How are TSH and TRH measured in euthyroid sick syndrome?

Updated: Apr 27, 2017
  • Author: Serhat Aytug, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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Serum TSH is measured with immunometric assays. In describing a serum TSH assay, referring to its sensitivity in µU/L is preferable to using terms such as ultrasensitive or supersensitive.

Immunometric assays in general perform well, but the sensitivity of the same commercial kit assay in different laboratories can vary substantially. In this method, 2 monoclonal antibodies are used, between which TSH becomes "sandwiched." Usually, the antibody to which TSH first is bound is immobilized on a solid surface. After separation of the solid phase, the bound TSH is quantified with a second anti-TSH antibody labeled with iodine-125, an enzyme, a fluorescent probe, or a chemiluminescent tag. In general, the assays using a chemiluminescent principle seem to perform best. Serum TSH in NTI typically is within the reference range or reduced. Serum TSH may be markedly low, although it usually is not less than 0.05 µIU/mL. These low TSH levels are often observed without significant decrease in T4.

Some patients with NTI have slightly elevated serum TSH, which is thought to have reduced biological activity. After recovery from severe NTI, transient elevation of TSH to above-normal limits commonly occurs. Some authors interpret this TSH elevation as a sign of recovery from a hypothyroid state. Despite the distortion of TSH in some euthyroid patients with NTI, patients with NTI who have significant elevation of TSH usually have underlying primary hypothyroidism.

Inappropriately low levels of serum hormones T3 and T4 and low TSH response suggest central down-regulation of the hypothalamic-pituitary-thyroid axis. This is supported by the observation that TRH gene expression in the paraventricular nucleus of the hypothalamus in postmortem hypothalamic tissue of patients who died after prolonged illness was less than in patients who died of acute cardiac arrest. In addition, TRH mRNA expression in the paraventricular nucleus correlates positively with premortem serum TSH and T3 levels. [13]

Responsiveness of the pituitary to TRH during NTI varies; some patients respond normally, while many have a less-than-normal response. Normal responsiveness in the presence of low TSH may suggest that a hypothalamic abnormality is causing the low TSH and low T4. The down-regulation at the hypothalamus-pituitary level provides an explanation for the decreased sensitivity of TSH secretion to low serum T3 and T4 concentrations in patients with NTI. A diminution, or loss, of the diurnal rhythm of TSH also occurs, and some studies have produced evidence for a reduction of TSH glycosylation with lower TSH bioactivity.

That TSH is not elevated in the presence of low T4 indicates that the patients are not hypothyroid. Diminished release of TRH also is thought perhaps to result in low TSH and, thus, low output of thyroid hormones by the thyroid. Low TRH mRNA in hypothalamic paraventricular nuclei also has been demonstrated.

The role of cytokines, especially IL-1 beta, in the activity of the hypothalamic-pituitary-adrenal axis is well known. Cytokines also affect TRH in rats. IL-1 beta decreases the release of TSH in cultured rat anterior pituitary cells, but the role of TNF-alpha on TSH release is disputed. IL-6 decreases TSH secretion. In rodents, leptin has been demonstrated as a major mediator of changes in hypothalamic-pituitary-thyroid function during fasting. However, TSH secretion and thyroid gland function are less affected during NTI in humans than they are in animals. The role of leptin in patients with NTI is unclear. Leptin concentrations often are elevated during critical illness and increase acutely in response to administration of TNF-alpha or IL-1; however, the leptin increase is not related to changes in serum T3 and T4 concentrations.

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