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Hypothyroidism is common. It could be due to a primary disorder within the thyroid gland or secondary to pituitary or hypothalamic disease. The clinical presentation of hypothyroidism depends on the duration and severity of the disease. Since thyroid hormones affect the metabolism and function of virtually all nucleated cells, it has diverse clinical manifestations. The most important diagnostic test is the thyroid function test (TFT). Screening for thyroid function is recommended for neonates and elderly patients. Replacement therapy with levothyroxine is indicated. Sickle cell anemia (SCA) is an inherited hemoglobinopathy that frequently causes hypothyroidism. One study conducted among patients with SCA who have high serum ferritin levels assessed the association between gonadal and thyroid hormones with iron indices; it was found that there was a significant relation between serum ferritin level and free T3 and free T4. This was probably due to endocrine dysfunction secondary to high ferritin levels and iron overload.
Faculty of Medicine, Department of Internal Medicine, University of Gezira, Sudan
Mohab Elmubarak
University of Gezira, Sudan
*Address all correspondence to: sawsanomer63@yahoo.co.uk
1. Introduction
Hypothyroidism is one of the commonest endocrine disorders following obesity and diabetes mellitus [1]. The prevalence of thyroid disorders in mountain areas like the Himalayas where iodine deficiency is common exceeds 10%, and 4% of females aged 20–50 years in the UK have thyroid disorder [2]. The metabolism of almost all tissues is virtually controlled by thyroid hormones [1]. Endocrine disorders present in many different ways with nonspecific symptoms or with asymptomatic biochemical abnormalities. For example, thyroid disorders, which are common occurring in 5% of population and mainly affect females, has diverse clinical manifestations [2]. Hypothyroidism is commonly due to primary disorder within the thyroid gland itself but could be secondary to pituitary disease. Primary hypothyroidism is one of the commonest endocrine disorders, with a prevalence of over 2% in women in the UK but less than 0.1% in men, and lifetime prevalence increases with age, with 9% for women and 1% for men around 60 years. The prevalence of subclinical hypothyroidism varies from 1 to 10% worldwide [2]. Patients with sickle cell anemia with chronic anemia and frequent blood transfusion will have iron overload and other factors like vaso-occlusive occlusion, infraction, or hypoxia associated with chronic anemia, and this could be responsible for endocrine dysfunction in such patients. Thyroid disorders were frequently reported in patients with sickle cell anemia. So, these patients need frequent screening for serum ferritin level and hormonal assays including thyroid hormones [3].
Since hypothyroidism is a common condition and may present with nonspecific symptoms with different varieties of causes and clinical presentation, in this chapter, elaboration of causes, clinical presentation, screening, diagnosis, and therapeutic approach for hypothyroidism will be discussed in addition to the relation between sickle cell anemia and endocrine disorders including thyroid disorders.
The thyroid gland lies in the anterior part of the neck; it consists of two lobes connected by an isthmus. It is closely attached to the thyroid cartilage and to the upper end of the trachea and hence moves with swallowing. It has rich blood supply from superior and inferior thyroid arteries. Histologically, the thyroid gland consists of follicles surrounded by basement membrane. Each follicle is lined by cuboidal epithelioid cells that contain the colloid (the iodinated glycoprotein thyroglobulin), which is synthesized by the follicular cells [1]. Between the follicles lie the parafollicular cells that secrete calcitonin, which has no apparent physiological effect on the human body [2].
The thyroid synthesizes two hormones: triiodothyronine (T3), which acts at the cellular level, and L-thyroxine (T4), which is the prohormone. T4 is produced more than T3, but in some peripheral tissues like liver, kidney, and muscles, it is converted to the more active T3 [1]. The follicular epithelial cells synthesize thyroid hormones by incorporating iodine into the amino acid tyrosine on the surface of thyroglobulin, a protein secreted into the colloid of the follicle. Iodide is essential for thyroid hormone synthesis, and the daily requirement should be around 100 μg/day to maintain normal thyroid function [2]. In plasma, more than 99% of T3 and T4 is bound to thyroxine-binding globulin (TBG), thyroid-binding prealbumin (TBPA), and albumin. The free T3 and T4 hormones diffuse in tissues and exert different metabolic effects in tissues, so in assessment of thyroid function, free T3 and T4 levels should be measured because they are not affected by changes of binding proteins levels in the plasma. For example, if TBG is increased by estrogen (in contraceptive pills), this will lead to a false increase in total T3 and T4 levels. The secretion of thyroid hormones by the thyroid gland is a continuous process. T4 has a half-life of 7–10 days, while T3’s half-life is 6–10 hours, with little variation in level all the time. The secretion of thyroid hormones is controlled by the hypothalamic-pituitary-thyroid axis (shown in Figure 1), where thyrotropin-releasing hormone (TRH), a peptide hormone produced by the hypothalamus, stimulates the anterior pituitary gland to secrete thyroid-stimulating hormone (TSH). TSH stimulates the growth and activity of thyroid follicular cells via G-protein coupled with TSH membrane receptors, and the secreted T3 and T4 hormones are released in the circulation, and they exert negative feedback on the pituitary and hypothalamus. In primary hypothyroidism, low levels of T3 and T4 will stimulate the secretion of TSH, and its level will be elevated [1, 2].
Figure 1.
The hypothalamic-pituitary-thyroid axis.
3.2 Effects of thyroxine
The effects of thyroxine include the following [1, 2]:
Increases the heart rate and cardiac output.
Increases bone turnover and resorption.
Maintains normal hypoxic and hypercapnic drive in the respiratory center.
Increases gut motility.
Increases oxygen release to tissues by increasing 2,3-biphospoglycerate (2,3-BPG).
Increases speed of muscle contraction and relaxation and muscle protein turnover.
Increases hepatic gluconeogenesis/glycolysis and intestinal glucose absorption.
Increases lipolysis and cholesterol synthesis and degradation.
Hypothyroidism results from an insufficient production or action of thyroid hormones that leads to decreased metabolism in almost all tissues [4]. The causes could be as follows (shown in Table 1).
Causes of hypothyroidism
Primary causes
Neonatal
Thyroid gland aplasia hypoplasia or failure to descend
Inability to synthesize hormones
Peripheral resistance to thyroid hormone action
Anti-thyroid drugs or iodine during pregnancy
Acquired
Hashimoto’s disease
Iodine deficiency
Treatment of hyperthyroidism (radioactive iodine, subtotal thyroidectomy, etc.)
Drugs like amiodarone or lithium carbonate or antithyroid
Subacute thyroiditis
Secondary causes
Anterior pituitary gland disease
Pituitary adenoma
Surgery for pituitary tumors
Postpartum pituitary necrosis (Sheehan syndrome)
After head/neck injury
Infiltration of the pituitary by amyloidosis or sarcoidosis
Tertiary causes
TRH deficiency
Hypothalamic lesions
Table 1.
Causes of hypothyroidism.
4.1 Primary hypothyroidism
It is due to a disease process in the thyroid gland leading to a loss of negative feedback mechanism and subsequent elevation in the thyroid-stimulating hormone from the anterior pituitary gland [1]. Primary hypothyroidism is the most common form and can be subdivided into neonatal or acquired hypothyroidism [4].
4.1.1 Neonatal hypothyroidism
It results from thyroid gland aplasia, hypoplasia, or failure to descend during embryonic development or from the inability of the thyroid gland to synthesize hormones as a result of inherited defects. Peripheral resistance to thyroid hormone action could be a very rare cause of neonatal hypothyroidism. The use of anti-thyroid drugs or iodine during pregnancy may result in neonatal hypothyroidism. Endemic cretinism may occur in areas where there is iodine deficiency [4].
4.1.2 Acquired hypothyroidism
Chronic autoimmune thyroiditis (Hashimoto’s disease) is the most common cause of acquired hypothyroidism. Other causes include iodine deficiency in endemic areas, treatment of hyperthyroidism with radioactive iodine, subtotal thyroidectomy for nodular goiter, excessive intake of iodides in radiocontrast dyes, or drugs like amiodarone or lithium carbonate or anti-thyroid. Subacute thyroiditis may rarely cause hypothyroidism [2, 4].
4.2 Secondary hypothyroidism
There is an inappropriate low level of TSH due to anterior pituitary gland disease, leading to low circulating levels of T3 and T4 [1]. This may be caused by hypopituitarism due to pituitary adenoma, surgery for pituitary tumors, postpartum pituitary necrosis (Sheehan syndrome), or after head/neck injury. It can also be caused by infiltration of the pituitary glands by amyloidosis or sarcoidosis [2, 4].
4.3 Tertiary hypothyroidism
This occurs due to decreased level of TRH because of hypothalamic lesions [4].
4.4 Hashimoto’s thyroiditis
It is also known as autoimmune thyroiditis and is the most common cause of hypothyroidism and goiter in children and young adults in areas with no iodine deficiency. There is a rare variant of chronic thyroiditis know as Riedel thyroiditis, which causes fibrous destruction of the thyroid cells, causing a firm mass in the thyroid with retrosternal extension extending outside the gland. It may be confused with thyroid cancer.
4.4.1 Pathogenesis of Hashimoto’s thyroiditis
It is an autoimmune disorder causing lymphocytic destruction of the thyroid tissues with increased titers of thyroid peroxidase antibodies in the plasma with increased thyroglobulin antibodies and TSH receptor antibodies. The female-to-male ratio prevalence of Hashimoto’s thyroiditis is 4:1, respectively. It may be associated with autoimmune polyglandular diseases like Addison’s disease, diabetes mellitus type 1, and so on. The common clinical presentation of Hashimoto’s thyroiditis is diffused painless goiter. Patients are usually euthyroid or have only mild hypothyroidism but may suffer from severe hypothyroidism in case of severe destruction of the thyroid gland.
Prevalence of hypothyroidism is around 5%, and females are affected approximately six times more frequently than males [2].
The clinical presentation of hypothyroidism depends on the duration and severity of the disease. Patients who have developed complete thyroid failure insidiously may present with many of the clinical features of hypothyroidism that are mentioned below. Prolonged hypothyroidism results in the infiltration of many body tissues by the mucopolysaccharides hyaluronic acid, and chondroitin sulphate, resulting in many clinical features like a low-pitched voice, poor hearing, slurred speech due to a large tongue (macroglossia), and compression of the median nerve at the wrist (carpal tunnel syndrome). Infiltration of the dermis gives rise to non-pitting edema (myxedema), which is most marked in the skin of the hands, feet, and eyelids [2].
5.1 Neonatal hypothyroidism
It is manifested as poor feeding, respiratory difficulty, cyanosis, jaundice, hypotonia, muscle weakness, umbilical hernia, and growth retardation [4]. In the Pendred syndrome, neonates have goiter, deafness, and mental retardation. In infants, muscle involvement may result in the Kocher-Debré-Sémélaigne syndrome or “infant Hercules” [5].
5.2 Hypothyroidism in children
Clinical features include growth and mental retardation, a puffy face and hands, retardation in bone maturation, and neurological signs of pyramidal and extrapyramidal tract abnormalities [4].
5.3 Hypothyroidism in adults
The common symptoms include chronic fatigue, inability to concentrate, coldness, weight gain, constipation, and menstrual irregularities. In addition to periorbital swelling, swollen hands and feet (non-pitting oedema), a hoarse voice, and a thickening of the tongue, patients may complain of paraesthesia, muscle cramps, and muscle weakness [4] as well as hypothermia, bradycardia, dry skin with yellow tone (carotenemia), and deafness. Features of other autoimmune endocrinopathies may also be found [5, 6]. The best single clinical indicator for hypothyroidism is delayed relaxation of ankle jerk (Woltman’s sign), and patients may have goiter. In adults, the presence of painful myopathy and myotonia with myxedema is known as Hoffmann syndrome [5].
Severe form of hypothyroidism leads to myxedema coma, which is associated with decreased level of consciousness, profound hypothermia, hypoventilation, hypotension, striking bradycardia, and pleural and pericardial effusions [6].
5.4 Differential diagnosis
Differential diagnosis of hypothyroidism includes the following conditions: (Table 2) [2, 6].
Chronic fatigue syndrome
Congestive heart failure
Primary amyloidosis
Depression
Exposure hypothermia
Parkinson’s disease.
Clinical features of hypothyroidism
Neonates
Poor feeding
Respiratory difficulty
Cyanosis
Jaundice
Hypotonia
Muscle weakness
Umbilical hernia
Growth retardation
Children
Growth and mental retardation
Retardation in bone maturation
Puffy hands
Neurological signs of pyramidal and extrapyramidal abnormalities
Anemia may be microcytic or macrocytic due to impaired hemoglobin synthesis or impaired intestinal absorption of iron, folic acid, or due to pernicious anemia (in association with other polyglandular autoimmune disease) [4]. Hyponatremia and hyperprolactinemia with elevated serum cholesterol and creatinine kinase levels may be detected [5].
The most important diagnostic test is thyroid function test (TFT). TSH and free T4 and free T3 are measured by immunoassay technique at any time since there is no circadian rhythm for thyroid hormone secretion. In primary hypothyroidism, there is an elevated serum TSH level (>10 mIU/L) with low free T4; serum triiodothyronine (T3) concentrations are a poor indicator of hypo-thyroid state [5]. In secondary hypothyroidism, free T4 will be low, and TSH is also low normal or subnormal. Thyroid autoantibodies (peroxidase antibodies) will be found in autoimmune thyroiditis. MRI brain for the pituitary gland is needed if secondary hypothyroidism is suspected [4]. Isolated elevation of TSH may be detected in cases of mild (subclinical) hypothyroidism and use of some medications like amiodarone and lithium [5].
In severe hypothyroidism, ECG changes in form of bradycardia, with low voltage complex and ST segment and T-wave abnormalities, are found [2].
In severely ill patients, there is low total and free T4 and T3 serum levels with a normal or low normal TSH level (sick euthyroid’ syndrome); this change is probably mediated by interleukins IL-1 and IL-6. TFT should be repeated after the patient illness is resolved to exclude hypothyroidism [1].
The occurrence of hypothyroidism with autoimmune alopecia and transient acantholytic dermatosis is known as Grover’s disease [5].
Increased threshold for suspicion of hypothyroidism is the best screening test for hypothyroidism; however, elderly people especially female should be screened after the age of 50 years. The mean average age at diagnosis was 58–59 years, and the probability of developing hypothyroidism increased steadily with age. Screening for congenital hypothyroidism is essential since it is relatively common (1:4000 births); blood sample from heel prick is taken for TSH assessment. Serious results may occur from delay in diagnosis of congenital hypothyroidism such as brain damage with mental and physical retardation [7].
Screening of inpatient for hypothyroidism is ineffective because the nonspecific effect of acute illness on thyroid function test corrected itself after recovery [7].
7.1 Screening in special groups
Hypothyroidism occurs after all types of treatment for hyperthyroidism, for example, iodine therapy or thyroidectomy, so such patients need annual checkup for thyroid function. Patients taking lithium or amiodarone are at risk for both hypothyroidism and hyperthyroidism and need regular monitoring of thyroid function as well as female patients with type 1 diabetes mellitus or unexplained infertility. Also, women who have had postpartum thyroiditis should be screened annually for thyroid function since 25% of these women will develop overt hypothyroidism within the next 5 years. Patients with Turner’s and Down’s syndromes have a high prevalence of hypothyroidism than the general population and should be screened. Patients with bipolar affective disorder with recurrent cycling of refractory depression should be screened for hypothyroidism. Patients with dementia may be worth screening for thyroid function. It is uncertain whether patients with breast cancer may benefit from screening for hypothyroidism or not, because there is uncertain association between breast cancer and autoimmune (Hashimoto’s) thyroiditis, with a threefold increase in the prevalence of thyroid antibodies [7]. Patients with sickle cell anemia need testing for thyroid function because SCA results in sickling of erythrocytes that cause micro-vascular obstruction leading to acute complications and chronic organ damage, and endocrine glands are commonly affected. Thyroid disorders were frequently reported in patients with SCA [3]. Indications for screening for hypothyroidism are shown in Table 3 [3, 7].
Indications for screening for hypothyroidism
Elderly patients
For congenital hypothyroidism
Following treatment of hyperthyroidism
Neck irradiation
Pituitary surgery or irradiation
Patients on medications like lithium or amiodarone
Treatment for hypothyroidism is thyroid hormone replacement therapy for life, with levothyroxine starting with a low dose of 50 μg once per day for 3 weeks and increasing gradually until patients become euthyroid with a maintenance dose of 100–150 μg per day; it should be taken on empty stomach. In younger patients, levothyroxine can be started in a dose of 100 μg for rapid response and normalization of TFT [2, 5, 6]. Dose adjustment should be done every 3 weeks depending on clinical response and suppression of the elevated TSH level [5]. Response to treatment occurs within 2–3 weeks. Reduction in weight and periorbital puffiness occurs quickly, but resolution of effusions and restoration of hair and skin texture may take 3–6 months [2]. If there is no response to thyroxine therapy, patient compliance should be assessed; alternative diagnosis should be ruled out underlying psychiatric disorder, presence of pernicious anemia, or association with other endocrine disorders such as Addison’s disease. In pregnant ladies who are known to have hypothyroidism, the dose of levothyroxine should be increased to up ~50% in the first half of pregnancy because inadequate treatment of hypothyroidism during pregnancy may result in impaired cognitive development in the fetus. Elderly patients or patients with ischemic heart disease should be started with low dose thyroxine (25 μg) to avoid development of angina [2, 5].
This is a very rare presentation of severe hypothyroidism and is a medical emergency where there is decreased level of consciousness usually in an elderly patient with severe hypothyroidism and myxedema. It is also associated with hypothermia (body temperature may be 25°C), and convulsions are not uncommon. Mortality rate is very high and may reach up to 50%. Early recognition is essential for proper treatment. Suspected cases should be treated before laboratory confirmation of diagnosis [2]. Rewarming of the patient is essential as the first measure of treatment. Intravenous levothyroxine is given, and intravenous hydrocortisone may be added if adrenal insufficiency is suspected [6].
Liothyroine in a dose of 20 μg is given, then injections of 20 μg three times daily until the patient improves clinically. The body temperature rises in the first 24 hours, and after 2–3 days, the patient can be shifted to a dose of 50 μg levothyroxine once per day. If the patient is not known to have primary hypothyroidism, thyroid failure should be suspected to be secondary to pituitary or hypothalamic disease, and treatment with intramuscular hydrocortisone in form of 100 mg three times a day until the biochemical results of TFT and cortisol is obtained [2].
In this condition, serum TSH is elevated with low normal serum levels of T3 and T4. This may persist for many years, and there is risk for conversion to overt hypothyroidism especially if thyroid antibodies are present or if TSH is above 10 mIU/L. Such patients should be treated with levothyroxine. Patients with nonspecific symptoms and with laboratory findings of subclinical hypothyroidism should be treated with levothyroxine, and the dose should be sufficient to make TSH serum level within normal [2].
11. Sickle cell anemia and hypothyroidism
Sickle cell anemia is an inherited hemoglobinopathy resulting in sickling of erythrocytes that cause micro-vascular obstruction, leading to acute complications and chronic organ damage. Adults with SCA have endocrine complications and metabolic alterations. A study was conducted among patients with SCA who have high serum ferritin level to assess the association between gonadal and thyroid hormones with iron indices. It was found that there was a significant relation between serum ferritin level in patients with sickle cell who have high serum ferritin level and the following: serum iron, TIBC, serum testosterone, LH, prolactin, free T3, and free T4. This was most likely due to endocrine dysfunction secondary to high ferritin level and iron overload. The explanation of endocrine dysfunction is due to vaso-occlusion secondary to polymerization of red blood cells, leading to microcirculation and endocrine organ damage. In addition, the damage to endocrine system in SCA could be indirect via anemia, tissue hypoxia, and iron overload. Endocrine system dysfunction was reported as the most common and earliest complication of sickle cell disease. Thyroid disorders were frequently reported in patients with SCA. So, such patients need regular clinical monitoring with frequent checkup for serum ferritin level and hormonal assays, including test for thyroid hormones [3]. However further studies are recommended to detect if the severity of sickle cell disease affects hormonal levels in these patients.
12. Conclusions
In conclusion, hypothyroidism is a common condition and has a variety of causes and needs high clinical suspicion for diagnosis and screening because it has diverse clinical manifestations. Screening for neonates, elderly, and special groups of population (patients who have had treatment of hyperthyroidism or neck irradiation, etc.) is recommended. TFT is the diagnostic test for hypothyroidism, and the definitive treatment is hormone replacements for life. Patients with SCA need frequent checkup for hypothyroidism as it is one of the most frequent complications of SCA.
Acknowledgments
Special thanks to my son, Mohab Abdallhameed, for helping me with this book chapter and for being there for me throughout all of my other publications. No matter how much I write I cannot thank him enough. I’d also like to thank my family for their tremendous support and endless love despite being displaced from home because of the war in Sudan. Hoping that the disastrous war will end soon and I, along with my Sudanese brothers and sisters will return safely to our homes and we will meet once again soon.
Conflict of interest
The authors declare no conflict of interest.
Thanks
I’d like to thank Mr. Dorian Salatic, the publishing process manager of Intechopen for his help and support and my thanks extends to all the team of Intechopen.
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3.Mostafa GG, Zahran FE, Omer SA, Ibrahim A, Elhakeem H. The effect of serum ferritin level on gonadal, prolactin, thyroid hormones, and thyroid stimulating hormone in adult males with sickle cell anemia. Journal of Blood Medicine. 2020;11:27-32. DOI: 10.2147/jbm.s232562
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Written By
Sawsan A. Omer and Mohab Elmubarak
Submitted: 07 April 2024Reviewed: 21 April 2024Published: 21 June 2024
Open access peer-reviewed chapter - ONLINE FIRST
