Gamberini Maria Rita, De Sanctis Vincenzo, Gilli Giuseppe
Department of Reproduction and Growth, Paediatric and Adolescent Unit, S. Anna Hospital, Ferrara, Italy.
Pediatr Endocrinol Rev. 2008 Oct;6 Suppl 1:158-69.
273 patients with thalassaemia major followed from diagnosis in the Ferrara Centre were divided into 3 cohorts (C) according to the year of birth (C1=1954-1964, 85 patients; C2=1965-1974, 129 patients; C3=1975-2001, 59 patients) in order to study the trends of endocrine complications. Menarche occurred in 52 out of 112 patients (46%), without significant differences among the 3 groups, at the mean age of 13.9+/-1.4 years. Sixty-five percent of these patients had secondary amenorrhoea at the mean age of 18.8+/-3.7 years. In males complete pubertal development occurred in 48% of patients (C1:31%, C2: 44%, C3: 63%, p<0.05) followed by secondary hypogonadism in 24% of patients above 21 years of age. Primary (80%) and central 20%) hypothyroidism were diagnosed in 31% of patients (C1: 55%, C2: 31.5%, C3: 13.4%, p<0.05), diabetes mellitus (DM) in 17% of patients (C1: 28.6%, C2: 17.2%, C3: 3.4%, p<0.05), and hypoparathyroidism in 10.6% of cases (C1: 18.7%, C2: 10.1%, C3: 3.4%, p<0.05). No difference was found in patient mean age of diagnosis of hypothyroidism, DM or hypoparathyroidism (20.4+/-8.2 years, 19+/-5 yrs and 18.5+/-5.8 yrs respectively) but in all three groups age at diagnosis significantly increased over time (hypothyroidism and DM: p<0.001; hypoparathyroidism: p<0.01). Over time the prevalence of hypothyroidism, diabetes mellitus and hypoparathyroidism increased to 24.4%, 14.7%, and 6.7%, respectively, at the time of the study. Incidences peaked in the early 1980's, and declined in the following years (primary hypothyroidism from 6.5% in 1981 to 0.9% in 2007, p<0.01; DM from 3.9% in 1986 to 0.8% in 2007, p<0.05; hypoparathyroidism 2.4% in 1984 to 0% in 2007, p<0.01) and correlated with the decrease in annual mean serum ferritin levels in all patients (p<0.001). The main risk factors associated with endocrine complications were high serum ferritin levels, poor compliance with desferioxamine (DFO) therapy, early onset of transfusion therapy (only for hypogonadism) and splenectomy (only for hypothyroidism). Serum ferritin levels of approximately 2000 ng/ml were found to correlate with hypogonadism, and 3000 ng/ml for hypothyroidism, hypoparathyroidism and DM. The incidences of hypothyroidism, DM and hypoparathyroidism were not significantly different in 18 patients on long term treatment with deferiprone (DPO) compared with 64 patients continuously treated with DFO, from 1995 to 2007. In conclusion, our longitudinal study shows that in the last 30 years in the Ferrara Centre the incidences of hypothyroidism, diabetes mellitus, and hypoparathyroidism declined, and pubertal development in males with thalassemia major improved in patients, on DFO treatment, born after 1976. The efficacy of alternative chelation regimes with deferiprone or deferasirox to monotherapy with desferioxamine remains to be established.
在费拉拉中心，对273例从确诊开始随访的重型地中海贫血患者，根据出生年份分为3组队列（C）（C1 = 1954 - 1964年，85例患者；C2 = 1965 - 1974年，129例患者；C3 = 1975 - 2001年，59例患者），以研究内分泌并发症的趋势。112例患者中有52例（46%）出现月经初潮，3组之间无显著差异，平均初潮年龄为13.9±1.4岁。这些患者中有65%在平均年龄18.8±3.7岁时出现继发性闭经。男性患者中48%完成青春期发育（C1：31%，C2：44%，C3：63%，p<0.05），21岁以上患者中有24%出现继发性性腺功能减退。31%的患者被诊断为原发性（80%）和中枢性（20%）甲状腺功能减退（C1：55%，C2：31.5%，C3：13.4%，p<0.05），17%的患者患糖尿病（DM）（C1：28.6%，C2：17.2%，C3：3.4%，p<0.05），10.6%的病例患甲状旁腺功能减退（C1：18.7%，C2：10.1%，C3：3.4%，p<0.05）。甲状腺功能减退、糖尿病或甲状旁腺功能减退患者的平均诊断年龄无差异（分别为20.4±8.2岁、19±5岁和18.5±5.8岁），但在所有3组中，诊断年龄均随时间显著增加（甲状腺功能减退和糖尿病：p<0.001；甲状旁腺功能减退：p<0.01）。随着时间推移，在研究时甲状腺功能减退、糖尿病和甲状旁腺功能减退的患病率分别增至24.4%、14.7%和6.7%。发病率在20世纪80年代初达到峰值，随后几年下降（原发性甲状腺功能减退从1981年的6.5%降至2007年的0.9%，p<0.01；糖尿病从1986年的3.9%降至2007年的0.8%，p<0.05；甲状旁腺功能减退从1984年的2.4%降至2007年的0%，p<0.01），且与所有患者年均血清铁蛋白水平下降相关（p<0.001）。与内分泌并发症相关的主要危险因素为血清铁蛋白水平高、去铁胺（DFO）治疗依从性差、输血治疗开始早（仅针对性腺功能减退）和脾切除术（仅针对甲状腺功能减退）。发现血清铁蛋白水平约2000 ng/ml与性腺功能减退相关，3000 ng/ml与甲状腺功能减退、甲状旁腺功能减退和糖尿病相关。1995年至2007年，与64例持续接受DFO治疗的患者相比，18例接受去铁酮（DPO）长期治疗的患者中，甲状腺功能减退、糖尿病和甲状旁腺功能减退的发病率无显著差异。总之，我们的纵向研究表明，在过去30年里，费拉拉中心甲状腺功能减退、糖尿病和甲状旁腺功能减退的发病率下降，1976年后出生、接受DFO治疗的重型地中海贫血男性患者的青春期发育得到改善。去铁酮或地拉罗司替代去铁胺单药治疗的疗效仍有待确定。
