Transthyretin (Prealbumin) in Health and Disease: Nutritional Implications

Abstract

The name "transthyretin" reflects the dual physiological roles of this tetrameric unglycosylated plasma protein. TTR is one of three specific carrier proteins involved in the transport of both thyroid hormones and of retinol through the mediation of RBP. TTR is a product of the visceral compartment, and its hepatic synthesis is exquisititely sensitive to both the adequacy and levels of protein and energy intakes--hence the proposal of TTR as a nutritional marker. To date, 38 TTR variants have been described, most of which are associated with variable degrees of cardiac and/or neural tissue amyloid deposits. All known variants arise from a single AA substitution due to single point mutation in the coding region of the TTR gene. Under acute stress conditions, the synthesis of TTR, RBP, and CBG is abruptly depressed by a cytokine-directed orchestration of new metabolic priorities, with a redistribution of organ and tissue protein pools. It is proposed that TTR, RBP, and CBG behave as acute-booster reactants (ABRs), actively participating in the cascade of metabolic events characterizing the stress reaction along pathways best explained by the free hormone/vitamin hypothesis. The latter is governed by the law of mass action--the spontaneous dissociation and instant uptake by hepatocytes of the ligands freed from their specific carrier proteins, which creates a transient hyperthyroid, hyperretinoid, and hypercortisolic climate. This response generally does not exceed four or five days because the initial impact of injury normally subsides, but it may last longer if complications occur. The magnitude and adequacy of the stress responses depend on the preceding nutritional status as assessed by TTR plasma levels and are proportionate to the severity of insult. Clinical, animal, and molecular studies concur to demonstrate the dualistic stimulatory or inhibitory effects triggered by the ligands, whose unmetabolized fractions are excreted in the urinary output. Thyroid hormones and retinoids appear to control the early maturation processes and the synthesis of primary transcripts, whereas cortisol preferentially modulates the secondary responses and confers a protective effect on healthy tissues. During acute stress, the evolutionary patterns of visceral proteins and inflammatory markers exhibit compulsory mirror images. However, they change in independent ways under more chronic circumstances. A relatively simple biochemical micromethod based on the simultaneous measurement of plasma TTR, albumin, CRP, and orosomucoid aggregated into a PINI is proposed for the early recognition and follow-up of both nutritional and inflammatory facets of the disease spectrum.