Relationship of Iron Overload with Insulin Resistance in a group of Children with β-Thalassemia Major
Due to regular transfusion, iron overload in thalassemic patients may give damaging effects to number of organs including liver, pancrease, heart which may arise complication. Study was designed to see the relationship of iron overload with insulin resistance in a group of children with β-thalassaemia major. The study was included 75 diagnosed beta thalassemia major patients (40 male and 35 female) with age range 10-25 years receiving regular blood transfusion. The levels of hemogobin and percentage of hematocrit is estimated. Level of serum ferritin, total iron binding capacity, fasting blood glucose and serum insulin were estimated by standard methods. Insulin resistance was calculated by formula. Mean age of male and female was 10 and 12 years with low body weight. Blood transfusion was started at the age of 5-6 month with duration of 1-2 per month. Decreased level of hemoglobin and percentages of hematocrit was observed in both sexes. Level of serum ferritin was high in both sexes. Values of TIBC and level of fasting blood sugar was normal in both sexes. Level of serum insulin was high in both sexes where as value of insulin resistance was mildly high only in male. Positive Pearson coefficient correlation was observed between TIBC and insulin resistance and also between serum ferritin and insulin resistance. A positive association of serum ferritin and TIBC (iron over load related parameters) with insulin resistance may indicate an increase risk of developing type 1diabetes in children with beta thalassemia. It is therefore a need of regular follow-up of transfusion dependent thalassaemic patients with respect to iron overload to ensure proper management of iron overload associated complications.
Key Words: beta thalassemia, serum ferritin, insulin resistance.
β-thalassemia are a set of hereditary blood disorders distinguished by abnormalities in the production of the beta chains of hemoglobin as it affects only mRNA for the production of beta chain.
It has been estimated that about 1.5% of the global population are carriers of beta thalassemia, with about 60,000 symptomatic people born yearly, especially in the developing world. The prevalence rate of diabetes in thalassemic children is three times more than controls
Due to regular transfusion, iron overload is observed in thalassemic patients4. In iron overload condition, there is a saturation of transferrin results in serum free iron. This free form of iron shows damaging effects as it synthesize hydroxyl radicals and accumulate in organs including liver, pancrease, heart.
According to studies, insulin resistance and lack of insulin are the good indicator of prediabetic state in thalassemia. However, it is found that the defect in insulin secretion is prior to insulin resistance. The reason of insulin resistance is due to iron overload that excess of iron precipitate due to decrease level of hepcidin especially in thalassemic patients.
In beta thalassemia, disparity of globin chains cause hemolysis and impair erythropoiesis. An enhanced absorption of iron is due to impair erythropoiesis. The reason is again the hepcidin which controls the absorption of iron, level of iron in plasma and its tissue distribution. Hepcidin also decreases the movement of iron in the blood from gut, hepatocytes, and macrophages, resulting in decreased level of serum iron. Malfunctions of the hepcidin are responsible for iron overload.
Iron plays an important role in pathogenesis of diabetes mainly due to failure of β-cell and insulin resistance. It is proposed that increase iron entry into cells increases the process of oxidation, and on the contrary, the metabolic fortune of glucose is dependent on the accessibility of iron. Iron overload exerts sympathoexcitatory effects related with a reduce insulin sensitivity.
Study was therefore designed to find out the relationship of iron overload with insulin resistance in a group of children with β-thalassaemia major.
Material and Methods
The study was included 75 diagnosed beta thalassemia major patients (40 male and 35 female) with age range 10-25 years receiving regular blood transfusion. Patients were taken from local clinics of thalasssemia centre. Letter of consent was taken from the parent of each patient. Patient with any other disease were excluded from the study. Study was approved by ethical committee of hospital. Detailed data of children were entered in Proforma.
Level of hemoglobin and percentage of hematocrit is estimated by SWISS intermist. Level of serum ferritin, total iron binding capacity, fasting blood glucose and serum insulin were estimated by standard methods. Homeostasis model assessment (HOMA) index was calculated as a marker of insulin resistance.
Data was analyzed by CPSS 18.0. Variables were expressed as mean±SD. Student ‘t’ test was used for comparison of variables. Correlation between variables was calculated using Pearson correlation coefficient. P<0.05 was considered as significant.
Demographics of male/female children with beta thalassemia shows that mean age of male and was 10 and 12 years respectively. Their body weight was 24 and 26 kg. Transfusion starts at the age of 5 and 6 months respectively. Duration of transfusion in both sexes was 1-2 months.
Table 2 shows the level of iron related parameters and insulin resistance in male/female children with beta thalassemia. It is observed that the level of hemoglobin (7.8 versus 7.39 gm/l) and percentages of hematocrit was (25.25 versus 25.84%). Level of serum ferritin was 4369.0 and 4105.1 ng/ml respectively. Values of TIBC were 253 and 260 respectively. Fasting blood glucose was 87.53 and 88.78 mg/dl respectively. Level of serum insulin was 5.92 and 3.05 µIU/ml respectively. Value of insulin resistance was 1.3 and 0.57 respectively.
Positive Pearson coefficient correlation was observed between TIBC and insulin resistance with r value 0.35. Positive correlation was also observed between serum ferritin and insulin resistance with r value 0.28. (Table 3 and fig a & b ).
The relationship between diabetes and excess of iron was widely recognized in the diseases of thalassemia and hemochromatosis. However, increase level of iron also increase the risk of developing diabetes.
According to our study the mean age of children was in a range of 10-12 years with low body weight. Gender difference is not seen in whole of the study. It is found that beta thalassemia major was diagnosed usually in the age 2-3 years however due to iron over load multiple complications are develop and patient die at the age of 30 years due to cardiac complications. A study is reported that thalassemic children have severe anemia. They body weight is low as compared to normal children of same age and their pattern of growth is failure to thrive and later on they suffer with jaundice. A study reported that with moderately larger spleen and deprived of growth lead to low body weight.
We found that tansfusion starts at the age of 5 and 6 months respectively. Duration of transfusion in both sexes was 1-2 months. According to a study the severity of β-thalassemia phenotype, is related with age. Study reported that standard for initiating the transfusion is greater than 2 weeks with level of hemoglobin 7.0 gm/dl, without any infection. The time of transfusion was calculated as the time between delivery and the first blood transfusion or between delivery and the last follow-up for patients who were not on transfusion therapy.
Our study is in accord with studies who reported low level of hemoglobin and percentages of hematocrit in beta thalassemic children. Due to these low values children develop severe form of anemia slow growth, delayed puberty etc.
We observed an increased level of serum ferritin in both sexes. It is reported increased level of serum ferritin i.e. < 2,500 ng/ml is a marker of iron over load and its value >2500 ng/ml may be a marker of survival from different complications faced by beta thalassemic children. However, a study found that serum ferritin is not a marker when liver disease is exist.
Our study is inline with a study who observed that hyperferritinemia may be a feature of newly diagnosed diabetes and serum ferritin level seems to be positively associated to insulin resistance. Possible explanations of hyperferritinemia might be that by binding iron, ferritin protects against formation of free hydroxyl groups. It could also be due to endothelial/subendothelial inflammation or simply leakage of ferritin from hepatic cells.
Our study observed hyperinsulinemia with normal fasting blood glucose level and with mild to moderate value of insulin resistance. According to a study hyperinsulinemia with normal blood glucose level may be a predictor of dysglycemia in the later years of life.
Positive correlation was observed between TIBC or total iron binding capacity and insulin resistance. According to a study correlation between TIBC and insulin resistance shows a negative impact of iron on insulin sensitivity. The liver increases the production of transferrin, to increase the use of iron thus raising TIBC. TIBC has been used as a marker of end-organ toxicity and also shows the response of deferoxamine therapy.
A positive association of serum ferritin and TIBC with insulin resistance may indicate an increase risk of developing type 1 diabetes in children with beta thalassemia. It is therefore a need of regular follow-up of transfusion dependent thalassaemic patients with respect to iron overload to ensure proper management of iron overload associated complications.
- Weatherall (2015). “The Thalassemias: Disorders of Globin Synthesis”. Williams Hematology (9e ed.). McGraw Hill Professional. p. 725.
- Galanello R and Origa R. Review Beta-thalassemia. Galanello and Origa Orphanet J of Rare Dis 2010, 5:11
- Baker KS, Ness KK, Steinberger J, Carter A, Francisco L, Burns LJ, Sklar C, Forman S, Weisdorf D, Gurney JG, Bhatia S. Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. 2007;109:1765–1772.
- Weatherall DJ. Pathophysiology of thalassaemia.Bailliere’s clinical haematology. 1998;11:127–146.
- Patel M and Ramavataram DVSS. A simple, rapid and improved colorimetric assay for non transferrin thalassemia patients bound iron estimation in thalassemia patients. Int. J. of Pharm. & Life Sci. (IJPLS) 2013; 4(1): 2294-2305
- Stankowski JN,Dawson VL, Dawson TM.Ironing out tau’s role in parkinsonism. Nat Med. 2012 Feb 6;18(2):197-8.
- Merkel PA, Simonson DC, Amiel SA, Plewe G, Sherwin RS, Pearson HA, Tamborlane WV. Insulin resistance and hyperinsulinemia in patients with thalassemia major treated by hypertransfusion.N Engl J Med. 1988;318:809–814.
- Messina MF, Lombardo F, Meo A, Miceli M, Wasniewska M, Valenzise M, Ruggeri C, Arrigo T, De Luca F. Three-year prospective evaluation of glucose tolerance, beta-cell function and peripheral insulin sensitivity in non-diabetic patients with thalassemia major.Journal of Endocrinol Invest. 2002;25:497–501.
- Jaruratanasirikul S, Chareonmuang R, Wongcharnchailert M, Laosombat V, Sangsupavanich P, Leetanaporn K. Prevalence of impaired glucose metabolism in beta-thalassemic children receiving hypertransfusions with a suboptimal dosage of iron-chelating therapy.Eur J Pediatr. 2008;167:873–876.
- Gamberini MR, De Sanctis V, Gilli G. Hypogonadism, diabetes mellitus, hypothyroidism, hypoparathyroidism: incidence and prevalence related to iron overload and chelation therapy in patients with thalassaemia major followed from 1980 to 2007 in the Ferrara Centre.Pediatr Endocrinol Rev. 2008;6(Suppl 1):158–169.
- 11. Muncie HL and Campbell JS. Alpha and Beta Thalassemia. Am Fam Physician. 2009 Aug 15;80(4):339-344.
- Rochette L, Guenancik A, Guenancia C, Zeller M, Cottin Y and Vergely C. The iron-regulatory hormone hepcidin: A possible therapeutic target?. Pharmacol & Therapeu 2015; 146: Pages 35–52
- Ganz T and Nemeth E. Hepcidine and Disorder of Iron metabolism. Ann Review of Med 2011; 62:347-360
- Sumcox JAand McClain Iron and Diabetes Risk.Cell Metab. 2013 Mar 5; 17(3): 329–341.
- Seravalle G,Trevano FQ, Boggioni I, Buzzi S, Mancia G, Grassi G. Iron over load exert sympathoexcitatory effects in men with essential hypertension: microneurographic evidence. J Hypertens. 2015 Jun;33 Suppl 1:e22.
- Cao A, Galanello R. Beta-thalassemia. Genet Med. 2010 Feb;12(2):61-76.
- Danjou F, Anni F, Perseu L, Satta S, Dessi C, Lai ME et al. Genetic Modifiers Of Β-Thalassemia And Clinical Severity As Assessed By Age At First Transfusion. Haematologica July 2012 97: 989-993;
- Hoffbrand AV, Cohen A, Hershko C. Role of deferiprone in chelation therapy for transfusional iron overload. 2003;102(1):17–24.
- Brittenham GM, Cohen AR, McLaren CE, et al. Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major.Am J Hematol. 1993;42(1):81–85.
- Brudevold R, Hole T, Hammerstrøm J. Hyperferritinemia Is Associated with Insulin Resistance and Fatty Liver in Patients without Iron Overload. PLoS ONE 2008; 3(10):e3547
- 21. Hsueh WA. Introduction: New insight into understanding the relation of type 2 diabetes mellitus, insulin resistance, and cardiovascular disease. The Am J of Cardio 2003; 92(4A):1J-2J
- Dankner R, Chetrit A, Shanik MH, Raz I, and Roth J. “Basal state hyperinsulinemia in healthy normoglycemic adults heralds dysglycemia after more than two decades of follow up,”Diabetes/Meta Res and Rev 2012; 28(7): 618–624.
- Zafar U, Qureshi HJ, Karim A. Insulin resistance and serum parameters of iron status in type 2 diabetics Pak J Physiol 2011;7(2):28-31
- Kasvosve I, Delanghe J.”Total iron binding capacity and transferring concentration in the assessment of iron status”. Clin Chem Lab Med 2002; 40 (10): 1014–8.
- Siff JE, Meldon SW, Tomassoni AJ. Usefulness of the Total Iron Binding Capacity in the Evaluation and Treatment of Acute Iron Overdose. Ann of Emerg Med 1999;33(1): 73–76