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USMLE Step 1 Review/Endocrine

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Thyroid

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Hypothalamic-pituitary-thyroid axis

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  • Hypothalamus → thyrotropin releasing hormone (TRH)
  • Pituitary → thyroid stimulating hormone (TSH)
  • Thyroid → T3, T4

Thyroid hormone synthesis

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  1. Plasma iodide enters thyroid follicular cells via sodium iodine (NaI) cotransporter via secondary active transport.
  2. Within the cell, thyroperoxidase (TPO) oxidizes iodide to either atomic iodine (I) or iodinium (I+).
  3. Oxidized iodine species bind tyrosine residues of thyroglobulin, the major protein of thyroid colloid.
    • Tyrosine + a single iodine atom: monoiodotyrosine (MIT)
    • Tyrosine + two iodine atoms: diiodotyrosine (DIT)
  4. MIT and DIT combine:
    • MIT + DIT: triiodothyronine (T3)
    • DIT + DIT: tetraiodothyronine (T4, also called thyroxine)
    • DIT + MIT: reverse T3 (rT3, which is biologically inactive)
  5. Proteases digest release thyroglobulin, releasing the active hormones T3 and T4 into the bloodstream.
  6. Peripherally, 5'-deiodinase converts T4 to the more active T3.

Pharmacology

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Antithyroid drugs

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Compete with iodide for the NaI cotransporter in thyroid follicular cells:

  • Perchlorate
  • Thiocyanate
  • Goitrin

Inhibit thyroperoxidase:

  • Propylthiouracil (also inhibits 5'-deiodinase)
  • Methimazole

Inhibit 5'-deiodinase:

  • Propylthiouracil (also inhibits thyroperoxidase)

Pathology

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Hashimoto's thyroiditis
Most common cause of primary hypothyroidism in the US, F > M. Autoimmune, demonstrating lymphocytic infiltration microscopically. Associated with HLA-DR5. Clinical course may begin with hyperthyroidism resulting from thyroid destruction and release of thyroid hormone; ultimately results in hypothyroidism (fatigue, cold intolerance, weight gain, constipation, fragile hair, dry skin). Treated with hormone replacement (T4, levothyroxine).
Graves' disease
Most common cause of hyperthyroidism in US, F > M. Autoimmune, resulting from autoantibody stimulating the TSH receptor on thyroid follicular cells. Results in hyperthyroidism (heat intolerance, tachycardia, weight loss, diarrhea, hair/skin changes), frequently a diffuse goiter, and characteristic pretibial myxedema, retroorbital fibrosis, and exophthalmos. Treated with antithyroid drugs (propylthiouracil, methimazole, radioactive iodine). Exophthalmos is irreversible despite treatment.

Thyroid cancer

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Psammoma body associations
  • Papillary thyroid carcinoma
  • Papillary renal cell carcinoma
  • Serous papillary ovarian adenocarcinoma
  • Endometrial adenocarcinomas (papillary serous carcinoma)
  • Meningioma
  • Mesothelioma
  1. Papillary thyroid carcinoma: Most common (75%), Orphan-Annie nuclei, psammoma bodies.
  2. Follicular thyroid carcinoma:
  3. Medullary thyroid carcinoma: Neoplastic parafollicular cells (C-cells), ↑calcitonin, derived embryologically from ultimobranchial body, associated with mutations in RET gene (same as in MEN type 2).
  4. Anaplastic thyroid carcinoma: Rare, poor prognosis.

Multiple endocrine neoplasia

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Conditions associated with marfanoid habitus
  1. Marfan's syndrome
  2. MEN type 2b
  3. Homocystinuria
  4. Ehlers-Danlos syndrome

All autosomal dominant. Consider MEN when there is a strong family history of medullary thyroid carcinoma.

Type Notes Gene
1 (Wermer syndrome) 3 Ps
  • Pituitary adenoma (eg, prolactinoma)
  • Parathyroid hyperplasia
  • Pancreatic tumors (eg, insulinoma)
 MEN1, chromosome 11
2a (Sipple syndrome)
  • Medullary carcinoma of the thyroid
  • Pheochromocytoma
  • Hyperparathyroidism
 RET, chromosome 10
2b (previously type 3)
  • Medullary carcinoma of the thyroid
  • Pheochromocytoma
  • Mucosal neuromas
  • Marfanoid body habitus
 RET, chromosome 10
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