Non-thyroidal illness syndrome (NTIS or euthyroid sick syndrome) is a complex endocrine condition that may occur in critically ill patients. It is associated with significant deterioration of prognosis.
NTIS is characterised by three components that may occur single or in combination:central hypothyroidism (transient thyrotropic insufficiency), impaired protein binding of thyroid hormones and reduced formation of T3 with simultaneously increased conversion to rT3 (low-T3-syndrome) [1
In 1973, characteristic alterations of thyroid metabolism have been first described in the starving organism [3
]. Additional observations could reveal that these alterations are also common in critically ill patients where they form the correlate of endocrine dysregulation with increased morbidity and mortality [5
However, explanation concepts for this complex constellation are different. Up to now, in essence five hypotheses are discussed in literature [2
1. All observed abnormalities are the result of test artefacts. In reality, the patients are euthyroid.
2. The changes in the levels of peripheral thyroid hormones mirror the effect of certain binding inhibitors that influence
A) laboratory results only or
B) also the transfer of thyroid hormones into the tissue of diseased persons and thus diminish binding of iodothyronines to T3 receptors.
3. Due to increased local deiodation, T3-levels are normal in the pituitary gland while they are low in the rest of the organism.
4. Levels of peripheral thyroid hormones are actually low so that affected patients are biochemically hypothyroid. However, this useful physiological function should not be manipulated.
5. NTIS is secondary or tertiary hypothyroidism. The resulting tissue hypothyroidism should be treated with appropriate substitution therapy [2
Despite of intensive and long lasting research to many of its details NTIS is still poorly characterized in an integrative view. Additionally, a clinically usable classification is lacking.
Given the fact that patients with NTIS are faced with poor prognosis, several studies have been conducted in the past evaluating the question of possible treatment [2
]. However, they did not yield unambiguous results. Some studies could show a benefit of substitution therapy with thyroid hormones, e.g. regarding the incidence of atrial fibrillation [2
] and hemodynamic parameters [11
] while others could not observe relevant differences in outcome between treated and untreated patients [13
]. Several studies even described detrimental effects of substitution therapy ranging from increased risk of hyperthyroidism [16
] over undesirably high protein catabolism [18
] to severe side effects in patients with adrenal insufficiency that may be difficult to identify during critical illness [19
]. Recently, a small trial investigating the effect of selenium substitution on the development of critically ill patients demonstrated improvements in prognosis, but, in spite of the known selenium-dependency of peripheral deiodinases, this outcome was not caused by a direct effect on thyroid homeostasis [20
The problem of inconclusive and partly contradictory study results is aggravated by the fact that there is no consistent definition of NTIS that delimits this constellation from euthyroid state and that weighs the associated components regarding their relevance. Therefore, it may be assumed that the mentioned studies compared inhomogeneous patient groups.
An additional challenge affecting clinical practice is the fact that partial thyrotropic insufficiency in the course of NTIS can hardly be distinguished from latent ("subclinical") hyperthyroidism – although pathophysiology and therapeutic implications are opposed.
Objectives of the AQUA FONTIS project
The AQUA FONTIS study (approach to a quantitative follow-up of non-thyroidal illness syndrome) is primarily intended to develop a clear-cut definition and classification of NTIS (Table ). Overall, this project is proposed to deliver a prognostic aid by providing a differentiated classification, to contribute to a standardised, rational and inexpensive diagnostic procedure in form of quantitative indices, and to lay the foundation for future therapeutic trials by identifying subgroups that may benefit from therapy.
Proposed "HPD" classification
Outcome measure of this primary objective is the comparison of different decision criteria as presented in Table . These criteria are assessed with regard to the prognosis of the patients. Additionally, the significance of an innovative physiological index approach (SPINA) [21
] is to be evaluated regarding its applicability for differential diagnosis between NTIS and latent thyrotoxicosis. It will therefore be evaluated in terms of sensitivity, specificity and likelihood ratios with ROC analysis.
As secondary objective, we plan to observe variables that quantify distinct components of NTIS in the context of independent predictors of evolution, survival or pathophysiological condition as well as influencing or disturbing factors like medication or medical procedures. Outcome measures are correlations between quantitatively described components and external factors as well as their distributions in the context of dichotomic influencing factors.