Sick Euthyroid Syndrome refers to abnormal thyroid function test results that occur during non-thyroidal illness without pre-existing thyroid dysfunction. It is characterized by low T3 and elevated reverse T3 levels. This pattern results from impaired conversion of T4 to T3 in tissues due to reduced activity of deiodinase enzymes from cytokines. The severity of the thyroid hormone changes correlates with the severity of the underlying illness. Treatment with thyroid hormone is controversial, and thyroid function usually normalizes as the illness improves.

1. Sick Euthyroid Syndrome
Guide : Dr Rajesh Verma Sir
Candidate : Dr Sagar Dagdiya

2. Sick Euthyroid Syndrome
• Abnormal findings in thyroid function tests
• Occur in the setting of a non thyroidal
illness(NTI)
• Without pre-existing hypothalamic-pituitary-
thyroid gland dysfunction.

3. FT3 Changes

5. Function of Deiodinase Enzyme
Parameters D1 D2 D3
Act on rT3 ,T4 T4 ,rT3 T3,T4
Tissue location Liver ,Kidney
Thyroid ,Pituitary
CNS, Pituitary
Skeletal muscle,
Placenta,
Thyroid, Heart
Placenta,CNS
Hemangiomas,
skeletal muscle
liver
Function Degradation of rT3
and T3 Synthesis
Main source of
T3
Inactivation of
T3 and T4

6. • Normally T3, T4 and TSH levels are well regulated
• Most prominent are low T3 & elevated rT3
• Leading to the term “low T3 syndrome.”
• As the severity of non thyroidal illness increases,
both T3 and T4 levels drop that usually normalizes
as the underlying illness recovers.

7. Mechanisms
• Cytokines particularly IL-1, IL-6, TNF-α and
Interferon-β.
• Impaired peripheral deiodination of T4 to T3.
• Decreased clearance of rT3.
• Inhibition of thyroid hormone binding to
thyroid hormone binding proteins and tissues.
• Insufficient levels of thyroid hormone binding
proteins(TBG, TBPA & TBA).

8. • During inflammatory states, there is increase
in Reactive Oxygen Species(ROS).
• The active centers of both D1 & D2 are
intracellular, and that of D3 is extracellular,
which do not pass easily through the cell
membrane.

9. • D1 & D2 inactivated
• However D3 is spared {and Type 2 Deiodinase
in Tanycytes is also spared}
• Leading to decreased T3 & Increased rT3
• Reduced clearance of rT3 due to reduced
activity of D1 & D2

10. • D2 is thought to be negatively regulated by
thyroid hormone
• Normal to increased production of T3 via
increased activity of D2 in Tanycytes
(Speciliased cells in the wall of 3rd Ventricle).

11. • Cytokines like IL-1, IL-6, TNF-α & Interferon-γ
also affect hypothalamus, pituitary and other
tissues.
• Interferon-γ inhibits TSH & cAMP induced up-
regulation of TSH receptors on thyroid cells.

12. • Interferon-γ and TNF-α inhibits TSH induced
mRNA expression and thyroid hormone &
thyroglobulin secretion.
• Interferon-γ inhibits TSH induced increase in
sodium iodide symporter (NIS) expression
• Diminished iodide uptake.

13. • Prolonged critical illness there is decreased
food intake
• Decreased level of hormone leptin
• Cytokines, cortisol and leptin alters secretion
of TRH and TSH
• Reduction in leptin levels cause increase in
Type 3 Deiodinase activity.

14. Effect of NTI on T3 & rT3
MCR : Metabolic Clearance Rate
PR : Production Rate

15. Diagnosis
• Low T3 and T4 levels.
• TSH : can be Low, Normal or slightly Elevated.
• Reverse T3(rT3) : Elevated.
• Sr. Cortisol levels : Usually Elevated.

16. Systemic and NTI
Condition T3 rT3 T4 FT4 TSH
Fasting
= =
Mild illness
= =, =
Critical illness
=,
Trauma /Burn
=,
CRF
= =, =, =,
Hepatitis
=, =, =, =, =
HIV infection
= = =, =,
Depression
=, =, =, =, =,

17. Differential Diagnosis
Hypothyroidism : Low T3 & T4 with markedly
increased TSH with low Cortisol.
Acute exposure to heat : Low T3 (free & total) with
increased rT3 and TSH.
Fasting/Starvation : Total T4 usually unchanged, free
T4 normal or elevated due to increase in FFA.
Total & free T3 decreased. Elevated rT3 with
diminished response of TSH to TRH.

18. Surgery : Total T3 level falls, free T3 level
increases on the day of surgery that eventually
falls postoperatively. T4 & TSH levels are
usually unaltered.
Myocardial Infarction : In 1-3 days post infarction,
total T3 low, rT3 elevated and TSH may be
normal or elevated.

19. CKD : Total & Free T4 normal or decreased, Total
& Free T3 reduced, rT3 unchanged, Basal TSH
unchanged or reduced. Low FT3 is an
independent predictor of death in
hemodialysis patients.
Liver Disease : Total T4 unchanged or increased,
Free T4 unchanged or reduced, Free T3
reduced or unchanged, rT3 elevated, TSH
reduced, normal or slightly elevated.

20. HIV Infection : Patients with asymptomatic HIV
infection have TFT results WNL or slightly
increased TSH levels.
Psychiatric Illness : In acute psychosis, there is
elevated T4. Patients with PTSD may have
slightly high serum T3 concentrations, but
their serum FT3, FT4, and TSH are normal.

21. Severity of Illness and Pattern of Sick
Euthyroid Syndrome
• The changes in hormonal status depends upon the
duration of the illness
-Acute illness -mild ,moderate ,severe
-Chronic illness
• Magnitude of change in T3 and rT3 reflects severity
of illness
• Total T3 fall is faster than FT3, T4 level is generally
within normal range, however T4 level may fall as the
severity of NTI increases.

22. • Low T3 - D2,D1 in peripheral
tissue
• TSH (N) with T3 : Suppression
of TSH by T3 produced by D2
located in tanycytes
TRH
TSH (N)
FT4 (N)
FT3 rT3
T2
D2,D1
D1,D2
D3
Free T3 Free T4 RT3 TSH Cause
N (2 -3 fold) N D2,D1 D350%
Mild Illness (acute illness)

23. Moderate To Severe Illness (Acute Illness)
• TSH - cytokine ,drugs
suppress H-P level
• FT4 ( ,N) even with TSH
FFA and other substances
reduce the binding to TBG
• in Tissue FT3 similar that of
serum FT3
TRH
TSH
FT4
FT3 rT3
T2
D2 ,D1 D3
(N , , )
D1,D2D3
Free T3 Free T4 RT3 TSH Cause
N, (2 -3 fold) N , D2,D1 ,D3
(N, )
50-70%

24. Changes in Chronic Critical Illness
TRH
TSH
FT4
FT3 rT3
T2
Free T3 Free T4 RT3 TSH Cause
D2,D1, D3
• FT4 and TSH marked
reduced
• FT3 marked reduced
,barely detected in
tissue level

25. Changes in Thyroid Hormone Levels
During Illness
Severity of
Illness
Free T3 Free T4 Reverse T3 TSH Probable
Cause
Mild N N D2,D1
Moderate N, , N, D2,D1,
? D3
Severe D2,D1,
D3
Recovery ?

26. Thyroid Hormone Concentration In
In-Patients
Severity Of Illness : Mild  Moderate  Severe

27. Treatment
• Treatment with Thyroid Hormone
Replacement is controversial.
• Whether there is any beneficial role behind
these alterations is still not clear.
• When the underlying illness is treated, results
of thyroid tests usually normalize of its own.

28. • The only positive outcomes of T3 treatment is seen
in patients undergoing cardiac surgery.
• Postoperative intravenous T3 therapy increases
cardiac index
• No difference in mortality benefit

29. • Co-infusion of GHRH plus TRH is better
• Induce restoration of pulsatile growth
hormone and TSH release
• Near-normal serum T4 and T3 values
• Shift from catabolism towards anabolism
• Rise in circulating rT3 avoided.