Mark Goodarzi, M.D.
THE THYROID – PHYSIOLOGY AND PATHOLOGY
I. Thyroid physiology
 | Thyroid gland produces all of body’s T4 (about 80-90 mcg/d), but only 20% of body’s T3 (~8 mcg). 80% of T3 is produced by peripheral deiodination of outer ring of T4 (by type I 5’-deiodinase, mainly in liver and kidney, little in heart). Total production of T3 is about 32-35 mcg/day. |
| Thyroglobulin (TG) is a glycoprotein involved in storage and synthesis of thyroid hormones. Most of it resides in the lumen of the follicles, which are lined by a single layer of cuboidal follicular epithelium. It is taken into follicular cells by endocytosis for use in thyroid synthesis. |
| Parafollicular (C) cells, which secrete calcitonin, do not border on the follicular lumen. |
| Iodide (I-) is trapped by thyroid cells (the rate-limiting step), iodide is then organified (oxidized to I+, hypoiodous acid (HOI) or enzyme-bound hypoiodite ([EOI]-) and then bound to tyrosyl residues of thyroglobulin), which forms mono-iodotyrosine (MIT) and di-iodotyrosine (DIT). When two DIT molecules fuse, thyroxine (T4, L-3,5,3’,5’-tetraiodothyronine) is formed; when MIT and DIT are coupled, triiodothyronine (T3, L-3,3’,5-triiodothyronine) is formed. Thyroid peroxidase, which is located on the apical side of the follicular epithelium, catalyzes organification and coupling. The newly formed hormones remain part of thyroglobulin. The ratio of T4 to T3 in thyroglobulin is 13:1. Thyroid hormone-TG complex is absorbed into vesicles. Thyroid hormones are released from TG by proteolysis. |
| All the steps above are stimulated by TSH. TSH secretion is controlled by TRH, plasma free T4 and T3 (negative feedback), and intrapituitary T4 to T3 conversion (T3 inhibiting TSH release). |
| Thyroid hormone increases the basal metabolic rate of most cells, is required for bone growth and maturation and maturation of neurologic tissue. It is also needed for normal lactation and is involved in protein, fat (stimulates lipolysis), carbohydrate, and vitamin metabolism. T3 increases cardiac output, contractility and heart rate and decreases systemic vascular resistance. |
| Most (75%) of T4 is bound to thyroid binding globulin (TBG), with a small amount (15%) bound to thyroid binding prealbumin (TBPA, transthyretin, a tetrameric protein), and to albumin (10%). Almost all (99.7%) of T3 is bound to TBG. |
| Free hormone is active. 99.98% of T4 is bound, 99.7% of T3 is bound. T3 is 3-5 times more potent than T4. T3 to TBG and T4 to albumin/TBPA are not tightly bound (as is T4 to TBG), so these hormones may be more available for tissue use. |
| Half life of T4 is 1 week; T3 half life is 1 day. |
| Reverse T3 (3,3’,5’-triiodothyronine) is formed from T4 (inner ring deiodination) by 5-deiodinase and is metabolically inactive. |
II. Thyroid function tests
| TSH (thyrotropin, normal 0.3-4.7 mIU/L). Availability of ultrasensitive assay which can distinguish TSH suppression by thyrotoxicosis from low normal values has made TRH stimulation test (formerly used to distinguish thyrotoxicosis, in which there is no response of TSH to TRH) virtually obsolete. |
| Total T4 (normal 5-11 mcg/dL): measures bound plus free T4. Since the majority of T4 is protein-bound, total T4 is affected by TBG concentrations and drugs/diseases affecting binding of T4 to TBG or TBG affinity for T4. Estrogens (not transdermal) increase the glycosylation (sialyation) of TBG, reducing its clearance. |
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Increased TBG |
Decreased TBG |
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Estrogens, oral contraceptives, tamoxifen, raloxifene |
Androgens, danazol |
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Pregnancy |
Anabolic steroids |
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Newborn state |
Large doses of glucocorticoids |
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Acute/chronic active hepatitis; hepatoma |
Cirrhosis |
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Acute intermittent porphyria |
Nephrotic syndrome, severe hypoproteinemia |
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Opiates: heroin, methadone |
Chronic renal failure |
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Clofibrate |
Severe systemic illness, especially CHF |
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5-fluorouracil, mitotane |
Active acromegaly |
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HIV infection |
L-asparaginase |
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Pancreatic neuroendocrine tumors can increase TBPA |
Colestipol plus niacin, slow-release nicotinic acid |
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Congenital increase in TBG |
Congenital decrease in TBG |
Transthyretin mutations with increased T4 affinity result in increased TT4 with normal TT3.
| T3 resin uptake (normal 25-35%). Measures unoccupied protein-binding sites for T4 or T3. Radiolabeled T3 is added to serum and then incubated with an insoluble resin which binds unbound hormone. Amount of labeled hormone taken up by resin is inversely proportional to unoccupied binding sites on TBG. Thyroid hormone binding ratio (THBR, normal 0.8-1.15) = ratio of T3 resin uptake in patient’s serum over that of control serum. THBR is helpful in distinguishing hypothyroidism (THBR low) from euthyroid sick syndrome (THBR normal or high). |
| Free T4 index (normal 5-11). Total T4 multiplied by THBR. May be spuriously elevated (patient euthyroid, normal TSH) in familial dysalbuminemic hyperthyroxinemia or anti-T4 antibodies. |
| Total T3 (normal 75-175 ng/dL): Measurement not indicated if hypothyroidism is suspected (will be normal in 20-30% of hypothyroid patients). In hyperthyroidism, T3 may increase disproportionately to T4 through augmented peripheral conversion as well as increased thyroidal secretion. |
| Free T3 index (normal 75-175). Total T3 multiplied by THBR. |
| Free T4 by equilibrium dialysis (normal 0.7-2.2 ng/dL) is most precise method since it measures free fraction directly (an earlier method used FT4D = TT4 x dialyzable fraction (%)). Heparin activates lipoprotein lipase, which causes in vitro generation during incubation of free fatty acids which displace T4 from TBG, causing elevation of FT4D. |
| Free T3 by dialysis (normal 210-440 pg/dL) |
| Thyroglobulin level: used in the management (not diagnosis) of thyroid cancer. After thyroidectomy and radioiodine ablation, thyroglobulin should be undetectable; residual or metastatic disease is associated with rise in thyroglobulin. A TSH-suppressed Tg level is 50% sensitive, 99% specific in detecting cancer. A Tg level during T4 withdrawal is 85-95% sensitive in detecting cancer. Tg level will be decreased in thyrotoxicosis factitia. |
| Reverse T3 (normal 10-24 ng/dL) is elevated in hyperthyroidism, low in hypothyroidism, and often elevated in euthyroid sick syndrome and with amiodarone use. |
| In thyrotoxicosis, a ratio of total T3/T4 (ng/mcg) > 20 suggests Graves’ disease or toxic multinodular goiter; T3/T4 < 15 suggests thyroiditis (subacute, silent), iodine-induced, or exogenous thyrotoxicosis. |
| Radioactive iodine uptake (RAIU). Patient should be on low iodine diet for 10 days before RAIU and scan. Use either 123I (short half-life, less radiation) or 131I. 6-hour uptake is normally 5-20%, 24-hour uptake 10-35%. Uptake correlates with level of thyroid hyperfunction or destruction. Particularly useful in differentiating Graves’ disease from thyroiditis. In treated thyroid cancer, two negative annual whole body scans is associated with 90-95% 10-year relapse-free survival. |
| Thyroid ultrasound is useful to characterize presence of nodules and size of the gland and is also useful in detecting local recurrence of thyroid cancer. |
| Fine needle aspiration (FNA) of the thyroid: 60% benign, 20% suspicious, 5% malignant, 15% inadequate. Especially pertinent is a history of low dose neck radiation, which confers a 40% risk of malignancy in a thyroid nodule. |
| Thyroid hormone’s influence on other lab tests: in hypothyroidism, cholesterol (via decreased LDL receptors), CPK, LDH, prolactin can be elevated, and hyponatremia and anemia may occur; in hyperthyroidism, cholesterol and CPK may be decreased, and elevations of serum calcium (rare, but hypercalciuria is common), alkaline phosphatase, hepatic enzymes, bilirubin, ferritin, and SHBG can be seen. |
III. Thyroid antibodies
| Antithyroperoxidase (anti-TPO, same antigen as antimicrosomal ab). 95% sensitive for Hashimoto’s thyroiditis, 75-85% sensitive for Graves’ disease. More sensitive and specific than anti-TG ab. However, patients with no evidence of thyroid disease can have positive antibodies. |
| Antithyroglobulin. 60% sensitive for Hashimoto’s, 30% sensitive for Graves’ disease. |
| Anti-TSH receptor antibodies: Stimulating (antibody which causes Graves’ disease) or blocking. Stimulating antibody levels do not directly correlate with degree of hyperthyroidism. Stimulating antibodies ~80% sensitive for Graves’ disease; not used as a routine diagnostic test since anti-TPO usually is positive in Graves’ disease. Also, variable assay quality may result in 30-75% sensitivity. Another factor may be exclusively intrathyroidal antibody production by the infiltrating lymphocytes. |
| Anti-T4 and anti-T3 antibodies, uncommonly found in patients with autoimmune thyroid disease, usually lead to spurious elevations of thyroid hormone measurements. If such antibodies are present, a dilution (1:2, 1:4) should result in a lower hormone concentration measurement. |
IV. Candidates for thyroid screening: listed by risk: low (prevalence <2%), moderate (3-10%), high (>10%):
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Patients over age 60, especially women Female psychiatric patients; psychiatric patients who have bipolar disorder with rapid cycling Dementia Hypercholesterolemia Sleep apnea |
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Patients with autoimmune disease (e.g. diabetes, pernicious anemia, Addison’s disease, vitiligo) or connective tissue disease or leukotrichia (prematurely gray hair) Patients with first-degree relative with thyroid disease Postpartum women 4 to 8 weeks after delivery Patients with goiter or nodular thyroid or Graves’ ophthalmopathy Psychiatric patients being treated with lithium |
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Patients with history of thyroidectomy or treatment with radioiodine Patients with history of high-dose radiation to the neck Patients on amiodarone Cases of suspected hypopituitarism Chronic autoimmune thyroiditis |
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Newborns: screening for congenital hypothyroidism is mandatory |
| The American Thyroid Association recommends a screening TSH for adults beginning at age 35 and every 5 years thereafter, particularly in women. |
V. Drugs affecting thyroid function or tests
| Thionamides: propylthiouracil and methimazole both inhibit organification and coupling reaction; only PTU also inhibits peripheral conversion of T4 to T3. Methimazole 10 times more potent (per mg) and can be given once a day; PTU preferred in pregnancy and breast feeding (more protein bound). |
| Propranolol blocks peripheral effects of thyroid hormone, and high doses (> 160 mg/d) inhibit conversion of T4 to T3. |
| Sodium ipodate (Oragraffin) or iopanoic acid (Telepaque) inhibit T4 to T3 conversion at 500 mg/d. |
| Perchlorate (ClO4-) inhibits transport of plasma I- into thyroid and causes discharge of iodine from the gland. May cause aplastic anemia or nephrotic syndrome. |
| Iodide (cough and cold medicine, contrast, kelp, antiseptics, herbal preparations, dietary supplements (e.g. Cellasene), amiodarone) |
-Wolff Chaikoff effect: Iodide can cause inhibition of release of hormone from the thyroid. May also decrease iodine transport, oxidation and organification. Escape from this effect (10-14 days) normally occurs because of limitation of iodine transport mechanism. Escape may not occur in Hashimoto’s thyroiditis or glands treated with radioiodine.
-Jodbasedow phenomenon: Iodine administration can cause thyrotoxicosis, particularly in glands with latent Graves’ disease or nodules. This usually develops within 3-8 weeks after an increase in iodine intake.
| Salicylates (> 2-3 g/d), salsalate (> 1.5-3 g/d) and furosemide (> 80 mg IV) decrease TT4 by interfering (competitive inhibition) with binding of T4 to plasma proteins, and may result in transient increases in FT4 and FT3 and decreased TSH that return to normal with continued medication administration (or may lead to accelerated T4 clearance). Diazepam, sulfonylureas, certain NSAIDS (naproxen, diclofenac, mefanamic acid and fenoclofenac) and heparin (via free fatty acids) also inhibit hormone binding to proteins (weakly). FT4 levels should be measured at least 1 hour after IV heparin and 10 hours after low molecular weight heparin. |
| Phenytoin and carbamazepine accelerate T4 and T3 metabolism (nondeiodinative) by inducing liver enzymes and are also weak competitive inhibitors of hormone binding to TBG, resulting in decreased TT4 & TT3 with free T4 usually normal. Ritonavir, rifabutin, rifampin, and phenobarbital can also accelerate hormone metabolism (glucuronidation, sulfation), typically unimportant in euthyroid patients but may increase thyroid replacement requirements in hypothyroid patients. Phenytoin and carbamazepine can produce seemingly sustained decreases in FT4 by assay interference. |
| Amiodarone inhibits T4 to T3 conversion, inhibits thyroid hormone entry into target cells, and inhibits pituitary T4 to T3 conversion. It may cause clinical hypothyroidism or hyperthyroidism. |
| Glucocorticoids inhibit T4 to T3 conversion and inhibit TSH release (> 20 mg/d prednisone, > 100 mg/d hydrocortisone, > 4 mg/d dexamethasone). |
| Dopamine (at least 1 µg/kg) also suppresses TSH, as do somatostatin/octreotide (at least 100 µg/d), high dose dobutamine, and retinoid X receptor-selective ligands (e.g. bexarotene for refractory cutaneous T-cell lymphoma), which can lead to decreased T4 and T3. |
| Isolated depressed TSH may be seen in the first trimester of pregnancy. |
| Lithium’s major action is to block release of T4 and T3. It can also inhibit thyroidal iodine transport. A smooth, nontender, goiter develops in ~50% but does not relate to thyroid function. Frequency of hypothyroidism (thyroid autoimmunity is major risk factor) on lithium is 20-30%. Prolonged lithium use may increase incidence of thyroid antibodies. Hyperthyroidism rarely may also occur. |
| Interleukin-2 or interferon alpha-2b can cause hyper or hypothyroidism (occasionally permanent), possibly related to underlying autoimmune disease and induction of antithyroid antibodies. Thyroid dysfunction may occur 6 weeks to 2 years after starting therapy. Hypothyroidism is more common. Risk factors: higher doses, female, thyroid autoantibodies prior to or during therapy. |
| Amphetamine or heroin use and acute non-thyroidal psychiatric illness may cause increased TSH and T4 levels. |
| Sertraline (Zoloft) may exacerbate or cause hypothyroidism, possibly by altered hormone clearance. |
| Aminoglutethimide can lead to hypothyroidism (e.g. 30% of patients on 1000 mg/d). |
| Controlled ovarian hyperstimulation has been associated with depressed free T4 and elevated TSH. |
VI. Hypothyroidism
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Clinical features |
Differential Diagnosis |
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* Most common causes in iodine-sufficient areas
| Prevalence of hypothyroidism in the adult population: 2% |
| Pituitary or hypothalamic hypothyroidism may be present despite a normal TSH; if suspected, a free T4 should be checked. Investigation for hypogonadism and hypoadrenalism should be done. |
| Treatment: In adults under age 50 therapy can start at full replacement dose of 1.6-1.7 mcg/kg/d. In elderly (may need less than 1 mcg/kg/d) or those with cardiac disease, start with 25-50 mcg qd. Increase dose every 6 weeks to target a normal TSH level. Absorption of oral L-T4 (jejunum & upper ileum) ranges from 40-80% and is best fasting. Absorption is delayed or prevented by calcium, magnesium, ferrous sulfate, aluminum hydroxide, kayexalate, sucralfate, cholestyramine, colestipol, soybean formulations, cotton seed meal, walnuts, dietary fiber. Levothyroxine administration should be spaced 4 hours apart from these medications. Pregnant patients and those on anticonvulsants may need an increased dose of levothyroxine. Once stable, periodic monitoring should be done every 6-12 months. |
| If patient is hypothyroid and hypocortisolemic, do not replace thyroid first; increased cortisol metabolism can put patient into adrenal crisis. Treatment of hypothyroidism may necessitate decrease in oral anticoagulant dosing, increased antidiabetic or insulin requirements, and increased digitalis requirements. |
| Hypothyroid women need on average 45% more thyroxine supplementation during pregnancy (50% increased TBG, increased maternal and placental T4 clearance, transfer of T4 to fetus). A study of hypothyroid postmenopausal women given standard hormone replacement therapy showed a 50% increase in TBG, increased TT4, decreased THBR, decreased free T4, increased TSH. The changes, which plateaued at 12 weeks, were small but potentially clinically important (7 of 18 had TSH go over 7 mU/L). In normal women, HRT led to decreased THBR and increased TBG and TT4 only. |
| Situations where normal free T4 level (not TSH) is treatment goal: 1. Central hypothyroidism; 2. Amiodarone-induced hypothyroidism (may not be able to normalize TSH). In thyroid cancer after total thyroidectomy and radioiodine ablation, the goal TSH is < 0.1 mU/L. |
| Subclinical hypothyroidism (elevated TSH, normal T3/T4): Prevalence in adults of 5-17% (highest in elderly women), also called compensated hypothyroidism or low thyroid reserve. Treat if patient has symptoms, goiter, history of thyroid disease, hypercholesterolemia (total or LDL), or greater risk of progression [elderly or TSH > 10-14 mIU/L or positive antibodies]. Also treat if woman is pregnant or having ovulatory dysfunction. Benefit in cholesterol levels or symptoms is more likely when TSH > 10 mU/L. Overall progression to overt hypothyroidism is only 7%. In a study of elderly patients (n=258), 13.2% had subclinical hypothyroidism, and 4 years later 33% had overt hypothyroidism, including 100% of those who had TSH > 20 mU/L and 80% of those with positive antibodies. Of note, a study showed subclinical hypothyroidism in elderly women (TSH > 10) to be an independent risk factor for aortic atherosclerosis and myocardial infarction; other studies have not confirmed this. A study found a 3-fold increased lifetime prevalence of depression in women with subclinical hypothyroidism. |
VII. Hyperthyroidism (increased synthesis) and thyrotoxicosis (increased circulating thyroid hormones)
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Clinical features |
Differential diagnosis |
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Specific to Graves’ disease:
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* More common causes
| Prevalence of thyrotoxicosis in the adult population: 0.2% |
| If hyperthyroidism due to excess TSH is suspected, free T4 and free T3 must also be checked. |
| Graves’ disease: Most common cause (60-80%) of hyperthyroidism overall (multinodular goiter more common in elderly). Highest incidence in 20-40 year old patients. Women:men::4-10:1, uncommon in children, lower incidence in blacks compared to whites & Asians. Characterized by thyrotoxicosis, goiter, ophthalmopathy (affects 50%: exophthalmos, lid retraction (stare), lid lag, chemosis, periorbital edema), localized myxedema (1-2%; over dorsum of legs/feet, or other sites especially after trauma, skin raised, thickened, hyperpigmented, can be pruritic). Pathophysiology is production of thyroid stimulating IgG antibodies which activate the TSH receptor. Positive family history in 15% (20% monozygotic twin concordance). Treatment: |
| Thionamides: methimazole (10-40 mg/d, start 20-30 mg/d; half-life 4-6 hr), propylthiouracil (100-600 mg/d, start 100 mg tid; half-life 1-2 hr). When used as primary therapy, usually given for 6 months to 2 years (usually 12-18 mo.); may see remission in Graves' disease (30-50%). Adverse effects: minor: fever, transient leukopenia, rash, itching, arthralgias, hepatic dysfunction, nausea, anorexia, taste/smell alterations; major: agranulocytosis (0.3%, check if sore throat, oral ulcers, fever develop), thrombocytopenia, acute hepatic necrosis, cholestatic hepatitis, lupus-like syndrome, vasculitis, insulin-autoimmune syndrome. Patients tend to become euthyroid sooner with methimazole (6 weeks) than PTU (12 weeks). |
| Radioactive iodine (131I) is safe and effective, but contraindicated in pregnancy (defer for 4 months after RAI) or breast feeding. Principal side effect is late development of hypothyroidism; worsening of ophthalmopathy also associated with RAI (prevent with 40 mg/d prednisone, taper to off over 3 months). Pretreatment with thionamides is advisable to deplete the gland of stored hormone to minimize risk of exacerbation of hyperthyroidism due to RAI-induced thyroiditis. In some, thionamides will be needed for control several months after RAI, which takes weeks to months to have full effect. A RAI uptake test done to determine the appropriate 131I dose does not reduce incidence of hypothyroidism or recurrent hyperthyroidism; usual dose is 5-15 mCi in Graves, based on goiter size. |
| Thyroidectomy is rarely used for Graves’ disease (inorganic iodide given for 7 days before surgery), risks include hypoparathyroidism, injury to recurrent laryngeal nerve, laryngeal edema and hypothyroidism. Hyperthyroidism may persist or recur if insufficient tissue removed. |
| Propranolol (start 10 mg tid) can provide symptomatic improvement until euthyroid state is achieved. |
| Iodide: rarely used for Graves’ disease, unless thyrotoxicosis severe. Most use in thyroid storm, in preparation for surgery, or adjunctively after RAI. Lugol’s solution (8 mg iodide/drop, 3-5 drops tid) or saturated solution of KI (35-50 mg iodide/drop, 1 drop tid). |
| Also used as acute therapy: sodium ipodate or iopanoate (0.5-1 g/d) which inhibit T4 to T3 conversion and generate iodide. |
| Subclinical hyperthyroidism (decreased TSH, normal T3/T4): Prevalence in adults of 0.1-6%. Associated with risk of atrial fibrillation and reduced bone density. Consider treating if persistently depressed TSH, symptoms of hyperthyroidism, atrial fibrillation, other cardiac disorders (CHF, ischemic heart disease), or significant osteoporosis. Most common cause is exogenous thyroid hormone administration. Rate of progression to overt hyperthyroidism is 5%/yr with multinodular goiter, likely less for Graves’ disease given relapsing and remitting course and development of hypothyroidism in some. |
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