Non-Thyroidal Illness

1. Non-Thyroidal Illness Simona Glasberg , M.D.

2. Case #1 • 72 y.o. male • 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)

3. 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

4. Hypothalamus TRH Pituitary, ant. Target Tissues Heart Thyroid Gland Liver T4 TR T3 Bone T4è T3 Liver CNS Hypothalamic-Pituitary-Thyroid Axis Physiology – – TSH T4 T3 Adapted from Merck Manual of Medical Information. ed. R Berkow. 704:1997.

5. Thyroid Hormone Metabolism D1-3: Deiodinases

6. Low T3 Syndrome • Pathophysiology • 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

7. Low T3 SyndromeDiagnosis • 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

8. 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.

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

10. 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

11. 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

12. Low T3 SyndromeSummary • When to test • 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

13. Case #1 • 72 y.o. male • 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)

14. 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)

15. 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.

16. 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

17. 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)

18. 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

19. 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

20. 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

21. 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

22. Amiodarone-Induced HyperthyroidismDifferentiating 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)

23. Amiodarone-Induced HyperthyroidismTreatment • Amiodarone • 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

24. Amiodarone-Induced HyperthyroidismTreatment • 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

25. 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)