**Transthyretin in the Evaluation of Health and Disease in Human and Veterinary Medicine in Human and Veterinary Medicine**

**Transthyretin in the Evaluation of Health and Disease** 

DOI: 10.5772/intechopen.68725

Csilla Tóthová and Oskar Nagy Csilla Tóthová and Oskar Nagy Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68725

#### **Abstract**

Transthyretin (also known as prealbumin) is an important transport protein, which plays an essential role in the binding of thyroid hormones and retinol with varying affinities in mammalian, as well as avian species. The determination of transthyretin concentrations may be used as a diagnostic tool for some disease conditions in humans, but is more often used as a nutritional marker to assess protein-calorie malnutrition and as prognostic indicator in critically ill patients. Transthyretin has shorter half-life (2–3 days) than that of albumin and belongs to negative acute phase proteins. This may complicate the use of transthyretin as a nutritional marker and the interpretation of results in the diagnosis of diseases. Although some studies have been carried out to determine the usefulness of transthyretin in selected disease conditions and disorders also in animals, it is a relatively rarely used parameter to evaluate health state and illness in veterinary medicine. The usefulness of transthyretin in the diagnosis of diseases and evaluation of nutritional status in humans and animals are reviewed in this article, including the laboratory assays available to measure its concentrations and the possible clinical application of the results, as well as its usefulness as a prognostic indicator in some disease conditions.

**Keywords:** disease marker, nutritional state, prealbumin, serum proteins, transthyretin

#### **1. Introduction**

Transthyretin is an important transport protein of the blood, which was originally named prealbumin because it migrates faster than albumin, and is visible as a band anodic to the main albumin fraction on electrophoretic gels [1]. According to Hamilton and Benson [2], this property is attributed to human prealbumin, not to bovine. Kaneko [3] reported that prealbumin is not always visualized on electrophoretograms and may not exist in all animal species. In the 1980s, the name was changed to transthyretin (TTR) describing its ability to bind both

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© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

thyroid hormones and retinol-binding protein (RBP) [4]. Moreover, transthyretin is one of the precursors, which may be found in amyloid deposits [5]. In humans, analyses of the concentrations of TTR in serum are recommended by some investigators as a screening marker for inflammation, malnutrition, or both [6]. In animals, there are only scarce literature data about this protein as a biomarker of health state and its use in the laboratory diagnosis [7].

**3. Functions**

is markedly increased [21].

**4. Synthesis**

Transthyretin is a serum protein with multiple functional properties [13]. The main physio logical functions of TTR include the carriage of thyroid hormone and indirectly vitamin A, which may promote the maturation of lymphocytes [14, 15]. Although each monomer of the TTR molecule has two binding sites for thyroid hormones, the binding of one molecule of T3 or T4 may reduce the binding affinity for the second site [6]. Moreover, the binding affinity for T3 is lower compared with that for T4. Transthyretin binds and transports approximately 15–20% of thyroid hormones circulating in the serum and up to 80% of thyroxine in the central nervous system (CNS) [16]. About 70% of thyroid hormones are transported by thyroxin-binding globulin (TBG), which is the major serum transport protein in humans [17]. The remaining part of thyroid hormones is transported by albumin. These proteins are responsible for the transporting of thyroid hormones to cells and maintaining a large store of these hormones in the blood in a non-diffusible form [2]. Among animal species, the concentration of TBG in the dog is only 15% of those observed in humans [18]. Cats do not appear to have a high-affinity thyroid-binding protein such as TBG, but have only transthyretin and albumin [19]. Some other small molecules may bind in the thyroxine-binding sites of TTR, including some natural products, drugs or toxicants [20]. These interactions with TTR may be important when TTR becomes a major circulating thyroxine-binding protein, for example, in humans with complete or partial TBG deficiency, or when the concentration of thyroxine in the serum

Transthyretin in the Evaluation of Health and Disease in Human and Veterinary Medicine

http://dx.doi.org/10.5772/intechopen.68725

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In addition to the binding and carriage of thyroid hormones, transthyretin has a more important function, that is, the transport of retinol (vitamin A) through its association with retinol-binding protein (RBP) from its main storage site in the liver to target cells [22]. Retinol is bound to RBP, and then RBP binds to transthyretin. This binding of RBP to TTR was suggested to prevent the extensive loss of RBP, which is of low molecular weight and would be rapidly eliminated from plasma by glomerular filtration if it were not complexed to transthyretin [23, 24]. Although each of the four monomers has a binding site for RBP, the tetramer binds only one molecule of

Moreover, transthyretin acts as a negative acute phase reactant, serum concentrations of which fall due to decreased synthesis in inflammation, trauma, tissue injury or stress [26].

Transthyretin is synthesized mainly by hepatic parenchymal cells and in the choroid plexus of the brain, which has the highest concentration of TTR in the body [27, 28]. In cerebrospinal fluid, it is the second most abundant protein, which may be involved in the pathogenesis of Alzheimer´s disease, depression and lead intoxication [29]. Other tissues have been reported also to produce TTR, but in much lower concentrations [30]. Small amounts of TTR are also produced by retinal pigment epithelium and the pineal gland [31]. Transthyretin has also been found in adult pancreatic islet cells, enterochromaffin cells in the gastrointestinal mucosa, as well as kidney cells [32, 33]. Neoplastic tissues, including choroid plexus papillomas,

RBP with high affinity, and possibly a second with lower affinity [25].

#### **2. Structure**

Transthyretin is a small globular non-glycosylated tryptophan-rich protein of a homotetrameric structure, composed of four identical subunits with two thyroxine-binding sites per tetramer [8]. The binds for retinol-binding protein are placed at the surface of the molecule and do not interfere with thyroxin binding (**Figure 1**) [9]. Its molecular mass is of 54.98 kDa, which is small enough to penetrate the vascular wall and migrate into the extravascular space as easily as albumin or transferrin [10]. In some conditions, the transthyretin molecules may aggregate and form insoluble fibrillar deposits, which may be associated with amyloid diseases, predominantly senile systemic amyloidosis or neurodegenerative familial amyloidotic polyneuropathy [11, 12].

**Figure 1.** The three-dimensional structure of transthyretin displayed as a dimer (A) and a tetramer in complex with thyroxine (B) and retinol-binding protein (C) [103].
