Hyperthyroidism and Thyrotoxicosis

• Hyperthyroidism involves the thyroid gland producing excessive amounts of thyroid hormones.
• Thyrotoxicosis is the clinical condition caused by prolonged exposure to elevated levels of thyroid hormones.
• In hyperthyroidism, the secretion of thyroid hormone is not regulated by the hypothalamic-pituitary center.
• Hyperthyroidism results in low levels of thyroid stimulating hormone(TSH) in the bloodstream.

Causes of Hyperthyroidism

• Thyroiditis, or thyroid inflammation, causes irritation and excess thyroid hormone entering the blood and is often short term.
• Pregnancy can lead to cases of thyroiditis which are short term.
• Thyroid nodules can cause hyperthyroidism and hypothyroidism.
• Thyroid nodules can increase in size causing the production of too much thyroid hormone.
• Graves' disease is an autoimmune condition and the most common hyperthyroidism cause.
• Graves' disease causes antibodies to stimulate excessive thyroid hormone secretion.
• Benign tumors of the thyroid can lead to hyperthyroidism.
• High amounts of tetraiodothyronine from supplements or medication can cause hyperthyroidism.
• Excess iodine, a key part of both T4 and T3 hormones, can lead to hyperthyroidism.
• Trophoblastic tumors that secrete hCG might cause hyperthyroidism.

Graves’ Disease

• Graves’ disease is an autoimmune disorder leading to overproduction of thyroid hormones and thus Hyperthyroidism.
• In Graves' disease, thyroid-stimulating receptor antibodies (TSHR ab) bind to TSHr, chronically stimulating the thyroid can generate too much thyroid hormone.
• Graves' disease is more common in women.
• Graves' disease has a tendency to run in families, suggesting a genetic link.

Clinical Symptoms

• High amounts of T4 and T3 cause hypermetabolic state.
• Hypermetabolic state can cause rapid heart rate, increased cardiac output, heart failure, elevated blood pressure, and hand tremors.
• Excessive sweating and low tolerance for heat is a clinical symptom.
• GI system symptoms include frequent bowel movements and weight loss due to increased calorigenesis, malabsorption and steatorrhea
• Gynecomastia, decreased libido, and decreased/abnormal sperm are symptoms in men.
• Irregular menstrual cycles and anovulatory infertility are symptoms in women.
• Low total cholesterol is a clinical symptom related to serum lipids.
• Exophthalmos is the bulging of the eye as the immune system attacks muscles around the eye.
• Impaired eye muscle function results in Diplopia.
• Conjunctival edema and pain, corneal ulceration, optic neuritis, and even blindness can occur.
• Skin becomes warm and may be erythematous due to increased blood flow.
• Onycholysis is the loosening of nail beds and softening of nails which results in the painles detachment of the nail.
• Other symptoms of hyperthyroidism include increased appetite, nervousness, restlessness, inability to concentrate, weakness, irregular heartbeat, difficulty sleeping, fine and brittle hair, itching, and hair loss.

Diagnosis

• Hyperthyroidism diagnosis starts with a complete medical history and physical exam.
• Common signs of hyperthyroidism include weight loss, rapid pulse, elevated blood pressure, protruding eyes, and an enlarged thyroid gland.
• A cholesterol test can be used to determine low cholesterol levels, a sign an elevated metabolic rate.
• Free T4 and T3 tests can reveal increase thyroid hormone levels.
• Thyroid stimulating hormone level test can reveal normal/high thyroid hormone levels with low TSH.
• An abnormally low TSH can be the first sign of hyperthyroidism.
• A triglyceride test can used to detect low triglyceride levels, which is an indicator of an elevated metabolic rate.
• Ultrasound can measure the size of thyroid glands and their masses.
• CT or MRI scans can identify pituitary tumors.

Hyperthyroidism Treatment: β-Blockers

• Manifestations of hyperthyroidism mediated by the adrenergic system include, tremors, anxiety, heat intolerance, rapid pulse, high blood pressure which beta blockers such as propranolol can relieve.
• Beta-blockers do not reduce thyroid hormone synthesis so other therapy must be used.

Methods to Reduce Thyroid Hormone Synthesis

• Excess thyroid hormone production can be reduced through iodides, antithyroid drugs, radioactive iodine and surgery.

Iodide

• Potassium iodide can be administered as a saturated solution (SSKI) that contains 38 mg iodide per drop or as Lugol's solution that contains 6.3 mg iodide per drop..
• The usual Lugol's Solution dose is 3-5 drops three times a day, and SSKI is 1-3 drops three times a day.
• Large iodine doses inhibit synthesis and hormone release which can reduce serum T4 levels within 24 hours and can last 2-3 weeks.
• Acute iodide excess results in decreased intrathyroidal organification and release of thyroid hormones from the thyroid gland in a process known as the Wolff-Chaikoff effect.
• Inhibition of the peroxidase enzyme organification of iodide can also occur.
• Iodopeptides form and temporarily inhibit thyroid peroxidase (TPO) mRNA and protein synthesis and thyroglobulin iodinations.
• The acute Wolff-Chaikoff effect will last for a few days and then the organification of intrathyroidal iodide can resume because of the "escape phenomenon".
• Escape phenomenon occurs in the event autoregulatory mechanisms inhibit thyroid iodide transport and concentration of inorganic iodine in the thyroid follicle decreases.
• Failure to escape results in hypothyroidism, particularly with thyroiditis, postpartum thyroiditis, or surgical therapy.
• Preterm babies are susceptible to iodine-induced hypothyroidism because of the autoregulation of the thyroid gland via immaturity.
• The effects are transient and last a few days or weeks before antithyroid action of iodine wanes and thyrotoxicosis recurs or worsens.
• Short-term iodide therapy prepares patients for surgery in combination with thionamide drug.
• Iodine manages severe thyrotoxicosis as it inhibits thyroid hormone release acutely.

Anti-thyroid Drugs

• Thionamide agents such as propylthiouracil (PTU) and methimazole (MMI) are used to treat hyperthyroidism.
• In some countries the MMI prodrug Carbimazole is used. 10 mg carbimazole = 6 mg MMI.
• Thionamide agents inhibit hormone synthesis by interfering with thyroid peroxidase-mediated iodination of tyrosine residues in thyroglobulin.
• PTU inhibits T4 to T3 conversion and both thionamides have immunosuppressant effects.
• Thionamides decrease TSHr-Ab levels and other immune mediators over time in Graves disease patients.
• Both drugs are well absorbed from the gastrointestinal (GI) tract and PTU's half-life is 1 to 2.5 hours, whereas MMI’s half-life is 6 to 9 hours.
• MMI use has increased since the mid-1990s as compared to PTU.
• MMI given daily can be safer with less hepatotoxicity although PTU has the advantage of inhibiting T4-to-T3 conversion.
• Antithyroid drugs treat Graves disease or prepare for surgery/radioactive iodine when used as primary therapy.
• Remission from Graves disease occurs in 40%-60% of patients after 1-2 years of therapy, then antithyroid therapy will be tapered off for 12-24 months.
• Relapse usually occurs in the first 3-6 months after stopping the therapy with antithyroid medications.
• Overall antithyroid drugs have an associated low rate of adverse effects but serious adverse effects can occur.
• Skin rash, arthralgias, and GI upset are seen in 5% of patients.
• Hepatotoxicity is an uncommon but serious adverse effect, occurring in 0.1% - 0.2% of patients.
• Transient rises in aminotransferase enzyme levels are seen in up to 30% of patients treated with PTU.
• Agranulocytosis is one of the most serious adverse effects of therapy with antithyroid medication.

Radioactive Iodine

• Radioactive iodine, like I, produces thyroid ablation without surgery.
• I is well absorbed after oral administration and concentrated in the thyroid gland with a half-life of 8 days.
• Thyroid cells that have taken up the iodine develop abnormalities and necrosis that leads to thyroid cells being destroyed and reduced hormone production over a period of weeks.
• After a single dose, 40%-70% of patients are euthyroid in 6-8 weeks, and 80% will be cured.
• Hypothyroidism will develop in most patients, where long-term LT4 replacement is necessary.
• Because I has a slow onset, most patients are initially treated with B-blockers and antithyroid drugs to prevent iodine-induced thyroid storm; MMI is the preferred agent before I administration.
• MMI should be discontinued 3-5 days before iodine administration to allow maximum isotope trapping by the thyroid.
• Ablative effects begin within 2-3 months, and patients with mild or moderate disease might not need to restart their drug treatments, though close monitoring is often needed.
• Patients who have severe thyrotoxicosis may need to restart their antithyroid drugs on day 3 with MMI then being withdrawn every 4-6 weeks as the thyroid function normalizes.
• B-Blockers may be continued during iodine therapy.
• Radioactive iodine therapy is not used during pregnancy and breastfeeding.
• Common side effects include dry mouth, dry eyes, sore throat, and changes in taste.

Surgery

• Subtotal thyroidectomy is indicated for patients with very large goiters and thyroid malignancies, as well as who do not respond or cannot tolerate other therapies.
• If they are to undergo surgery, patients must be euthyroid.
• Often, iodide will be administered preoperatively to reduce gland vascularity.
• Postoperative hypothyroidism occurs in 10% of patients who undergo subtotal thyroidectomy.
• Monitoring of serum calcium and intact parathyroid hormone levels for early identification of postoperative hypoparathyroidism is needed after thyroidectomy.
• Postoperative administration of calcium and calcitriol may be given within 1-2 weeks of surgery if the patient does not develop hypoparathyroidism.

Graves Disease and Pregnancy

• Pregnancy can precipitate or worsen thyrotoxicosis in women with underlying Graves disease because of the TSH agonist effect of β-hCG.
• Untreated maternal thyrotoxicosis can lead to increased rates of miscarriage, premature delivery, eclampsia, and low-birth-weight infants.
• Fetal and neonatal hyperthyroidism can occur due to placental passage of TSHr-abs,
• Radioactive iodine is counter-indicated and surgery best to avoid during pregnancy which means most patients are treated with antithyroid medication.
• PTU is considered the treatment of choice, particularly during the first trimester while MMI is thought to have a significantly higher teratogenic potential.
• Patients receiving prepregnancy MMI should be switched to PTU as soon as the pregnancy is confirmed.
• The dose of PTU should be the lowest possible required to maintain maternal euthyroidism.
• Given the potential maternal adverse effects of PTU, switching from PTU to MMI is preferable during the second and third trimesters.
• excessive Doses of Antithyroid therapy can suppress fetal thyroid function.
• Nursing mothers should switch to MMI after delivery despite finding PTU and MMI in breast milk due to the risk of hepatotoxicity from PTU in the mother and infant.

Pediatric Hyperthyroidism

• For children with hyperthyroidism, beta-blockers will be given to children who are symptomatic or have a heart rate surpassing 100 beats per minute.
• MMI with a dose of 0.2 to 0.5 mg/kg/day is the preferred antithyroid therapy for children.
• MMI doses can be reduced by 50% or more to maintain euthyroid following achievement of the initial euthyroid.
• Antithyroid drugs are administered to children with Graves disease for 1 to 2 years, as for adults.

Thyroid Storm

• Thyroid storm is a life-threatening condition caused by severe thyrotoxicosis.
• Signs/symptoms of thyroid storm include high fever, tachycardia, tachypnea, dehydration, delirium, coma, and GI disturbances.
• Thyroid storm is precipitated in a hyperthyroid patient by infection, trauma, surgery, and sudden withdrawal from antithyroid drugs.
• Patients with thyroid storm should be treated with a short-acting beta-blocker such as intravenous (IV) esmolol.
• Patients with thyroid storm should be treated with IV/oral iodide, high doses of PTU (500-1000 mg); then 250 mg every 4 hours) or MMI (60-80 mg/day)., supportive care with acetaminophen to suppress fever and fluid and electrolyte management.
• Antiarrhythmic agents form components of therapy.
• IV hydrocortisone (300 mg initially; then 100 mg every 8 hours) is used often because of the potential presence of adrenal insufficiency.

Test your knowledge about hyperthyroidism and thyrotoxicosis. These questions cover causes like Graves' disease and excessive iodine intake. Also includes diagnosis methods and underlying mechanisms contributing to symptoms.