**6. Factors influencing the concentrations of TTR**

The concentration of TTR in serum is affected by many factors, including age, gender, as well as blood-drawing methods. In humans, the concentrations of transthyretin increase gradually after birth until they reached the adult values of 20–40 mg/dL [45]. A progressive increase of TTR concentrations with postnatal age was reported also by Kanakoudi et al. [46] in infants. Similarly, Cardoso and Falção [47] observed a marked increase of TTR concentrations in the period from birth till day 28 of age in preterm infants with very low birth weight. According to these authors, the serum concentrations of transthyretin in this important period of life are associated with the recent protein status, and reflect the balance between synthesis and degradation. Moreover, MacDonald et al. [48] stated that TTR values may predict future weight gain and concluded that if the serum concentrations of TTR remain stable or increase, it can be expect that the newborn is in reasonable nitrogen balance and will gain weight subsequently. According to Benvenga et al. [49], the concentrations of TTR progressively decrease after 50–60 years. Approximately from the year 60 of age, muscle mass undergoes stepwise shrinking leading to sarcopenia, which may be responsible for the aforementioned decrease in the concentrations of TTR [50, 51]. In animals, the influence of age on the concentrations of TTR during the growth and development is not well described. A marked increase of TTR values from 72.9 to 251.4 mg/L was observed by Tóthová et al. [7] in calves 1 day after colostrum intake with a consecutive gradual decrease till the end of the third month of life. Rona [52] described that bovine colostrum contains among other bioactive molecules a small amount of prealbumin (transthyretin). Thus, the increase of serum TTR concentrations observed in calves after colostrum intake may reflect the adequate nutrition, as well as its hepatic synthesis due to adequate protein and energy intake [14]. In neonatal rats, low concentrations of TTR were found in the immediate postnatal period, which increases at the time when the concentrations of both thyroxine and corticosterone increase [53]. On the other hand, there were no significant differences in the serum concentrations of TTR in three different age groups of pigs from 10 to 25 weeks [54].

glucagonomas and gut carcinomas, have been reported also to secrete transthyretin [33]. During fetal life, TTR is synthesized by the embryonic yolk sac endothelium [34]. Any alteration in energy-to-protein balance impairs the body mass reserves and causes early depression

The major sites of transthyretin degradation are the liver, muscles and skin, but a small amount of TTR may be catabolized by other tissues, including kidneys, adipose tissues, testes, as well as the gastrointestinal tract [36]. Transthyretin has a half-life in plasma of approximately 2 days, which is much shorter than that of albumin [37]. Transthyretin is therefore more sensitive to changes in protein-energy status, but its concentrations closely reflect the

Transthyretin is considered a more sensitive indicator of visceral protein status than albumin and transferrin because of its short half-life and low concentration in the body [40]. Conventionally, radial immunodiffusion and electroimmunodiffusion have been used for routine determination of transthyretin in humans [41]. Faster and more precise immunonephelometric and immunoturbidimetric assays have been developed also, which are easily applicable to many laboratory-automated equipments available in hospitals [6, 42]. Moreover, a sensitive enzyme immunoassay (enzyme-linked immunosorbent assay (ELISA)) for the determination of TTR values has been described, but this method is more time consuming and expensive compared with the above mentioned, and is more applicable, for example, for the estimation of TTR in the cerebrospinal fluid in nanogram amounts [43]. In veterinary medicine, species-specific ELISA is the most common analytical tool for the detection and quantification of transthyretin, utilizing monoclonal anti-TTR antibodies. In some avian species, for example, in budgerigars (*Melopsittacus undulatus*) transthyretin (prealbumin) constitutes as high as 75% of the total albumin concentration [44]. Therefore, it may be visualized

The concentration of TTR in serum is affected by many factors, including age, gender, as well as blood-drawing methods. In humans, the concentrations of transthyretin increase gradually after birth until they reached the adult values of 20–40 mg/dL [45]. A progressive increase of TTR concentrations with postnatal age was reported also by Kanakoudi et al. [46] in infants. Similarly, Cardoso and Falção [47] observed a marked increase of TTR concentrations in the period from birth till day 28 of age in preterm infants with very low birth weight. According to these authors, the serum concentrations of transthyretin in this important period of life are associated with the recent protein status, and reflect the balance between synthesis and degradation. Moreover, MacDonald et al. [48] stated that TTR values may predict future weight gain and concluded that if the serum concentrations of TTR remain stable or increase, it can

recent nutritional status rather than the overall nutritional support [38, 39].

in the production of transthyretin [35].

54 Pathophysiology - Altered Physiological States

and quantified easily by protein electrophoresis.

**6. Factors influencing the concentrations of TTR**

**5. Laboratory assays**

The concentrations of transthyretin linearly increase after birth without marked sexual differences during infant growth [55]. During human puberty, major hormonal and metabolic alterations occur, which result in increased height, weight gain and a substantial redistribution of body tissues. While androgens promote the development of muscle mass in male teenagers, oestrogens contribute to minimal enlargement of the female musculature and stimulate the accretion of subcutaneous fat depots [56]. These differences lead to higher concentrations of TTR in male adolescents compared with values recorded in teenage girls [57]. Higher concentrations of TTR in males compared with females were found also by Benvenga et al. [49] and Gaggiotti et al. [58]. Studies dealing with the evaluation of genderrelated differences in the concentrations of TTR in animals were not found.

Pregnancy, hormonal changes, physiological status and stress are other factors that may influence the concentrations of transthyretin. In humans, the concentrations of TTR were evaluated by Zhu et al. [59] during normal pregnancy. The values of TTR increased significantly in the third month of gestation and rapidly decreased following 20 weeks of gestation. Transthyretin was measured also in females with severe preeclampsia, showing significantly decreased TTR concentrations in these patients compared with the control group. Transthyretin is synthesized also by placental trophoblasts, which are critical to the normal fetal development. Thus, disorders caused by the production of TTR may result in fetal distress [60]. The aforementioned results indicated that TTR may be a reliable biomarker for the diagnosis of severe preeclampsia [59]. Similarly, Kalkunte et al. [61] suggested a relationship between reduced TTR production and preeclampsia. The importance, functional role and alterations in the concentrations of TTR during pregnancy in animals have not been reported. Our findings suggest no significant changes in TTR concentrations during the last week of pregnancy and early stages of lactation in dairy cows (unpublished data). However, further evaluations are needed to establish the values of transthyretin and its possible changes in pregnant and lactating cows, which may be useful for veterinary practitioners in the early diagnosis, prevention and finding therapeutic solutions in periparturient dairy cows.

In humans, for the measurement of concentrations of TTR, it was recommended to take blood samples after 15–20 min in the sitting position [6]. Lower values are expected in bedridden patients, while standing position prior to blood sampling may result in higher concentrations.

TTR values in patients who died compared to survivors suggesting its role in predicting the

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

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

57

Pneumonia in children caused by *Mycoplasma pneumonia* was also associated with lower TTR concentrations compared to a healthy control group [76]. Similarly, Luo et al. [77] recorded reduced TTR values in patients with tuberculosis and lung cancer, while the serum concentrations of TTR were lower in patients suffering from tuberculosis than in patients with lung cancer. Moreover, the changes in TTR values were in accordance with the therapeutic effects of anti-tuberculosis drugs, which may be useful by the monitoring of therapy in these patients. However, seeing that nutritional imbalance is very common in patients with tuberculosis and after chemotherapy in subjects with lung cancer, poor performance status should be taken into consideration when interpreting

The concentrations of transthyretin may be altered also by thyroid diseases, especially endemic goitre [6]. Low concentrations of TTR were found by Vergani et al. [78] in patients with untreated thyrotoxicosis, but the values recorded in the majority of cases with untreated hypothyroidism were within normal range. The concentrations of transthyretin were measured also by Ishida et al. [79] in patients with various thyroidal states. In patients with untreated hyperthyroidism, markedly low serum TTR values were found, but were normalized by treating with anti-thyroid drug. Similarly, the aforementioned authors observed markedly low TTR concentrations in patients with subacute thyroiditis, but in patients with

Changes in the concentrations of TTR were evaluated also in subjects affected by proteinlosing enteropathy, which is characterized by marked losses of serum proteins through the bowel wall into the gastrointestinal tract resulting in hypoproteinaemia [80]. Despite hypoproteinaemia, Takeda et al. [81] observed TTR values within the normal range in patients with protein-losing gastroenteropathy. This phenomenon may be explained by the slightly increased production of rapidly turned-over proteins (including TTR) by the liver in response

prognosis of patients with decompensated liver cirrhosis.

serum TTR values in these patients and should be further investigated.

hypothyroidism the TTR values were within the normal range.

**Alteration Associated disease condition**

Increase Dehydration

Decrease Inflammatory diseases, infections, trauma, malignancy

diseases

Severe sepsis, multiple injuries

Thyroid diseases, endemic goitre Protein-losing enteropathy Chronic malnutrition

Acute alcohol intoxication

Chronic renal failure, renal insufficiency Anti-inflammatory therapy, anabolic steroids

Hodgkin´s lymphoma, pancreatic cancer

**Table 1.** Abnormalities in the serum concentrations of transthyretin and associated diseases (adapted from Ref. [6]).

Liver cell damage, liver cirrhosis, hepatocellular carcinoma, chronic liver

to the gastrointestinal losses.
