The Retinol Circulating Complex Releases Hormonal Ligands During Acute Stress Disorders

Abstract

Intensive care workers actively participate in very hot debates aiming at defining the true metabolic, hormonal and nutritional requirements of critically ill patients, the contributory roles played by thyroid and retinoid ligands being largely underestimated. The present article makes up for redressing the balance on behalf of these last hormonal compounds. The retinol circulating complex is transported in the bloodstream in the form of a trimolecular edifice made up of transthyretin (TTR), retinol-binding protein (RBP) and its retinol ligand. TTR reflects the size of the lean body mass (LBM) and is one of the 3 carrier-proteins of thyroid hormones whereas RBP is the sole conveyor of retinol in human plasma. In acute inflammatory disorders, both TTR and RBP analytes experience abrupt cytokine-induced suppressed hepatic synthesis whose amplitude is dependent on the duration and severity of the inflammatory burden. The steep drop in TTR and RBP plasma values releases thyroxine and retinol ligands in their physiologically active forms, creating free pools estimated to be 10-20 times larger than those described in healthy subjects. The peak endocrine influence is reached on day 4 and the freed ligands undergo instant cellular overconsumption and urinary leakage of unmetabolized fractions. As a result of these transient hyperthyroid and hyperretinoid states, helpful stimulatory and/or inhibitory processes are set in motion, operating as second frontlines fine-tuning the impulses primarily initiated by cytokines. The data explain why preexisting protein malnutrition, as assessed by subnormal LBM and TTR values, impairs the development of appropriate recovery processes in critically ill patients. These findings have survival implications, emphasizing the need for more adapted therapeutic strategies in intensive care units.

Keywords: cytokines; immune responses; lean body mass; retinoids; retinol-binding protein; stress disorders; thyroid function; transthyretin.

Figure 1

Evolutionary patterns of LBM values throughout the human lifespan. Compilation of 7 different clinical investigations performed in healthy subjects from birth to very old age and showing body accretion TBK values determined by the measuremement of the naturally occuring radioisotope ⁴⁰ K using dual-energy X-ray absorptiometry (DXA). The results are plotted against age on double-logarithmic coordinates. Ninety-five percent of TBK is sequestered within metabolically active tissues and narrowly correlated with total body N (TBN), making this last parameter a valuable tool to appraise LBM values in health and disease (18). Figure shows that normal TBK concentrations are approximately 140–160 g in adult men and 90–110 g in adult women.

Figure 2

Evolutionary patterns of TTR concentrations throughout the human lifespan. TTR concentration are measured in the blood samples on 67,720 healthy US citizens using immunoturbidimetric analysis (19). TTR and LBM values manifest closely superimposable trajectories: Lowest values measured at birth, linear progression without sexual difference until the onset of puberty, occurrence of sexual dimorphism with more pronounced rise in adult males because of a large musculature, followed by plateau levels until the age of 60y, and finally gradual downsizing toward sacropenia in both sexes with a steeper slope observed in elderly males. Both TTR and LBM curves show comparable abrupt S-shape elevations from the onset of adolescence until the beginning of adulthood, which are here partially obliterated due to changes in the graduation of the abscissa scales.