Iron and the Response to Treatment of Hepatitis C

dadadada

Although this study is of patients with Hepatitis C, might just be

applicable to us with "B" too...........Sheree

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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 t