Physiological effects of thyroid hormones are listed below:

• Increases the basal metabolic rate
• Depending on the metabolic status it can induce lipolysis or lipid synthesis
• Stimulate the metabolism of carbohydrates
• Anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses
• Permissive effect on catecholamines
• In children, thyroid hormones act synergistically with growth hormone to stimulate bone growth
• The impact of thyroid hormone in CNS is important. During the prenatal period, it is needed for the maturation of the brain. In adults, it can affect mood. Hyperthyroidism can lead to hyperexcitability and irritability. Hypothyroidism can cause impaired memory, slowed speech, and sleepiness.
• Thyroid hormone affects fertility, ovulation, and menstruation

Thyroid hormones are lipophilic and circulate bound to the transport proteins. Only a fraction (~0.2%) of the thyroid hormone (free T4) is unbound and active. Transporter proteins include thyroxine-binding globulin (TBG), transthyretin, and albumin. TBG transports the majority (two-thirds) of the T4, and transthyretin transports thyroxine and retinol. When it reaches its target site, T3 and T4 can dissociate from their binding protein to enter cells either by diffusion or carrier-mediated transport. Receptors for T3 bind are already bound to the DNA in the nucleus before the ligand binding. T3 or T4 then bind to nuclear alpha or beta receptors in the respective tissue and cause activation of transcription factors leading to the activation of certain genes and cell-specific responses. Thyroid hormones are degraded in the liver via sulfation and glucuronidation and excreted in the bile. [8]

Thyroid receptors are transcription factors that can bind to both T3 and T4. However, they have a much higher affinity for T3. As a result, T4 is relatively inactive. Deiodinases convert T4 to active T3 or inactive reverse T3 (rT3). There are three types of deiodinases: type I, II, and III. Type I (DIO1) and II (DIO2) are located in the liver, kidneys, muscles, and thyroid glands. Type III (DIO3) deiodinases are located in the CNS and placenta. DIO1 and DIO2 convert T4 to active form T3, and DIO3 converts T4 into inactive form rT3. [8]

Hypothalamus releases thyrotropin-releasing hormone (TRH) that stimulates the secretion of TSH in the pituitary gland. Increased free T4 and T3 inhibit the release of TRH and TSH through a negative feedback loop. As a result, T3 and T4 secretion, and iodine uptake are reduced. Other hormones, such as somatostatin, glucocorticoids, and dopamine, also inhibit TSH production. Cold, stress, and exercise increase TRH release.

The initial tests of choice to screen for any thyroid abnormality are a TSH and free thyroxine (free T4) test. These determine whether the abnormality arises centrally from the thyroid gland (primary), peripherally from the pituitary (secondary), or hypothalamus (tertiary). In primary hypothyroidism is suspected, the thyroid gland is not releasing enough thyroid hormones. Therefore, TSH levels will be appropriately elevated, while free T4 levels will be lower. In primary hyperthyroidism, free T4 levels abnormally increased, and TSH levels will be appropriately decreased. Other lab tests such as TSH receptor antibodies or antibodies to thyroid peroxidase can help aid in the diagnosis of Graves disease or Hashimoto thyroiditis, respectively.[9]

In pregnant women, thyroid-binding globulin production is increased because of estrogen and beta-human chorionic gonadotropin (beta-HCG). More free T4 will be bound to TGB, leading to increased production of T4. TSH levels and free T4 levels will normalize, and total T4 will increase. Therefore, laboratory values will show normal TSH, normal free T4, and elevated total T4.  [10]

Hyperthyroidism: Disorders of the thyroid gland can result in excess T3 and T4 production along with the compensatory decrease of TSH. In addition, thyrotroph adenoma can produce unregulated TSH and can lead to increased T3 and T4 production. In some conditions, there is an ectopic production of thyroid hormone leading to increased thyroid hormones and compensatory TSH decrease.

Hypothyroidism: In primary hypothyroidism, decreased production of thyroid hormones by the thyroid gland causes a compensatory increase of TSH. Secondary hypothyroidism is caused by pituitary disorders causing decreased TSH release and decreased T3/T4 levels. Tertiary hypothyroidism is caused by hypothalamic disorders which result in decreased TRH levels, decreased TSH, and T3/T4 levels.

Two of the most common causes of hyperthyroidism and hyperthyroidism are below:

Graves Disease

Graves disease is the most common cause of hyperthyroidism. It is an autoimmune disease caused by the production of TSH receptor antibodies that stimulate thyroid gland growth and thyroid hormone release. Patients will have abnormally increased T4 and T3 levels and a decrease in TSH. A positive TSH-receptor IgG immunoglobulin test confirms the diagnosis. Immunoglobulin G (IgG) against TSH-receptor leads to increased thyroid function and growth. Patients will often present with symptoms of hyperthyroidism and diffuse goiter. TSH-receptor antibodies can also activate orbital fibroblasts leading to fibroblast proliferation and differentiation to adipocytes. As a result, there is increased production of hyaluronic acid and glycosaminoglycan (GAG), leading to an increased volume of intraorbital fat and muscle tissue. It causes exophthalmos, lid retraction, and diplopia due to ocular motility problems. Pretibial myxedema is another finding in Graves' disease. It is due to the stimulation of dermal fibroblasts that leads to depositions of GAGs in the connective tissue. 70% of patients with Graves disease have elevated anti-TPO antibodies.

Hashimoto Thyroiditis

The most common cause of hypothyroidism in iodine-sufficient areas is Hashimoto Thyroiditis. It is caused by autoimmune-mediated destruction of the thyroid gland. CD8+ T-cells cause thyroid follicular cell death. The release of IFN-gamma by TH1 cells causes recruitment and activation of macrophages. During the early stage of the disease, the patient may develop a non-tender, symmetrical, and painless goiter. As inflammation continues, thyroid follicles are damaged and can rupture. When thyroid follicles rupture, the patient may be asymptomatic or can experience Hashitoxicosis (thyroid hormone from ruptured follicles, causing symptoms of hyperthyroidism). As the disease progresses, the thyroid gland may become normal-size or small, depending on the extent of fibrosis. As a result, the patient can develop the symptoms of hypothyroidism. In addition to cell-mediated destruction, anti-thyroid autoantibodies (anti-thyroglobulin and anti-TPO) are also produced leading to anti-body dependent cell-mediated cytotoxicity. Hashimoto thyroiditis is diagnosed via ultrasound, antibody detection, and thyroid function testing. Radioactive iodine uptake test and fine-needle aspiration can be performed to exclude malignancy.

Symptoms of Hypothyroidism

Generalized decreased basal metabolic rate can present as apathy, slowed cognition, skin dryness, alopecia, increased low-density lipoproteins, and increased triglycerides. Hypothyroidism must be ruled out in psychiatry patients presenting with apathy and slowed cognition. Hypothyroidism can decrease sympathetic activity leading to decreased sweating, bradycardia, and constipation. Patients can present with myopathy and decreased cardiac output because of decreased transcription of sarcolemmal genes.

Hyperprolactinemia can be caused by hypothyroidism. Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates prolactin and TSH release. Prolactin release can suppress testosterone, LH, FSH, and GnRH release. Prolactin can also cause breast tissue growth.

Patients with hypothyroidism may present with myxedema caused by decreased clearance of complex glycosaminoglycans and hyaluronic acids from the reticular layer of the dermis. Initially, the nonpitting edema is pretibial. As the state of hypothyroidism continues, patients can develop generalized edema.

Symptoms related to decreased metabolic rate:

• Bradycardia
• Fatigue
• Cold intolerance
• Weight gain
• Poor appetite
• Hair loss
• Cold and dry skin
• Constipation
• Myopathy, stiffness, cramps, entrapment syndromes
• Delayed deep tendon reflex relaxation

Symptoms from generalized myxedema:

• Myxedematous heart disease
• Puffy appearance with doughy skin texture
• Hoarse voice with difficulty articulate words
• Pretibial and periorbital edema

Symptoms of hyperprolactinemia:

• Amenorrhea or menorrhagia
• Galactorrhea
• Erectile dysfunction, infertility in men
• Decreased libido

Other symptoms:

• Depression
• Impaired concentration and memory
• Goiter
• Hypertension

Congenital hypothyroidism:

• Umbilical hernia
• Hypotonia
• Prolonged neonatal jaundice
• Poor feeding, absence of thirst (adipsia)
• Decreased activity
• Pot-belly, puffy-face, protuberant tongue
• Poor brain development

Symptoms of Hyperthyroidism

Generalized hypermetabolism from hyperthyroidism causes increased Na+/K+-ATPase to promote thermogenesis. There is increased catecholamine secretion and, beta-adrenergic receptors are also upregulated in various tissues. As a result of the hyperadrenergic state, peripheral vascular resistance is decreased. In the heart, hyperthyroidism causes a decreased amount of phospholamban, a protein that normally decreases the affinity of calcium-ATPase for calcium in the sarcoplasmic reticulum. As a result of decreased phospholamban, there is increased Ca+ movement between the sarcoplasmic reticulum and cytosol, leading to increased contractility. Increased beta-receptors on the heart also leads to increased cardiac output.

General

• Heat intolerance
• Weight loss
• Increased appetite
• Increased sweating from cutaneous blood flow increase
• Weakness
• Fatigue
• Onycholysis (separation of nails from nail beds)
• Pretibial myxedema

Eyes

• Lid lag (when looking down, sclera visible above cornea)
• Lid retraction (when looking straight, sclera visible above the cornea)
• Graves ophthalmopathy

Goiter

• Diffuse, smooth, non-tender goiter
• The audible bruit can be heard at the superior poles

Cardiovascular

• Tachycardia (can be masked by patients taking beta-blockers)
• Palpitations
• An irregular pulse from atrial fibrillation
• Hypertension
• Widened pulse pressure because systolic pressure increases and diastolic pressure decreases
• Heart failure (elderly patients)
• Chest pain
• Abnormal heart rhythms

Musculoskeletal

• Fine tremors of the outstretched fingers. Face, tongue, and head can also be involved. Tremors respond well to treatment with beta-blockers.
• Myopathy affecting proximal muscles. Serum creatine kinase levels can be normal
• Osteoporosis caused by the direct effects of T3. Elderly patients can present with fractures.

Neuropsychiatric system

• Restlessness
• Anxiety
• Depression
• Emotional instability
• Insomnia
• Tremoulousness
• Hyperreflexia

Conditions associated with hypothyroidism

• Iodine deficiency [11]
• Cretinism [12]
• Wolff-Chaikoff effect [13]
• Subacute thyroiditis [14]
• Postpartum thyroiditis [15]
• Riedel thyroiditis [16]
• Hashimoto thyroiditis [17]
• Drug-induced [18]

Conditions associated with hyperthyroidism

• Graves disease [19]
• Iodine excess [20]
• Struma ovarii [21]
• Thyrotropic pituitary adenoma [22]
• Jod-Basedow phenomenon [23]
• Drug-induced: amiodarone, lithium [24]
• Thyrotoxicosis and thyroid storm [25]
• Toxic multinodular goiter [26]
• Thyroid adenoma [27]

Antithyroid drugs that work in the thyroid gland [28]

• Perchlorate – inhibits Na+/I- symporter – blocks iodide uptake
• Thionamides – inhibits TPO – block thyroid hormone synthesis
• Iodide > 5mg – inhibits Na+/I- symporter and TPO – blocks iodide uptake and thyroid hormone synthesis
• Lithium – inhibits thyroid hormone release (off-label use for thyroid storm)

Antithyroid drugs that work in peripheral tissue – all these drugs inhibit the deiodinase enzymes. Deiodinase enzymes normally convert T4 into the active form T3. These drugs inhibit the conversion of T4 to T3 and reduce its activity.

• Propylthiouracil (thionamide)
• Dexamethasone
• Amiodarone
• Propranolol