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Euthyroid Sick Syndrome

Euthyroid sick syndrome occurs secondary to underlying acute or chronic severe non-thyroid illness in individuals with absolutely normal thyroid gland function. The levels of thyroid hormones T3 and T4 are significantly declined and the alteration is directly related to duration and severity of underlying illness. Recovery from the illness usually normalizes thyroid profile results within normal range without the need of a definite treatment. 


Presentation

NTIS possesses no characteristic clinical signs and symptoms as the syndrome is itself a manifestation of an underlying illness. The physical examination and laboratory data reveal findings specific to the disease the patient is suffering from. However, the clinical presentation of NTIS is differed in cases when thyroid dysfunction coincides with the syndrome since an obvious picture of definite hypothyroidism and hyperthyroidism manifests.

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Workup

Establishment of correct diagnosis requires clinical evaluation to assess abnormal thyroid function tests. If thyroid dysfunction is suspected, the diagnostic tests should be aimed at determining whether the patient is suffering from hypothyroidism or euthyroid sick syndrome. Tests specific for detecting thyroid abnormalities such as thyroid sonogram, thyroid uptake and scan, imaging and radiological studies are of no use as a diagnostic tool in patients solely suffering from NTIS.

In hypothyroidism, the TSH level is highly elevated with normal serum cortisol. On the contrary, TSH remains low or normal and cortisol levels are elevated in euthyroid sick syndrome. There is no need to suggest thyroid function tests in hospitalized, critically ill patients admitted in intensive care unit in the absence of thyroid dysfunction. As described previously, the levels of thyroid hormones vary with disease severity. In mild to moderate NTIS, T3 and TSH levels are reduced whereas T4 and free T4 lie within normal reference range limit. Severe NTIS is characterized by findings of reduced T3, T4 and TSH while the free T4 appears to be within normal range. 

Treatment

Treatment of euthyroid sick syndrome is aimed at correcting the underlying cause which in turn adjusts thyroid levels back to their normal range. Once the patient recovers from the primary illness, the hypothalamic-pituitary-thyroid function is restored without further pharmacological intervention. 

In a study conducted on determination of hypothalamic-pituitary-thyroid dysfunction in NTIS, De Groot suggested use of pituitary hormones, hypothalamic factors and thyroid hormones as replacement therapies to correct NTIS [12]. In another research, the use of thyroid hormone for treating NTIS was examined. Treatment with T4 administration was found to be of no value as the enzyme responsible for conversion of T4 to the active T3 (deiodinase) is often downregulated in NTIS [13]. The data for use of T3 for treating NTIS is still insufficient.  

Prognosis

The prognosis depends upon the stage rather than the type of the underlying disease and certainly worsens with advancement of disease severity. The reduction in levels of T3 and T4 directly correlate with the period of illness and disease severeness [7] [8]. Excessively lowered T4 levels along with duration of serious illness determine the ensuing risk of morbidity and mortality [9] [10] [11]. According to a study, the probability of death from NTIS is 50% when serum T4 levels are below 4mcg/dL and approaches to 80% when the T4 levels decline below 2mcg/L. On the contrary, the characteristic signs of euthyroid sick syndrome disappear readily following recovery from the underlying non-thyroidal disease. 

Etiology

As described above, presence of preexisting underlying disease or state of severe illness can mimic thyroid illness by altering serum thyroid levels in euthyroid patients. Disorders and disease conditions that have been found to precipitate euthyroid sick syndrome comprise myocardial infarction (MI), chronic renal failure, malignancy, thermal injury or hypothermia, pneumonia, cirrhosis, diabetic ketoacidosissepsis, bone marrow transplantation, conditions of severe starvation such as anorexia nervosa, severe stress such as major trauma and any form of acute or chronic severe illness. Certain drugs also alter thyroid levels and indicate false positive hypothyroidism. Once the drugs are discontinued, the serum T3 and T4 levels regress to their normal range. 

Epidemiology

Euthyroid sick syndrome can affect people of any race and possesses no gender predominance. There are no age restrictions of the syndrome but elderly patients suffering from chronic illnesses are more prone to develop alterations in thyroid function tests. NTIS, being a typical endocrine condition, possesses an incidence rate of 70% among hospital inpatients and 10% in patients who have been reported to be hospitalized with lowered TSH levels. It has been estimated that serum levels of T3 are reduced by 40%-100% in patients with euthyroid sick syndrome with further decrease in T4 levels in severe illnesses [5].

Sex distribution
Age distribution

Pathophysiology

Several pathophysiological pathways are presumed to be responsible for modifications in pituitary-thyroid function and altered T3 and T4 levels. The levels of thyroid hormones are reduced in both serum and at tissue level with indication of false tissue hypothyroidism

The pathophysiological hormonal changes that precipitate NTIS include suppressed TRH release, reduced generation of T3 from the liver, reduced formation of T3 from T4, decreased clearance and increased formation of rT3, alteration in binding of thyroid hormones to thyroid binding proteins and reduced activation of T3 due to inhibition of intracellular iodothyronine deiodinases and downregulation of thyroid hormone receptors (THR). These findings vary with underlying disease conditions since every disease carries specific alteration patterns in metabolic and immunologic function, which in turn affect hormone levels. At gene level, reduction in TR expression and DNA binding may also contribute in altering thyroid gland physiology. 

The exact mechanism of NTIS development largely remains unclear but proinflammatory cytokines have been suspected to be involved in the pathogenesis of the syndrome. One such cytokine, tumor necrosis factor-a (TNF-a), is thought to be responsible for pathophysiological modification in euthyroid sick syndrome. Therefore, augmentation in production and release of cytokines may contribute in developing NTIS, however, sufficient scientific evidence is still needed to endorse this theory [6].

Prevention

Managing the underlying illness so that the patient has completely recovered from NTIS will itself correct the endocrinal dysfunction and the altered serum thyroid hormone levels [14].

Summary

Euthyroid sick syndrome, also referred to as "non-thyroidal illness syndrome" (NTIS) [1] and "low T3 syndrome" is an abnormal reversible finding of serum thyroid hormones on thyroid functions tests in critically ill, euthyroid patients [2]. The condition is characterized by presence of a non-thyroidal illness without endocrine dysfunction at the level of the hypothalamic-pituitary axis and thyroid gland and results in alterations in serum levels of thyroid hormones. Typically, the levels of serum triiodothyronine (T3) and free triiodothyronine (FT3) drop in mild NTIS but thyroxine (T4), free thyroxine (FT4), and thyrotropin (TSH) levels are also altered in prolonged, severe illness. Numerous underlying disease conditions and potentially any kind of severe stress or illness (acute or chronic) can alter serum levels of thyroid hormones [3] [4]. The exact pathogenetic mechanism of NTIS is not fully known yet. However, the proposed causes linked to the development of euthyroid sick syndrome include inhibition of secretion of thyroid releasing hormone (TRH) and thyroid stimulating hormones (TSH), inhibition of transport of iodothyronines through plasma membrane, inhibition or downregulation of deiodinase enzymes, decrease in levels of thyroid binding globulin (TRBs) and over production and release of inflammatory cytokines. 

Diagnosis of euthyroid sick syndrome requires ruling out the presence of hypothyroidism by comparing levels of thyroid hormone and cortisol. Physical examination of the thyroid gland typically reveals a completely normal assessment. If treated well, NTIS shows good clinical outcome. Treatment is aimed at curing the underlying illness because the thyroid profile normalizes as soon as the patient recovers from that. Use of thyroid hormones to treat NTIS is not suggested. In cases where the underlying disease becomes severe and is not treated adequately, the condition worsens with further decline in serum thyroid hormone levels. NTIS possesses a high mortality rate in severe, uncontrolled underlying illness as the thyroid profile fails to normalize with disease progression.

Patient Information

As the name indicates, euthyroid sick syndrome is a condition characterized by abnormal levels of thyroid hormones on thyroid profile tests in patients with normal functioning thyroid gland. The syndrome is synonymously known as "non-thyroidal illness syndrome" (NTIS) and "low T3 syndrome". It can occur in people of all races, all age groups and all genders. NTIS normally manifests in response to an underlying illness (which can be acute or chronically severe), severe stress, surgery or during prolonged fasting and starvation. Certain disease conditions found to be associated to the development of NTIS are myocardial infarction (MI), chronic renal failure, malignancy, thermal injury or hypothermia, pneumonia, cirrhosis, diabetic ketoacidosis, sepsis, bone marrow transplantation and anorexia nervosa. Since the elderly people often suffer from various forms of severe illnesses, they are more vulnerable to develop euthyroid sick syndrome.

NTIS is characterized by abnormally low levels of tryiodothyronine (T3), which is the active form of thyroid hormone. The levels of T3 are significantly reduced by 40%-100% in such cases. In later stages, the levels of tetraiodothyronine (T4) hormone, thyroid releasing hormone (TRH) and thyroid stimulating hormone (TSH) are also altered. In more complex cases, the biological enzyme deiodinase, which is responsible for the active conversion of T4 to T3, is also inhibited. Levels of several other important serum markers of hypothalamic-pituitary-thyroid axis are disturbed in NTIS.

There are no specific signs and symptoms of the NTIS as the syndrome does not present clinically. In most cases, the signs and symptoms will be those of  the underlying illness. In certain cases where the patient suffers from both NTIS and thyroid disease, expert physical assessment is needed to establish correct diagnosis and design appropriate treatment regimen. In patients suffering solely from NTIS, the thyroid gland appears normal on physical examination but thyroid levels show altered values upon laboratory investigation.  

NTIS shows a good outcome if its underlying cause is treated accordingly. Patients easily recover with indication of normal thyroid hormone levels. However, if the non-thyroid illness persists and becomes severe overtime, the patient's condition worsens and death may occur. 

Management and treatment require curing the underlying disease condition. The use of thyroid hormones to treat NTIS is still under investigation. 

References

Article

  1. Chopra IJ. Nonthyroidal illness syndrome or euthyroid sick syndrome? Endocr Pract. 1996;2(1):45-52.
  2. Pappa TA, Vagenakis AG, Alevizaki M. The nonthyroidal illness syndrome in the non-critically ill patient. Eur J Clin Invest. 2011;41(2):212-220.
  3. Chopra IJ. Euthyroid sick syndrome: Abnormalities in circulating thyroid hormones and thyroid hormone physiology in nonthyroid illness (NTI) Med. Grand Rounds. 1982;1:201–212.
  4. Wartofsky L, Burman KD. Alterations in thyroid function in patients with systemic illness: the "euthyroid sick syndrome". Endocr Rev. 1982 Spring;3(2):164-217.
  5. Larsen P. R., Davies T. F., Schlumberger M. J., Hay I. A. (2008). “Thyroid Physiology and diagnostic evaluation of patients with thyroid disorders,” In: Williams Textbook of Endocrinology, eds Kronenberg H. M., Melmed S., Polonsky K. S., Larsen P. R., editors. (Philadelphia, PA: Saunders Elsevier; ), 499–442.
  6. The NHS in Scotland. Laboratory statistics 1999. Edinburg: Information and Statistics Division, 1999.
  7. Rasmussen AK. Cytokine actions on the thyroid gland. Dan Med Bull 2000;47:94-114.
  8. Wehmann RE, Gregerman RI, Burns WH, et al: Suppression of thyrotropin in the low-thyroxine state of severe nonthyroidal illness. N Engl J Med 1985;312:546-552
  9. Slag MF, Morley JE, Elson MK, et al: Hypothyroxinemia in critically ill patients as a predictor of high mortality. JAMA 1981;245:43-45
  10. Coceani M, Iervasi G, Pingitore A, et al. Thyroid hormone and coronary artery disease: from clinical correlations to prognostic implications. Clin Cardiol. 2009;32(7):380-5.
  11. Tognini S, Marchini F, Dardano A, et al. Non-thyroidal illness syndrome and short-term survival in a hospitalised older population. Age Ageing. 2010;39(1):46-50.
  12. Bello G, Pennisi MA, Montini L, et al. Nonthyroidal illness syndrome and prolonged mechanical ventilation in patients admitted to the ICU. Chest. 2009;135(6):1448-1454.
  13. De Groot LJ. Non-thyroidal illness syndrome is a manifestation of hypothalamic-pituitary dysfunction, and in view of current evidence, should be treated with appropriate replacement therapies. Crit Care Clin. 2006;22(1):57-86, vi
  14. Kaplan MM. Thyroid hormone therapy. What, when and how much. Postgrad Med 1993;93:249-252

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Last updated: 2018-06-21 23:30