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\def\RunningAuthor{Saurabh Hadke et al.}
\firstPage{304}
\articleType{Original Article}
\receivedDate{14 Oct 2020}
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\title{Endocrinopathies and its relationship with Thalassemia}
\author{Ranjit~S~Ambad\textsuperscript{1},  
            Roshan~Kumar~Jha\textsuperscript{2},  
            Saurabh~Hadke\textsuperscript{*}\textsuperscript{3}, 
            Sonal~Muley\textsuperscript{4}~\\[5pt]{\textsuperscript{1}Department of Biochemistry, Datta Meghe Medical College, Shalinitai Meghe Hospital \& Research Centre, Hingana, Nagpur, Maharashtra-441110, India}~\\{\textsuperscript{2}Department of Biochemistry, Jawaharlal Nehru Medical College, AVBRH (Datta Meghe Institute of Medical Sciences) Sawangi, Wardha-442001, India}~\\{\textsuperscript{3}Department of Medicine, Datta Meghe Medical College, Shalinitai Meghe Hospital \& Research Centre, Nagpur-441110, Maharashtra, India}~\\{\textsuperscript{4}Department of Ophthalmology, Datta Meghe Medical College, Shalinitai Meghe Hospital \& Research Centre, Nagpur-441110, Maharashtra, India}}

\begin{abstract}
Thalassemia is a common genetic blood disorder that places a burden on patients and the healthcare system, particularly in developing countries. Thalassemia is an inherited hemoglobinopathy that is transmitted to an individual as a result of a gene mutation that creates the alpha or beta-globin chains. Unless the genes are defective for beta chains, it may result in beta-thalassemia. If both beta genes are defective, the person has significant thalassemia and extreme anemia. Thalassemia is associated with several disorders of the endocrine that include pituitary, thyroid, pancreas, gonads, parathyroid and bone. This cross-sectional study was carried out on 100 Thalassemia patients, and 100 healthy controls and the levels of Minerals, Hormones, Diabetic Profile and Vitamin D was assessed in both the groups. Vitamin D deficiency was the commonest endocrine complications, followed by LH/FSH deficiency, hypothyroidism (32\%), diabetes mellitus (6.7\%) hyperparathyroidism and adrenal insufficiency. Seven out of thirty-two patients with hypothyroidism presented with subclinical hypothyroidism. In our study total, 41\% of patients had Vitamin D deficiency, 13 \% had vitamin D insufficiency, and 46\% had sufficient levels. Diabetes Mellitus with high fasting levels was seen in 16\% of patients. In our study, 10\% of patients had no Endocrine Disorder. The present study suggests that early screening programs for iron overload should be implemented to prevent endocrinopathies in children and adults and supplemented with prophylactic vitamin D.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Thalassemia,\newline Genetic disorder,\newline Hemoglobinopathies,\newline Vitamin D,\newline Ferritin
\end{keywords}
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\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Saurabh~Hadke~\\ Phone:\ 9890959395~\\  Email:\ saurabhhadke2@gmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
Thalassemia is a common genetic blood disorder that places a burden on patients and the healthcare system, particularly in developing countries. \unskip~\citep{970334:21105161} Thalassemia is an inherited hemoglobinopathy that is transmitted to an individual as a result of a gene mutation that creates the alpha or beta-globin chains. Unless the genes are defective for beta chains, it may result in beta-thalassemia. If both beta genes are defective, the person has significant thalassemia and extreme anemia \unskip~\citep{970334:21105162,970334:21105166}. 

In Mediterranean areas, some portions of North and West Africa, the Middle East, the Indian Peninsula, the Far East, and Southeast Asia, this disease is prevalent. The above-mentioned areas are known as "the thalassemia belt". \unskip~\citep{970334:21105162} Beta-thalassemia major is an inherited condition characterized by the lack or inadequacy of a synthesis of the beta-globin chain. \unskip~\citep{970334:21105172} Globally, 300,000{\textendash}400,000 babies are born with thalassemia and sickle cell disease.

According to most recent reports, an estimated 1.5 per cent of the global population are carriers of beta-thalassemia and an approximate number of annual births ranging from 50,000 to 60,000 with extreme types with beta-thalassemia \unskip~\citep{970334:21105158}. Beta-thalassemia major is a monogenic condition inherited and first identified by Cooley and\unskip~\cite{970334:21105168}. It is caused by a mutation in the {\ss}-globin gene locus that results in the accumulation of the \ensuremath{\alpha }-globin chain that is precipitated in the bone marrow inside erythroid precursors associated with extreme erythropoietic anemia. \unskip~\citep{970334:21105174}

Beta-thalassaemia is a disease in which iron overload and iron deposition in tissues is a serious and debilitating problem if proper precautions are not taken. Beta-thalassemia is a group of recessively inherited hemoglobin disorders characterized by decreased beta-globulin chain synthesis. About 3 per cent of the world population bears genes for \ensuremath{\beta }-thalassemia. The homozygous condition results in severe anemia, which requires daily transfusion of blood. Transfusion and chelating therapy treatment in thalassaemic patients have extended the survival considerably \unskip~\citep{970334:21105167}. In addition to iron overload, other factors such as poor diet, chronic anemia, chelating agents, liver disease, and genetic susceptibility have been related to slow growth and endocrinopathies in BTM. \unskip~\citep{970334:21105169,970334:21105155} Thalassemia major is a common genetic disorder of Hemoglobin synthesis with a defect in the development of one or more hemoglobin chains \unskip~\citep{970334:21105165}.

 The homozygous condition results in extreme anemia and is considered to affect a significant population in Mediterranean countries, the Middle East, Northern India, and parts of Southeast Asia. The combination of transfusion therapy and chelation therapy has only resulted in improved life expectancy of thalassemic patients but is also associated with specific complications. 

A number of these complications arise from the iron overload caused by frequent transfusions. \unskip~\citep{970334:21105166} Excessive iron is concentrated in most of the body's tissues, including the liver, heart, and endocrine glands. \unskip~\citep{970334:21105175} Iron accumulation in tissues leads to endocrine dysfunction, a well-recognized complication in patients with transfusion-dependent thalassemia. \unskip~\citep{970334:21105159,970334:21105177} The impact of iron toxicity on endocrine glands has been well illustrated in numerous histological studies. \unskip~\citep{970334:21105160,970334:21105176} Endocrine complications in patients with thalassemia: delayed puberty, diabetes mellitus, hypothyroidism, and hypoadrenalism are some of the complications in thalassemia patients. \unskip~\citep{970334:21105170,970334:21105154} The most significant cause of hypogonadism is gonadal iron accumulation resulting in primary gonadal failure. \unskip~\citep{970334:21105178} Chronic blood transfusion (CBT) is the cornerstone of treatment for people with \ensuremath{\beta }thalassemia major (BTM) to avoid growth retardation, skeletal changes resulting from bone marrow expansion, and mass development from extramedullary hematopoiesis. 

Despite this, CBT causes iron-overload, which requires long-term iron chelation therapy to control and manage. The primary causes of death are insufficient chelation therapy, cardiac arrhythmias, cardiomyopathy, and heart failure, while endocrine defects and chronic liver disease contribute greatly to morbidity and mortality. The iron chelation therapy will usually be begun as soon as the patient is filled with iron. A significant iron load amounts to about 1,000 ng / mL of serum ferritin. The concentration of liver iron (LIC) is considered the best indicator of the total iron charge. Before beginning chelation, LIC should have a dry weight of at least 3 mg Fe /gram \unskip~\citep{970334:21105156}. Thyroid dysfunction in patients with thalassemia has been reported with varying degrees of prevalence.

For example, Najafipour and colleagues showed a 16 per cent prevalence of thalassemia hypothyroidism in their patients, while other authors reported a 13-60 per cent prevalence of hypothyroidism. The authors hypothesized that its patients will be affected by more subclinical forms of hypothyroidism \unskip~\citep{970334:21105164}. It should be noted that thyroid dysfunction and the use of levothyroxine will increase the risk of bone mineral depletion \unskip~\citep{970334:21105157,970334:21105171}. Hb E/\ensuremath{\beta }-thalassemia accounts for over 50 per cent of the burden of thalassemia disease in the Indian state of West Bengal \unskip~\citep{970334:21105163}.

\textbf{Aim}

To study endocrinopathies and its relationship with thalassemia.

\textbf{Objective}

To correlate the levels of minerals, Hormones, Diabetic Profile and Vitamin D levels between patients and healthy controls (age-matched) attending AVBRH Wardha and SMHRC Nagpur.
    
\section{Materials and Methods}
The present study was carried out in the Department of Biochemistry and General Medicine at Datta Meghe Medical College, Shalinitai Meghe Hospital and Research Centre, Nagpur in collaboration with Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences, Sawangi (Meghe) Wardha Maharashtra. 

Total of 200 subjects were selected for the study. Out of which 100 patients are age and gender-matched healthy control, 100 were suffered from Thalassemia. Informed consent was taken from all participants included in the study.

\textbf{Sample Collection}

Blood sample were collected, and all patients and controls (n=200) gave informed consent for participation to the study. Vitamin D was estimated by Dry Chemistry analyzer. Electrolyte levels were measured by electrolyte analyzer, as electrolyte analyzer has different electrodes, specific for different ions of interest. Each electrode has an ion-selective membrane that undergoes a specific reaction with the corresponding ions contained in the sample being analyzed. Levels of Hormones, Alkaline phosphatase and ferritin was measured by Dry Chemistry analyzer.

\textbf{Inclusion Criteria}

All patients with thalassemia are selected for the study.

\textbf{Statistical Analysis}

All estimated results were expressed as mean \ensuremath{\pm}SD. Mean values will be assessed for significance by unpaired student {\textendash}t-test. Statistical analysis will be performed using the Statistical Package for the Social Science program (SPSS, 24.0). Frequencies and percentages will be used for the categorical measures. Probability values p \textless\ 0.05 will be considered statistically significant.
    
\section{Results and Discussion}
Thalassemia derives from the Greek words Thalassa meaning "water" and haema means "of blood." It was first identified in people living in the Mediterranean. The disease is particularly prevalent in countries of the Mediterranean, the Middle East and South-East Asia. Thalassemia can now be found across the globe, however, due to widespread migration. Every year on May 8, World Thalassemia Day is celebrated to raise awareness of the disease among the public. The clinical continuum of thalassemia involves asymptomatic carriers to the main patients with serious thalassemia who require lifelong blood transfusions and iron chelation. Optimal iron overload regulation increases survival, but this improved lifespan is associated with a higher complication burden. Endocrine defects are among major \ensuremath{\beta }-thalassemia complications. 

The iron which is metabolically active is stored in endocrine organs. Timely chelation of the iron can reduce hyperferritinemia, thereby improving endocrinopathies. Thalassemia is associated with several disorders of the endocrine that include pituitary, thyroid, pancreas, gonads, parathyroid and bone. Bone disease Thalassemia is a widespread but poorly understood condition that affects both younger and relatively older cohorts of patients. The multiple factors which contribute to bone loss pose a diagnostic and therapeutic challenge. The May 2019 issue of the Indian Journal of Child Health publishes an article by Kataki and Bharati, where authors identified the effect of ferritin levels in early detection of endocrinopathy among 70 children aged 5{\textendash}18 from northeastern India \unskip~\citep{970334:21105173}. 

In understanding endocrine problems, current literature stressed the use of judicious blood transfusions and serial ferritin measurement \unskip~\citep{970334:21105153}. Hypophyseal damage from iron overload is the underlying pathogenetic cause in hypogonadism and leads partly to poor growth \unskip~\citep{970334:21105152}. Puberty is the stage of an insult to full development. The standard protocol is to initiate iron chelation therapy when the amount of serum ferritin exceeds 1000 ng/ml or when the child exceeds 3 years of age or has obtained approximately 10{\textendash}20 transfusions. In this study, we saw the role of endocrinopathies in patients attending AVBRH Wardha with thalassemia showed in Table~\ref{tw-7318303905b1}.

In our study, we have taken 100 patients out of which 52 were male, and 48 were female showed in Table~\ref{tw-70484ddf5fb8}. In all 90.0\% of all patients suffered from at least one endocrine complication, 70\% have one endocrinopathy, 48.9\% with two types of endocrinopathies and 15.1\% of them have three or more types of endocrinopathies. Vitamin D deficiency was the commonest endocrine complications, followed by LH/FSH deficiency, hypothyroidism (32\%), diabetes mellitus (6.7\%) hyperparathyroidism and adrenal insufficiency showed in


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\caption{\boldmath {Clinical characteristics of Patients} }
\label{tw-8fe31cbef3dc}
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\cAlignHack Diabetes Mellitus &
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\cAlignHack Hypothyroidism &
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  \cAlignHack 11.30\\
\cAlignHack LH/FSH Deficiency &
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  \cAlignHack 16 &
  \cAlignHack 19 &
  \cAlignHack 15.4\\
\cAlignHack Short Stature &
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  \cAlignHack 7 &
  \cAlignHack 15 &
  \cAlignHack 12.81\\
\cAlignHack Hyperparathyroidism &
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  \cAlignHack 12.47\\
\cAlignHack Adrenal Insufficiency &
  \cAlignHack 8 &
  \cAlignHack 3 &
  \cAlignHack 5 &
  \cAlignHack 13\\
\cAlignHack Vitamin D Deficiency &
  \cAlignHack 54 &
  \cAlignHack 28 &
  \cAlignHack 26 &
  \cAlignHack 10.54\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Concentration of Biochemical Parameters in thalassaemic patients} }
\label{tw-7318303905b1}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.2234\linewidth-2\tabcolsep}p{\dimexpr.2396\linewidth-2\tabcolsep}p{\dimexpr.24299999999999997\linewidth-2\tabcolsep}p{\dimexpr.13720000000000002\linewidth-2\tabcolsep}p{\dimexpr.1568\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Biochemical Parameters & \cAlignHack Thalassemia patients & \cAlignHack Healthy controls & \cAlignHack T-test & \cAlignHack P-value\\
\tblmidrule 
Hb &
  \cAlignHack 7.8\ensuremath{\pm}2.379 &
  \cAlignHack 13.3\ensuremath{\pm}4.392 &
  \cAlignHack 11.011 &
  \cAlignHack {\textless}0.0001\\
Serum Ferritin &
  \cAlignHack 645.56\ensuremath{\pm}363.97 &
  \cAlignHack 178.35\ensuremath{\pm}337.98 &
  \cAlignHack -9.406 &
  \cAlignHack {\textless}0.0001\\
Fasting Blood Sugar &
  \cAlignHack 154.8\ensuremath{\pm}24.92 &
  \cAlignHack 80.48\ensuremath{\pm}12.34 &
  \cAlignHack -26.726 &
  \cAlignHack {\textless}0.0001\\
Glycated Hb &
  \cAlignHack 7.9\ensuremath{\pm}1.9 &
  \cAlignHack 5.4\ensuremath{\pm}0.9 &
  \cAlignHack -11.891 &
  \cAlignHack {\textless}0.0001\\
Sodium  &
  \cAlignHack 147.21\ensuremath{\pm}7.08 &
  \cAlignHack 138.45\ensuremath{\pm}9.8 &
  \cAlignHack -7.246 &
  \cAlignHack {\textless}0.0001\\
Potassium &
  \cAlignHack 7.4\ensuremath{\pm}5.26 &
  \cAlignHack 4.5\ensuremath{\pm}3.21 &
  \cAlignHack -4.706 &
  \cAlignHack {\textless}0.0001\\
PTH &
  \cAlignHack 108.65\ensuremath{\pm}19.82 &
  \cAlignHack 14.39\ensuremath{\pm}2.3 &
  \cAlignHack -47.241 &
  \cAlignHack {\textless}0.0001\\
Morning Cortisol &
  \cAlignHack 6.2\ensuremath{\pm}1.83 &
  \cAlignHack 17.31\ensuremath{\pm}3.41 &
  \cAlignHack 28.708 &
  \cAlignHack {\textless}0.0001\\
T3 &
  \cAlignHack 109.45\ensuremath{\pm}22.064 &
  \cAlignHack 164\ensuremath{\pm}18.31 &
  \cAlignHack 19.026 &
  \cAlignHack {\textless}0.0001\\
T4 &
  \cAlignHack 3.14\ensuremath{\pm}1.024 &
  \cAlignHack 9.31\ensuremath{\pm}1.41 &
  \cAlignHack 35.407 &
  \cAlignHack {\textless}0.0001\\
TSH &
  \cAlignHack 8.15\ensuremath{\pm}1.95 &
  \cAlignHack 2.5\ensuremath{\pm}0.89 &
  \cAlignHack -26.359 &
  \cAlignHack {\textless}0.0001\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Result of Vitamin D, Calcium, Alkaline phosphatase and phosphorous} }
\label{tw-8dd89a9950e3}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.22450000000000003\linewidth-2\tabcolsep}p{\dimexpr.10749999999999998\linewidth-2\tabcolsep}p{\dimexpr.1975\linewidth-2\tabcolsep}p{\dimexpr.14650000000000002\linewidth-2\tabcolsep}p{\dimexpr.1585\linewidth-2\tabcolsep}p{\dimexpr.1655\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\multicolumn{2}{p{\dimexpr(.332\linewidth-2\tabcolsep)}}{\cAlignHack Variables} & \cAlignHack Patients  & \cAlignHack Control & \cAlignHack t value & \cAlignHack P-value\\
\tblmidrule 
\multicolumn{2}{p{\dimexpr(.332\linewidth-2\tabcolsep)}}{\cAlignHack Serum Vitamin D} &
  \cAlignHack 19\ensuremath{\pm}6.31 &
  \cAlignHack 38.65\ensuremath{\pm}4.02 &
  \cAlignHack 11.746 &
  \cAlignHack {\textless}0.0001\\
\cAlignHack Deficiency  &
  \cAlignHack 41 &
  \multicolumn{1}{p{\dimexpr(.1975\linewidth-2\tabcolsep)}}{\multirow{3}{\linewidth}{\cAlignHack }} &
  \multicolumn{1}{p{\dimexpr(.14650000000000002\linewidth-2\tabcolsep)}}{\multirow{3}{\linewidth}{\cAlignHack }} &
  \multicolumn{1}{p{\dimexpr(.1585\linewidth-2\tabcolsep)}}{\multirow{3}{\linewidth}{\cAlignHack }} &
  \multicolumn{1}{p{\dimexpr(.1655\linewidth-2\tabcolsep)}}{\multirow{3}{\linewidth}{\cAlignHack }}\\
\cAlignHack Insufficiency  &
  \cAlignHack 13 &
   &
   &
   &
  \\
\cAlignHack Sufficiency  &
  \cAlignHack 46 &
   &
   &
   &
  \\
\multicolumn{2}{p{\dimexpr(.332\linewidth-2\tabcolsep)}}{\cAlignHack Alkaline Phosphatase} &
  \cAlignHack 421.34\ensuremath{\pm}189.34 &
  \cAlignHack 126\ensuremath{\pm}52.84 &
  \cAlignHack -6.719 &
  \cAlignHack {\textless}0.0001\\
\multicolumn{2}{p{\dimexpr(.332\linewidth-2\tabcolsep)}}{\cAlignHack Serum Calcium} &
  \cAlignHack 8.42\ensuremath{\pm}0.71 &
  \cAlignHack 9.76\ensuremath{\pm}0.42 &
  \cAlignHack 7.265 &
  \cAlignHack {\textless}0.0001\\
\multicolumn{2}{p{\dimexpr(.332\linewidth-2\tabcolsep)}}{\cAlignHack Serum Phosphorous} &
  \cAlignHack 2.82\ensuremath{\pm}0.43 &
  \cAlignHack 3.20\ensuremath{\pm}0.44 &
  \cAlignHack 2.762 &
  \cAlignHack 0.0088\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Levels of Gonadal and Pituitary Hormones in Patients and Healthy Controls} }
\label{tw-70484ddf5fb8}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1795\linewidth-2\tabcolsep}p{\dimexpr.1795\linewidth-2\tabcolsep}p{\dimexpr.1675\linewidth-2\tabcolsep}p{\dimexpr.1914\linewidth-2\tabcolsep}p{\dimexpr.1496\linewidth-2\tabcolsep}p{\dimexpr.1325\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Variables & \multicolumn{2}{p{\dimexpr(.347\linewidth-2\tabcolsep)}}{\cAlignHack Patients} & \cAlignHack Control & \cAlignHack t-value & \cAlignHack P-Value\\
\tblmidrule 
\cAlignHack LH &
  \multicolumn{2}{p{\dimexpr(.347\linewidth-2\tabcolsep)}}{\cAlignHack 0.82\ensuremath{\pm}0.40} &
  \cAlignHack 3.02\ensuremath{\pm}0.98 &
  \cAlignHack 12.240 &
  \cAlignHack {\textless}0.0001\\
\cAlignHack FSH &
  \multicolumn{2}{p{\dimexpr(.347\linewidth-2\tabcolsep)}}{\cAlignHack 1.21\ensuremath{\pm}0.70} &
  \cAlignHack 2.84\ensuremath{\pm}1.98 &
  \cAlignHack 4.592 &
  \cAlignHack {\textless}0.0001\\
\cAlignHack Prolactin &
  \multicolumn{2}{p{\dimexpr(.347\linewidth-2\tabcolsep)}}{\cAlignHack 19.33\ensuremath{\pm}2.78} &
  \cAlignHack 14.85\ensuremath{\pm}5.60 &
  \cAlignHack -4.239 &
  \cAlignHack 0.001\\
\cAlignHack Estrogen  &
  \multicolumn{2}{p{\dimexpr(.347\linewidth-2\tabcolsep)}}{\cAlignHack 20.42\ensuremath{\pm}5.89} &
  \cAlignHack 34.53\ensuremath{\pm}8.02 &
  \cAlignHack 8.389 &
  \cAlignHack {\textless}0.0001\\
\multicolumn{1}{p{\dimexpr(.1795\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{\cAlignHack Testosterone}} &
  \cAlignHack Male N=52 &
  \cAlignHack 34.61\ensuremath{\pm}24.920 &
  \cAlignHack 351.72\ensuremath{\pm}427.77 &
  \cAlignHack 5.337 &
  \cAlignHack {\textless}0.0001\\
 &
  \cAlignHack Female N=48 &
  \cAlignHack 2.18\ensuremath{\pm}0.86 &
  \cAlignHack 23.69\ensuremath{\pm}19.44 &
  \cAlignHack 7.656 &
  \cAlignHack {\textless}0.0001\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
Table~\ref{tw-8fe31cbef3dc} and Table~\ref{tw-70484ddf5fb8}. There was more number of male then female patients with hypogonadism. Seven out of thirty-two patients with hypothyroidism presented with subclinical hypothyroidism. In our study total, 41\% of patients had Vitamin D deficiency, 13 \% had vitamin D insufficiency, and 46\% had sufficient levels showed in Table~\ref{tw-8dd89a9950e3}. Diabetes Mellitus with high fasting levels was seen in 16\% of patients. In our study, 10\% of patients had no Endocrine Disorder.
    
\section{Conclusions}
Thalassemia is an inherited blood disorder, prompt identification of these disorders by screening should be done in all patients to facilitate care as soon as possible, education programs should be placed in a place for the production and tracking of early detection and replacement therapy in which endocrine abnormalities may be minimized in future. Deficiency of vitamin D, delayed puberty, short stature, hypothyroidism are common complications of iron overload. The present study suggests that early screening programs for iron overload should be implemented to prevent endocrinopathies in children and adults and supplemented with prophylactic vitamin D.

\textbf{Conflict of Interest}

The authors declare that they have no conflict of interest for this study.

\textbf{Funding Support}

The authors declare that they have no funding support for this study.
    

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