Beta-thalassemia major (TDT) is a hereditary anemia necessitating lifelong transfusions. Resultant iron overload contributes to organ dysfunction, particularly affecting endocrine glands. Long-term extravascular hemolysis caused by TDT enhances the digestive tract's ability to absorb iron. This, combined with repeated blood transfusions (BT), might result in iron toxicity & iron deposition in the tissues. It can induce gradual tissue injury in the liver, heart, endocrine glands as well as other organs by producing free radicals and oxidative damage [1,2,3].

The frequency of impaired glucose homeostasis in TDT has steadily risen in recent years, possibly due to patients' longer life expectancies and rising concerns about the coexistence of thalassemia and diabetes. By destroying membrane lipids and other macromolecules, free iron facilitates the creation of reactive oxygen species, which induce cell death and eventually organ failure. Iron buildup ismeasured using serum ferritin, serumiron,and transferrin levels, and the iron saturation % is calculated.

Although iron excess contributes to the emergence of endocrine problems, the severity of clinical symptoms is mostly controlled by the type of underlying globin gene alteration, which are typically mutations or gene deletions. The majority of individuals will require regular transfusions to live.

Mutations in the β-globin gene (HBB) cause TDT, but mutations and genetic modifiers affecting fetal γ-globin expression primarily dictate how severe the disease becomes. [4]. Co inheritance of α-thalassemia also reduces the severity of TDT. Furthermore, chronic liver illness caused by iron overload and hepatic viral infections, primarily hepatitis C virus, caused by multiple transfusions play a substantial influence in TDT patients' endocrinopathies, particularly the development of diabetes mellitus.

This study aims to determine the prevalence of diabetes mellitus and other endocrine   disorders in children with TDT and assess their correlation with iron overload about which there is very limited data from central India particularly from Vindhya region and Madhya Pradesh.

A case-control study was conducted on 100 children with TDT (aged 2–18 years) receiving regular transfusions at Shyam Shah Medical College, Rewa, and 100 healthy controls. Informed consent and ethical clearance were obtained.

Inclusion of cases and controls :

• Cases : All children with TDT (Aged 2-18years) diagnosed by HPLC and/or screening of parents wherever required on regular transfusion protocols of leucoreduced PRBC transfusion every 2-3 weekly as per requirements to maintain a pre transfusion hemoglobin between 9.5-11 g/dl and were on regular chelation therapy started once serum ferritin reaches more than 1000 ng/ml with regular monitoring and investigations as per TIF (Thalassemia international federation ) guidelines [5].
• Controls : healthy controls of same age group attending our department OPD for consultations of routine pediatric disorders excluding anemia or thalassemia .

Measurements: Anthropometry, Tanner staging, fasting and post-load glucose, HbA1c, serum ferritin, TSH, T3, T4, calcium, phosphate, and vitamin D levels were recorded.

Definitions:

• Diabetes : FBG ≥126 mg/dL, 2-hr IGT ≥200 mg/dL, or HbA1c ≥6.5%
• Hypothyroidism: TSH >5.4 mIU/L
• Short stature: Height <-2 SD for age and sex was considered as short stature. Mid parental height (MPH) as well as target height were also calculated to rule out other causes of short stature like constitutional and familial short stature
• Delayed puberty: Detailed menstrual history was obtained. Tanner’s staging was done on all males older than 14 years and females older than 13 years of age. Delayed puberty was described in girls as the age of more than 13 years & not having attained the tanner B2 stage or age of more than 15 years with primary amenorrhea. In males, it was defined as the age of more than 14years and not having achieved tanner stage G2 or on hormonal replacement therapy.
• Lab Investigations: Venous blood samples were taken from all patients and divided into two tubes: 2 ml blood in an EDTA vials for complete blood count (CBC) and glycosylated haemoglobin (HbA1C) and 6 ml blood in 2 red coloured serum vials for ferritin level, TSH, triiodothyronine(T3), thyroxine(T4), serum calcium , phosphate & vitamin D levels.
• Statistical Analysis: SPSS software version 28.0 was used ; t-test, Chi-square, Pearson's correlation. Significance at p<0.05.

Table 1: Demographics and Anthropometry

Table 2: Endocrine Complications

Table 3 : Correlation between Serum ferritin with Blood glucose level (FBS)

Table 4: Correlation Analysis (Pearson’s r) shows statistically significant correlation of serum ferritin with blood glucose (FBG) and hypothyroidism and negative correlation with serum calcium levels.

Table  5 study population according to mean Height between two groups

There was statistically significant difference in comparison of height (m) between two groups, with p-value {p<0.05}. In Children with TDT mean height was less than in normal children.

Our study revealed a high prevalence of DM and other endocrine abnormalities in TDT children, consistent with prior studies. In the current study, the overall percentage of endocrinal anomalies was 80%, that is greater than that reported by previous studies done. Significant correlations between serum ferritin and glycemic parameters and TSH underscore the role of iron overload. No significant association was observed between Tanner staging and ferritin, though the sample size was less . In accordance with earlier studies [6] the presence of endocrine problems was not significantly related with risk variables such as hemoglobin concentration prior to transfusion or splenectomy history which was in eight percent (8%) children with TDT in our examined group.

This study showed a 4% frequency of hypothyroidism in children with TDT  and 1% in controls , which is lower than the results of Sharma et al. (8.9%)[7], Fung et al. (10%) [8], and  Najafipour et al. (16%) [9], although Baul et al. [10] discovered a significantly higher percentage. Diabetes, IFG, and IGT were found to be 19%, 11%, and 7% prevalent in cases, and 0%, 10%, and 2% prevalent in controls , respectively in our study.

Serum ferritin and serum calcium exhibited a statically meaningful mild negative association in our investigation (table 4). Many studies, on the other hand, found no link among serum ferritin and the occurrence of endocrinopathy .\

Tanner staging was employed in only 10 cases in the case group and 5 cases in the control group, with 20% (n=2/10) of the case group experiencing delayed puberty, which was lower than in previous research. No delay in puberty was found in control group. Delayed  Puberty didn’t show any statistically meaningful association with serum ferritin as contrary to the studies like Dixit etal  & Sutay etal. A meta-analysis [11] of 44studies from around the world revealed that the percentage of diabetic mellitus, impaired fasting glucose, and impaired glucose tolerances in children with TDT were 6.54%, 17.21%, and 12.46%, correspondingly. In terms of the age difference between the first transfusion and the start of chelation, TDT patients with diabetes differed significantly from those without diabetes, as observed in the Gamberini et al. study [12]

Limitations:

1.Lack of MRI-based iron quantification and hormonal assays for gonadal and adrenal function.

2. Number of patients assessed for puberty is small in this study.
3. Serum ferritin may not fully reflect iron overload in TDT patients
4. Larger studies with more number of cases might help in deriving stronger correlations.

Endocrine dysfunctions, particularly diabetes and growth disorders, are common in children with TDT, though clinically less significant, correlating with iron overload. Routine endocrine monitoring and timely intervention are crucial. In the current scenario, holistic management with effective transfusion/regular chelation, regular surveillance for signs and symptoms of endocrine dysfunctions by pediatricians/physicians, and timely referral to endocrinologist and hemoglobinopathy clinic is the key to reducing comorbidities, and further analyses can be done to see the consequences of early lifestyle modifications and dietary modifications on endocrine complications in thalassemia children.

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