Interpretation of TFT in Non – thyroidal illness I liked things better when I didn't understand them. (Bill Watterson) 8/19/2015 8:36:26 PM 1 Prashanth.B

Interpretation of TFT in Non – thyroidal illness

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

04/19/23 06:51 AM

1

Prashanth.B

Undertaking

The facts presented here are not based on author’s personal experience

These are evidence based information taken from the following sources without permission

Harisson’s Principles of Internal Medicine,17th edi

Uptodate.com, PC ver 17.1, updated upto Jan 2009

The Nonthyroidal Illness Syndrome, Endocrinol Metab Clin N Am, 36 (2007) 657–672

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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

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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, NF-kB, and IL-6

Impaired uptake of T4 into hepatocytes

Measured to differentiate NTI from hyperthyroidism

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Thyroid function in nonthyroidal illness. Douglas S Ross, MD Uptodate.com Last literature review version 17.1: Jan 2009, last updated: August 25, 2008

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 normalT3-resin uptake test fails to correct for the binding-

protein deficiency adequatelySo serum free T4 index is lowAbnormal binding of T4 is due to increased FFAs like oleic

acid

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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.

Normal T3 Resin Uptake

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In TBG deficiency

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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 AIDSDistinguish between NTI and central hypothyroidism

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Chopra, IJ. An assessment of daily turnover and significance of thyroidal secretion of reverse T3. J Clin Invest 1975; 58:32.

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

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Chopra, IJ. Euthyroid sick syndrome: Is it a misnomer? J Clin Endocrinol Metab 1997; 82:329.

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

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Attia, J, Margetts, P, Guyatt, G. Diagnosis of thyroid disease in hospitalized patients: A systematic review. Arch Intern Med 1999; 159:658.

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

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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.

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


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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.

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


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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.

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


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Surks MI, Sievert R. Drugs and thyroid function. NEJM 1995;333:1688–94.

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


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Wartofsky L, Burman KD. Alterations in thyroid function in patients with systemic illness:the ‘‘euthyroid sick syndrome’’. Endocr Rev 1982;3:164–217.

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)


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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 Clin Endocrinol Metab 1981;53:997–1001.

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


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Burman KD, Wartofsky L. Endocrine and metabolic dysfunction syndromes in the criticallyill: thyroid function in the intensive care unit setting. Crit Care Clin 2001;17:43–57.

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

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Thyroid function in nonthyroidal illness. Douglas S Ross, MD Uptodate.comLast literature review version 17.1: January 2009 | This topic last updated: August 25, 2008

Decreased T4 binding to TBG Salicylates Salsalate Furosemide Heparin (via free fatty

acids) NSAIDs

Increased T4 clearance Phenytoin Carbamazepine Rifampin Phenobarbital


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Suppression of TSH secretion Dobutamine Glucocorticoids Octreotide

Impaired conversion of T4 to T3 Amiodarone Glucocorticoids Contrast agents for

oral cholecystography (eg, iopanoic acid)

Propylthiouracil Propanolol Nadolol


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Prognosis

The magnitude of the changes in TFT in patients with nonthyroidal illness varies with the severity of the illness

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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.

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

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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

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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.


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Thank you

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

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Interpretation of TFT in Non – thyroidal illness I liked things better when I didn't understand them. (Bill Watterson) 8/19/2015 8:36:26 PM 1 Prashanth.B