Thyroid

• Thyroid gland


  Facilitates normal growth and maturation by maintaining a level of metabolism in the tissues that is optimal for their normal function

  
• Thyroid hormones


  Triiodothyronine (T3; the most active form) and thyroxine (T4)

  
• Inadequate secretion of thyroid hormone (hypothyroidism)


  Results in bradycardia, poor resistance to cold, and mental and physical slowing (in children, this can cause mental retardation and dwarfism)

  
• Excess of thyroid hormones (hyperthyroidism)


  Tachycardia and cardiac arrhythmias, body wasting, nervousness, tremor, and excess heat production can occur

  
• Thyroid gland


  • Made up of multiple follicles that consist of a single layer of epithelial cells surrounding a lumen filled with thyroglobulin, which is the storage form of thyroid hormone

  
• Thyroid hormone synthesis and secretion

  1. Iodide (I-) uptake

  2. Oxidation to iodine by a peroxidase

  3. Iodination of tyrosines on thyroglobulin

  4. Condensation of two diiodotyrosine residues gives rise to T4

  5. Condensation of a monoiodotyrosine residue with a diiodotyrosine residue generates T3

  6. Hormones are released following proteolytic cleavage of the thyroglobulin

  
• Regulation of synthesis


  1. Thyroid function is controlled by thyroid-stimulating hormone (TSH; thyrotropin)

  2. TSH is a glycoprotein, structurally related to LH and FSH, which is synthesized by the anterior pituitary

  3. TSH generation is governed by the hypothalamic thyrotropin-releasing hormone (TRH)

  4. TSH action is mediated by cAMP and leads to stimulation of iodide (I–) uptake

  
• Regulation of secretion


  1. Secretion of TSH by the anterior pituitary is stimulated by hypothalamic TRH

  2. Feedback inhibition of TRH occurs with high levels of circulating thyroid hormone

  3. Dopamine, somatostatin, or glucocorticoids can also suppress TSH secretion

  
• Mechanism of action


  • T4 and T3 must dissociate from thyroxine-binding plasma proteins prior to entry into cells
  • In the cell, T4 is enzymatically deiodinated to T3, which enters the nucleus and attaches to specific receptors
  • The activation of these receptors promotes the formation of RNA and subsequent protein synthesis, which is responsible for the effects of T4
• Pharmacokinetics


  • T4 and T3 are absorbed after oral administration
  • Food, calcium preparations, and aluminum-containing antacids can decrease the absorption of T4 but not of T3
  • T4 is converted to T3 by one of two distinct deiodinases, depending on the tissue
  • Drugs that induce the P450 enzymes, such as phenytoin, rifampin, and phenobarbital, accelerate metabolism of the thyroid hormones
• Effects of thyroid hormones on the human body


  • Metabolic effects
  • Cardiovascular effects
  • Developmental effects

  
• Metabolic effects


  • Increase the basal metabolic rate and have effects on almost all body tissues
  • Influence appetite, absorption of substances, and gut motility
  • Increase the absorption in the gut, generation, uptake by cells, and breakdown of glucose
  • Stimulate the breakdown of fats, and increase the number of free fatty acids
  • Decrease cholesterol levels, perhaps by increasing the rate of secretion of cholesterol in bile
• Cardiovascular effects


  • Increase the rate and strength of the heartbeat
  • Increase the rate of breathing, intake, and consumption of oxygen, and increase the activity of mitochondria
  • Increase blood flow and the body's temperature
• Developmental effects


  • Increase the growth rate of young people
  • Cells of the developing brain are a major target for the thyroid hormones T3 and T4
  • Play a crucial role in brain maturation during fetal development

  
• Hypothyroidism


  • A common disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone
  • Can cause poor ability to tolerate cold, a feeling of tiredness, constipation, depression, and weight gain
  • Myxedema coma is a rare but life-threatening state of extreme hypothyroidism

  
• Causes of hypothyroidism


  • Inadequate function of the gland itself (primary hypothyroidism)
  • Inadequate stimulation by thyroid-stimulating hormone from the pituitary gland (secondary hypothyroidism)
  • Inadequate release of thyrotropin-releasing hormone from the brain's hypothalamus (tertiary hypothyroidism)

  
• Primary hypothyroidism


  • About a thousand fold more common than central hypothyroidism
  • Iodine deficiency is the most common cause
  • Hashimoto's may be associated with a goiter
  • Characterized by infiltration of the thyroid gland with T lymphocytes and autoantibodies against specific thyroid antigens

  
• Autoimmune thyroiditis is associated with other immune-mediated diseases such as diabetes mellitus type 1, pernicious anemia, myasthenia gravis, celiac disease, rheumatoid arthritis, and systemic lupus erythematosus
• Thyroid hormone


  • Required for the normal functioning of numerous tissues in the body
  • In health, the thyroid gland predominantly secretes thyroxine (T4), which is converted into triiodothyronine (T3) in other organs by the selenium-dependent enzyme iodothyronine deiodinase
  • Triiodothyronine binds to the thyroid hormone receptor in the nucleus of cells, where it stimulates the turning on of particular genes and the production of specific proteins
  • The hormone also binds to integrin αvβ3 on the cell membrane, thereby stimulating the sodium–hydrogen antiporter and processes such as formation of blood vessels and cell growth
  • In blood, almost all thyroid hormone (99.97%) is bound to plasma proteins such as thyroxine-binding globulin; only the free unbound thyroid hormone is biologically active

  
• Overt primary hypothyroidism


  TSH levels are high and T4 and T3 levels are low
• Subclinical hypothyroidism


  A milder form of hypothyroidism characterized by an elevated serum TSH level, but with a normal serum free thyroxine level
• Congenital hypothyroidism (CH)


  • A condition of thyroid hormone deficiency present at birth
  • If untreated for several months after birth, severe congenital hypothyroidism can lead to growth failure and permanent intellectual disability
  • Treatment consists of a daily dose of thyroid hormone (thyroxine) by mouth

  
• Treatment of hypothyroidism


  • Hypothyroidism usually results from autoimmune destruction of the gland or the peroxidase and is diagnosed by elevated TSH
  • It is treated with levothyroxine (T4)
  • The drug is given once daily because of its long half-life
  • Steady state is achieved in 6 to 8 weeks
  • Toxicity is directly related to T4 levels and manifests itself
• Congenital hypothyroidism (CH)


  A condition of thyroid hormone deficiency present at birth. If untreated for several months after birth, severe congenital hypothyroidism can lead to growth failure and permanent intellectual disability
• Treatment of congenital hypothyroidism


  1. Daily dose of thyroid hormone (thyroxine) by mouth

  2. Newborn screening to detect and treat congenital hypothyroidism in the first weeks of life

  
• Hypothyroidism


  Usually results from autoimmune destruction of the gland or the peroxidase and is diagnosed by elevated TSH
• Treatment of hypothyroidism


  Levothyroxine (T4) given once daily because of its long half-life. Steady state is achieved in 6 to 8 weeks
• Toxicity of levothyroxine


  Directly related to T4 levels and manifests itself as nervousness, heart palpitations and tachycardia, intolerance to heat, and unexplained weight loss
• Hyperthyroidism


  The condition that occurs due to excessive production of thyroid hormone by the thyroid gland

  
• Thyrotoxicosis


  The condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism

  
• Symptoms of hyperthyroidism/thyrotoxicosis


  • Irritability, muscle weakness, sleeping problems, a fast heartbeat, heat intolerance, diarrhea, enlargement of the thyroid, and weight loss. Symptoms are typically less in the old and during pregnancy
• Graves' disease


  An autoimmune disease, it is eight times more common in females than males and often occurs in young females, around 20 – 40 years of age
• Other causes of hyperthyroidism/thyrotoxicosis

  • Toxic thyroid adenoma
  • Toxic multinodular goiter
  • Hashimoto's thyroiditis
  • Oral consumption of excess thyroid hormone tablets
  • Consumption of ground beef contaminated with thyroid tissue
  • Amiodarone, an antiarrhythmic drug
  • Postpartum thyroiditis (PPT)
  • Struma ovarii (a rare form of mono-dermal teratoma that contains mostly thyroid tissue)

  
• Treatment of hyperthyroidism/thyrotoxicosis


  The goal is to decrease synthesis and/or release of additional hormone. This can be accomplished by removing part or all of the thyroid gland, by inhibiting synthesis of the hormones, or by blocking release of the hormones from the follicle
• Inhibition of thyroid hormone synthesis


  1. The thioamides, propylthiouracil (PTU), and methimazole are concentrated in the thyroid, where they inhibit both the oxidative processes required for iodination of tyrosyl groups and the condensation (coupling) of iodotyrosines to form T3 and T4

  2. PTU can also block the conversion of T4 to T3

  3. These drugs have no effect on the thyroglobulin already stored in the gland, so observation of any clinical effects may be delayed until thyroglobulin stores are depleted

  4. The thioamides are well absorbed from the gastrointestinal tract, but they have short half-lives. Several doses of PTU are required per day. Methimazole is administered in 3 equally divided doses at approximately 8-hour intervals

  5. Relapse may occur. Relatively rare adverse effects include agranulocytosis, rash, and edema. Because of the potential for liver toxicity or liver failure PTU should be reserved for patients who are intolerant of methimazole

  
• Thyroid storm


  Thyroid storm presents with extreme symptoms of hyperthyroidism. The therapeutic options are the same as those for hyperthyroidism, except that the drugs are given in higher doses and more frequently
• Treatment of thyroid storm


  1. β-Blockers that lack sympathomimetic activity, such as propranolol, are effective in blunting the widespread sympathetic stimulation

  2. Intravenous administration is effective

  3. An alternative in patients suffering from severe heart failure or asthma is the calcium-channel blocker, diltiazem

  4. Other agents used include PTU, iodides, iodinated contrast media, and glucocorticoids
• Blockade of hormone release


  A pharmacologic dose of iodide inhibits the iodination of tyrosines and inhibits the release of thyroid hormones from thyroglobulin. Iodide is rarely used as the sole therapy, but is employed to treat potentially fatal thyrotoxic crisis (thyroid storm) or prior to surgery, because it decreases the vascularity of the thyroid gland. Iodide is not useful for long-term therapy, because the thyroid ceases to respond to the drug after a few weeks
• Antithyroid drugs


  Two are currently available: propylthiouracil and methimazole (brand name: Tapazole). Carbimazole (which is converted into methimazole in the body) is available in Europe and parts of Asia but not in the United States
• Methimazole


  Methimazole is usually preferred over propylthiouracil because it reverses hyperthyroidism more quickly and has fewer side effects. Methimazole requires an average of six weeks to lower T4 levels to normal and is often given before radioactive iodine treatment. Methimazole can be taken once per day