Hyperthyroidism, a common thyroid disorder, refers to increased synthesis and secretion of thyroid  hormones by the thyroid gland. Most common causes of hyperthyroidism are Graves’ disease (GD), toxic multinodular goiter and toxic adenoma. There are three therapeutic choices for hyperthyroidism : thyroid surgery as the oldest modality, radioactive iodine (RAI) and antithyroid drugs (ATDs).

       
           
       
Propylthiouracil Methimazole

Thyroid disease is common and becomes more common with age. 5-9% of adults have subclinical thyroid disease, and 0.8-7.5% have thyroid disease. Thyroid hormone is the only biologically active substance containing iodine, which is known to have two important functions. They are important determinants of normal development during animal and human development, especially in the central nervous system (CNS). In adults, thyroid hormones play a role in the regulation of metabolism in homeostasis and affect the functioning of almost all organs. The metabolism of thyroid hormone occurs primarily in the liver, but local metabolism also occurs in tissues such as the brain. In classical negative feedback, the amount of thyroid hormone is controlled by the pituitary hormone thyrotropin. The main effects of thyroid hormones are mediated by binding to the thyroid hormone receptor (TR) and regulating the transcription of specific genes. These receptors constitute the nuclear receptor superfamily. The thyroid gland secretes three hormones: thyroxine (T4), triiodothyronine (T3), and calcitonin. Subclinical thyroid disease is characterized by abnormal thyroid-stimulating hormone (TSH) but normal T4 and T3 levels and does not require treatment; patients with thyroid disease have abnormally mobile TSH, T4, and T3 levels that must be corrected. Known risk factors for thyroid disease include autoimmunity, external irradiation of the head and neck, defects in iodine tissue biosynthesis, tumor replacement of the thyroid gland, and use of certain medications. Other factors associated with the risk of thyroid disease include sex, age, and iodine deficiency. There are two major TR isoforms encoded on different genes: TR? and TR?. TR binds to thyroid hormone response elements in the promoters of targets to regulate their transcription. TSH is a heterodimer composed of two subunits: TSHa and TSH?. TSH?, known as the subunit of glycoprotein hormone ?, is also a subunit of several other glycoprotein hormones such as LH, FSH, and human chorionic gonadotropin, while TSH? is specific for TSH. T3 negatively regulates TSH by decreasing the TSH? and TSH? genes and the transcription of the TRH gene. The major thyroid hormone in the brain is 3,5,3?-triiodothyronine (T3), which is derived primarily from the 5? deiodination of parent thyroxine (T4) by local brain deiodinases D2 and D3. Maternal T4 and T3 are transported from the mother's blood to the fetal brain across the blood-brain barrier. Hypothyroidism, in severe cases called myxedema, is the most common thyroid disorder. The disease is characterized by high levels of antibodies to thyroid peroxidase and, to a lesser extent, to thyroglobulin. In addition, blocking of antibodies to TSH receptors may also occur, which can lead to further adverse reactions. The failure of the thyroid gland to produce enough thyroid hormone is the most common cause of thyroid insufficiency, called primary hypothyroidism. Central hypothyroidism occurs rarely and is caused by a decrease in TSH in the thyroid gland due to insufficiency of the pituitary gland (secondary hypothyroidism) or the hypothalamus (tertiary hypothyroidism). Hypothyroidism present at birth (congenital hypothyroidism) is the most common mental retardation in the world. There are several treatment options for patients with hyperthyroidism, including the use of antithyroid drugs to reduce hormone synthesis and secretion, radioactive iodine administration, or surgical removal of the tumor. In general, the results of treatment for thyroid disease are quite satisfactory, and most patients can be cured or controlled. This enzyme catalyzes the oxidation of iodide, iodination of tyrosine residues in thyroglobulin, and the synthesis of iodotyrosine (monoiodotyrosine, MIT, and diiodotyrosine, DIT), producing thyromydine, tetraiodothyronine (T3), and thyroxine (Thyroxine). ATD also has anti-inflammatory properties, which may be part of its role in the treatment of Graves' hyperthyroidism. The term "thyrotoxicosis" also includes conditions not related to hyperthyroidism but related to the process of thyroid destruction or the administration of exogenous thyroid hormones.

Classification of different forms of thyrotoxicosis

Hyperthyroidism in pregnancy is a serious condition that increases the risk of adverse outcomes such as miscarriage, stillbirth, preterm birth, and fetal growth restriction. Management is difficult and is currently a major debate among endocrinologists. Antithyroid drugs (ATDs) have been used since the 1940s and are the treatment of choice during pregnancy. Radioactive iodine is strictly contraindicated, and thyroidectomy is more likely to occur during pregnancy than in nonpregnant women and may increase the risk of fetal thyrotoxicosis. A randomized controlled trial of measures in pregnant women with hyperthyroidism. However, carbimazole (CBZ) and its metabolites methimazole (MMI) and propylthiouracil (PTU) are both considered effective in the treatment of hyperthyroidism. Therefore, the choice of ATD is not based on relative therapeutic benefits, but on the risk of side effects and particularly serious consequences such as teratogenicity and severe pain. The aim of this review is to explore considerations regarding the choice of ATD used during pregnancy and when planning to become pregnant.

Vitamin D And the Thyroid –

Vitamin D is necessary for the normal functioning of many organs, including the thyroid gland. It is, therefore, not surprising that vitamin D deficiency is considered a risk factor for the development of many thyroid disorders, including autoimmune thyroid diseases and thyroid cancer. However, the interaction between vitamin D and thyroid function is still not fully understood.

- Vitamin D in Autoimmune Thyroid Diseases-

thyroid disease is characterized by the immune system of the thyroid gland. Vitamin D supplementation has been shown to be beneficial in animal models of Graves' disease and thyroiditis. In addition, a meta-analysis by Xu et al, which included 26 studies (1,748 Graves' disease and 1,848 controls), noted that patients with Graves' disease were more likely to have vitamin D deficiency. Vitamin D can regulate the function of many aspects of the immune system and participate in the regulation of the body. Vitamin D inhibits the production of proinflammatory cytokines such as IL-6, IL-8, IL-9, IL-12, IFN-?, and TNF-?. It also increases the production of anti-inflammatory cytokines such as IL-10, IL-5 and IL-4. All the benefits of vitamin D are thought to be preventive. Although many studies have been conducted to show the role of vitamin D in the development of autoimmune thyroid diseases, it is still unclear whether vitamin D deficiency is a factor in the disease or a result of autoimmune thyroid disease.

-  Vitamin D in Thyroid Cancer-

The incidence of thyroid cancer is increasing. In 2017, 255,490 new cases of cancer were diagnosed worldwide, compared to only 95,030 in 1990. The various types of thyroid cancer (papillary, Hurthle cell, and follicular thyroid cancer), benign thyroid cancer, and anaplastic thyroid cancer arise from follicular thyroid cancer cells. Medullary thyroid carcinoma results from malignant transformation of parafollicular neuroendocrine cells. The most common type of thyroid cancer is differentiated thyroid cancer, with papillary thyroid cancer accounting for 85% of cases. Vitamin D has been shown to be effective in cancer treatment by both in vitro and in vivo studies. In vitro studies have shown that calcitriol and its analog (MART-10) can inhibit the growth and metastatic potential of anaplastic thyroid cancer cells, respectively. In addition, the expression of VDR and other genes involved in vitamin D expression was increased in breast cancer cells, suggesting that vitamin D may play a tumor-protective role in cancer treatment. In vivo studies have shown that calcitriol treatment reduces tumor size in follicular thyroid cancer and metastatic follicular thyroid cancer mouse models.

The Effect Of Vitamin D On Secretion Of Tsh, Thyroid Hormones & Anti-Thyroid Antibodies-

Studies in healthy participants have generally shown variability or lack of correlation between TSH and 25(OH)D levels, and the same pattern has been observed in studies in cancer patients. Conflicting results have been found regarding thyroid hormones, with positive, negative, or no effects on 25(OH)D levels in healthy participants. Studies in patients with autoimmune thyroid disease are also controversial. Two-thirds of studies found no association, and one-third found an interaction between TSH and 25(OH)D levels. On the other hand, most studies in patients with autoimmune thyroid disease found no association between thyroid hormones and 25(OH)D levels. Regarding antithyroid antibodies, most studies found a positive correlation between antithyroid antibodies (antithyroid peroxidase antibody [TPOAb], antithyroglobulin antibody [TgAb], or TSH receptor antibody [TSHRAb]) and 25(OH)D levels, but many studies failed to assess this association.

Symptoms Of Hyperthyroidism And Hypothyrodism-

Symptoms of Hypothyroidism (An underactive thyroid)-

Fatigue; exhaustion feeling run down and sluggish depression, moodiness difficulty concentrating; brain fog;unexplained or excessive weight gain; dry, coarse and/or itchy skin; dry, coarse and/or thinning hair; feeling cold, especially in the extremities; constipation; muscle cramps; increased menstrual flow; more frequent periods; infertility/miscarriage; low blood pressure; frequent infections; bloating/puffiness in hands, feet, eye area, face, etc. Symptoms of Hyperthyroidism (An overactive thyroid)- Nervousness; irritability; increased perspiration;thinning of your skin; fine brittle hair; muscular weakness especially involving the upper arms and thighs; shaky hands; panic disorder; insomnia; racing heart; more frequent bowel movements; weight loss despite a good appetite; lighter flow, less frequent menstrual periods,etc.

Adverse Effects of Antithyroid Drugs-

Thyroid hormone, especially thyroxine, are widely used either at replacement doses to correct hypothyroidism or at suppressive doses to abolish thyrotropin (thyroid-stimulating hormone) secretion in patients with differentiated thyroid carcinoma after total thyroidectomy or with diffuse/ nodular nontoxic goitre. In order to suppress thyrotropin secretion, it is necessary to administer slightly supraphysiological doses of thyroxine. Possible adverse effects of this therapy include cardiovascular changes (shortening of systolic time intervals, increased frequency of atrial premature beats and, possibly, left ventricular hypertrophy) and bone changes (reduced bone density and bone mass), but the risk of these adverse effects can be minimised by carefully monitoring serum free thyroxine and free liothyronine (triiodothyronine) measurements and adjusting the dosage accordingly. Thionamides [thiamazole (methimazole), carbimazole, propylthiouracil] are the most widely used antithyroid drugs. They are given for long periods of time and cause adverse effects in 3 to 5% of patients. In most cases, adverse effects are minor and transient (e.g. skin rash, itching, mild leukopenia). The most dangerous effect is agranulocytosis, which occurs in 0.1 to 0.5% of patients. This life-threatening condition can now be effectively treated by granulocyte colony-stimulating factor administration. Other major adverse effects (aplastic anaemia, thrombocytopenia, lupus erythematous-like syndrome, and vasculitis) are exceedingly rare.

Effects Of Anti Thyroids Drugs-

Various effects of antithyroid drugs include inhibition of thyroid hormone synthesis and reduction of intrathyroidal immune dysregulation and (in the case of propylthiouracil) peripheral conversion of thyroxine to triiodothyronine. Tyrosine-Tg represents the tyrosine residue in thyroglobulin, I+ represents the iodinated environment, and TPO represents thyroid peroxidase.

Antithyroid medications are first-line treatment for adults with mild to moderate hyperthyroidism or goiter and are also a treatment for children, adolescents, and pregnant or breast-feeding women. Radioactive iodine may be more appropriate as a first-line treatment for adults in the United States, but it is not the case for adults in other parts of the world. Subtotal or near-total thyroidectomy is an option for some patients after antithyroid drug therapy. Radioactive iodine therapy is the preferred option for adults who relapse. Some patients prefer secondary thyroid medications, and this strategy is appropriate for children and adolescents. CBC stands for complete blood count.

Antithyroid Activity of Herbal Plants-

Some plants isoflavonoids have profound effects on thyroid hormones and on the hypothalamus–pituitary axis. Genistein and daidzein from soy (Glycine max) inhibit thyroperoxidase that catalyses iodination and thyroid hormone biosynthesis. Other plants with hypothyroid effects include pearl millet (Pennisetum glaucum) and fonio millet (Digitaria exilis); thiocyanate is found in Brassicae plants including cabbage, cauliflower, kale, rutabaga, and kohlrabi, as well as in tropical plants such as cassava, lima beans, linseed, bamboo shoots, and sweet potatoes. Tobacco smoke is also a source of thiocyanate.

The antithyroid and goitrogenic effects of Brassicae plants (Family Cruciferae) have long been known including cabbage (Brassica oleracea), broccoli, cauliflower, kale, kohlrabi, Brussels sprouts, and rutabaga (swede or yellow turnip, Brassica napobrassica), rapeseed and mustard. SCN interferes with active uptake and concentration of inorganic iodide by the thyroid and inhibits the enzyme thyroperoxidase thereby preventing the incorporation of iodine into thyroglobulin. Rutabaga and turnips contain a thiourea like product (progoitrin), a precursor of goitrin that also interferes with thyroperoxidase.

The most useful herbal remedies for both under and overactive thyroid are sea plants. Bladder wrack, a form of kelp, is used in both western and Chinese herbal medicine. It can be taken as a supplement or as an infusion. Pour boiling water over 2 to 3 tsp. of the dried herb and steep for 10 minutes. This remedy is useful if there is a deficiency of iodine in the diet. Bitters are helpful for mild cases of hypothyroidism. These can be found in natural foods stores usually as a liquid supplement. Hyperthyroidism can be supported by an herb called bugleweed. This herb should not be taken without a doctor's support. It can interfere with thyroid replacement therapy, should not be taken by pregnant women, and can result in enlargement of the thyroid. Insomnia associated with hyperthyroidism can be helped by valerian and passion flower. To use these herbs, take 15 drops of each tincture in water, one half hour before bed. Many more like botanical name of herbal thyroid stimulant, Gum guggle is commiphora mukul. The yellow resinous extract derived from the stem part of Mukul myrrh tree consists of volatile oils and resins in abundance. The pungent smell and acrid taste of this herb. The active compound in Guggle is called guggulsterone and has the power to influence thyroid function and improve the condition of hypothyroidism. A published journal titled ‘Phototherapy research ‘confirms the role of guggulsterone. An added advantage of having the herb is a decrease in the level of harmful cholesterol, one of the features of hypothyroidism. The incidence of side effect is low, but can range from headache, gastric upset, skin rash and rarely, hiccups.

Side Effects-

Antithyroid drugs can cause a variety of minor side effects as well as life-threatening and even fatal problems. The side effects of methimazole are dose-dependent, whereas the side effects of propylthiouracil are not significant. For patients with moderate hyperthyroidism, this may suggest a lower dose of methimazole instead of propylthiouracil. Agranulocytosis is the most concerning side effect of antithyroid drugs. In the largest series, agranulocytosis (absolute granulocyte count less than 500 cells per cubic millimeter) occurred in 0.37% of patients treated with propylthiouracil and 0.35% of patients treated with methimazole. Other rare side effects of antithyroid drugs are listed i.e,

Skin Reactions-

Rash, urticaria, and minor allergic skin reactions such as hives are the worst side effects and usually occur within the first few weeks of treatment. In a meta-analysis of 5,136 patients, 6% of MMI users and 3% of PTU users reported rash, while 2% to 3% of patients had pruritus but no rash. In another randomized trial, skin reactions were described in 22% and 6% of patients treated with 30 mg MMI and 15 mg MMI, respectively. Approximately one-third of patients switched to another ATD after experiencing mild drug reactions and adverse events. Current ATA guidelines recommend antihistamine therapy without discontinuation of the ATD in patients with mild skin reactions, continuation or modification of the ATD in patients with moderate reactions, and avoidance of all ATDs in patients with more severe skin conditions. The median time from onset of skin reactions is approximately 20 days. Time to Onset of Complications After the Initiation of Antithyroid Drugs.

Agranulocytosis-

Agranulocytosis is generally defined as a granulocyte matter of <500>

Hepatotoxicity-

ATD-induced hepatotoxicity ranges from mild transaminase elevation to fatal hepatic necrosis. In the United States, 1 to 3 liver transplants associated with PTU are reported to the FDA each year (1990 through 2007). Hepatotoxicity was reported in 0.3% and 0.15% of patients exposed MMI and PTU, respectively. Noninfectious liver disease was significantly higher in the MMI group than in the PTU group (0.25% vs. 0.08%). In contrast, patients with PTU had higher rates of morbidity than patients with MMI. The incidence of cholestasis was similar with both drugs. A second study from China (80) reported that in 90 patients with severe hepatotoxicity

Vasculitis-

Lupus erythematosus caused by ATD was first described in 1970. Compared with other rare cases of ATD, it usually occurs after many years of treatment. Surprisingly, patients with GD and those who remain asymptomatic while receiving ATD may be ANCA positive in the absence of ATD. Routine screening for ANCA positivity is not recommended. The usual presentation is fever, malaise, and joint pain. Patients may have clinical signs of cutaneous, pulmonary, and renal vasculitis involvement. Symptoms usually improve after regular drug therapy, but some patients require antidiarrheal therapy and hemodialysis.

Arthralgias/ Arthritis-

Joint pain occasionally occurs during ATD treatment. Arthritis was reported in 1.6% of patients treated with ATD. These patients had joint pain in the hands, shoulders, hips, knees, or ankles and required general anesthesia for 1 to 3 weeks to control the pain. Joint swelling and erythema were rare.

Thyroid Hormones And Their Roles-

The role function of the thyroid gland is to produce two steroid hormone ( T3 & T4) and one peptide hormone ( Calcitonin ). Iodinated tyrosine residue is the main ingredient for thyroid hormones. Per molecule of T3 and T4 are comprises of 3 atoms and 4 atoms of iodine respectively hence the name Triiodothyronine and Tetraiodothyronine. In the body the thyroid hormones regulate mainly three function. These includes:

• Metabolic: Thyroid hormones influence metabolic activity by increasing the basal metabolic rate. The hormones facilitate the breakdown, absorption and cellular uptake of glucose. They also stimulate the breakdown of fats, and increase the number of free fatty acids. Despite increasing free fatty acids, thyroid hormones decrease cholesterol levels, perhaps by increasing the rate of secretion of cholesterol in bile.
• Cardiovascular: The rate and force of cardiac contraction is also influenced by the hormones. Both rate of breathing and oxygen consumption is increased by enhancing the activity of cell mitochondria. All these events combined, increase blood flow and the body’s temperature.
• Development: Thyroid hormones are important for normal development. They increase the growth rate in young ones, and cells of the developing brain are a major target for the thyroid hormones T3 and T4. Thyroid hormones play a crucial role in brain maturation during foetal development and first few years of postnatal life.
• Moreover, the thyroid hormones also play a role in maintaining normal sexual function, sleep, and thought patterns.

Only a fraction of thyroid hormone travel freely in blood after its release from gland. Most are bound to thyroxine-binding globulin (TBG) and to a lesser extent to transthyretin, and albumin. The hormonal activity lies in only 0.03% of T4 and0.3% of T3 traveling in the body in unbound form. In addition, up to 85% of the T3 in blood is produced following conversion from T4 by iodothyronine deiodinases in organs around the body. Once the hormone crosses the cell membrane it goes and binds to nuclear thyroid hormone receptors TR-?1, TR-?2, TR-?1 and TR-?2, the hormone receptor complex then bind with hormone response elements and transcription factors and modulate DNA transcription of the specific protein. Including all these role, thyroid hormones also interacts with enzyme like calcium ATPase and adenylyl cyclase, and glucose transprters in the cell cytoplasm.

The pharmacokinetic data of T4 and T3.