Hypothyroidism (Underactive Thyroid): Causes

Pathogenesis (development of disease)

Iodine deficiency is still the most common cause of hypothyroidism worldwide. In congenital (inherited) hypothyroidism, the defect is most often due to thyroid dysgenesis (thyroid malformation), and less commonly to a genetic defect in hormone synthesis. The pathogenesis of autoimmune hypothyroidism is based in part on genetic disorders as well as environmental factors (radiation damage). These factors lead to infiltration of lymphocytes into the thyroid gland, which in turn leads to fibrosis of the tissue. In iatrogenic (“caused by medical action”) hypothyroidism, the pathomechanism is radiation damage or destruction of the cells of the thyroid gland (strumectomy (removal of the thyroid gland), radioiodine therapy). The following forms of hypothyroidism in adults are distinguished:

• Primary (thyrogenic) hypothyroidism [regulatory circuit in the thyroid gland is interrupted].
  • Most commonly the result of an autoimmune disease such as Hashimoto’s thyroiditis
  • Iatrogenically caused (caused by medical procedures) – after strumectomy (removal of thyroid tissue), after radioiodine therapy, drug-induced (e.g., thyrostatic drugs, lithium, sunitinib, amiodarone)
• Secondary pituitary hypothyroidism [regulatory circuit in the pituitary gland is interrupted, e.g., due to insufficiency/weakness of the anterior lobe of the pituitary gland]
• Tertiary hypothalamic hypothyroidism [default of the set point is absent due to TRH deficiency, e.g., in the context of damage to the hypothalamus, Pickardt syndrome, or euthyroid sick syndrome] (very rare)

Etiology (causes)

Biographical causes

Biographical causes

• Genetic burden, e.g., mutation of hormone receptors
  • Genetic diseases
    • Hemochromatosis (iron storage disease) – genetic disease with autosomal recessive inheritance with increased deposition of iron as a result of increased iron concentration in the blood with tissue damage.
• Anatomical variants – aplasia (lack of attachment of a thyroid gland); ectopic thyroid (anatomical location of the thyroid gland in the wrong place).
• Hormonal factors
  • Hormone resistance – the body does not respond to the thyroid hormones T3 (triiodothyronine) and T4 (thyroxine).
  • Mutation of the hormone receptors

Behavioral causes

• Nutrition
  • Iodine deficiency – see micronutrient therapy.

Causes related to disease

• Amyloidosis – extracellular (“outside the cell”) deposits of amyloids (degradation-resistant proteins) that can lead to cardiomyopathy (heart muscle disease), neuropathy (peripheral nervous system disease), and hepatomegaly (liver enlargement), among other conditions.
• Autoimmune thyroiditis (Hashimoto’s thyroiditis) – autoimmune disease of the thyroid gland; initially with increased secretion of thyroid hormones, later with gradual transition to hypothyroidism (hypothyroidism).
• Hemochromatosis (iron storage disease, English : hematochromatosis; from Greek haima = blood, chroma = color) – autosomal recessive hereditary disease; men are much more often affected than women. In the disease, there is increased absorption (absorption) of iron in the upper small intestine.
• Brain tumors
• Pituitary insufficiency (hypofunction of the pituitary gland) – e.g., pituitary adenoma (benign tumor of the pituitary gland), pituitaryitis, or hypothalamic disease
• Traumatic brain injury (TBI) – craniocerebral injuries.
• Sarcoidosis – inflammatory systemic disease affecting mainly the skin, lungs and lymph nodes.
• Scleroderma – autoimmune disease that leads to hardening of the skin and connective tissue.
• Thyroiditis (inflammation of the thyroid gland).
• TSH deficiency (thyroid-stimulating hormone) – deficiency of the hormone stimulating the thyroid glands.
• Tumors of the thyroid gland

Medication

• Amiodarone (iodine-containing antiarrhythmic drug) → amiodarone-induced hypothyroidism (amiodarone-triggered autoimmune thyroiditis).
• Antibiotics
  • Aminosalicylic acid – agents used to treat inflammatory bowel diseases such as ulcerative colitis or Crohn’s disease.
• Atypical neuroleptics (esp. clozapine and quetiapine).
• Bexarotene – retinoid analog approved for the treatment of cutaneous T-cell lymphoma.
• HCV protease inhibitors (telaprevir).
• Hormones
  • Antiestrogens such as aminoglutethimide (aromatase inhibitors).
• Contrast media containing iodine
• Lithium → lithium-induced hypothyroidism
• Thyrostatic drugs (carbimazole)
• Cytokines
  • Interferon α

Operations

• Thyroidectomy (thyroidectomy).

Radiotherapy

• Ablative therapy using radioiodine (radioiodine therapy) – therapy of hyperthyroidism or thyroid carcinoma with radioactive substances.
• Radiation thyroiditis (inflammation of the thyroid gland (thyroiditis) as a result of radiotherapy) after external radiatio (radiotherapy) of the neck region – e.g. due tomalignant lymphoma.