Interpretation of TFT in Non – thyroidal illness

1. Interpretation of TFT in Non – thyroidal illness I liked things better when I didn't understand them. (Bill Watterson)

2. Hypothalamus TRH Pituitary 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.

3. Thyroid Function Tests • TSH • FT4, (T4) • T3, FT3 • Thyroglobulin & Anti thyroglobulin AB • Thyroid stimulating immunoglobulin (TSI) or TSHR antibody • Antithyroid peroxidase antibodies (Anti TPO)

4. Introduction • Assessment of TFT in patients with NTI is difficult • TSH, T4 and T3 are variable • Previously called euthyroid-sick syndrome • Current evidence - 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

5. Low T3 syndrome • Majority of hospitalized patients • T4  5'-deiodination  T3 (5'-monodeiodinases) • Inhibition of 5'-monodeiodination • High serum cortisol • Circulating inhibitors such as non-esterified FFA • Drugs such as amiodarone and high doses of propranolol • Cytokines (such as TNF, IFN – α, and IL-6 • Impaired uptake of T4 into hepatocytes Thyroid function in nonthyroidal illness. Douglas S Ross, MD Uptodate.com Last literature review version 17.1: Jan 2009, last updated: August 25, 2008

6. Low T4 syndrome • 15 to 20 % of hospitalized patients and up to 50 % of patients in ICUs • Reductions in the serum concentrations THBPs • TBG, TBPA/TTR and albumin • TBG may be low or abnormal • fT4 is usually normal Docter, R, Krenning, EP, de Jong, M, Hennemann, G. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf) 1993; 39:499. Chopra, IJ, Trong, UT, Le, A. Simultaneous measurement of free thyroxine and free 3,5,3'-triiodothyronine in undiluted serum by direct equilibrium dialysis/ radioimmunoassay: evidence that free triiodothyronine and free thyroxine are normal in many patients with the low triiodothyronine syndrome. Thyroid 1998; 8:249.

7. rT3 • Product of 5-monodeiodination of T4 (type III T4-5-deiodinase) • rT3 concentrations are high except in those with renal failure and some with AIDS • Distinguish between NTI and central hypothyroidism Chopra, IJ. An assessment of daily turnover and significance of thyroidal secretion of reverse T3. J Clin Invest 1975; 58:32.

8. Transient central hypothyroidism • Patients with severe NTI may have acquired transient central hypothyroidism • Serum TSH fell coincident with declines in serum T4 in patients undergoing bone marrow transplantation • Rise in serum TSH preceded normalization of serum T4 in patients recovering from critical illness • Blunted nocturnal rise in serum TSH, but a normal serum TSH response to TRH • TRH infusion in patients with critical illness raises serum TSH, T4 and T3 concentrations • Infusion of IFN-α to normal men caused a fall in serum TSH and T3, and a rise in the serum rT3 and IL-6 Chopra, IJ. Euthyroid sick syndrome: Is it a misnomer? J ClinEndocrinolMetab 1997; 82:329.

9. Serum TSH • Low but detectable (>0.05 mU/L and < 0.3 mU/L)  most will be euthyroid when reassessed after recovery from their illness • Undetectable (<0.01 mU/L)  75 percent of patients have hyperthyroidism • High (up to 20 mU/L)  Can be transient • Very high (> 20 mU/L)  Permanent hypothyroidism Attia, J, Margetts, P, Guyatt, G. Diagnosis of thyroid disease in hospitalized patients: A systematic review. Arch Intern Med 1999; 159:658.

10. Renal failure and TFT • ESRD alters the HPT axis • Reduced T4 to T3 conversion • Chronic metabolic acidosis contribute to low free T3 levels • Reduced conversion of T4 to rT3 with redistribution of rT3 from vascular to extravascular spaces of rT3 • fT4 may be increased in the setting of heparin used for hemodialysis • TSH glycosylation is abnormal, which may affect the plasma ½ - life of TSH • TSH response to TRH is typically blunted Kaptein, EM, Feinstein, EI, Nicoloff, JT, Massry, SG. Serum reverse triiodothyronine and thyroxine kinetics in patients with chronic renal failure. J Clin Endocrinol Metab 1983; 57:181. Kaptein, EM. Thyroid hormone metabolism and thyroid diseases in chronic renal failure. Endocr Rev 1996; 17:45.

11. HIV and TFT • T3, free T4, and TSH, remain normal unless severe disease is present • Increases in TBG have been observed due to altered TBG sialylation, which is known to decrease TBG clearance • PCP + AIDS + Low T3  Increased mortality • Unlike other causes rT3 levels are not markedly elevated • 10 – 12% patients receiving HAART have lower fT4 and higher TSH levels, s/o subclinical or mild hypothyroidism • Due to immune reconstitution with the unmasking of underlying Hashimoto disease LoPresti, JS, Fried, JC, Spencer, CA, Nicoloff, JT. Unique alterations of thyroid hormone indices in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989; 110:970. Ricart-Engel, W, Fernandez-Real, JM, Gonzalez-Hulx, F, del Pozo, M, Mascaro, J, Garcia-Bragado, F. The relation between thyroid function and nutritional status in HIV-infected patients. Clin Endocrinol 1996; 44:53.

12. Acute Hepatitis and TFT • Increased TBG is released from the liver as an acute-phase reactant • Elevations in serum total T3 and total T4 levels • fT4 and TSH are most commonly normal • Minimal elevations in rT3 and reductions in fT3 may be observed • rT3:T3 ratio may have value in the prognostication of patients who have FHF Gardner DF, Carithers RL, Galen EA, et al. Thyroid function tests in patients with acute and resolved hepatitis B infection. Ann Intern Med 1982;96:450–2. Kano T, Kojima T, Takahashi T, et al. Serum thyroid hormone levels in patients with fulminant hepatitis: usefulness of rT3 and the rT3/T3 ratio as prognostic indices. Gastroenterol Jpn 1987;22:344–53.

13. Glucocorticoids • Affect the HPT axis at multiple levels • Acute suppression of TSH secretion • Down-regulation of T4 to T3 conversion by 5’-deiodinase • Decrease of TBG concentration and hormone-binding capacity • Low TSH, low T3, low T4, and normal to slightly low free T4 • Within 24 to 36 hours after first dose Surks MI, Sievert R. Drugs and thyroid function. NEJM 1995;333:1688–94.

14. Dopamine • Prolonged use can result in precipitous TSH suppression • Low T4, free T4, T3, and free T3 • Lead to secondary hypothyroidism • Worsening of prognosis until thyroid hormone replacement is given

15. Amiodarone • High iodine content reported to be 37% • May increase or decrease thyroid hormone secretion • Inhibits T4 to T3 conversion by 5’-deiodinase, resulting in decreased T3 and increased rT3 levels • Slows T4 metabolism, leading to T4 and free T4 elevations • Most remain euthyroid • Hypothyroidism in 5% to 25% (more common in regions with adequate iodine intake) • Hyperthyroidism in 2% to 10% (in iodine-deficient regions) Cavalieri RR. The effects of disease and drugs on thyroid function tests. Med Clin North Am 1991;75:27–39. Melmed S, Nademance K, Reed AW, et al. Hyperthyroxinemia with bradycardia and normal thyrotropin secretion after chronic amiodarone administration. J ClinEndocrinolMetab 1981;53:997–1001.

16. Iodine • Constituent of the IV contrast agents • Acutely reduces thyroid hormone secretion and exacerbate hypothyroidism • Large iodine loads can precipitate thyrotoxicosis in patients who have underlying autonomous thyroid function Burman KD, Wartofsky L. Endocrine and metabolic dysfunction syndromes in the critically ill: thyroid function in the intensive care unit setting. Crit Care Clin 2001;17:43–57.

17. Drugs causing abnormal TFT • Low serum TBG • Androgens • Danazol • Glucocorticoids • Slow-release niacin (nicotinic acid) • L-asparaginase • High serum TBG • Estrogens • Tamoxifen • Raloxifene • Methadone • 5-fluouracil • Clofibrate • Heroin • Mitotane Thyroid function in nonthyroidal illness. Douglas S Ross, MD Uptodate.com Last literature review version 17.1: January 2009 | This topic last updated: August 25, 2008

18. Drugs causing abnormal TFT • Decreased T4 binding to TBG • Salicylates • Salsalate • Furosemide • Heparin (via free fatty acids) • NSAIDs • Increased T4 clearance • Phenytoin • Carbamazepine • Rifampin • Phenobarbital Thyroid function in nonthyroidal illness. Douglas S Ross, MD Uptodate.com Last literature review version 17.1: January 2009 | This topic last updated: August 25, 2008

19. Drugs causing abnormal TFT • Impaired conversion of T4 to T3 • Amiodarone • Glucocorticoids • Contrast agents for oral cholecystography (eg, iopanoic acid) • Propylthiouracil • Propanolol • Nadolol • Suppression of TSH secretion • Dobutamine • Glucocorticoids • Octreotide Thyroid function in nonthyroidal illness. Douglas S Ross, MD Uptodate.com Last literature review version 17.1: January 2009 | This topic last updated: August 25, 2008

20. Prognosis • The magnitude of the changes in TFT in patients with nonthyroidal illness varies with the severity of the illness 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 ClinEndocrinolMetab 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.

21. Recommendations • Thyroid function tests not be measured on seriously ill patients unless there is a strong suspicion of thyroid dysfunction • Measurement of serum TSH alone is inadequate for the evaluation of thyroid function • In cases where it is necessary , measure full panel • i.e. TSH, T4, fT4, and T3. However, the diagnosis may still be in doubt Thyroid function in nonthyroidal illness. Douglas S Ross, MD Uptodate.com Last literature review version 17.1: January 2009 | This topic last updated: August 25, 2008

22. Treatment • Low T3 and/or low T4 syndrome with no other clinical signs of hypothyroidism, do not treat (Grade 2B) • In previously euthyroid patients undergoing CABG, do not treat in the immediate post-operative period (Grade 1A) • 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 Thyroid function in nonthyroidal illness. Douglas S Ross, MD Uptodate.com Last literature review version 17.1: January 2009 | This topic last updated: August 25, 2008

23. What to give? • TRH infusion may be a safer alternative to thyroid hormone administration with greater likelihood of avoiding supra-physiologic thyroid hormone levels • Van den Berghe G, Baxter RC, Weekers F, et al. The combined administration of Ghreleasing peptide-2 (GHRP-2), TRH and GnRH to men with prolonged critical illness evokes superior endocrine and metabolic effects compared to treatment with GHRP-2 alone. Clin Endocrinol (Oxf) 2002;56:655–69. • Intravenous T3 administration is preferred over T4 due to reduced 5’-deiodinase activity • Brent GA, Hershman JM. Thyroxine therapy in patients with severe nonthyroidal illnesses and lower serum thyroxine concentration. J Clin Endocrinol Metab 1986;63:1–8.

24. Case A 70 yo male patient was admitted to ICU 3 days ago for pneumonia, COPD exacerbation which required intubation. He was successfully extubated and transferred to telemetry floor yesterday. Overnight the telemetry shows sinus rhythm 80 to sinus tachycardia 105 with few atrial ectopy and a normal EKG. He is on Levaquin 750mg daily, duoneb Q4H, and hydrocortisone 60mg Q6H. He appears frail, weak and complains only of no appetite. The BP 98/70 T.99, P.100, RR. 20, pulsox 96% on 2L. On exam, he has RLL rhonchi but no crackles, heart rate is slightly fast but no murmur or rub. The remaining of his exam was unremarkable. AM lab shows WBC 13.0 Hb 12 Plt 200K, band 6%, seg. neutrophil 80%, normal C7, TSH 0.15 (0.45-4.5), T4 normal and T3 low. Which of the following would be appropriate to do next? • This patient has lab result suggestive of central hypothyroidism so MRI of the head should be done first. • Order a baseline cortisol level and do a cosyntropin test to rule out adrenal insufficiency. • Order a serum rT3 level and if the level is high no other test is necessary. • Start patient on levothyroxine 0.025mg daily for hypothyroidism

25. Amiodarone and Thyroid • Causes both hypothyroidism and hyperthyroidism • Hypothyroidism • “Wolff-Chaikoff” effect: iodine load decreases iodine uptake, organification, and release of T4 & T3 • Inhibits coversion of T4 -> T3 • Direct/immune-mediated thyroid destruction • Hyperthyroidism • Type 1 = underlying MNG or autonomous thyroid tissue • Type 2 = destructive thyroiditis • Increased release of preformed T4 and T3  hyperthyroidism  hypothyroidism  recovery

26. Amiodarone induced thyrotoxicosis • About 3% of amiodarone-treated patients in the United States become hyperthyroid. (Hypothyroidism is more common than hyperthyroidism) • Two basic mechanisms in AIT Type I – Increase synthesis of T4 and T3 - Pre-existing multinodular goiter or latent Graves’ disease. More commonly seen in iodine-deficient areas of the world Type II – Direct toxic effect of amiodarone causing thyroiditis and hence release of T4 and T3 without increased hormone synthesis. More commonly seen in iodine-sufficient countries

27. Amiodarone induced thyrotoxicosis • Distinction between the two types is critical because the treatment is different. • Criteria used to attempt to distinguish type I from type II are 24-hour radioiodine uptake – if detectable, it suggest type I AIT Goiters – if has multinodular or diffuse goiter, it is more likely type I AIT. • Serum thyroglobulin – higher in type I • Serum IL-6 – higher in type II • Color-flow Doppler sonography – may distinguish type I (increased vascularity) from type II (absent vascularity) hyperthyroidism.

28. Amiodarone induced thyrotoxicosis Should amiodarone be discontinued? • There are no good data that answer this question; however, the following should be considered: • Amiodarone may be necessary to control a life threatening arrythmia. • It has a very long half-life so stopping it would not give any immediate benefit. • Amiodarone appears ameliorate hyperthyroidism by blocking T4 to T3 conversion, beta-adrenergic receptors, and possibly T3 receptors. Stopping amiodarone might actually exacerbate hyperthyroid symptoms and signs.

29. Amiodarone induced thyrotoxicosis treatment • Type I AIT . Drugs-Thionamide (PTU or methimazole) is the first line therapy (whether amiodarone is continued or discontinued). Higher than average doses are often needed . Radioiodine ablation – if the RAIU is high enough. . Surgery – only if refractory to antithyroid drug therapy. • Type II AIT . Glucocorticoids – Prednisone 40-60 mg/day. Continue therapy for one to two months before tapering • “Mixed” type I and type II AIT . Combination of glucocorticoids and thionamine initially. A rapid response suggests type II, the thionamide can then be tapered or stopped. A poor or slow initial response argues for type I AIT

30. Case A 60 year old woman with hxafib, HTN, and DM type 2 presents to ED complaining of feeling nervous and difficulty with sleep. She admits to have only mild palpitation but no CP or diaphoresis and the remaining of ROS are negative. Her medication includes amiodarone 200mg daily, metoprolol XL 50mg daily, metformin 500mg BID, and simvastatin 20mg bedtime. She Appears mild anxious but no distress. VS. BP 134/78, T. 98.7, P.108, R.22 Neck exam shows slight tenderness and mild enlarged thyroid, heart exam is tachycardia with regular rhythm and a soft systolic murmur. The remaining of exam is within normal. Lab shows TSH is 0.01 (0.5-5.0 mU/L), FT4 50.3 (10.3-30.6 pmol/L). Remaining labs are within normal including C7, CBCD, CK, and TnT. Which of the following statements are true? • Patient has amiodarone induced thyroditis so amiodarone must be stopped immediately and start on PTU or methimazole low dose. • The color flow Doppler of thyroid gland, RAUI, and IL6 may help to determine the type of thyrotoxicosis • Treat patient with both a thionamide and prednisone, continue amiodarone, and recheck TSH and FT4 in 2-4 weeks • Stop amiodarone and recheck TSH, FT4 in 4-6 weeks. • She should be start on ASA and prednisone if the RAIU is high

31. Case answer B and C are the correct statement. A is false because amiodarone has a very long half-life so stopping it would not have any immediate benefit and potentially can cause arrhythmia. D is false because patient needs treatment for thyrotoxicosis E is false because in acute thyrotoxicosis state aspirin can exacerbate the condition because it binds to TBG and causing more available unbound thyroxine.

32. Thank you I liked things better when I didn't understand them. (Bill Watterson)