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Racial differences in the relationship between hepatitis C infection and iron stores
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Hepatology 2003;37:795-801. George N. Ioannou et al, Department of Medicine and Division of Gastroenterology, University of Washington.
Relative to whites, black patients with hepatitis C virus (HCV) infection are more resistant to antiviral treatment with interferon, pegylated interferon, or
combination of interferon and ribavirin. Interracial differences in viral loads and the prevalence of HCV genotype 1 infection only partly account for the
observed differences in response to antiviral treatments.
Previous studies have suggested that patients with chronic HCV commonly have elevated levels of serum markers of iron stores (ferritin, transferrin-iron
saturation [TS], or iron). The presence of elevated body iron stores and, in particular, elevated hepatic iron levels, is one of the strongest predictors of
resistance to interferon treatment for HCV.
We used data from the third National Health and Nutrition Examination Survey (NHANES III) to determine whether there are differences between HCV-infected
blacks and HCV-infected nonblacks with respect to the likelihood of increased iron stores. We hypothesized that among persons with HCV infection, a greater
percentage of blacks than nonblacks would have elevated iron stores, because such a finding would be in agreement with the observed lower response of
blacks to antiviral treatment. Also, we asked whether any difference in iron stores between HCV-infected blacks and other races might be attributed to a
response to the HCV infection itself, rather than an underlying excess of iron stores in blacks without HCV infection.
Black race and increased hepatic iron stores predict poor response to interferon treatment for chronic hepatitis C virus (HCV) infection. We tested the hypothesis that these 2 observations are linked by investigating whether HCV-infected African-Americans have increased iron stores relative to
uninfected persons. Using data from the third National Health and Nutrition Examination Survey (NHANES III), we determined the risk of having increased
iron stores, defined as elevation of both serum ferritin and transferrin-iron saturation (TS), in HCV-RNA-positive blacks (n = 100) and nonblacks (n = 126)
relative to HCV-RNA-negative blacks (n = 4,002) and nonblacks (n = 10,943). HCV-positive blacks were 5.4 times (95% CI, 1.2 to 24) more likely to have
increased iron stores than HCV-positive nonblacks. The proportion of HCV-positive blacks who had increased iron stores was 16.4% among those with
abnormal liver enzymes and 2.8% among those with normal liver enzymes, compared with only 0.6% among HCV-negative blacks. After adjustment for
age, alcohol intake, gender, menopausal status, education, body mass index, and poverty index, HCV-positive blacks with abnormal liver enzymes had
an elevated risk of having increased iron stores (odds ratio, 17.8; 95% CI, 5.1 to 63). In contrast, among persons of other races, there was a much
smaller difference in the proportion of persons with increased iron stores between HCV-positive persons with (3.4%) or without (1.4%) abnormal liver
enzymes and HCV-negative persons (0.9%). In conclusion, a greater proportion of blacks than persons of other races respond to HCV infection with an
increase in iron stores. This finding may partly explain the reduced response of HCV-positive African-Americans to antiviral treatment.
Results and Author Discussion
Compared with other HCV-positive persons, HCV-positive blacks were younger and leaner but otherwise were similar in regard to gender distribution, alcohol
consumption, educational attainment, income level, and the prevalence of abnormal levels of liver enzymes or undetectable levels of C-reactive protein.
Compared with black or non-black HCV-negative participants, those who were HCV positive were younger, leaner, had lower educational attainment and
income, consumed more alcohol, and were more likely to be male and to have abnormal liver enzyme levels and undetectable levels of C-reactive protein. The prevalence of elevations in serum ferritin, TS (transferrin-iron saturation), or both was higher in HCV-infected blacks than HCV-infected persons of other races.
The levels of serum ferritin, TS, and iron, were 121 ng/mL (95% CI, 56 to 186), 7.5% (95% CI, 2.5 to 12.4), and 34.4 µg/dL (95% CI, 19.6 to 49.2), respectively,
higher in HCV-positive blacks with abnormal liver enzyme levels compared with HCV-negative blacks after adjustment for gender, menopausal status, age,
education, poverty index, body mass index, and alcohol consumption. HCV-positive blacks with normal liver enzyme levels also had elevations in serum
ferritin, TS, and iron, but the magnitude of these elevations was approximately half of that observed in HCV-positive blacks with abnormal liver enzymes.
The extent to which these differences in iron stores can explain the previously described racial differences in response to antiviral treatment depends on the
extent to which the association between elevated iron stores and improved response to interferon treatment is believed to be causative. Increased body or
hepatic iron stores may be surrogate markers for other factors associated with a low likelihood of response, such as advanced fibrosis, HCV genotype 1, high
viral load, male gender, and long duration of HCV infection. On the other hand, the fact that iron depletion by phlebotomy in patients with HCV reduces serum
aminotransferase levels38-43 and, in combination with interferon, may have improved antiviral efficacy compared with interferon alone39,41,43 suggests that increased iron stores may be the cause of the reduced response to interferon.
Although the presence of increased iron stores is a recognized predictor of poor response to interferon monotherapy, the association between increased
iron stores and response to combination treatment with interferon and ribavirin or pegylated interferon and ribavirin has not been investigated adequately. Only one such study is currently available in which 40 patients were treated with interferon and ribavirin, of whom 18 had sustained virologic response. There was no difference in hepatic iron concentration between responders and nonresponders; however, given the small number of subjects involved, it is difficult to exclude a type 2 error. Of note, in this study, the mean serum ferritin concentration was higher in nonresponders (244 ng/mL) than in responders (189 ng/mL), although, again, this difference was not statistically significant. Therefore, larger, prospective studies are required to evaluate whether iron stores are associated with response to combination treatment, and whether such an association is modified by race.
Our finding that HCV-positive blacks were 5.4 times more likely to have increased iron stores than HCV-positive nonblacks may have implications beyond potentially explaining racial differences in treatment response rates. Hepatic iron increases the production of reactive oxygen species, which may lead to lipid peroxidation, steatosis, depletion of glutathione stores, and accelerated liver damage. Furthermore, the presence of increased iron stores may be a predictor of developing hepatocellular carcinoma in patients with chronic HCV infection. Thus, the presence of increased iron stores may predispose blacks to worse clinical outcomes related to HCV infection compared with whites. Indeed, the incidence of hepatocellular carcinoma in the United States is 2 to 3 times greater in blacks than in white persons. On the other hand, retrospective studies have suggested that the rate of histologic progression in chronic HCV infection is either similar or lower in blacks than in whites. However, these studies are subject to both selection bias and to great inaccuracies in the calculation of histological progression, which was based on duration of infection estimated from the earliest potential exposure to the virus.
We observed that HCV infection was associated with much greater elevations in serum markers of iron stores in patients with abnormal liver enzymes compared
with patients with normal liver enzymes. One potential explanation for this finding is that elevated liver enzymes are a sign of ongoing hepatic
necroinflammation, which may lead to elevations in serum markers of iron stores through release of iron-loaded ferritin from dying hepatocytes. Alternatively, if hepatitis C infection has effects on gastrointestinal iron absorption or iron metabolism, then these effects may be more pronounced in patients with active disease as evidenced by elevated liver enzymes.
Our study is limited by the fact that the hepatic iron concentration, which is a better predictor of response to interferon than serum markers of iron stores, was not available because liver biopsies were not performed in this population-based study. Nonetheless, serum ferritin and TS levels have been shown to have good correlation to hepatic iron concentration levels.7,11,50 Future studies will be required to determine if hepatic iron concentration also is higher in blacks compared with whites with chronic HCV infection. Also, future studies should investigate whether the lower response of blacks than persons of other races to antiviral treatment is restricted to persons with evidence of elevated hepatic iron concentration or serum markers of iron stores.
In summary, we observed that HCV-infected blacks are 5 times more likely to have elevated serum markers of iron stores than HCV-infected nonblacks. This
finding is, in turn, the result of a particularly strong association between HCV infection and increased iron stores among blacks. Future studies should
investigate whether these findings can partly explain the relatively low response of blacks to antiviral treatment.
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