Non-Thyroidal Illness Simona Glasberg , M.D.

Case #1 72 y.o. male Laboratory results PMH: COPD, CHF Admitted to ICU with urosepsis Septic shock. Intubated Laboratory results TSH 0.03 mIU/L (nl 0.35-4.0) FT4 10.5 pmol/L (nl 10-20) TT3 <0.3 nmol/L ( nl 0.92-2.79)

Non-Thyroidal Illness Previously called euthyroid-sick syndrome AKA – Low T3 Syndrome Assessment of TFT in patients with NTI is difficult TSH, T4 and T3 are variable Similarities to central hypothyroidism May be acquired transient central hypothyroidism Mimics the abnormalities seen during starvation or fasting Reductions in T4/T3 seen in calorie deficiency to prevent catabolism Thyroxine replacement in such patients may increase the catabolic rate and may be harmful

Hypothalamic-Pituitary-Thyroid Axis Physiology Hypothalamus TRH – Pituitary, ant. – T4 TSH Heart Liver Bone CNS TR Target Tissues Thyroid Gland T3 This diagram illustrates the hypothalamic-pituitary-thyroid axis. The hypothalamus synthesizes thyrotropin-releasing hormone (TRH). TRH stimulates the anterior pituitary gland to produce thyroid-stimulating hormone (TSH). TSH stimulates the thyroid gland to produce the thyroid hormones thyroxine (T4) and triiodothyronine (T3). In the liver, T4 is converted to T3, which is active in target tissues including the heart, liver, bone, and central nervous system (CNS). Levels of T4 and T3 in the blood in turn regulate the levels of TRH and TSH via a negative feedback loop: If levels of T4 and T3 are sufficient, amounts of TRH and TSH are reduced. If levels of T4 and T3 are too low, formation and secretion of TRH and TSH are increased. This negative feedback loop is most important in control of thyroid hormone levels. T4 è T3 Liver T4 T3 Adapted from Merck Manual of Medical Information. ed. R Berkow. 704:1997.

Thyroid Hormone Metabolism The metabolism of T3 and T4 into active and inactive intermediates involves the action of 3 types of deiodinases. Deiodination occurs mainly within the cells (cell-specific) - Three deiodinases are found in humans: (1) Type 1 (found mainly in the liver and kidney), which can remove iodine both rings; (2) Type 2 (found mainly in skeletal muscle and in the heart, fat, thyroid, and central nervous system [including the brain]), which can induce deiodination in the outer ring, making it the main activating enzyme; and (3) Type 3 (found in fetal tissue and in the placenta), which induces deiodination in the inner ring only and, thus is the main inactivating enzyme. Reverse triiodothyronine (3,3’,5’-triiodothyronine, reverse T3, or rT3) is an isomer of triiodothyronine (3,5,3’ triiodothyronine, T3). Reverse T3 is the third-most common iodothyronine the thyroid gland releases into the bloodstream, of which 0.9% is rT3; tetraiodothyronine (levothyroxine, T4) constitutes 90% and T3 is 9%. The levels of rT3 increase in conditions such as euthyroid sick syndrome resulting from decreased clearance. It increases in sick euthyroid syndrome because its clearance decreases while its production stays the same. The decreased clearance is possibly from lower 5'-deiodinase activity in the peripheral tissue or decreased liver uptake of rT3. T0, T1 and T2 are hormone precursors and byproducts of thyroid hormone synthesis. They do not act on the thyroid hormone receptor and appear to be totally inert. D1-3: Deiodinases

Low T3 Syndrome Pathophysiology Causes Decreased D2 (the main activating enzyme), increased D3 (the main activating enzyme) Decreased T3, increased rT3 Hypothalamic unresponsiveness Mimics Central Hypothyroidism (transient) Causes Common in severely ill patients Drugs: Steroids, High dose beta-blockers, amiodarone, Cytokines

Low T3 Syndrome Diagnosis Thyroid function tests: Very low T3 Normal or low T4 (low T4 is poor prognostic sign) Inappropriately low TSH (usually detectable) High rT3 (test not clinically available) Exclude central hypothyroidism

Low T3 Syndrome - Prognosis Low FT4 associated with up to 85% mortality Peeters, RP, Wouters, PJ, van Toor, H, et al. Serum 3,3',5'-triiodothyronine (rT3) and 3,5,3'-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. J Clin Endocrinol Metab 2005; 90:4559. Slag, MF, Morley, JE, Elson, MK, et al. Hypothyroxinemia in critically ill patients as a predictor of high mortality. JAMA 1981; 245:43.

Low T3 Syndrome Recovery Phase TSH increases and may be above upper limit of normal T4 concentrations increase to baseline levels T3 concentrations increase to baseline levels.

Low T3 Syndrome - Treatment Who to treat: Low T3 and/or low T4 syndrome with no other clinical signs of hypothyroidism, do not treat (Grade 2B) If there is additional evidence to suggest a diagnosis of hypothyroidism in critically ill patients, give replacement treatment (Grade 2C) In the absence of suspected myxedema coma, repletion should be cautious How to Treat T3 preferred due to decreased deiodinase activity

Low T3 Syndrome – Thyroid Hormone Treatment Non-Thyroidal Low T3 Syndrome No improvement in hospital stay No improvement in overall prognosis Some studies show WORSENING of prognosis Severe hypothyroid critically ill patient High mortality Loading dose replacement therapy IMPROVES prognosis

Low T3 Syndrome Summary When to test What to test Treatment Only if true hypothyroidism is suspected What to test TSH, FT4, T3 May need pituitary imaging to exclude central hypothyroidism Treatment None unless clearly hypothyroid Not Myxedema Coma – Low dose oral T4 Myxedema Coma – High dose IV T4 or T3

Case #1 72 y.o. male Laboratory results PMH: COPD, CHF Admitted to ICU with urosepsis Septic shock. Intubated Laboratory results TSH 0.03 mIU/L (nl 0.35-4.0) FT4 10.5 pmol/L (nl 10-20) TT3 <0.3 nmol/L ( nl 0.92-2.79)

Case #2 64 yo male Meds: Amiodarone – started 6 months ago Recurrent VT unresponsive to other treatment c/o rapid weight loss, tremor, proximal muscle weakness. Activation of implanted defibrilator x 2 in previous week. Thyroid function tests: TSH < 0.01 mU/L (nl 0.5 – 4.5 mIU/L FT4 95 pmol/l (nl 10-20) TT3 7.5 nmol/l (nl 0.92-2.79)

Amiodarone Induced Thyroid Dysfunction Class III antiarrhythmic Structure 2 Iodine atoms (3 mg I / 100 mg drug) Normal daily iodine intake is about 0.3 mg Structurally similar to T3 Lipophilic – T1/2 100 days.

Amiodarone and the Thyroid Intrinsic drug effects Decreases Type 2 Diodinase (decreased T3, increased rT3) Blocks T3 receptor binding May be toxic to thyroid cells – Thyroiditis Iodine effects Failure of auto-regulation (Wolff-Chaikoff effect) Hyperthyroidism (Jod-Basedow) Failure to escape from Wolff-Chaikoff effect Hypothyroidism

Amiodarone Effect on Thyroid Function Normal thyroid Initial T4 increased, T3 decreased, rT3 increased, TSH increased (nl or slightly elevate) After 6 months TSH normal, T4 and rT3 slightly elevated, T3 low normal or slightly low Abnormal thyroid Hypothyroid Elevated TSH, low T4 and T3 Hyperthyroid Suppressed TSH, elevated T4 and T3 (T4 >>>T3)

Risk of Amiodarone Induced Thyroid Dysfunction Underlying thyroid disease Autoimmune MNG Iodine intake Iodine sufficient areas: 22% hypothyroid; 2% hyperthyroid Iodine deficient areas: 5% hypothyroid; 10% hyperthyroid

Amiodarone-Induced Thyroid Disease Symptoms Hypothyroid Like any other hypothyroid Hyperthyroid Symptoms may be masked by beta-blockers Tachyarrythmias LV dysfunction Weight loss to the point of cachexia Proximal muscle wasting

Amiodarone-Induced Thyroid Disease Treatment Hypothyroid Treat with T4 (may need higher dose) Continue Amiodarone If discontinued, follow thyroid function closely and consider stopping replacement. Hyperthyroid Onset may be after years of taking the drug or even after stopping the drug. Patients often critically ill with high mortality Treatment is difficult

Amiodarone-Induced Hyperthyroidism Type 1 Increased T4 and T3 production Background MNG or Graves common Type 2 Destructive thyroiditis No background thyroid disease Hormone spillage, not new production

Amiodarone-Induced Hyperthyroidism Differentiating Type 1 and 2 Iodine uptake Type 1 low due to iodine overload (but may be detectable) Type 2 undetectable due to gland destruction + Iodine overload Prior history / Physical exam MNG suggestive of Type 1 IL-6 measurements – controversial Color doppler – T1 vascular, T2 avascular – controversial Tc - scan – T1 increased, T2 decreased uptake (Not clinically validated yet)

Amiodarone-Induced Hyperthyroidism Treatment May be treating life-threatening arrhythmia T1/2 -- 100 days. Stopping may increase T3 receptor function and T4->T3 conversion. Usually stop, but if needed can continue Type 1 Thionamides – high dose PTU or Mercaptizol Perchlorate (blocks uptake) Lithium (blocks release) Surgery

Amiodarone-Induced Hyperthyroidism Treatment Type 2 Prednisone 40-60 mg/d for 2-3 months, then taper In reality most patients have Type 1, and some have mixed, but pure Type 2 is rare Differentiation is difficult Recommend Prednisone 40 mg + Methimazol 40 mg If rapid response, taper and stop Methimazol If slow response, taper and stop steroids

Case #2 64 yo male Meds: Amiodarone – started 6 months ago Recurrent VT unresponsive to other treatment c/o rapid weight loss, tremor, proximal muscle weakness. Activation of implanted defibrilator x 2 in previous week. Thyroid function tests: TSH < 0.01 mU/L (nl 0.5 – 4.5 mIU/L FT4 95 pmol/l (nl 10-20) TT3 7.5 nmol/l (nl 0.92-2.79)