predicted subsequent late clinical events suggests that the load of the initial viral inoculum may modify either the innate cytotoxicity of the virus or the immunological response of the host.

Gender

Male sex may be another risk factor for more rapid progression of fibrosis (47,54). Or, conversely, female sex may be protective. In the studies of women who acquired hepatitis C after anti-D immunoglobulin, rates of development of cirrhosis, after approx 20 yr of infection, were 0.4-4% (19,20). In contrast, a group of predominantly male injection drug users experienced an 8% risk of cirrhosis after 25 yr (34). Patients in the latter study, however, also had other risk factors for disease progression, such as heavy alcohol consumption. One report of a small number of patients (35) suggested that the risk of cirrhosis in males, without other risk factors for disease progression, followed for 45 yr, was 18.2%. It is intriguing to speculate that disease expression might be modified by gender, because several investigations have demonstrated significant differences in effects of male and female steroid hormones on hepatic metabolism and protein synthesis.

Race

Existing data, although inconclusive, suggest that African Americans may have slower rates of disease progression than their white counterparts. Also, results from therapeutic trials suggest that the ability of African Americans to clear hepatitis C, when treated with current antiviral regimens, is limited. Additional studies are needed to determine if these observations are true, or simply reflect other confounding variables, such as duration of disease, mode of acquisition, viral factors, or other extraneous risk factors.

Pediatric Populations

Hepatitis C is acquired by infants and young children via transfusion of blood or blood products, by vertical transmission from an infected mother at the time of delivery, or by horizontal transmission from infected siblings or playmates. In general, pediatric cases of CHC are mild, with little evidence of disease progression for at least two decades. A minority will develop fibrosis that progresses with age and duration of disease (68,69). Vogt et al. (70) examined the outcome of hepatitis C in children who had undergone cardiac surgery prior to 1991, at a mean age of 2.8 yr. They identified 67 cases that were hepatitis C virus antibody-positive, out of a cohort of 458 children. The mean follow-up after the first operation was 19.8 yr. 37/67 who had positive hepatitis C virus antibody also tested positive for HCV RNA; infection had supposedly cleared in the other 30. Only 1/37 had abnormal liver enzymes, but this patient also had congestive hepatopathy from right heart failure. 17 had liver biopsies, 14 were essentially normal, but 3 did show evidence for progressive liver damage. 2/3 had congestive heart failure, and the third was co-infected with hepatitis B. Thus, for at least 20 yr, children infected with hepatitis C have an excellent prognosis, with little evidence of either chronic hepatitis or disease progression. Long-term follow-up for 3050 yr will be required to determine whether the disease remains quiescent, or becomes progressive with risk of fibrosis, cirrhosis, or liver cancer (71).

Severity of Hepatic Inflammation

Other factors that predict more rapid progression of disease are highgrade inflammation or fibrosis on initial liver biopsy (47). Two studies indicate that patients with severe grades of inflammation or more extensive fibrosis are more likely to progress to either cirrhosis or decompensation within a follow-up period of 10 yr (48,49).

Immunologic Response

Hepatitis C persists as a chronic infection, despite a diversified host humoral and cellular immune response. Host defense mechanisms against viral pathogens include antibody formation, natural killer cells, interferon production, and CD4 and CD8 T-cell responses (72). Viruses persist by interfering with one or several of the mechanisms of viral clearance. One mechanism by which hepatitis C avoids immunologic clearance is the development of a limited and inadequate T-cell response, because of minimal expression of viral proteins at the cell surface, a single viral pep-tide-HLA complex (73). Although several immunologic mechanisms have been proposed, and are currently under investigation, there is no unifying theme linking specific immunologic responses to fibrosis, disease progression, decompensation, or development of HCC (74).

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Alcohol No More

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