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

2. 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 )
FT pmol/L (nl 10-20)
TT3 <0.3 nmol/L ( nl )

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. 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.

5. 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

6. 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

7. 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

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 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.

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 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

13. 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 )
FT pmol/L (nl 10-20)
TT3 <0.3 nmol/L ( nl )

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)
TT nmol/l (nl )

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 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)

23. Amiodarone-Induced Hyperthyroidism Treatment
May be treating life-threatening arrhythmia
T1/ 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 Hyperthyroidism Treatment
Type 2
Prednisone 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)
TT nmol/l (nl )