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- Materials and methods
Recently introduced chelation regimens that combine deferoxamine (DFO) and deferiprone have been shown to have greater efficacy in promoting iron excretion than either chelator alone and have been associated with rapid reduction of the iron load in the heart and liver, and with reversal of cardiac dysfunction. It is unclear whether this combined therapy could be associated with a reduction in iron load or decline in the severity of iron-induced endocrinopathies. Starting in January 2001, 42 patients with β-thalassaemia major, previously maintained on subcutaneous DFO only, were switched to combined treatment with DFO and deferiprone. The primary endpoint was to investigate the effects of this therapy on the glucose metabolism characteristics of this population. Combination therapy markedly decreased ferritin levels (638 ± 1345 vs. 2991 ± 2093 μg/l, P < 0·001). Glucose responses were improved at all times during an oral glucose tolerance test, particularly in patients in early stages of glucose intolerance. Glucose quantitative secretion also decreased significantly with combined therapy, while no significant change occurred in insulin levels in any group. Insulin secretion, according to the homeostasis assessment model, markedly increased in all groups, while overall reduction in insulin sensitivity did not reach statistical significance. This study showed that the combination of DFO and deferiprone was associated with an improvement in liver iron deposition and glucose intolerance.
Traditionally, insulin deficiency (Saudek et al, 1977) and long-standing insulin resistance (De Sanctis et al, 1988; Merkel et al, 1988; Pappas et al, 1996) that result from direct toxic damage by iron to pancreatic-beta cells are thought to be the main underlying mechanisms leading from mild glucose intolerance to overt diabetes. As these endocrine complications result from chronic iron overload, they are much more common in patients whose chelation therapy is insufficient.
On the other hand, although deferoxamine (DFO) is still widely used in chelation therapy, deferiprone has become a promising alternative for the treatment of iron overload. Another encouraging new approach to chelation therapy has been the combined administration of deferiprone and DFO (Link et al, 2001; Mourad et al, 2003). Several clinical studies have demonstrated that long-term combination therapy, in which deferiprone is given every day and DFO is given on 2–4 d/week, is effective in reducing serum ferritin and liver iron levels in patients who were inadequately chelated on DFO or deferiprone alone (Hoffbrand et al, 2003; Mourad et al, 2003). Considering that the efficacy in mobilising iron deposition seems to be tissue specific and differs from the results obtained with deferiprone or DFO alone (Saudek et al, 1977; Pappas et al, 1996), the overall effects of such a combination on beta-cell function remain unknown. Currently, there are no available data regarding the effects of deferiprone on glucose metabolism while poor compliance, iron overload and liver disease (cirrhosis or severe fibrosis) have emerged as the main risk factors associated with diabetes in patients treated with DFO (Gamberini et al, 2004). The present study aimed to determine the effects of combined therapy on glucose metabolism in β-thalassaemic patients without overt diabetes who had been inadequately chelated with DFO monotherapy. Possible correlations between the various insulin secretion and sensitivity indices during an oral glucose tolerance test (OGTT), with the treatment parameters were further assessed.
- Top of page
- Materials and methods
Deferoxamine has been an important chelator (Brittenham et al, 1994), but its large, positively charged and relatively lipophobic molecule that undergoes conformational change upon binding iron, makes it unsuitable for chelation of intracellular iron, except when an active excretion pathway is present (Piga et al, 2003). Deferiprone, on the other hand, can penetrate the cell membrane and chelate toxic intracellular iron species (Shalev et al, 1995), leading to a more potent removal of myocardial iron (Shalev et al, 1995; Piga et al, 2003; Pennell et al, 2006; Borgna-Pignatti et al, 2006).
Because of these differences in chelation properties of DFO and deferiprone, combination therapy with these chelators has been an attractive alternative for the treatment of transfusional iron overload (Mourad et al, 2003). Indeed, the combined use of both chelators is associated with additive or synergistic iron excretion, a rapid reduction of the iron load in the heart and liver and reversal of cardiac dysfunction (Alymara et al, 2004; Origa et al, 2005; Kattamis et al, 2006). Whether the overall improvement in glucose metabolism that was achieved in our patients can be solely attributed to the intensification of chelation therapy and better compliance or if there is a tissue-specific effectiveness of deferiprone in iron removal from pancreas is debatable.
Although iron deposition on pancreatic parenchyma seems to play a major role in the onset of diabetes, no link has been shown between the development of the disease and ferritin levels in long-term chelated patients (De Sanctis et al, 1986; Telfer et al, 2000). This indicates that additional factors, such as genetic susceptibility and insulin resistance, may also be important in its underlying aetiology. It is noteworthy that insulin resistance may originate from iron deposition in both the liver (where iron deposits may interfere with insulin's ability to suppress hepatic glucose production) and muscle tissue (where iron deposits may decrease glucose uptake because of muscle damage) (Merkel et al, 1988).
Based on the above, a reduction in liver iron concentration could be associated with increased insulin sensitivity. Interestingly, such an improvement in the current cohort of patients was scant and only observed in the IFG and diabetes groups, supporting the concept that a defect in insulin secretion would be more crucial in the progress of glucose intolerance than would a decrease in insulin sensitivity. In support of the above speculation, we did not detect significant differences in insulin sensitivity between normal and abnormal glucose metabolism, either before or after combination therapy.
Chern et al (2001) reported that chronic hepatitis C infection was an independent risk factor for abnormal glucose tolerance. In contrast, we found no relationship between hepatitis C infection and glucose intolerance, probably because none of our patients had evident hepatic dysfunction or signs of cirrhosis. Although liver biopsies were not available in the present study, none of our patients showed increased liver enzymes during combination therapy, in accordance with previous reports (Wonke et al, 1998; Mourad et al, 2003; Origa et al, 2005).
To our knowledge, this is the first report documenting the beneficial effect of long-term combined therapy on glucose metabolism in thalassaemic patients. Not only was NGT achieved in a significant proportion of our patients, but also the cumulative glucose response significantly improved with this regimen. A profound improvement in glucose disturbances (reflected by the AUC calculation) was found in IGT and IFG patients, although the improvement in diabetic patients was less impressive. Our interpretation of this finding is that beta-cell dysfunction in diabetic patients is more severe, and thus probably irreversible by intensive chelation, in the majority of this population. Both insulin secretion and sensitivity was noticeably increased in this group, but did not sufficiently affect hyperglycaemia.
Ferritin levels did not accurately predict development of abnormal glucose metabolism, and this was also the case prior to initiation of combined therapy. It was recently demonstrated that the degree of iron overload, at least reflected by ferritin levels, was not associated with the development of other endocrine complications (Cario et al, 2003; Angelopoulos et al, 2005, 2006a,b,c,d,e). This indicates that long-term iron balance, rather than current iron status, is related to the development of glucose intolerance. In view of that observation, insulin secretion decreased, whereas the integrated glucose concentration during the OGTT was increased, with age. Early onset of chelation therapy also seems to have played an important role in ameliorating the detrimental effect of iron accumulation. We speculate that this excessive iron overload initially led to an immediate impairment of beta-cell function. However, the impairment was temporary in some patients, and their secretory capacity improved, suggesting that iron-induced toxicity is mainly time dependent.
In conclusion, we found that combination therapy with deferiprone and DFO results in an overall improvement in glucose metabolism disorders in β-thalassaemia. However, prospective trials are needed to compare the safety and efficacy of combined therapy to that of DFO or deferiprone alone in resolving other iron-induced endocrinopathies. Nevertheless, physicians caring for patients with thalassaemia major should be particularly alert to glucose metabolism, given that subclinical glucose intolerance may be present for a long period before overt diabetes develops.