Hormone related problems (Endocrinopathies and osteoporosis) Vincenzo de Sanctis Ferrara.

Transcription

1 Hormone related problems (Endocrinopathies and osteoporosis) Vincenzo de Sanctis Ferrara 6 th EUROPEAN SYMPOSIUM ON RARE ANAEMIAS 1 st Dutch-Belgian meeting for patients and health professionals 21 st - 22 nd November 2015 Amsterdam - The Netherlands

2 This talk is applicable for: Definite Thalassemia s x - Sickle cell disease x - Membrane disorders (e.g. sferocytosis) - - Enzym defects (e.g. PKD, G6PD) - - PNH - - Other forms of hemolytic disease - - Probable

3 SCD (25 pts.) NTDT (60 pts.) Beta thalassemia major ( > 1000 pts. and 700 BMT pts.) Personal experience

4 Disclosures Company name Quisisana Hospital Research support Employee Consultant Stockholder Speakers bureau Advisory board Other None - Pediatrics and Adolescent Medicine

5 Outline Brief presentation of : 1.Prevalence of endocrine complications in TM -TI and SCD 2. Emerging problems in TM and TI 3.Osteopenia/osteoporosis in TM -TI and SCD 4.Conclusions

6 The prevalence of growth retardation and endocrine complications Endocrinopathies present in 3,174 TM patients around the world

7 THALASSEMIA Endocrine complications (% in both sexes) Cyprus (n = 435) North America (n = 262) Italy (n = 1,861) Country Iran (n = 220) Turkey (n = 252) Oman (n=144) Hypogonadism DM/IGT / /11.8 Short stature/ghd / (GHD) (GHD) Primary hypothyroidism Hypoparathyroidism DM, diabetes mellitus; GHD, growth hormone deficiency; IGT, impaired glucose tolerance. 1. Cunningham MJ, et al. Blood. 2004;104: De Sanctis V, et al. Clin Endocrinol.1995;42: Fung E, et al. Br J Haematol. 2006;135: Kattamis C, et al. Semin Hematol.1995;32: Thalassaemia International Federation Toumba M, et al. Ped Endocrinol Rev. 2007;5: Vichinsky E, et al. Am J Hematol. 2005;80: Yaprak I, et al. Klinik Arastirma. 2002;12:

8 AGE OF APPEARANCE OF ENDOCRINE COMPLICATIONS IN THALASSEMIA More than half of patients with TM, even in paediatric cohorts, have at least 1 endocrinopathy. (Early assessment) The frequency of endocrine organ damage related to iron overload increased with age (median age 36 years: 67% had hypogonadism, 14% hypothyroidism

9 NTDT encompasses a wide clinical spectrum 20 parameters were selected for inclusion in the disease severity scoring system. An additional six parameters, largely related to growth and development, were selected specifically for pediatric patients ( 16years of age). Eur J Intern Med.2015 Nov 3.. [Epub ahead of print] Development of a new disease severity scoring system for patients with non-transfusion-dependent thalassemia. Cappellini MD et al.

10 50 TI PATIENTS (21 males) ; yrs. ( mean 28.7 yr)

11 In the following years..

12 SCD SCD NTDT Beta thalassemia major

13 Growth failure and endocrine complications in SCD compared to TM Clinical evidence suggests that SCD patients are less likely to have endocrine complications

14 Subjects divided into paediatric (<21 years of age) and adult sub groups (>21 years) SUMMARY For the paediatric subgroup: Thal subjects were more likely to have growth failure, hypogonadism and diabetes compared with Tx-SCD (41.3% vs. 5.3%, 34.2% vs. 5.8%, and 10.9% vs.0.9% respectively). There were no significant differences between Tx-SCD and non-tx-scd for any of the endocrinopathies For adults: Thal subjects were more likely than Tx-SCD subjects to have growth failure (29.2% vs. 9.5%; p:0.001), hypogonadism (40.6% vs. 2.4%,p: < 0.001), hypothyroidism (12.9% vs. 1.2%, P: 0.003) and diabetes (13.7% vs. 3.5%;p:0.02). Neither recent serum ferritin levels nor LIC by biopsy was a significant predictor of endocrinopathy. There were no significant differences between Tx-SCD and non-tx-scd subjects.

15 The evidences Despite iron overload, endocrinopathy was not increased in Tx-SCD versus non-tx-scd, suggesting that the underlying disease may modulate iron-related endocrine injury. However, because transfusion duration remained a significant predictor of endocrinopathy, these data should be confirmed in SCD subjects that have been chronically transfused for longer periods of time. The protective factors in SCD

16 The protective factors in SCD Malondialdehyde levels are higher in thalassaemia compared with SCD. PROTECTIVE FACTORS In contrast, several inflammatory markers appeared higher in SCD. This inflammation in SCD may generate increased levels of γ- tocopherol, leading to decreased tissue peroxidation and injury.

17 The causes: in addition to iron overload Anaemia Chronic liver diseases Iron toxicity Ineffective erytropoiesis Nutricional deficiences Episodes of intravascular sickling, vaso-occlusion and infarction Short Stature/ Endocrine Complications/ Reduced BMD

18 Associated factors Overall, the prevalence of growth, endocrine disorders and reduced BMD is affected also by other factors such as: age of first transfusion, haemoglobin level attained before blood transfusion, degree and type of chelation, compliance with chelation, age of first exposure to chelation therapy, association with other endocrine complications and genotype.

19 Splenectomy

20 Emerging problems Malignancies/Microprolactinoma Hypoadrenalism Osteoporosis and fractures Emerging Complications HPT and intracranial calcifications Vit. D deficiency Growth hormone deficiency in adults Testicular microcalcinosis Central hypothyroidism

21 Bones in thalassemias and SCD In SCD patients an high prevalence (76%) of osteopenia in young adults: 50% spine, 31% hip.

22 Prevalence of reduced BMD in NTDT compared to TM

23 Factors contributing to reduced BMD

24 Prevalence of fractures in β- thalassemia Prevalence of fractures according to age and fracture site

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26 In summary: from the literature Despite similar iron burden, transfused patients with Thal are at greater risk for fracture than subjects with SCD. In multivariate analysis, the significant predictors of fracture prevalence were Thal diagnosis (Odds Ratio: 2.3; ; 95%CI), male gender (OR: 2.6; ), hypothyroidism (OR: 3.3; ) and age (OR: 1.1; ). Transfused subjects with SCD had no greater risk of fracture compared to nontransfused SCD. Though ethnic differences in fracture risk cannot be ignored, endocrinopathy is rare in TxSCD which may also provide some protection from fracture.

27 Osteoporosis: Prevention & Treatment

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29 Denosumab RANKL/OPG Balance Drives Osteoclast Activity Is a fully human monoclonal antibody to the receptor activator of nuclear factor kappab ligand (RANKL). Inhibits osteoclast formation Decreases bone resorption Increases bone mineral density (BMD)

30 Results and side effects Results: Denosumab therapy for a year Significant increase in BMD of : 9.2% (95% CI, 8.2 to 10.1) at the lumbar spine and 6.0% (95% CI, 5.2 to 6.7) at the total hip. Side effects in our patients Pain in the back and/or extremities 4/30 Nausea 3/30. Asymptomatic hypocalcaemia in 2/30

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32 Final considerations

33 Anemia,growth and IGF-1

34 Anemia and spermatogenesis Eighteen young adults with SCD on packed cell transfusion (10 on TTx, and eight on ETx after previous stroke during their childhood period. Patients were on iron chelation therapy using oral deferasirox in the last 3-4 years (30-40 mg/kg body weight once a day). Top-up transfusion (TTx); exchange transfusion (ETx) After PCTx significant increase of Hb from 8.5 ± 1.2 g/dl to 10.5 ± 0.4 g/dl was associated with increased concentrations of T (from 12.3 ± 1.2 nmol/l to 14.2 ± 1.2 nmol/l), LH (from 4.4 ± 0.9 U/L to 5.7 ± 0.85 U/L), and FSH (from 5.4 ± 1.46 U/L to 6.6 ± 1.8 U/L). Total sperm count increased significantly from 87.4 ± 24.6 million/ml to 146 ± 51 million/ml and rapid progressive sperm motility (RPM) increased from 29.3 ± 8.75 million/ml to 67.4 ± 29.1 million/ml. Blood transfusions packed red cell transfusion (PCTx)

35 Chelation therapy and endocrine complications: The personal experience

36 The major difficulties reported by doctors : A personal survey

37 Bulgaria- Cyprus - Egypt - Jordan Greece India Indonesia- Iran Malaysia- Oman - Qatar Romania- Russia Saudi Arabia Turkey- UK- USA

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