Non-thyroidal Illness Syndrome: where do we stand?

Dr. Hemanta Kumar Gogoi

Sometimes diseases unrelated to the thyroid gland may influence the functions of the gland and thereby have great consequence on the wellbeing of the individuals. These individuals would have abnormal thyroid function tests without evidence of preexisting hypothalamic-pituitary or thyroid dysfunction which returns to normal after recovery from the illness. This condition is known as Nonthyroidal Illness Syndrome (NTIS) or Euthyroid Sick Syndrome (ESS) or low T3 Syndrome.

 Salient features of the syndrome are:

·       Develop during the course of an acute, severe illness in the absence underlying thyroid disease.

·       Low serum triiodothyronine (T3)

·       Normal to low thyroxine (T4)

·       High reverse T3 (rT3).

·       There may be mild increase or decrease in TSH level.

This peculiar condition has drawn up many controversies and researches among the medical fraternity. Many questions remain unanswered as to whether thyroid hormone replacement is beneficial or harmful to treat the condition; whether it is a defensive mechanism of the body to conserve energy during illness?

Pathophysiology:

What actually happens during acute or chronic illness to the thyroid? It has been found that during severe illness there is disruption of thyroid hormone profile like low T3, low T4 and low TSH during severe illness pointing towards down-regulation of the hypothalamic-pituitary-thyroid (HPT) axis.  The changes may take place in the level of the hypothalamus, pituitary and thyroid gland to produce the final clinical picture.

1.     Role of hypothalamus:

·       No definite role of thyroid hormone transporters has been established in NTIS.

·       There are altered deiodinase expressions which are responsible for metabolism of thyroid hormones. There is increased expression of D2 in both acute and chronic illness.  Expression of D3 decreases in both acute and chronic inflammation.

·       The role thyroid receptors (TR) have not been well established in NTIS.

·       Hypothalamic up-regulation of D2 and down-regulation of D3 which results in increased local production of T3 leads to decreased TRH mRNA in illness.

2.     Role of pituitary:

·       No definite action of thyroid hormone transporters during NTIS has been reported.

·       There is down-regulation of pituitary TSHβ during illness due to increased D2 expression with increased T3 production.

·       Acute inflammation decreases TRβ2 mRNA expression in the pituitary.

·       There is altered negative physiological feedback mechanism of the HPT axis during NTIS whereby the pituitary becomes unresponsive to low thyroid hormone levels.

3.      The thyroid hormones:

Triiodothyronine:

About 30-40% of circulating T4 is converted to the active form T3 by the enzyme 5’-deiodinase which form 80-90% of T3, the rest 10-20% being secreted by the thyroid directly. In NTIS there is inhibition of 5’-deiodinase resulting in low conversion of T4 to T3 and there by low serum T3. Drugs like iodine, amiodarone, corticosteroid administered in the hospital setting ; free non-esterified fatty acids, cytokines like tumor necrosis factor, interferon-alpha, NF-kB and interlukin-6 , also reduce conversion of T4 to T3 (Economidou et al 2011).

 Serum reverse triiodothyronine (rT3):

Another hallmark of NTIS is increased rT3 which occurs through the ‘inactivating pathways’. The conversion of rT3 from diiodothyronine (T2) is reduced due to inhibition of 5’-monodeiodinase activity.   

Thyroxine (T4):

Thyroxine levels may be increased or decreased in NTIS according to the disease condition. But initially there is a decreased T4 level due to decreased binding to the carrier proteins like Thyroid hormone binding globulin (TBG), transthyretin (TTR), or thyroxine-binding pre-albumin and albumin (Afandi et al 2000).

Many drugs which compete with thyroid hormones for binding with TBG may reduce total T4 and increased free T4 levels in blood. Drugs like salicylates, phenytoin, carbamazapine, furosamide, etc. increase plasma clearance of T4. In prolonged illness, suppression of the hypothalamic-pituitary axis may lead to decreased TSH, low T4 and low free T4, which are of grave prognostic consequence.

Thyrotropin (TSH):

Most of the patients have normal TSH level (so called Euthyroid) but have decreased level during prolonged illness. Interestingly, abnormal thyroid function tests with normal or raised TSH and raised T4 have been reported in psychiatric illness as well (Premachandra et al 2006). Low TSH is found in very prolonged illness only.

4.      Altered thyroid functions during various clinical conditions:

·       Starvation and fasting:

There is down-regulation of the hypothalamic- pituitary-thyroid axis leading to decreased production of thyroid hormone. This has been postulated to be body’s defense mechanism to conserve energy. There is decreased total and free T3. Increased free fatty acids during fasting causes reduced plasma binding and thereby increase in T4 levels in some cases initially. Fasting also reduces leptin levels causing decreased expression of TRH or decreased response of TSH to TRH.

In the fasting rabbit models replacement of parenteral glucose has been found to increase the T3 levels in critically ill rabbits (Mebis et al 2012).

·       Infectious diseases and sepsis:

There is decreased TSH secretion from the pituitary, reduced T4 and T3 secretion from the thyroid as well as reduced peripheral conversion of T4 to T3. Cytokines like IL-1β, soluble IL-2 receptor, IL-6, TNF-α, and nuclear factor κB may suppress TSH in sepsis.

·       Systemic diseases and drugs:

NTIS like thyroid features are also observed in patient with cardiovascular events, hepatic and renal diseases.  Many drugs likewise may affect hypothalamus-pituitary-thyroid axis to produce a picture similar to NTIS and must be taken into consideration while diagnosing and treating such cases.

Laboratory Diagnosis:

Is testing a thyroid profile indicated in all critically ill patients?  It should be undertaken when seriously suspected.

·       Sensitive serum TSH estimating methods which can detect TSH <0.01 mIU/L should be used.

·       Measurement of TSH alone is not sufficient.

·       Clinical interpretation should be made on critical analysis of the thyroid function test which includes TSH, total and free thyroid hormone and rT3 levels.

·       Interpretation should be made from history of illness as well as drug history.

Is thyroid hormone replacement indicated in Non-thyroidal Illness?

It remains a controversial subject on the utility of thyroid hormone replacement in Nonthyroidal illness syndrome as it has been not been found to be very useful or rather harmful in body’s adaptive changes to conserve energy especially in the fasting state.  It has been showed that proper nutrition replacement corrects the circulating thyroid hormone imbalance (ENDO 2010). A combination of thyrotropin-releasing hormone (TRH) plus growth-hormone releasing peptide (GHRP) may provide benefits in prolonged, critically ill patients; more so, when associated malnutrition is adequately corrected.  

Conclusion:

Euthyroid Sick Syndrome or Nonthyroidal Illness Syndrome may occur in patients who are critically ill or malnourished and needs proper diagnosis and management. The underlying causes must be delineated first and treated accordingly. Offending drugs are to be stopped and supportive measures to improve under nourishment. Thyroid hormone replacement must be considered with caution although TRH plus GHRP may be considered in selected cases.

Ref:

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2.     Afandi B, Vera R, Schussler GC, Yap MG. Concordant decreases of thyroxine and throxinebinding protein concentrations during sepsis. Metabolism (2000); 49:753-754

3.     Boelen A, Kwakkel J, Fliers E.  Beyond Low Plasma T3: Local Thyroid Hormone Metabolism during Inflammation and Infection. Endocrine Reviews 32: 670-693, 2011

4.     Economido F, Douka E, Tzanela M, Nanas S, Kotanodou A. Thyroid function during critical illness. Hormones 2011, 10(2):117-124

5.     Mebis L, Eerdekens A, Guiza F, Princen L, Derde S, Vanwijingaerden YM, Vanhorebeek I, Darras VM, Van de Berghe G, Langouche L. Contribution of Nutritional deficit to the pathogenesis of Nonthyroidal illness syndrome in critical illness: A rabbit model study. Endocrinology 153: 973-984, 2012

6.     Premachandra BN, Kabir MA, Williams IK. Low T3 syndrome in psychiatric depression. Journal of endocrinological Investigations 2006 (29); 568-572

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8.     Van de Verghe G, Kaptain E. Is thyroid hormone therapy indicated for sick Euthyroid syndrome? From ENDO 2010 The Endocrine Society Annual Meeting, San Diego, June 19-22, 2010  available at http://www.gghjournal.com/volume26/1/ab13.cfm accessed  on 3/2/2013

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