December 2007 Vol 8 After Meeting.indd SULTAN QABOOS UNIVERSITY MEDICAL JOURNAL DECEMBER 2007 VOL 7, NO. 3, P. 215-218 SULTAN QABOOS UNIVERSITY© SUBMITTED - 14TH APRIL 2007 ACCEPTED - 19TH SEPTEMBER 2007 1Faculty of Medicine, Cairo University, Cairo, Egypt; 2Pharmacy Department, Sultan Qaboos University Hospital, Muscat, Oman; 3Royal Hospital, Muscat, Sultanate of Oman *To whom correspondence should be addressed. Email: ial_zakwani@yahoo.com Hypoparathyroidism in Adult Patients with Beta-Thalassemia Major Gihan Ali A M Sleem,1 *Ibrahim S Al-Zakwani,2 Muhanna Almuslahi3 ABSTRACT Objective: To evaluate the prevalence of hypoparathyroidism in adult transfusion-dependent patients with beta-tha- lassemia major in a teaching referral hospital in Oman. Methods: All adult (>3 years) patients with beta-thalassemia major seen at Royal Hospital in Oman between 2004 and 2006 were studied. Demographic, pharmaceutical, clinical and biochemical data were collected for all the subjects. Analyses were performed using both descriptive and univariate statistics. Results: A total of 3 patients were included into the study with an overall mean age of 9±3 years ranging from 4 to 30 years. Just over half of the subjects were males (n=6; 52%). All the patients were on hypertransfusion and combined chelation therapy with desferrioxamine 40-60 mg/kg 5 days per week and deferiprone 75 mg/kg/day. Three of the patients had low levels of parathyroid hormone (<.6 pmol/l). A further three patients had normal levels of parathyroid hormone (.6 – 9.3 pmol/l) in the presence of low serum calcium levels (<2. mmol/l). These patients (with normal hypoparathyroid hormone levels, but lower calcium levels) were also defined to have hypoparathyroidism bringing the total prevalence of hypoparathyroidism in this cohort of adult patients with Beta-thalassemia major to 9% (6 out of 3). The patients with hypoparathyroidism had statistically significantly lower levels of parathyroid hormone (2.7 versus 5.3 pmol/l; p=0.03) and serum calcium (.7 versus 2.3 pmol/l; p=0.004) compared to those without hypoparathyroidism. Conclusion: The preva- lence of hypoparathyroidism in adult beta-thalassemia major patients at this referral center was significantly higher (9%) than those reported elsewhere (2.5 and 0.7%). Keywords: Hypoparathyroidism; Thalassemia major; Beta-thalassemia; Oman. الدم ثالسيميا مبرض املصابني البالغني املرضى لدى رَيْقات الدُّ صورُ قُ بيتا نوع الرئيسي املصلحي مهنا ، الزكواني سعود إبراهيم ، سليم عبداملولى جيهان علي نقل على واملعتمدين بيتا نوع ــي الدم الرئيس ــيميا ثالس مبرض املصابني املرضى البالغني لدى رَيْقات قُصورُ الدُّ ــار إنتش معدل امللخص: الهدف: تقييم مبرض واملصابني 13 سنة) من (أكثر املرضى البالغني جميع املقطعية الدراسة هذه الطريقة: شملت مان. عُ في مستشفى تعليمي مرجعي في الدم الدميغرافية املعطيات جمع مت .2006 – 2004 بني ما مان للفترة عُ في السلطاني املستشفى في العالج تلقوا ممن بيتا نوع الرئيسي الدم ثالسيميا االحادي. واملتغير الوصفي االحصائي التحليل ــتخدام باس البيانات حتليل مت املرضى. جلميع احليوية بالكيمياء املتعلقة واملعلومات ــريرية والدوائية والس بقليل النصف من أكثر الذكور عدد كان ــنة. 14 - 30 س ، ومداها مابني ــنة 19 ± 3 س أعمارهم ــط متوس 31 مريضا ــة الدراس ــملت النتائج: ش 40-60 ملجرام/ ديسفيروكسامني اخلَلْب باستخدام لعالج باالضافة ، مفرط بشكل الدم نقل لعملية املرضى جميع خضع (%52) (16 مريضا). 1.6 (أقل من 3 مرضى ــي ف منخفضاً ة كان رَيقَ الدُّ ــون هرم وجد أن معدل يومياً. ــم 75 ملجرام/كج وديفيربرون ــبوعياً ، أس ــة أيام خمس ــم ملدة كج 2.1 (أقل من الدم لكالسيوم منخفض معدل مع (1.6 - 9.3 بيكومول/لتر) آخرين 3 مرضى لدى طبيعياً الهرمون معدل كان بينما بيكومول/لتر)، من يعانون كمرضى الدم) ــيوم لكالس منخفض ومعدل الدريقة غدد هرمون من عادي معدل لديهم (ممن الثالثة املرضى هؤالء تعريف مت لتر). ملمول/ يصل الرئيسي بيتا نوع الدم ثالسيميا مبرض واملصابني البالغني املرضى من اموعة هذه في املرض إنتشار معدل يجعل مما الدريقة نشاط غدد إنخفاض معدل منخفض لديهم املصابني أن وجد املصابني, ــع غير م الدريقة غدد ــاط بانخفاض نش املصابني املرضى مقارنة عند .(31 أصل (6 من 19% ــى إل كانت . 2.3 بيكومول/لتر) (1.7 مقابل لكالسيوم الدم ومعدل منخفض ((p=0.031 5.3 بيكومول/لتر) (2.7 مقابل الغدد تلك هرمون من نوع الرئيسي الدم ثالسيميا مبرض واملصابني البالغني املرضى في الدريقة غدد نشاط إنخفاض إنتشار معدل اخلالصة: أن قيمة احصائية. النتائج ذات .(10.7% (2.5 و أماكن أخرى في املسجلة من املعدالت بوضوح أعلى وهو ،(19%) هو املرجعي املركز هذا في بيتا . عمان ، بيتا نوع ثالسيميا الدم ، الرئيسي الدم ثالسيميا رَيْقات ، الدُّ الكلمات: قُصورُ مفتاح C L I N I C A L A N D B A S I C R E S E A R C H 216 G I H A N A L I A B D U L M AW L A S L E E M , I B R A H I M S AU D A L - Z A K WA N I A N D M U H A N N A A L M U S L A H I BETA-THALASSEMIA MAJOR, FIRST DESCRIBED by Cooly and Lee in 1925,1 is a haemoglob-inopathy caused by a defect in the produc- tion of the B globin chain. The disease is manifested by anaemia, hepato-splenomegaly, growth retarda- tion, bone changes and jaundice. The combination of regular blood transfusion and chelation has extended the life span of these patients.2, 3 However, despite che- lation therapy, regular blood transfusion led to iron overload, that resulted in frequent endocrine compli- cations including hypogonadism, diabetes mellitus, hypothyroidism and hypoparathyroidism.4 Hypoparathyroidism secondary to siderosis, first described by Gabriele in 1971,5 is now a well recog- nized complication of regular blood transfusion oc- curring in the second decade of life; however, the in- cidence of hypoparathyroidism varies from centre to centre.6 Asymptomatic hypocalcaemia is common in these patients and may be missed for some; thus it is important to check for hypocalcaemia in the presence of mild hypoparathyroidism, especially in the second decade of life. Improvement in chelation therapy has largely resulted in the reduction of the prevalence of hypoparathyroidism, but has yet to eliminate it entirely.7, 8 The current study was conducted to determine the prevalence of hypoparathyroidism as well as the description of the various clinical and biochemical parameters in a group of adult patients with beta-tha- lassemia major at the Royal Hospital, a tertiary care hospital in Muscat, Sultanate of Oman. M E T H O D S The study included all adult patients (>13 years) with beta-thalassemia major being treated at the Royal Hos- pital in Oman. All the patients were on a hypertrans- fusion regimen and combined chelation therapy with desferrioxamine 40-60 mg/kg 5 days per week and de- feriprone 75 mg/kg/day. The demographic and clinical data of all the patients studied were obtained including age, sex, height, body weight, age at first blood trans- fusion , age at start of regular desferrioxamine chela- tion, duration of iron chelation, compliance, history of splenectomy and laboratory investigations, including average serum ferritin level in the last year and hepa- titis C virus (HCV) seropositivity. All patients were tested to detect whether they are hypoparathyroid. The tests included serum calcium (total), phosphorus, alkaline phosphatase and parathyroid hormone levels. Hypoparathyroidism was defined as low levels of par- athyroid hormone (<1.6 pmol/l) or normal levels of parathyroid hormone (1.6-9.3 pmol/l) in the presence of low serum calcium levels (<2.1 mmol/l). R E S U L T S A total of 31 patients were included in the study. The demographic and clinical characteristics of the study cohort are shown in Table 1. Just over half of the pa- tients were males (n=16; 52%). The overall mean age of the cohort was19±3 years; the age range being from 14 to 30 years. The mean age at first blood transfusion and start of iron chelation therapy was 18±18 months and 9±6 years, respectively. Less than half of the co- hort had good compliance with iron chelation therapy (n=13; 42%). Nearly two thirds of the cohort had hepa- titis C antibodies (n=18; 58%), while just under a third of the patients had had their spleens removed (n=9; 29%). Three of the patients had low levels of parathy- roid hormone (<1.6 pmol/l). A further three patients had normal levels of parathyroid hormone (1.6-9.3 pmol/l) in the presence of low serum calcium levels (<2.1 mmol/l). These were also considered to be in a Advances in Knowledge Despite the small sample size, this study provides the only available published literature on the prevalence estimate of hypoparathyroidism in adult patients with beta-thalassemia major in the Arabian Gulf. It also adds to the cur- rent scant evidence that no correlation exists between serum ferritin and parathyroid hormone levels. Application to Patient Care Because of its significant prevalence (19%), all adult beta-thalassemia major patients should be routinely moni- tored for any signs and symptoms of hypoparathyroidism. Serum ferritin is not a good or reliable indicator of the development of hypoparathyroidism. It is therefore recommend that the parathyroid function be tested periodically, particularly when iron overload-associated complications occur. 217 H Y P O PA R AT H Y R O I D I S M I N A D U LT PAT I E N T S W I T H B E TA -TH A L A S S E M I A M A J O R hypoparathyroidism state bringing the total preva- lence of hypoparathyroidism in this cohort of major beta-thalassemia patients to 19% (6 out of 31). The patients with hypoparathyroidism had statisti- cally significantly lower levels of parathyroid hormone compared to those without hypoparathyroidism, (2.7 versus 5.3 pmol/l; p=0.031). All the patients in the hy- poparathyroidism group had hepatitis C antibodies compared to only 48% in the cohort without hypopar- athyroidsm, and this difference was statistically sig- nificant (100% versus 48%; p=0.025). The cohort with hypoparathyroidism also had statistically significantly lower levels of serum calcium than those without hy- poparathyroidism (1.7 versus 2.3 pmol/l; p=0.004). The hypoparathyroidism group had also higher levels of serum ferritin (5967 versus 5340 mcg/l; p=0.788), phosphorous (2.1 versus 1.6 mmol/l; p=0.072), and alkaline phosphatase (182 versus 124 iu/l; p=0.182). However, the differences were not statistically signifi- cant. Furthermore, there was also no correlation be- tween serum ferritin levels and parathyroid hormone levels (r=-0.015; p=0.935). D I S C U S S I O N Endocrinopathies, of which hypoparathyroidism is one of the most common, are a well recognized com- plication of beta-thalassemia major due to chronic anaemia, hypoxia and iron overload.9, 10 The prevalence of hypoparathyroidism in our study was 19%, which is significantly higher compared to other studies (2.5% and 10.7%).11, 12 One of the possible explanations of this finding is the older age at which regular home chela- tion by desferrioxamine was initiated in our patients. Contrary to expectations of a positive correlation between serum ferritin levels and hypoparathyridism, there were no significant differences in serum ferri- tin levels between those with hypoparathyridism and those without hypoparathyridism. Several explana- tions can be put forth for this finding. The serum fer- ritin level can be subjected to changes with intercur- rent infection and hence it is not a reliable indicator of the development of hypoparathyroidism. Another explanation is the individual susceptibility to iron toxic effect or the development of organ damage by severe iron overload in the many years preceding the initiation of chelation therapy. Angelopoulos et al.13 also found no correlation between serum ferritin lev- els and hypoparathyroidism. They went on to recom- Characteristic All (n=31) Hypoparathyroidism* No (n=25) Yes (n=6) p-value Age, years, mean±SD 19±3 18±3 21±5 0.172 Male gender, n (%) 16 (52%) 13 (54%) 3 (43%) 1.000 Age at first blood transfusion, months, mean±SD 18±18 14±11 31±30 0.170 Age at start of iron chelation therapy, years, mean±SD 9±6 8±5 10±8 0.297 Number of patients with good compliance**, n (%) 13 (42%) 11 (44%) 3 (43%) 1.000 Ferritin, mcg/l, mean±SD 5461±3268 5271±2775 5340±2738 0.788 Calcium, mmol/l, mean±SD 2.2±0.26 2.3±0.08 1.7±0.28 0.005 Phosphorous, mmol/l, mean±SD 1.7±.35 1.6±0.26 2.1±0.47 0.072 Alkaline phosphatase, iu/l, mean±SD 135±58 125±44 182±91 0.182 Parathyroid hormone, pmol/l, mean±SD 4.8±2.1 5.3±1.7 2.7±2.2 0.031 Hepatitis C infection, n (%) 18 (58%) 11 (46%) 6 (100%) 0.028 Splenectomized, n (%) 9 (29%) 6 (25%) 3 (50%) 0.320 *Hypoparathyroidism was defined as those who had low levels of parathyroid hormone (<1.6 pmol/l) or those with normal levels of parathyroid hormone (1.6 – 9.3 pmol/l), but with lower levels of serum calcium (<2.1 mmol/l). **Good compliance was defined as the regular use of subcutaneous desferrioxamine in a dose of 40-60 mg/kg 5 times per week. SD = Standard deviation; Percentages are column percents; p-values were generated using Student’s t-tests, Pearson’s χ2test, and Fisher’s Exact test whenever appropriate. Table 1: Demographic and clinical characteristics of the major beta-thalassemia cohort stratified by hypoparathyroidism* status (N=31) 218 G I H A N A L I A B D U L M AW L A S L E E M , I B R A H I M S AU D A L - Z A K WA N I A N D M U H A N N A A L M U S L A H I mend that the parathyroid function to tested periodi- cally, particularly when other iron overload-associated complications occur. Several studies have implicated genetic risk fac- tors in the development of chronic complications of beta-thalassemia major. Filosa et al. 14 have shown that hypogonadism and severity of osteoporosis in patients with transfusion dependant beta-thalassemia major are related to the haematologic phenotype; patients with B0/B0 phenotype presented more frequently with hypogonadism and severe osteoporosis. Previous published reports have already demonstrated a rea- sonable correlation between hypoparathyroidism and other endocrinopathies; 15, 16 therefore, it is reasonable to assume that the beta-thalassemia genotype is also responsible for the expression of endocrinopathies. However, this is only an assumption and further stud- ies are needed to corroborate this hypothesis. The re- sults of this study should only be applied in the context of its limitations, namely: small sample size, testing of B0/B0 genotyping, as well as lack of the details of some of laboratory measurements such as vitamin D and magnesium. A C K N OW L E D GE ME N T The authors would like to thank Mr. Waiel Al-Naeem for his help in providing the Arabic translation. R E F E R E N C E S 1. Cooly TB, Lee P. A series of cases of splenomegaly in children with anaemia and peculiar bone changes. Trans Am Pediatr Soc 1925; 37:29-30. 2. Zurlo MG, De Stefano P, Borgna-Pignatti C, Di Palma A, Piga. A, Melevendi C, et al. Survival and cases of death in thalassemia major. Lancet 1989; 2:27-30. 3. Borgna-Pignatti C, Rugolloto S, De Stefano P, Piga A, Di gregorio F, Gamberini MR, et al. Survival and disease complication in thalassemia major. Ann NY Acad Sci 1998; 850:227-231. 4. Italian Working Group on endocrine complications in non endocrinal diseases. Multicentre study on preva- lence of endocrine complications in thalassemia major. Clin Endocrinol 1995; 42:581-586. 5. Gabriele OF. Hypoparathyroidism associated with tha- lassemia. South Med J 1971; 64:115-116. 6. Chern JP, Lin KH. Hypoparathyroidism in transfusion dependent patients with beta- thalassemia. J Pediatr Haematol Oncol 2002; 24:291-293. 7. Olivieri NF. Medical Progress: the beta-thalassemias. N Engl J Med 1999; 341:99-109. 8. Rund D, Rachmilewitz E. Thalassemia major 1995: older patients, new therapy. Blood Rev 1995; 9:25-32. 9. Oerter KE , Kamp GA, Munson PJ, Nienhis AW, Cas- sorla FG, Manasco PK. Multiple hormone deficiencies in children with haemochromatisis. J Clin Endoc Metab 1993; 76:357-361. 10. Sonakal D. Endocrine pathology. In: Brancati C, ed. Thalassemia, Endocrine Disorders. Berlin: Springer- Verlag, 1995. p. 75-82. 11. Gabutti V, Piga A. Results of long-term iron–chelating therapy. Acta Hematol 1996; 95:6-36. 12. Chern JP, Lin KH. Hypoparathyroidism in transfusion- dependent patients with beta-thalassemia. J Pediatr He- matol Oncol 2002; 24:291-293. 13. Angelopoulos NG, Goula A, Rombopoulos G, Kaltzidou V, Katounda E, Kaltsas D, et al. Hypoparathyroidism in transfusion-dependent patients with beta-thalassemia. J Bone Miner Metab 2006; 24:138-145. 14. Filosa A, Di Maio S, Vocca S, Saviano A, Esposito G, Pagano L et al. Longitudinal monitoring of bone min- eral density in thalassemic patients: genetic structure and osteoporosis. Acta Paediatr 1997; 86:342-346. 15. Borgna-Pignatti C, De Stefano P, Zonta L, Vullo C, De Sanctis V, Melevendi C, et al. Growth and sexual matu- ration in thalassemia major. J Pediatr 1985; 106;150- 155. 16. Aydinok Y, Dacran S, Plat A, Kavakli K, Nigli G, Coker M, et al. Endocrine Complications in patients with beta- thalassemia major. J Trop Pediatr 2002; 48:50-54.