Sarah Chaudhry and Eugenia Gisin Thyroid disorders Sarah Chaudhry and Eugenia Gisin 10/21/13

Lecture Overview Review of normal thyroid function Thyroid disorders Hyperthyroidism Causes, effects, treatment Graves’ Disease Hypothyroidism Hashimoto’s Disease

Anatomy Gland is located below larynx, and consists of two lobes – one on each side of trachea Lobes connected by isthmus Two types of cells: Follicular cells Majority Secrete iodine-containing hormones: triiodothyronine (T3) and tetraiodothyronine or thyroxine (T4) Parafollicular cells Secrete calcitonin

Production of t4 and t3 Thyroglobulin is made/secreted Iodination occurs on tyrosine residue of thyroglobulin Proteolysis occurs resulting in T4 and T3 being cleaved off of thyroglobulin

Functions Calcitonin: calcium regulation T3 and T4: increase the basal metabolic rate ↑ body temperature ↑ pulse ↑ attention and reflexes In children: Promotion of brain maturation Promotion of growth Cells are working harder = need more energy! Food is utilized more quickly ↑ breakdown of energy resources

Regulation Hypothalamus releases thyroid releasing hormone (TRH) ↓ Pituitary gland releases thyroid stimulating hormone (TSH) Thyroid gland releases T4/T3 Target tissues Negative feedback to hypothalamus and pituitary TSH = thyrotropin

Disorders: hyperthyroidism Abnormal increase in thyroid hormone production Speeds up metabolism and can cause: Hot flushes, sweating Trembling Racing heart Weight loss Nervousness, hyperactivity Irritableness Insomnia and restlessness

Graves’ disease Autoimmune disease that causes thyroid to swell and become overactive Leading cause of hyperthyroidism More common in women Named after Sir Robert Graves who characterized it in the 19th century Highly manageable

Autoimmune disorders Normal immune response Antigens: foreign substances that stimulate an immune response Response = production of antibodies that recognize and bind to that antigen Autoimmune disorder Immune system mistakes healthy tissue for being harmful Illicits an immune response (antibodies) in response to normal tissue

Graves’ disease: cause Immune system releases abnormal antibodies that mimic TSH (a.k.a. thyrotropin) and bind to its receptors Antibodies: thyrotropin receptor antibodies – TRAb “Antigen”: thyrotropin receptor Unsure about why these antibodies are produced Genetics? Environmental? Likely both Normal Graves’ Disease

Graves’ disease: Effect Normal Graves’ Disease TRAb HYPERTHYROIDISM!

Graves’ disease: effect Generalized symptoms resulting from hyperthyroidism Increased basal metabolic rate Increased body temperature Increased heart rate Tremors, restlessness, irritability, insomnia Graves’ ophthalmopathy Thought to be caused by TRAb causing inflammation in retro-occipital tissue Goiter Can be caused by lack of iodine Hyperthyroidism Hypothyroidism

Graves’ disease: treatment Treatment with radioactive iodine Most common treatment in United States Capsule/liquid Destroys cells in thyroid gland and halts excess hormone production Periodic check-ups to monitor hormone levels Second dose can be given after three months if necessary Many people become develop hypothyroidism as a result

Graves disease: Treatment Antithyroid drugs: thioamides Interferes with T3/T4 production Blocks enzyme (thyroperoxidase) that adds iodine to thyroglobulin May take several months to be effective Relapse is common Ex: methimazole Surgery: thyroidectomy For young or pregnant patients Are usually prescribed meds to prevent hypothyroidism Ex: levothyroxine  (thyroperoxidase)

Disorders: hypothyroidism Under production of T3 and T4 What Can Cause It? Congenital thyroid abnormalities (ex. Thyroid Deficiency at birth) Autoimmune disorders (ex. Hashimoto’s) Iodine deficiency Thyroid removal (ex. Cancer or excessive hyperthyroidism) Secondary Pituitary dysfunction Tertiary hypothalamic dysfunction

Disorders: hypothyroidism Symptoms: Abnormal weight gain Tiredness Baldness Cold Intolerance Slow movement and speech Constipation Bradycardia (low heart rate) Thyroid grows (due to increased TSH and lack of negative feedback loop) Cognitive impairment

Hashimoto’s Disease: Background First described in a pathology report by Dr. Hashimoto in 1912 Individuals had large goiters (enlarger thyroid) and their thyroid cells showed high infiltration of lymphocytes Autoimmune disorder (1st one recognized) Autoimmune-mediated destruction of the thyroid gland involving apoptosis of thyroid epithelial cells Most common cause of hypothyroidism More common in women: 5 to 1 Gradual loss of thyroid function

Hashimoto’s: Causes Self-reactive CD4+ T(helper T) lymphocytes recruit B cells and CD8+ T (killer T) cells into the thyroid. Both autoantibodies (from B cells) and thyroid-specific cytotoxic T lymphocytes (CTLs) have been proposed to be responsible for autoimmune thyrocyte depletion. Disease progression leads to the death of thyroid cells and hypothyroidism. Early apoptosis may cause thyroid follicular disruption and thyroid hormone release, causing transient hyperthyroidism sometimes referred to as Hashitoxicosis

Hashimoto’s: Causes Still very unclear!!! Genetics? Clusters in families and higher occurrence in siblings 30 to 60% in identical twins The thyroglobulin gene has been linked to autoimmune thyroid disease and has been suggested to code for Tg forms with different immune reactivity Increased frequency in patients with Turner’s and Down’s syndrome Theories: molecular mimicry and bystander activation Molecular Mimicry: immune response to a foreign antigen that is structurally similar to an endogenous substance Bystander activation: The arrival of a thyroid-cell virus or activated non- specific lymphocytes within the thyroid may cause the local release of cytokines, which may activate resident local thyroid-specific T cells

HASHIMOTO’s: Diagnosis Some clinicians consider the presence of serum thyroid autoantibodies as sufficient evidence for Hashimoto's disease. This logic is based upon the observation that thyroid antibodies correlate well with the presence of a lymphocytic infiltrate in the thyroid gland at autopsy examination of individuals with no history of thyroid failure High levels of TSH (which eventually lead to goiters in some patients) Low levels of T3 and T4 Ultrasound of thyroid Often misdiagnosed, because the symptoms resemble many other disorders

Hashimoto’s: encephalopathy Very rare condition associated with Hashimoto’s 2.1/100,000 with a male to female ratio of 1:4 Immune-mediated disorder rather than representing the direct effect of an altered thyroid state on the central nervous system Elevated antithyroid antibodies, an essential feature of this disorder, are consistent with an active autoimmune process Symptoms: personality changes aggression delusional behavior concentration and memory problems coma Disorientation headaches partial paralysis on the right side psychosis

Hashimoto’s: Treatment Thyroid Hormone replacement agents Levothyroxine (synthetic T4) Triiodothyronine (T3) Desiccated Thyroid extract (usually from pork or beef)- ex. Armour Thyroid

Hypothyroidism: Other Causes Iodine Deficiency Most common in developing world- remote inland areas and semi-arid equatorial climates where no marine foods are eaten Used to synthesize thyroid hormones Leads to goiters- which are caused from low levels T3 and high levels of TSH which stimulate cell proliferation in the thyroid Leads to cretinism- increased mental retardation

Hypothyroidism: Other Causes Secondary or Tertiary hypothyroidism- related to problems with the pituitary and hypothalamus Examples: Sheehan’s Syndrome (postpartum hypopituitarism) – rare complication of child birth Tumors and head injury can result in decreased TSH production

Anatomy Gland is located below larynx, and consists of two lobes – one on each side of trachea Lobes connected by isthmus Two types of cells: Follicular cells Majority Secrete iodine-containing hormones: triiodothyronine (T3) and tetraiodothyronine or thyroxine (T4) Parafollicular cells Secrete calcitonin

Summary! T3 and T4: increase the basal metabolic rate ↑ body temperature ↑ pulse ↑ attention and reflexes

Thyroid Disorder summary

Questions?????

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