interpretation of tft in non – thyroidal illness

04/20/23 01:38 AM1

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

T4

T3

Hypothalamic-Pituitary-Thyroid Axis Physiology

2

Pituitary

Thyroid Gland

Hypothalamus TRH

T4 T3 Liver

T4 T3

Heart

Liver

Bone

CNS

TR

Target Tissues

–

–

TSH

Adapted from Merck Manual of Medical Information. ed. R Berkow. 704:1997.

Thyroid Function Tests

TSH FT4, (T4) T3, FT3 Thyroglobulin & Anti thyroglobulin

AB Thyroid stimulating immunoglobulin

(TSI) or TSHR antibody Antithyroid peroxidase antibodies

(Anti TPO)

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, and IL-6

Impaired uptake of T4 into hepatocytes

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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 normal

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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.

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

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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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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

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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.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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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?A. This patient has lab result suggestive of central

hypothyroidism so MRI of the head should be done first.B. Order a baseline cortisol level and do a cosyntropin test to rule

out adrenal insufficiency.C. Order a serum rT3 level and if the level is high no other test is

necessary.D. Start patient on levothyroxine 0.025mg daily for

hypothyroidism

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

25

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


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.


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.

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

CaseA 60 year old woman with hx afib, 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?A. Patient has amiodarone induced thyroditis so

amiodarone must be stopped immediately and start on PTU or methimazole low dose.

B. The color flow Doppler of thyroid gland, RAUI, and IL6 may help to determine the type of thyrotoxicosis

C. Treat patient with both a thionamide and prednisone, continue amiodarone, and recheck TSH and FT4 in 2-4 weeks

D. Stop amiodarone and recheck TSH, FT4 in 4-6 weeks.E. She should be start on ASA and prednisone if the RAIU

is high

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.

Thank you

04/20/23 01:38 AM32

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

interpretation of tft in non – thyroidal illness

Documents

normalization of serum

undiluted serum

serum tshlow

serum rt3

normal serum tsh response

serum concentrations

low t4 syndrome15

free triiodothyronine