去铁酮用于重型地中海贫血的铁螯合疗法的长期安全性和有效性

Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major.

作者信息

Olivieri N F, Brittenham G M, McLaren C E, Templeton D M, Cameron R G, McClelland R A, Burt A D, Fleming K A

机构信息

Department of Medicine, University of Toronto, ON, Canada.

出版信息

N Engl J Med. 1998 Aug 13;339(7):417-23. doi: 10.1056/NEJM199808133390701.

DOI:10.1056/NEJM199808133390701

PMID:9700174

Abstract

BACKGROUND

Deferiprone is an orally active iron-chelating agent that is being evaluated as a treatment for iron overload in thalassemia major. Studies in an animal model showed that prolonged treatment is associated with a decline in the effectiveness of deferiprone and exacerbation of hepatic fibrosis.

METHODS

Hepatic iron stores were determined yearly by chemical analysis of liver-biopsy specimens, magnetic susceptometry, or both. Three hepatopathologists who were unaware of the patients' clinical status, the time at which the specimens were obtained, and the iron content of the specimens examined 72 biopsy specimens from 19 patients treated with deferiprone for more than one year. For comparison, 48 liver-biopsy specimens obtained from 20 patients treated with parenteral deferoxamine for more than one year were similarly reviewed.

RESULTS

Of the 19 patients treated with deferiprone, 18 had received the drug continuously for a mean (+/-SE) of 4.6+/-0.3 years. At the final analysis, 7 of the 18 had hepatic iron concentrations of at least 80 micromol per gram of liver, wet weight (the value above which there is an increased risk of cardiac disease and early death in patients with thalassemia major). Of 19 patients in whom multiple biopsies were performed over a period of more than one year, 14 could be evaluated for progression of hepatic fibrosis; of the 20 deferoxamine-treated patients, 12 could be evaluated for progression. Five deferiprone-treated patients had progression of fibrosis, as compared with none of those given deferoxamine (P=0.04). By the life-table method, we estimated that the median time to progression of fibrosis was 3.2 years in deferiprone-treated patients. After adjustment for the initial hepatic iron concentration, the estimated odds of progression of fibrosis increased by a factor of 5.8 (95 percent confidence interval, 1.1 to 29.6) with each additional year of deferiprone treatment.

CONCLUSIONS

Deferiprone does not adequately control body iron burden in patients with thalassemia and may worsen hepatic fibrosis.

摘要

背景

去铁酮是一种口服活性铁螯合剂，正在作为重型地中海贫血铁过载的一种治疗方法进行评估。动物模型研究表明，长期治疗与去铁酮疗效下降及肝纤维化加重有关。

方法

每年通过对肝活检标本进行化学分析、磁测法或两者结合来测定肝脏铁储存量。三位对患者临床状况、标本获取时间及标本铁含量不知情的肝脏病理学家检查了19例接受去铁酮治疗一年以上患者的72份活检标本。作为对照，同样检查了20例接受肠外去铁胺治疗一年以上患者的48份肝活检标本。

结果

在接受去铁酮治疗的19例患者中，18例持续用药，平均（±标准误）4.6±0.3年。在最终分析时，18例中有7例肝脏铁浓度至少为每克肝脏湿重80微摩尔（重型地中海贫血患者该值以上时心脏病风险及早期死亡风险增加）。在19例接受一年以上多次活检的患者中，14例可评估肝纤维化进展情况；在20例接受去铁胺治疗的患者中，12例可评估进展情况。5例接受去铁酮治疗的患者出现纤维化进展，而去铁胺治疗组无一例出现（P = 0.04）。通过寿命表法，我们估计去铁酮治疗患者纤维化进展的中位时间为3.2年。在对初始肝脏铁浓度进行校正后，去铁酮治疗每增加一年，纤维化进展的估计比值增加5.8倍（95%置信区间，1.1至29.6）。