TPO

**1. Thyroid peroxidase (most common USMLE meaning)**

*Function:* TPO is a membrane-bound, heme-containing enzyme on the apical surface of thyroid follicular cells. It does three things: - Oxidizes iodide (I⁻) to reactive iodine (I₂/I⁰), using H₂O₂. - Iodinates tyrosine residues on thyroglobulin (organification), forming MIT and DIT. - Couples MIT and DIT: DIT + DIT gives T4, and MIT + DIT gives T3.

*Pathway:* Na⁺/I⁻ symporter (NIS) traps iodide, pendrin moves it into the colloid, and TPO then oxidizes, organifies, and couples it. TSH stimulates all of these steps.

*Pharmacology:* - Propylthiouracil (PTU) and methimazole inhibit TPO. This blocks organification and coupling. - PTU also inhibits peripheral 5'-deiodinase, so it blocks T4→T3 conversion. This makes it useful in thyroid storm. - PTU is preferred in the first trimester of pregnancy because methimazole is teratogenic (aplasia cutis, choanal atresia). - Adverse effects of both drugs: agranulocytosis, aplastic anemia, and rash. PTU also causes hepatotoxicity.

*Clinical associations:* - **Hashimoto thyroiditis:** Anti-TPO (anti-microsomal) and anti-thyroglobulin antibodies are present, with a high titer of anti-TPO. It is associated with HLA-DR5 and has a Th1 and CD8⁺ cytotoxic T-cell-mediated component. Histology shows lymphocytic infiltrate with germinal centers and Hürthle (oncocytic) cells. Complications include hypothyroidism and an increased risk of primary thyroid B-cell lymphoma (MALT type). - **Graves disease:** Anti-TPO antibodies are positive in many patients. The main pathogenic antibody is TSH receptor-stimulating IgG (TSI). - **Postpartum thyroiditis:** Anti-TPO positivity predicts risk. - **Subclinical hypothyroidism:** Positive anti-TPO predicts progression to overt hypothyroidism. - **Congenital TPO deficiency:** A cause of dyshormonogenetic goiter and congenital hypothyroidism. It is autosomal recessive and the most common defect of thyroid hormone synthesis. It can occur with a positive perchlorate discharge test. - **Pendred syndrome:** A pendrin defect causing deafness and goiter. It is not a TPO defect, but it is often tested alongside TPO.

*Other uses:* The Wolff-Chaikoff effect (high iodine transiently inhibits organification) acts at the TPO step. Anti-TPO levels are used for diagnosis and risk stratification, and they help differentiate autoimmune from non-autoimmune hypothyroidism.

**2. Thrombopoietin (also abbreviated TPO)** - Produced mainly by the liver (constitutively), with some from the kidney. - Binds the c-Mpl receptor on megakaryocytes and platelets. This activates JAK2/STAT and drives megakaryocyte proliferation and maturation. - Platelets clear TPO by binding it, so low platelet mass raises free TPO, and high platelet mass lowers it. - TPO receptor agonists: romiplostim (a peptibody), eltrombopag, avatrombopag, and lusutrombopag. They are used in ITP, chronic liver disease-associated thrombocytopenia before procedures, and aplastic anemia. - Chronic liver disease lowers TPO production, which contributes to thrombocytopenia. - Mutations in MPL or THPO are associated with hereditary thrombocytosis. Loss of MPL function causes congenital amegakaryocytic thrombocytopenia.

**3. Other, rarer uses** - Third-party or institutional abbreviations also exist, such as total parenteral nutrition-adjacent contexts and "thrombopoietin" in transfusion medicine. Always use context.

**High-yield takeaway:** If the question mentions thyroid, think thyroid peroxidase and anti-TPO antibodies in Hashimoto thyroiditis. If it mentions platelets or megakaryocytes, think thrombopoietin.