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发表于 2002-4-11 03:00
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
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