Comprehensive coverage on non-Thyroid illness Syndrome

1. NON THYROIDAL ILLNESS
SYNDROME
DR LAVANYA BONNY
SR, DEPT OF ENDOCRINOLOGY
ST JOHNS MEDICAL COLLEGE
BANGALORE

2. INTRODUCTION
 The evaluation of altered thyroid function parameters in systemic illness and stress
remains complex because changes occur at all levels of the HPT axis.
 ‘‘nonthyroidal illness syndrome’’
 also known as the low T3 syndrome or euthyroid sick syndrome

3. INTRODUCTION
 not a true syndrome
 reflects alterations in TFTs in a variety of clinical situations that commonly include a
low serum T3, normal to low T4, and a high rT3

4. INTRODUCTION
 In mild illness - only a decrease in T3 levels.
 as the severity and length of the illness increases - drop in both serum T3 and T4.
 seen in starvation, sepsis, surgery, MI, bypass, bone marrow transplantation, and in
fact probably any severe illness
 may be observed in up to 75% of hospitalized patients

5. EFFECT ON T3
 Low serum T3 is the most common manifestation of altered thyroid economy in
nonthyroidal illness.
 5’-deiodinase catalyzes the monodeiodination of 35% to 40% of circulating T4 to
produce T3 (accounts for 80% to 90% of T3 in the circulation)
 10% to 20% of T3 is directly secreted by the thyroid.
 In NTIS - Inhibition of 5’-deiodinase ------decrease in T4 to T3 conversion in a
variety of tissues -----low serum T3

6. LOW T3 STATES
 Starvation ( carbohydrate deprivation) rapidly inhibits deiodination of T4 to T3 by
type 1 iodothyronine deiodinase in the liver
 Patients who have only a drop in serum T3 do not show clinical signs of
hypothyroidism.
 represents the mildest form of the NTIS
 No adverse physiological effect or increased mortality

7. EFFECT ON T4
 Generally, decreases of serum T4 are seen in nonthyroidal illness
 can be due to HP suppression, disordered iodine uptake, abnormal peripheral
metabolism, or decreased binding to carrier proteins such as TBG.
 FT4 is commonly within the normal reference range - may be low or slightly
increased depending upon the specific underlying disease process

8. NTIS WITH LOW SERUM T4
 A marked decrease in serum T3 and T4 in NTIS is associated with a high probability
of death
 When T4 < 4 mcg/dL, the probability of death is about 50%
 with T4 levels < 2 mcg/dL, the probability of death reaches 80%.

9. EFFECT ON REVERSE T3
 rT3 is usually elevated in nonthyroidal illness.
 T4 to rT3 conversion by 5- deiodinase is called the ‘‘inactivating pathway.’’
 With impairment of 5’-deiodinase activity reducing metabolism of T4 by the
activating pathway, more T4 substrate is available for 5-deiodinase action via the
inactivating pathway
 In addition, 5’-deiodinase ordinarily converts rT3 to T2, and reduced activity of 5’-
deiodinase slows clearance of rT3, further elevating rT3 levels

10. EFFECT ON TSH
 TSH levels may be low
 usually not less than 0.05 μU/mL.
 only on rare occasions are TSH levels undetectable due to nonthyroidal illness
alone.
 TSH may be transiently elevated even to greater than 20 mU/L during nonthyroidal
illness recovery

11. EFFECT ON TSH
 Serum TSH in patients with NTIS may have reduced biological activity, perhaps
because of reduced TRH secretion and reduced glycosylation
 There is also a diminution or loss of the diurnal rhythm of TSH

12. EFFECT ON TSH
 hypothalamic abnormality may be a cause of the low TSH and low T4
 Other hormones like test, LH and FSH also fall
 Some patients have apparent transient central hypoadrenalism, have low or normal
serum ACTH, and cortisol levels under 20 μg/dL

13. ALTERED THRYOID ECONOMY IN
STARVATION AND FASTING
 The fasting state causes a down-regulation in the HPT axis and hence decreased
thyroid hormone levels
 decreased serum T3 in starvation may be an attempt by the organism to conserve
energy by reducing metabolic expenditure
 starvation-associated alterations in thyroid function may represent appropriate
alterations reflecting maintenance of homeostasis

14. ALTERED THRYOID ECONOMY IN
STARVATION AND FASTING
 substantial decreases in serum total and free T3 are seen within 24 to 48 hours
 This is due to the down-regulation of peripheral 5’-deiodination of T4 to T3
 The increase in rT3 during fasting is mainly due to decreased metabolic clearance
of rT3 by 5’-deiodinase

15. ALTERED THRYOID ECONOMY IN
STARVATION AND FASTING
 total T4 concentration may change little
 free T4 levels most commonly remain unchanged or may show slight increases due
to fasting-induced elevations in plasma FFA which inhibit hormone protein binding
 Free T4 returns to normal within 2 weeks of continued fasting

16. ALTERED THRYOID ECONOMY IN
STARVATION AND FASTING
 total T4 may exhibit steady decreases corresponding to the fall in TBG seen with
prolonged minimal caloric intake
 Long-term caloric restriction in humans (range, 3–15 years) with adequate protein
intake is associated with a ‘‘chronic’’ low T3 syndrome

17. ALTERED THRYOID ECONOMY IN
STARVATION AND FASTING
 changes also occur centrally.
 Reduced thyroidal secretion of thyroid hormones is thought to be due in part to
suppression of TRH leading to decreased stimulation of TSH production
 TSH response to TRH is also blunted
 A key factor causing a fall in TRH expression is a rapid decrease in the hormone
leptin

18. ALTERED THRYOID ECONOMY IN
STARVATION AND FASTING
 Reduced carbohydrate intake causes decreased T3, increased rT3, and decreased
TBG levels
 Because 5’-deiodinase contains selenium, a relationship between selenium
deficiency and low T3 levels during fasting or nutritional deficiency had been
surmised
 Studies - low T3 levels not directly related to selenium deficiency

19. IN CRITICAL ILLNESS
 Plasma TSH transiently rises only in the first hours of critical illness, followed by a
transient increase in plasma T4
 plasma T3 concentrations may already be low and rT3 concentrations high due to
acute changes in peripheral thyroid hormone metabolism
 When patients require prolonged intensive care, plasma T3 concentrations remain
suppressed and accompanied by low plasma T4 and TSH concentrations
 This can be explained by reduced hypothalamic TRH expression

21. IN CRITICAL ILLNESS
 In prolonged critical illness, peripheral tissues appear to activate compensatory
mechanisms to restore T3 availability, for example by upregulating D2 activity
 Also, the thyroid hormone transporter monocarboxylate transporter 8 was found to
be upregulated in muscle and liver of prolonged critically ill patients

23. IN INFECTIOUS DISEASE
 involves central and peripheral mechanisms
 decreased TSH secretion from the pituitary, reduced thyroidal secretion of T4 and
T3, and impaired peripheral T4 to T3 conversion.
 These changes contribute to low T4, free T4, T3, and TSH and occur early in the
course of sepsis

24. IN INFECTIOUS DISEASE
 cytokines IL-1b, soluble IL-2 receptor, IL-6, tumor necrosis factor–a, and nuclear
factor kB have roles in the direct suppression of TSH in sepsis
 Nutritional deprivation during sepsis and severe illness also contributes

25. IN INFECTIOUS DISEASE
 In most patients with infections d/t HIV, T3, free T4, and TSH, remain normal unless
severe disease is present due to low CD4 cell counts
 Increases in TBG have been observed in the HIV population
 The mechanism might relate to altered TBG sialylation, which is known to decrease
TBG clearance as seen in pregnancy and other states of elevated serum estrogen
levels

26. IN CARDIAC DISEASE
 Alterations in TFTs are frequently observed with cardiac ischemia, congestive heart
failure, and after coronary artery bypass grafting.
 Decreased T3, increased rT3, and decreased TSH and T4 have been found in acute
MI and UA
 degree of T3 decrease and rT3 increase proportional to the severity of disease.

27. IN CARDIAC DISEASE
 The prevalence of NTIS in congestive heart failure is approximately 18%
 Deaths in heart failure patients who have NTIS are significantly more frequent than
in heart failure patients who have normal TFTs
 Low T3 has been prospectively shown to be an independent predictor of mortality
in hospitalized cardiac patients

28. IN RENAL DISEASE
 In nephrotic syndrome, T3 levels are decreased.
 This was thought to be due to loss of TBG in the urine along with other proteins
 however, TBG levels are normal in many patients who have nephrotic syndrome
and a preserved GFR but are decreased if the degree of proteinuria is high
secondary to a severely reduced GFR
 Serum rT3 levels are typically normal to low in nephrotic syndrome

29. IN RENAL DISEASE
 Free T4 and free T3 are typically normal in nephrotic syndrome
 thyroid hormone supplementation should be reserved for patients who have at
least mild TSH elevations as a consequence of large-scale proteinuria and excess
thyroid hormone wasting in the urine or with low serum free T4 in the setting of
glucocorticoid use.

30. IN RENAL DISEASE
 ESRD alters the HPT axis in addition to peripheral thyroid hormone metabolism
 ESRD leads to decreased total and free T3 because of reduced T4 to T3 conversion
 low free T3 has been prospectively shown to be an independent predictor of
mortality in hemodialysis patients

31. IN RENAL DISEASE
 A striking difference - absence of a coexisting increase in the conversion of T4 to
rT3 because rT3 levels are most commonly normal in ESRD
 although the clearance rate of serum rT3 is impaired in ESRD, there is redistribution
of rT3 from vascular to extravascular spaces and enhanced intracellular entry of rT3
 So there is no further increase in serum rT3 levels

32. IN RENAL DISEASE
 Total and free T4 are generally slightly decreased or normal
 free T4 may be increased in the setting of heparin used for anticoagulation during
hemodialysis because heparin is known to inhibit T4 binding
 Hemodialysis does not normalize the abnormal thyroid function parameters
observed in ESRD
 largely reversed after renal transplant.

33. IN HEPATIC DISEASE
 The most common TFT abnormalities in cirrhosis are low total T3, low free T3, and
elevated rT3.
 The plasma T3:rT3 ratio is inversely related to the severity of cirrhosis
 Free T4 may increase and total T4 may decrease secondary to changes in TBG and
albumin binding properties and concentrations.
 Although patients who have cirrhosis may have increased rather than normal TSH
levels typically seen in NTIS, they generally remain clinically euthyroid

34. IN HEPATIC DISEASE
 ACUTE HEPATITIS
 TFT differ markedly from those seen with other forms of liver disease and severe
illness.
 Increased TBG is released from the liver as an acute-phase reactant with
concomitant elevations in serum total T3 and total T4 levels.
 Free T4 and TSH are most commonly normal, but minimal elevations in rT3 and
reductions in free T3 may be observed

35. IN HEPATIC DISEASE
 chronic autoimmune hepatitis and primary biliary cirrhosis are chronic diseases
 their associated TFT abnormalities more closely parallel those of acute hepatitis
than those of cirrhosis.
 Similar to acute hepatitis, serum TBG levels are elevated, with an associated
increase in total T4 and T3
 In contrast to cirrhosis and acute hepatitis, free T4 and free T3 levels are more likely
to be low

36. EFFECT OF GLUCOCORTICOIDS
 Leads to acute suppression of TSH secretion, down-regulation of T4 to T3
conversion by 5’- deiodinase, and decrease of TBG concentration and hormone-
binding capacity
 Together, these alterations result in low TSH, low T3, low T4, and normal to slightly
low free T4
 these changes may be seen as soon as 24 to 36 hours after glucocorticoids are
initiated

37. EFFECT OF DOPAMINE
 Dopamine inhibits TSH secretion directly, depresses further the already abnormal
thyroid hormone production, and induces significant worsening of the low
hormone levels.
 Withdrawal of dopamine infusion is followed by a prompt dramatic elevation of
TSH, a rise in T4 and T3, and an increase of the T3/rT3 ratio.

38. EFFECT OF FUROSEMIDE
 Has effect at higher doses that may be used during hospitalization for aggressive
diuresis (ie, >80 mg intravenously)
 causes a transient elevation in free T4 and a decrease in T4 due to the
displacement of T4 from TBG

39. THYROID HORMONES IN TISSUES
 Tissue iodothyronine levels were positively correlated with serum levels, indicating
that the decrease in serum T3 during illness is associated with decreased levels of
tissue T3.
 Tissue rT3 and the T3/rT3 ratio were correlated with tissue deiodinase activities

40. MECHANISM OF THYROID HORMONE
SUPPRESSION IN NTIS
 the cause of NTIS is multifactorial and may differ in different groups of patients.
 decreased generation of T3 by type 1 iodothyronine deiodinase.
 selenium deficiency with malfunction of the selenium-dependent iodothyronine
deiodinase
 The overall daily metabolic consumption of thyroid hormone, both T4 and T3, is
radically diminished in NTIS syndrome in the presence of low hormone serum
levels.

41. MECHANISM OF THYROID HORMONE
SUPPRESSION IN NTIS
 Drop in TBG levels
 alteration in hypothalamic and pituitary function causes the low production of T4,
which in turn causes the low production of T3.
 stress-induced glucocorticoid elevation may be one factor affecting TRH and TSH
production.

42. MECHANISM OF THYROID HORMONE
SUPPRESSION IN NTIS
 augmented intrapituitary conversion of T4 to T3 allowed the pituitary gland to
remain “euthyroid” while the rest of the body was actually hypothyroid.
 So the pituitary production of TSH is diminished in the presence of low serum
thyroid hormone levels

43. OTHER FACTORS ALTERING SERUM T4
SUPPLY
 Altered CNS Metabolism
 reduced substrate or O2 supply to the CNS could induce hypothalamic/pituitary
dysfunction
 Glucagon
 stress-induced hyperglucagonemia may be a contributor to NTIS syndrome by
altering intracellular metabolism of T4

44. OTHER FACTORS ALTERING SERUM T4
SUPPLY
 ATRIAL NATRIURETIC PEPTIDES
 ANPs decreased circulating concentrations of total T4, free T4, and free T3, when
given to healthy humans for 60 minutes.

45. CLINICAL FEATURES
 the typical clinical parameters of severe hypothyroidism are absent in patients with
NTIS.
 these patients usually present with a serious illness and are diagnostically
challenging in view of their complicated state
 the common clinical picture of hypothyroidism does not develop within 2 to 3
weeks of complete thyroid hormone deprivation
 requires a much longer period for expression

46. DIAGNOSIS
 severely ill patient in whom there is no prior history suggestive of pituitary disease
 clinical findings of hypothyroidism are either absent or masked by other disorders
 a low T4, a low or normal TSH, and, if measured, a low T3.
 If T4 is below 4 μg/dL in this setting, the diagnosis of NTIS, associated with a
potentially fatal outcome, may be assumed

47. DIAGNOSIS
 An elevated TSH suggests the presence of prior hypothyroidism, which should be
treated.
 Finding positive antithyroid antibody titers supports the diagnosis of primary
hypothyroidism but does not prove it.
 Serum cortisol should be above 20 μg/dL, and commonly is above 30.
 If below 20, ACTH should be drawn, and the patient may be given supportive
cortisol therapy

48. TREATMENT
 The commonly held notion that patients who have nonthyroidal illness are
euthyroid continues to be debated
 there is no clear evidence that T4 or T3 treatment of NTIS in animals or man is
disadvantageous
 Also there is no certain proof that it is advantageous.
 In acute NTIS syndrome associated with operations, short-term treatment with T3
augments cardiac function, but has not been shown to alter the mortality.

49. TREATMENT
 Evidence suggests that T3 administration may exert negative effects on protein and
fat metabolism
 May adversely affect catecholamine levels and cause deleterious cardiac effects.
 Thyroid hormone replacement during fasting, in patients who have ESRD who are
on hemodialysis, and in burn victims has shown no beneficial effects.

50. TREATMENT
 among patients with NTIS, patients who are clearly hypothyroid—based on known
disease, treatment with dopamine, or elevated TSH—will need replacement therapy
 Treatment should include oral, or if this is impractical, intravenous T3
 75 mcg/day for 3 to 4 days to increase the body pool more rapidly, followed by
replacement doses at approximately 50 mcg/day given in divided doses.
 Also start replacement with T4

51. TREATMENT
 intravenous T3 administration is preferred over T4 due to reduced 5’-deiodinase
activity and hence decreased conversion of T4 to metabolically active T3 in the sick
patient
 Monitor T4 and T3 at frequent intervals (every 48 hours)
 dosages adjusted to achieve a serum T3 level at least low-normal (70 to 100 ng/dL)
prior to the next scheduled dose

52. TREATMENT
 T3 administration can gradually be reduced, and T4 administration can be
increased to replacement levels as deiodination increases
 giving TRH to stimulate TSH production and TH release, has been shown to be
effective in raising TH levels during short-term treatment.

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