Hypothyroidism in patients with thalassemia syndromes

Sixty transfusion-dependent thalassemic patients were studied by simultaneous measurement of circulating thyroid hormones, basal thyroid-stimulating hormone (TSH) and TSH response to thyrotropin-releasing hormone with the aim of evaluating the frequency of hypothyroidism in such patients, and the relationship between hypothyroidism and compliance with treatment and iron overload. Thyroid failure was present in 31 of the 60 patients. A correlation was found between impairment of thyroid functions, duration of chronic hypoxia and the activities of various transaminases. The results of this study emphasize the importance of early evaluation of thyroid function in thalassemic patients and suggest that anemia and hypoxia may potentiate the toxicity of iron deposition in endocrine glands.     

T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice

Objectives: Iron‐overload cardiomyopathy is a major cause of morbidity and mortality in patients with thalassemia. However, the precise mechanisms of iron entry and sequestration in the heart are still unclear. Our previous study showed that Fe²⁺ uptake in thalassemic cardiomyocytes are mainly mediated by T‐type calcium channels (TTCC). Nevertheless, the role of TTCC as well as other transporters such as divalent metal transporter1 (DMT1) and L‐type calcium channels (LTCC) as possible portals for iron entry into the heart in in vivo thalassemic mice under an iron‐overload condition has not been investigated. Methods: An iron‐overload condition was induced in genetically altered β‐thalassemic mice and adult wild‐type mice by feeding them with an iron diet (0.2% ferrocene w/w) for 3 months. Then, blockers for LTCC (verapamil and nifedipine), TTCC (efonidipine), and DMT1 (ebselen) as well as iron chelator desferoxamine (DFO) were given for 1 month with continuous iron feeding. Results: Treatment with LTCC, TTCC, DMT1 blockers, and DFO reduced cardiac iron deposit, cardiac malondialdehyde (MDA), plasma non‐transferrin‐bound iron, and improved heart rate variability and left ventricular (LV) function in thalassemic mice with iron overload. Only TTCC and DMT1 blockers and DFO reduced liver iron accumulation, liver MDA, plasma MDA, and decreased mortality rate in iron‐overloaded thalassemic mice. Conclusions: DMT1, LTCC, and TTCC played important roles for iron entry in the thalassemic heart under an iron‐overloaded condition. Unlike LTCC blocker, TTCC blocker provided all benefits including attenuating iron deposit in both the heart and liver, reduced oxidative stress, and decreased mortality in iron‐overloaded mice.     

T-type calcium channel as a portal of iron uptake into cardiomyocytes of beta-thalassemic mice

Objectives: Iron‐overload condition can be found in β‐thalassemic patients with regular blood transfusion, leading to iron deposition in various organs including the heart. Elevated cardiac iron causes iron‐overload cardiomyopathy, a condition that provokes mortality because of heart failure in patients with thalassemia. Previous studies demonstrated that myocardial iron uptake may occur via L‐type calcium channels (LTCCs). However, direct evidence regarding the claimed pathway in thalassemic cardiomyocytes has never been investigated. Methods: Hearts from genetic‐altered β‐thalassemic mice and adult wild‐type mice were used for cultured ventricular cardiomyocytes. Blockers for LTCC, T‐type calcium channel (TTCC), transferrin receptor1 (TfR1), and divalent metal transporter1 (DMT1) were used, and quantification of cellular iron uptake under various iron loading conditions was performed by Calcein‐AM fluorescence assay. Microarray analysis was performed to investigate gene expressions in the hearts of these mice. Results: This study demonstrated that iron uptake under iron‐overload conditions in the cultured ventricular myocytes of thalassemic mice was greater than that of wild‐type cells (P < 0.01). TTCC blocker, efonidipine, and an iron chelator, deferoxamine, could prevent iron uptake into cultured cardiomyocytes, whereas blockers of TfR1, DMT1, and LTCC could not. Microarray analysis from thalassemic hearts demonstrated highly up‐regulated genes of TTCC, zinc transporter, and transferrin receptor2. Conclusions: Our findings indicated that iron uptake mechanisms in cultured thalassemic cardiomyocytes are mainly mediated by TTCC, suggesting that TTCC is the important pathway for iron uptake in this cultured thalassemic cardiomyocyte model.     

Trace elements in glucometabolic disorders: an update

Background

Thalassemic patients suffer from diabetes mellitus secondary to hemosiderosis.

Aims

The study aimed to evaluate pancreatic iron overload by T2*-weighted Gradient-echo magnetic resonance imaging (MRI) in young beta-thalassemia major patients and to correlate it with glucose disturbances, hepatic hemosiderosis, serum ferritin and splenectomy.

Methods

Forty thalassemic patients (20 non diabetic, 10 diabetic, and 10 with impaired glucose tolerance) were recruited from Pediatric Hematology Clinic, in addition to 20 healthy controls. All patients underwent clinical assessment and laboratory investigations included complete blood count, liver function tests, serum ferritin and oral glucose tolerance test (OGTT). A T2*-weighted gradient-echo sequence MRI was performed with 1.5 T scanner and signal intensity ratio (SIR) of the liver and the pancreas to noise were calculated.

Results

Significant reduction in signal intensity ratio (SIR) of the liver and the pancreas was shown in thalassemic patients compared to controls (P < 0.0001), Thalassemic patients with abnormal glucose tolerance; including diabetics and thalassemics with impaired glucose tolerance; displayed a higher degree of pancreatic and hepatic siderosis compared to thalassemics with normal glucose tolerance or controls (P < 0.001, P < 0.0001). Splenectomized thalassemic patients had significantly lower SIR of pancreas compared to non splenectomized patients (P < 0.05). A strong correlation was present between hepatic and pancreatic siderosis in studied patients (P < 0.001).

Conclusions

pancreatic siderosis can be detected by T2* gradient-echo MRI since childhood in thalassemic patients, and is more evident in patients with abnormal glucose tolerance. After splenectomy, iron deposition may be accelerated in the pancreas. Follow up of thalassemic patients using pancreatic MRI together with intensive chelation therapy may help to prevent the development of overt diabetes.     

Pituitary iron and volume predict hypogonadism in transfusional iron overload

Hypogonadism is the most common morbidity in patients with transfusion‐dependent anemias such as thalassemia major. We used magnetic resonance imaging (MRI) to measure pituitary R2 (iron) and volume to determine at what age these patients develop pituitary iron overload and volume loss. We recruited 56 patients (47 with thalassemia major, five with chronically transfused thalassemia intermedia and four with Blackfan‐Diamond syndrome) to have pituitary MRIs to measure pituitary R2 and volume. Hypogonadism was defined clinically based on the timing of secondary sexual characteristics or the need for sex hormone replacement therapy. Patients with transfusional iron overload begin to develop pituitary iron overload in the first decade of life; however, clinically significant volume loss was not observed until the second decade of life. Severe pituitary iron deposition (Z > 5) and volume loss (Z < ?2.5) were independently predictive of hypogonadism. Pituitary R2 correlated significantly with serum ferritin as well as liver, pancreatic, and cardiac iron deposition by MRI. Log pancreas R2* was the best single predictor for pituitary iron, with an area under the receiving operator characteristic curve of 0.88, but log cardiac R2* and ferritin were retained on multivariate regression with a combined r² of 0.71. Pituitary iron overload and volume loss were independently predictive of hypogonadism. Many patients with moderate‐to‐severe pituitary iron overload retained normal gland volume and function, representing a potential therapeutic window. The subset of hypogonadal patients having preserved gland volumes may also explain improvements in pituitary function observed following intensive chelation therapy. Am. J. Hematol. 2011. © 2011 Wiley Periodicals, Inc.     

Evaluation of cardiac and hepatic iron overload in thalassemia major patients with T2* magnetic resonance imaging

Objectives: Recent advancements have promoted the use of T2* magnetic resonance imaging (MRI) in the non-invasive detection of iron overload in various organs for thalassemia major patients. This study aims to determine the iron load in the heart and liver of patients with thalassemia major using T2* MRI and to evaluate its correlation with serum ferritin level and iron chelation therapy.

Methods: This cross-sectional study included 162 subjects diagnosed with thalassemia major, who were classified into acceptable, mild, moderate, or severe cardiac and hepatic iron overload following their T2* MRI results, respectively, and these were correlated to their serum ferritin levels and iron chelation therapy.

Results: The study found that 85.2% of the subjects had normal cardiac iron stores. In contrast, 70.4% of the subjects had severe liver iron overload. A significant but weak correlation (r?=??0.28) was found between cardiac T2* MRI and serum ferritin, and a slightly more significant correlation (r?=?0.37) was found between liver iron concentration (LIC) and serum ferritin.

Discussion: The findings of this study are consistent with several other studies, which show that patients generally manifest with liver iron overload prior to cardiac iron overload. Moreover, iron accumulation demonstrated by T2* MRI results also show a significant correlation to serum ferritin levels.

Conclusion: This is the first study of its kind conducted in Indonesia, which supports the fact that T2* MRI is undoubtedly valuable in the early detection of cardiac and hepatic iron overload in thalassemia major patients.     

Morbidity and mortality of adult patients with congenital dyserythropoietic anemia type I

Congenital dyserythropoietic anemia type I (CDAI) is a rare autosomal recessive disease characterized by macrocytic anemia, ineffective erythropoiesis, and secondary hemochromatosis. To better define the natural history of the disease among adult patients, we studied 32 Bedouin patients (median age 34 yr; range 21–60) all carrying the same CDAN1 founder mutation. Follow‐up studies included complete blood count, blood chemistry, abdominal ultrasound, echocardiography, and T2*MRI. Main complications were due to anemia and ineffective erythropoiesis [osteoporosis (8/9, 89%), cholelithiasis (21/30, 70%), pulmonary arterial hypertension (PAH) (6/25, 24%)] and iron overload [hypothyroidism (9/24, 38%), and diabetes mellitus (6/32, 19%)]. T2* MRI revealed increased liver iron but no cardiac iron (13/13). Anemia improved in the majority of patients who underwent splenectomy (5/6). Three patients died (9%) at the age of 46–56 due to PAH (1) and sepsis (2). All previously underwent splenectomy. Analyzing both our patients and the 21 patients previously described by Heimpel et al. (Blood 107:334, 2006), we conclude that adults with CDA I suffer significant morbidity and mortality. Careful monitoring of iron overload and prompt iron chelation therapy is mandatory. Due to possible complications and inconsistent response to splenectomy α‐interferon, transfusion therapy or stem cell transplantation should be considered as alternatives to this procedure in severely affected patients.     

Cardiac iron overload in thalassemic patients: An endomyocardial biopsy study

Secondary heart failure induced by organ siderosis is the main cause of death in patients affected by thalassemia major. At present it cannot be predicted whether heart siderosis is correlated with iron overload and little is known about the real cardiac histological pattern of post transfusional hemochromatosis in patients with thalassemia major and intermedia. The study aim was to evaluate cardiac iron overload by non invasive and invasive techniques. Fifteen thalassemic patients were investigated and endomyocardial biopsy performed in ten revealed different grades of endomyocardial iron overload with histochemical positivity. Non invasive techniques are not able to furnish an exact picture of the cardiac hemochromatosis. There was a significant correlation between serum ferritin and myocardial iron grade.Patients with elevated ferritin levels and poor compliance to chelating therapy are at high risk of severe heart hemochromatosis. It was seen that endomyocardial biopsy is a useful tool in studying myocardial iron.     

Rapid iron loading in a pregnant woman with transfusion-dependent thalassemia after brief cessation of iron chelation therapy

In general, in women with transfusion-dependent thalassemia, during pregnancy, iron chelation therapy is ceased. We report a splenectomized patient, who was an excellent complier with chelation therapy, who before embarking on a pregnancy showed no evidence of iron overload, with normal cardiac, thyroid function and glucose metabolism. Laboratory findings showed ferritin 67 μg/L, myocardial T₂* of 34 ms and liver magnetic resonance imaging (MRI) liver iron concentration of 1 mg/g dry weight. She became pregnant by in vitro fertilization in October 2006, delivery occurred in June 2007. She breast fed for 2 months. After 12 months without iron chelation, ferritin was 1583 μg/L. Quantitative MRI showed myocardial T₂* of 27 ms, that the liver iron concentration had increased to 11.3 mg/g dry weight, indicative of moderate to heavy iron load. This case demonstrates that iron overload can develop rapidly and that physicians caring for patients with transfusion-dependent thalassemia should be particularly alert to any discontinuation of chelation therapy over time.     

Hypothyroidism in adults with sickle cell anemia.

Persons with sickle cell anemia have several indications for transfusion of red blood cells. One of the complications of transfusion of red blood cells is iron overload. Iron overload has been associated with multiple endocrine abnormalities. We report herein three cases of hypothyroidism in adult individuals with sickle cell disease. All three patients were over the age of 45 years at the time of the diagnosis and had received multiple units of transfused red blood cells and had serum ferritin levels of greater than 6,000 ng/mL. All patients were diagnosed during times when they were critically ill. Replacement therapy was instituted in all cases; however, all three patients died shortly after the diagnosis of hypothyroidism was made. Congestive heart failure appeared to be a primary cause of death in all three patients. In the one patient in whom a postmortem examination was done, there was evident extensive fibrosis of the thyroid gland as well as extensive deposition of iron in the cells lining the thyroid follicles. We believe that this represents the first report of clinical hypothyroidism in patients with sickle cell anemia who have received multiple transfusions. Awareness of this condition is especially important given that congestive heart failure is common in sickle cell disease.     

Endocrine function and bone disease during long‐term chelation therapy with deferasirox in patients with β‐thalassemia major

Iron overload in β‐thalassemia major (TM) typically results in iron‐induced cardiomyopathy, liver disease, and endocrine complications. We examined the incidence and progression of endocrine disorders (hypothyroidism, diabetes, hypoparathyroidism, hypogonadism), growth and pubertal delay, and bone metabolism disease during long‐term deferasirox chelation therapy in a real clinical practice setting. We report a multicenter retrospective cohort study of 86 transfusion‐dependent patients with TM treated with once daily deferasirox for a median duration of 6.5 years, up to 10 years. No deaths or new cases of hypothyroidism or diabetes occurred. The incidence of new endocrine complications was 7% (P = 0.338, for change of prevalence from baseline to end of study) and included hypogonadism (n = 5) and hypoparathyroidism (n = 1). Among patients with hypothyroidism or diabetes at baseline, no significant change in thyroid parameters or insulin requirements were observed, respectively. Mean lumbar spine bone mineral density increased significantly (P < 0.001) and the number of patients with lumbar spine osteoporosis significantly decreased (P = 0.022) irrespective of bisphosphonate therapy, hormonal replacement therapy, and calcium or vitamin D supplementation. There were no significant differences in the number of pediatric patients below the 5th centile for height between baseline and study completion. Six pregnancies occurred successfully, and four of them were spontaneous without ovarian stimulation. This is the first study evaluating endocrine function during the newest oral chelation therapy with deferasirox. A low rate of new endocrine disorders and a stabilization of those pre‐exisisting was observed in a real clinical practice setting. Am. J. Hematol. 89:1102–1106, 2014. © 2014 Wiley Periodicals, Inc.     

Chelation therapy for iron overload

Iron overload is characterized by excessive iron deposition and consequent injury and dysfunction of the heart, liver, anterior pituitary, pancreas, and joints. Because physiologic mechanisms to excrete iron are very limited, patients with iron overload and its complications need safe, effective therapy that is compatible with their coexisting medical conditions. The availability of three licensed iron chelation drugs (one parenteral, two oral) and the development and clinical investigation of other oral chelators represent new opportunities to prevent or manage iron overload in patients with heritable types of severe anemia, such as β-thalassemia major and sickle cell disease, and for the formulation of alternatives to phlebotomy therapy for patients with iron overload associated with the HFE gene and other adult age-of-onset types of hemochromatosis, African iron overload, and African-American iron overload.     

A novel mutation causing complete deficiency of thyroxine binding globulin

OBJECTIVE Recovery of thyroid function in patients following hypothyroidism induced by ¹³¹I therapy for Graves' disease has been described, but only a few detailed clinical and biochemical studies of this phenomenon (transient hypothyroidism) have been published. The prevalence, mechanism, and final outcome of transient hypothyroidism in 260 patients with Graves’ disease treated with ¹³¹I was studied. DESIGN A retrospective study. PATIENTS Two hundred sixty patients with Graves' disease, treated with ¹³¹I between 1 and 15 years previously, were categorized into 4 groups according to their thyroid function during and 1 year after therapy (Group 1: permanent hypothyroidism, 28 patients; Group 2: transient hypothyroidism, 39 patients; Group 3: euthyroidism without transient hypothyroidism, 83 patients; Group 4: hyperthyroidism, 110 patients). MEASUREMENTS We compared total T4, total T3, TSH, anti-thyroglobulin (TGHA) and anti-microsomal (MCHA) antibodies, the TSH-binding inhibitory immunoglobulin (TBII) index, thyroid weight, dose of ¹³¹I, and 24-hour ¹³¹I uptake as pretreatment variables. The mean time for permanent hypothyroidism to develop was estimated by the Kaplan–Meier product limit method. The TBII index and thyroid stimulating antibody (TSAb) activity were measured in seven patients from Group 1 and in nine patients from Group 2 at the time that they became hypothyroid. RESULTS Hypothyroidism developing within 12 months of therapy was transient in 58% (39/67) of patients. No pretreatment variables were found to differ between patients with and without transient hypothyroidism. The mean estimated time between therapy and the development of permanent hypothyroidism was 96 months in Group 2; this time interval was significantly shorter than 126 months in Group 3 and 129 months in Group 4 (P<0.05, P<0.01, respectively). TSAb activity was > 500% in 78% (7/9) of patients from Group 2, which was significantly higher than that found (14%, 1/7) in Group 1. CONCLUSIONS These results indicate that (1) more than half the patients who developed hypothyroidism within 6 months after ¹³¹I treatment for Graves' disease recovered spontaneously, (2) TSAb activity might play some role in the recovery of transient hypothyroidism, and (3) the development of transient hypothyroidism may influence long-term thyroid function.     

Effect of iodine administration on thyroid function in diabetic patients

Summary Iodide-induced hypothyroidism has been observed in subjects treated with compounds with mild antithyroid activity. The hypoglycemic agent tolbutamide belongs to the aminoheterocyclic group, a class of compounds with antithyroid effect. Thus it was thought interesting to study the effect of large doses of iodide on thyroid function in diabetics chronically treated with tolbutamide. Basal thyroid function as assessed by clinical examination and iodothyronine and TSH concentrations was normal in all patients. Furthermore, in diabetics treated with tolbutamide, hormone concentrations were not different from those of patients treated with insulin or diet. Serum T4, T3 and TSH did not show any significant variation throughout the investigation period. Our results suggest that thyroid function is not affected by chronic treatment with tolbutamide even when large doses of iodide are administered. Supported in part by grant No. 83.00471.04 ofConsiglio Nazionale delle Ricerche, Roma, Italy.     

Five Years of Deferasirox Therapy for Cardiac Iron in β-Thalassemia Major

Abstract

Myocardial siderosis in β-thalassemia major (β-TM) remains the leading cause of death. Deferasirox (DFX), a new iron chelation treatment, has proved to be effective in reducing or preventing cardiac iron burden in thalassemic patients according to clinical trials with maximum duration of up to 3 years except one that was recently published and lasted 5 years. The aim of this study was to evaluate the efficacy of DFX in reducing or preventing cardiac iron burden in 23 patients with β-TM after 5 years of therapy. All patients had a magnetic resonance imaging (MRI) T2* evaluation of their cardiac iron load before starting DFX therapy and after a period of 5 years. Ferritin levels and left ventricular ejection fraction (LVEF) were also evaluated at the same time. Deferasirox was administered in a starting dose of 30?mg/kg/day and never increased to more than 40?mg/kg/day. The MRI T2* cardiac iron load mean values before DFX was 32.82?±?10.86?ms, and after 32.13?±?7.74?ms, showing a stability in MRI T2* myocardial value but a significant improvement in two patients with an intermediate iron load (12 vs. 23?ms). The mean LVEF value was 68.43?±?7.08% before treatment with DFX and 67.95?±?5.94% after DFX therapy without significant change. Our results confirm previous studies that DFX is considered an effective chelating agent used as monotherapy for at least 5 years and is more efficacious in moderate to severe cardiac iron loaded thalassemic patients.     

Absence of HIV DNA Sequences in Seronegative Polytransfused Thalassemic Patients

The risk of infection with human immunodeficiency virus (HIV) by transfusion is not totally eliminated, since contaminated blood given before seroconversion to HIV is not detected on the actual biological screening. We used the polymerase chain reaction (PCR) assay (with one primer pair in the gag region and two in the pol region) to detect HIV DNA sequences in 30 seronegative polytransfused thalassemic patients and in 60 seropositive individuals (used as positive controls). We did not observe PCR-positive HIV-antibody-negative results in seronegative polytransfused patients.     

The effect of desferrioxamine chelation versus no therapy in patients with non transfusion-dependent thalassaemia: a multicenter prospective comparison from the MIOT network

We prospectively assessed by magnetic resonance imaging (MRI) the advantages of desferrioxamine (DFO) with respect to the absence of chelation therapy in non transfusion-dependent thalassaemia (NTDT) patients. We considered 18 patients non-chelated and 33 patients who received DFO alone between the two MRI scans. Iron overload was assessed by the T2* technique. Biventricular function parameters were quantified by cine sequences. No patient treated with DFO had cardiac iron. At baseline, only one non-chelated patient showed a pathological heart T2* value (<?20 ms) and he recovered at the follow-up. The percentage of patients who maintained a normal heart T2* value was 100% in both groups. A significant increase in the right ventricular ejection fraction was detected in DFO patients (3.48?±?7.22%; P?=?0.024). The changes in cardiac T2* values and in the biventricular function were comparable between the two groups. In patients with hepatic iron at baseline (MRI liver iron concentration (LIC)?≥?3 mg/g/dw), the reduction in MRI LIC values was significant only in the DFO group (??2.20?±?4.84 mg/g/dw; P?=?0.050). The decrease in MRI LIC was comparable between the groups. In conclusion, in NTDT patients, DFO therapy showed no advantage in terms of cardiac iron but its administration allowed an improvement in right ventricular function. Moreover, DFO reduced hepatic iron in patients with significant iron burden at baseline.     

RNAi‐mediated reduction of hepatic Tmprss6 diminishes anemia and secondary iron overload in a splenectomized mouse model of β‐thalassemia intermedia

Diminished β‐globin synthesis in β‐thalassemia is associated with ineffective erythropoiesis, leading to secondary iron overload caused by inappropriately low levels of hepcidin and to splenomegaly in the symptomatic thalassemias. Splenectomy is often employed in patients with β‐thalassemia to reduce hemolysis. Expression of the iron regulatory peptide hormone hepcidin is repressed by the serine protease TMPRSS6. Hepcidin induction by RNAi‐mediated inhibition of TMPRSS6 expression reduces iron overload and mitigates anemia in murine models of β‐thalassemia intermedia. To interrogate the efficacy of RNAi‐mediated reduction of Tmprss6 in splenectomized β‐thalassemia, splenectomized β‐thalassemic Hbb^th3/+ animals were treated with a GalNAc‐conjugated siRNA targeting Tmprss6 (GalNAc‐Tmprss6) and their hematological and iron parameters monitored. We demonstrate that treatment with GalNAc‐Tmprss6 significantly diminishes Tmprss6 expression and appropriately elevates hepcidin expression in splenectomized Hbb^th3/+ animals. Similar to unsplenectomized animals, treated animals have markedly improved anemia due to diminished ineffective erythropoiesis and reduced iron loading in both serum and tissue. These results suggest that RNAi‐mediated reduction of Tmprss6 may have positive outcomes even in splenectomized β‐thalassemia patients.     

Influence of compensated radioiodine therapy on thyroid volume and incidence of hypothyroidism in Graves' disease

Abstract. Objectives . To investigate the long-term effect of radioactive iodine (¹³¹I) on thyroid function and size in patients with Graves' disease. Setting . Out-patient clinic in Herlev Hospital. Subjects . One hundred and seventeen consecutive patients (104 women) with Graves' disease selected for ¹³¹I treatment and followed for a minimum of 12 months (range 1–10 years, median 5 years). Interventions . ¹³¹I dose was calculated based on thyroid volume and 24-h ¹³¹I uptake. Main outcome measures . Standard thyroid function variables and ultrasonically determined thyroid volume before treatment as well as 0.75, 1.5, 3, 6 and 12 months after treatment, and then once a year were investigated. Results . Seventy-eight patients were cured by one ¹³¹I dose and 30 by two doses, while the remaining nine patients received additional doses (range one to five doses, median one dose). Within one year, 25% developed hypothyroidism, and hereafter, hypothyroidism developed at a constant rate of 3% per year independent of antithyroid pretreatment. The cumulative 10-year risk of hypothyroidism was 60%. Initial median thyroid volume was 33 mL (range 9–106 mL). At 12 months after the last ¹³¹I dose, median thyroid volume was reduced to 14 mL (range 6–36 mL) (P < 0.00001). The median reduction being 58% (range 0–80%,), hereafter no further reduction occurred. A significant reduction in thyroid volume was also noted in patients needing subsequent ¹³¹I doses and in those developing hypothyroidism within the first year. Conclusions . ¹³¹I normalizes thyroid volume in patients with Graves' disease. Hypothyroidism seems an inevitable end result of this treatment. The present study suggests that it will be impossible to modify ¹³¹I therapy in a way to achieve both early control of hyperthyroidism and a low incidence of hypothyroidism.     

Cross-sectional and longitudinal study of the pituitary-thyroid axis in patients with thalassaemia major

OBJECTIVE AND DESIGN Thyroid dysfunction is known to occur frequently In thalassaemla major, but Its prevalence and severity varies in different cohorts, and the long-term natural history is poorly described. We evaluated the pituitary/thyroid axis in thalassaemia major patients in a cross-sectional study and correlated abnormalities with indices of iron overload. Furthermore, the course of thyroid disease in thalassaemia major patients was assessed In a 15-year longitudinal study. PATENTS AND MEASUREMENTS Cross-sectional study: pituitary-thyroid axis function was examined in 37 patients (22 F, 15 M; aged 10–39 years, mean ± SE = 21 ± 1.4) out of a total of 43 who attended the Haematology and Endocrinology Clinics of Hadassah Hospital on a regular basis. The mean pretransfusion Hb level was 85·20 g/l, and all patients except one were treated with desferrioxamine (DF, mean SE dose 20.2·2.6 mg/kg/day). Twenty-two had hypogonadotrophic hypogonadism (HH). Longitudinal study: 21 thalassaemia major patients were evaluated with TRH tests in 1976 and again in 1985. Fourteen of these and another eight were evaluated in both 1985 and 1991. RESULTS Cross-sectional study: no patient had any clinical signs or symptoms of hypothyroidism; however, one had abnormally low T4, borderline low FT4 and normal T3 levels associated with an exaggerated TSH response to TRH consistent with mild hypothyroidism. This patient did not have a previous TRH test, but serial basal determinations over 7 years revealed a progressive decrease in thyroid function. Thirty-six patients had thyrold hormone levels within the normal range. Nine of these (24.3%) had only an exaggerated TSH response to TRH whereas seven others (19%) also had borderline elevated basal TSH levels. TSH response to TRH was not correlated with age, serum ferrltin or liver function tests (ALT or GGT). Longitudinal study: mean TSH response to TRH decreased (P >0.002), and mean T3 levels Increased (P >0.001) between 1975 and 1985. These findings are probably related to the initiation of DF treatment in 1981. During the last 6 years, four patients with previously normal TSH responses to TRH developed elevated peak TSH levels. Mean T3 concentrations decreased and TSH response to TRH increased significantly (P >0.001 for both). CONCLUSIONS (1) In this patient group the thyroid pituitary axis is less sensitive than the gonadal axis to iron-induced damage; only one out of 37 patients developed mild uncompensated hypothyroidism. (2) As opposed to the gonadal axis, the thyrold gland appears to fail before the central components of the axis. (3) Abnormal thyroid function may be reversible in the early stages. (4) Progression is variable, and it may take years to progress from normal to uncompensated hypothyroidism.