Thyroid function in critically ill patients

Abstract

Patients in the intensive care unit (ICU) typically present with decreased concentrations of plasma tri-iodothyronine, low thyroxine, and normal range or slightly decreased concentration of thyroid-stimulating hormone. This ensemble of changes is collectively known as non-thyroidal illness syndrome (NTIS). The extent of NTIS is associated with prognosis, but no proof exists for causality of this association. Initially, NTIS is a consequence of the acute phase response to systemic illness and macronutrient restriction, which might be beneficial. Pathogenesis of NTIS in long-term critical illness is more complex and includes suppression of hypothalamic thyrotropin-releasing hormone, accounting for persistently reduced secretion of thyroid-stimulating hormone despite low plasma thyroid hormone. In some cases distinguishing between NTIS and severe hypothyroidism, which is a rare primary cause for admission to the ICU, can be difficult. Infusion of hypothalamic-releasing factors can reactivate the thyroid axis in patients with NTIS, inducing an anabolic response. Whether this approach has a clinical benefit in terms of outcome is unknown. In this Series paper, we discuss diagnostic aspects, pathogenesis, and implications of NTIS as well as its distinction from severe, primary thyroid disorders in patients in the ICU.

Figure 1. Schematic representation of hypothalamic thyroid hormone signalling during inflammation

Inflammation activates the NFκB pathway in tanycytes, specialised cells lining the third ventricle. Tanycytes express D2, the main T₃ producing enzyme in the brain, the promoter of which contains NFκB responsive elements. Binding of NFκB increases D2 expression and activity, and this stimulates the conversion of T₄ into T₃. T₃ will enter adjacent neurons and bind to neuronal TRβ thereby regulating transcriptional activity of TRH. T₃=tri-iodothyronine. TRβ=thyroid hormone receptor β. TRH=thyrotropin-releasing hormone. NFκB=nuclear factor kappa-light-chain-enhancer of activated B cells. D2=deiodinase type 2. T₄=thyroxine.

Figure 2. Schematic representation of cellular thyroid hormone metabolism

Cellular entry of thyroid hormones is necessary for intracellular conversion and for T₃ to exerts its actions in the nucleus. Two categories of thyroid hormone transporters have been noted: the organic anion transporters and the aminoacid transporters.^,– Once transported into the cell, thyroid hormones (T₄ and T₃) can be metabolised by outer or inner ring deiodination through the iodothyronine deiodinases. These enzymes belong to a selenocysteine containing enzyme family and comprise three types; type 1 (D1), 2 (D2), and type 3 (D3). D1 is able to deiodinate the inner ring and outer rings of T4 as well as the outer ring of rT3. D1 is expressed in the liver, kidney, thyroid, and pituitary and localised in the plasma membrane.^, D2 is localised in the endoplasmic reticulum and deiodinates T₄ into the biologically active T₃. D2 is the main enzyme involved in the production of tissue T₃ and therefore heavily involved in local thyroid hormone metabolism.^, D3 is localised in the plasma membrane and can be viewed as the major thyroid hormone inactivating enzyme, as it catalyses inner-ring deiodination of both T₄ and T₃, exclusively resulting in the production of biologically inactive rT₃ and rT₂, respectively. The balance between D2 and D3 determines the availability of cellular T₃, which enters the nucleus and binds to the nuclear receptor complex (RXR and TR). T₃ exerts its nuclear actions via the RXR and TR complex that binds to thyroid hormone response elements in target genes. TR complex regulates transcriptional activity of T₃-target genes. TR=thyroid hormone receptor. T₃=tri-iodothyronine. T₄=thyroxine. rT₃=reverse T₃. rT₄=reverse T₄. RXR=retinoid-X receptor. TRE=thyroid hormone response elements.

Figure 3. Simplified overview of various reported differential effects of NTIS on deiodinase activities in various tissues

Deiodinase effects probably induce interorgan differences in T₃ bioavailability in the presence of similarly decreased plasma concentrations of T₃. T₃=tri-iodothyronine. D1=deiodinase type 1. D2=deiodinase type 2. D3=deiodinase type 3.

Figure 4. Schematic representation of the effect of parenteral nutrition during NTIS

Critical illness-induced NTIS is characterised by low circulating T₃ and raised concentration of rT₃. Low hypothalamic TRH mRNA expression, low circulating TSH, and low T₄ are also reported during NTIS. When early, full parenteral support is used to resolve the caloric deficit, the peripheral changes in the thyroid axis partly normalise, but its central suppression does not. Solid arrows represent direction of change in concentration or activity. = represents normalisation of concentrations. NTIS=non-thyroidal illness syndrome. TRH=thyrotropin-releasing hormone. TSH=thyroid-stimulating hormone. T₄=thyroxine. T₃=tri-iodothyronine. rT₃=reverse T₃.

Figure 5. Schematic representation of the various changes during critical illness

The scheme is based on both experimental investigations and studies with people. The net result of altered tissue thyroid hormone metabolism could be beneficial or maladaptive, dependent on disease duration and severity. TH=thyroid hormone. T₃=tri-iodothyronine. Solid lines represent a causal association. Dashed lines represent a probable effect.