Iron and the Response to Treatment of Hepatitis C-->好阳光转移

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Although this study is of patients with Hepatitis C, might just be applicable to us with "B" too...........Sheree ------------------------------------------------- American Journal of Gastroenterology Editorial April 2002 Volume 97, Number 4 Pages 788-790 Iron and the Response to Treatment of Hepatitis C Adrian Griffiths, M.B.B.S., M.R.C.P.a,b and John K. Olynyk, M.D., B.Med.Sc., M.B.B.S., F.R.A.C.P.a,b Hepatitis C virus (HCV) is the commonest cause of chronic viral hepatitis in the majority of developed countries and a significant cause of cirrhosis, hepatic failure, and hepatocellular carcinoma. Interferon- is an effective treatment for hepatitis C. However, interferon monotherapy is only capable of inducing a sustained response in 15-25% of patients (1). Treatment efficacy is known to be enhanced by combining therapy with ribavarin and may potentially be improved by optimizing other factors that influence treatment response. There are several characteristics known to affect outcome of interferon treatment, including age, gender, duration of infection, mode of acquisition, stage of fibrosis on histology, HCV genotype and viral load, and iron status. Interest in the role of iron began in 1992 when DiBisceglie et al. (2) found that up to 36% of patients with chronic hepatitis C had elevated serum iron parameters. As some serum iron markers such as ferritin are also elevated as a result of inflammation, a more accurate assessment of iron overload is the hepatic iron content (HIC), measured by atomic absorption spectrophotometry. Approximately 10% of patients with hepatitis C have elevated HIC. In 1994, Van Thiel et al. (3) retrospectively examined the HIC of patients with a variety of different chronic viral hepatitis pathologies and found that it was lower in the group of patients who responded to treatment than in those who were nonresponders. This has been confirmed by others in hepatitis C (4, 5), and it was suggested by Olynyk et al. (6) that an HIC of greater than 1100 礸/g was predictive of nonresponse in nearly 90% of patients. However, Boucher et al. (7) found no difference in the HIC between responders and nonresponders to treatment with interferon and noted that the HIC decreases with interferon treatment whether patients clinically respond or not. The pathophysiological mechanisms involved in iron accumulation in the liver in hepatitis C are not well defined but may well be different than those underlying the classic iron overload syndromes. In hepatitis C, the areas of iron overload reflect the areas with the greatest degree of inflammatory activity. The resulting cellular damage leads to phagocytosis of the injured hepatocytes by the Kupffer cells. A key question is whether the iron directly contributes to liver injury or whether it is simply a reflection of hepatocellular damage. There are several mechanisms by which iron may contribute directly to cellular injury. Iron has been shown to increase the formation of reactive oxygen intermediates that lead to lipid peroxidation and subsequent oxidative damage to proteins and nucleic acids (8). Iron can also affect antigen-specific cellular responses by decreasing the generation of T cells and by the impairment of natural killer and T helper cell function (9). Iron is known to affect immune-mediated clearance of HCV by sinusoidal Kupffer cells and has recently been shown to decrease Kupffer cell production of proinflammatory cytokines (10). Is the impaired treatment response to interferon in patients with raised hepatic iron concentration due in some way to the presence of iron itself, or is it merely an association of iron overload with other factors known to affect treatment efficacy such as viral genotype, the degree of histological damage, and viral load? Several studies have attempted to answer this question by examining the role of iron depletion in the treatment of hepatitis C. Therapeutic phlebotomy alone has been shown to reduce serum transaminases in patients with hepatitis C (11, 12, 13). However, the histological response to phlebotomy has been variable, with some studies showing no effect (11, 12) whereas others have demonstrated an improvement in hepatic inflammation and fibrosis (13). It appears phlebotomy alone is unable to reliably reduce viral load. Two recent multicenter, prospective, randomized trials have examined iron reduction as an adjuvant therapy to interferon in previous nonresponders and interferon-naive patients. DiBisceglie et al. (14) showed that patients in the phlebotomy and interferon group exhibited a significant improvement in histological necroinflammatory activity but no benefit in viral clearance. Fontana et al. (15) demonstrated that iron reduction improved liver histology but also reduced end-of-treatment HCV RNA levels. Disappointingly, this did not correlate with any significant sustained viral eradication after 6 months. Similar negative results have been described (16, 17), although a few earlier studies did show some sustained virological response when iron reduction therapy was used in addition to interferon (18, 19, 20). In this issue, Sievert et al. (21) examine the response to treatment of a cohort of 28 patients with -thalassemia major, transfusion-acquired severe iron overload, and chronic hepatitis C infection. After 6 months of interferon treatment, eight patients (28%) achieved virological and biochemical responses that were sustained for a mean of 66 months. Interestingly, HIC was uniformly high in all patients and had no effect on the outcome of treatment. Factors that did predict poor response to treatment included high levels of HCV RNA and the presence of HCV genotype 1. Patients with -thalassemia present an interesting group in which to study the effects of parenterally acquired iron overload and hepatitis C. In view of the chronic hemolytic anemia, they require regular blood transfusions, which puts them at risk of acquiring blood-borne viruses and developing iron overload, which occurs despite chelation therapy with desferrioxamine. This is the first study to investigate the effects of iron overload on treatment response to interferon in adults with thalassemia and hepatitis C. Previous studies in children (22, 23) have shown response rates to interferon of up to 40% despite the presence of increased hepatic iron. In both of these studies nonresponders appeared to have higher HICs. In this patient group, HIC may not be a good predictor of response to treatment with interferon as it is primarily due to parenterally acquired iron. A raised HIC in thalassemic patients may not be directly comparable to a raised HIC in nonthalassemic patients. In the latter, a high HIC is perhaps a better reflection of disease severity than in thalassemia. In the Sievert study, the relatively high sustained response rates may in part be due to the young age of the patient group and the overall low fibrosis scores. However, in this group iron overload itself does not seem to be a major factor in the success of viral eradication. In patients with chronic hepatitis C with no other cause for iron overload, iron itself may be a cofactor in the development of liver injury and correlate with disease severity. This could explain the reduced response rates to interferon in patients with raised HIC and also the beneficial biochemical and histological findings after phlebotomy. Unfortunately, however, there is currently a paucity of evidence to show that iron reduction aids successful viral eradication, which remains the gold standard in the treatment of hepatitis C. aDepartment of Medicine, University of Western Australia, Perth, Australia bDepartment of Gastroenterology, Fremantle Hospital, Fremantle, Australia ----------------------------------------------------------------------------- To subscribe, send a blank message to mailto:[email protected] To unsubscribe, send a blank message to mailto:[email protected] To change your email address, send a message to mailto:[email protected] with your old address in the Subject: line Web Archive of all messages is at:http://dispatch.mail-list.com/archives/hbv_research