Topic: NON-THYROIDAL ILLNESS SYNDROME
Title: Frequency and outcome of patients with non-thyroidal illness syndrome in a medical intensive care unit
Reference: Metabolism 56: 239-244, 2007
Acute and chronic critical conditions are associated with reduced serum levels of free triiodothyronine (FT 3 ), free thyroxine (FT 4 ), and thyrotropin (TSH), known as non-thyroidal illness syndrome (NTIS). It is still controversial whether these changes reflect a protective mechanism or a maladaptive process during prolonged illness.
The present study was designed to determine the prevalence of NTIS and its association with outcome in a medical intensive care unit (ICU). Thyroid hormone levels were available for 247 of 743 patients admitted to the author-s ICU between October 2002 and February 2004, and this cohort was evaluated retrospectively. Acute Physiology and Chronic Health II scores, ICU mortality, length of stay, mechanical ventilation, and concomitant medication were recorded. Patients (N = 27) on T 4 or receiving antithyroid drugs were excluded from the final study group.
On blood samples drawn within 48 hours of admission, only 36% of the group had normal thyroid laboratory values for TSH, FT 3 , and FT 4 . Ninety-seven of the 220 patients (44.1%) had low FT 3 levels indicating a NTIS, either with normal (23.6%) or reduced (20.5%) serum TSH levels. Of 97 patients with NTIS, 24 (23.3%) also showed reduced serum FT 4 levels. One patient manifested an elevated FT 3 with low TSH and was clinically hyperthyroid, and 6 patients had evidence of hypothyroidism. NTIS was significantly positively associated with Acute Physiology and Chronic Health II scores, mortality, length of stay in the ICU, and mechanical ventilation. Patients with both low FT 3 and low FT 4 had a mortality rate of 45.9%, much greater than for euthyroid patients (P < 0.001).
In a multivariate Cox regression analysis, the combination of low FT 3 and low FT 4 was an independent increased risk factor for death. Non-thyroidal illness syndrome is frequent at a medical ICU. A reduction of FT 4 together with FT 3 is associated with an increase in mortality and might reflect a maladaptive process, thereby worsening the disease.
This study is hardly unique. Rather, it once again clearly demonstrates the depressed thyroid hormone levels (and often TSH) found in severely ill patients in every ICU. It also re-demonstrates the association of low thyroid hormone levels with adverse clinical outcome or, to be more specific, with death.
After being recognized first as a clinical entity in 1975 by Jack Oppenheimer and colleagues, several explanations were advanced for the apparently low thyroid hormone levels. One view was that the tests were simply a test artifact, and that euthyroidism would be evident if proper testing was carried out. A popular view, and one that has dominated thinking during the intervening 30 years, is that thyroid hormone changes are a -compensatory- change in the face of severe illness. In this construct the low hormone levels do not necessarily represent real hypothyroidism, are a beneficial adaptation, and should not be treated. There is, however, not a single piece of evidence that proves this view to be correct.
In the intervening years solid evidence has documented a decrease in TSH message in the pituitary of patients dying during NTIS, the low TSH, FT3 and FT4 (still some controversy here), the direct relation between these low hormone levels and the possibility of death, and the greatly diminished daily turnover of T3 & T4. These data have provided the basis for an alternate hypothesis, namely that NTIS represents failing adaptation of the endocrine system during prolonged severe illness which should be treated by hormone replacement. Only a few prospective randomized trials have been published, and the results have not so far proven the benefits of treatment, or that treatment worsens the clinical situation. Administration of l-T4 raised serum T4 levels immediately, proving that the problem was not as simple as a low TBG level, but, not surprisingly, failed to elevate serum T3 levels to normal within two weeks. Administration of supra-physiologic doses of l-T3 did not improve survival of seriously ill burn victims, in the one study available (references can be found in the bibliography of the paper under discussion).
More recently, Greet Van den Berghe and colleagues have carried out a remarkable series of studies on patients in ICU, and on animal models of the illness. Their results fit the hypothesis that, in prolonged severe illness, NTIS is at least in part a manifestation of a suppressed hypothalamic-pituitary function and represents true hypothyroidism. This group has demonstrated improved thyroid hormone levels following combined TRH/GHRH administration, and has supported this approach to replacement therapy. To date, large scale clinical studies using this treatment are not available.
Although extremely difficult and demanding, considering the up to 80% mortality associated with NTIS in the ICU, more clinical trials are urgently needed. Many strong positions on the cause of NTIS have been expressed, but the controversy on whether treatment (in some form) is good, or bad, or indifferent, will only be solved by further research. ( Summary and commentary prepared by Leslie DeGroot ) Present summary and commentary are related to Chapter N- 5b of TDM