**7. The usefulness of transthyretin in the human clinical practice**

#### **7.1. Nutritional marker**

Transthyretin may be used as important diagnostic tool for various disease conditions in humans, but is more often used as an indicator of malnutrition [62]. Several studies have shown a correlation between the concentrations of TTR and nutritional status [63, 64]. According to Ingenbleek and Young [14], low TTR concentrations are associated with inadequate protein calorie consumption or malnutrition. However, TTR may not serve as a reliable nutritional marker in patients with high concentrations of C-reactive protein (CRP), because of the activation of inflammatory responses [65]. This may complicate the use of TTR as an indicator of nutritional status, since inflammatory processes can lead to the decrease of serum TTR concentrations (negative acute phase protein) [66]. The CRP/TTR ratio may be a useful index in these cases to differentiate inflammatory states from protein malnutrition [67]. Very high ratios (>20) are indicative of acute phase response rather than protein malnutrition, while mild inflammatory processes may be accompanied by approximately a 10-fold increase in the concentrations of CRP and in CRP/TTR index values [6]. However, an inflammatory and nutrition index in animals was not yet established.

Surprisingly, extreme cases of starvation, including anorexia nervosa, have not been associated with a decrease of TTR concentrations. Nova et al. [68] reported normal values of transthyretin in patients with anorexia nervosa, which were comparable to values found in controls and did not differ after nutritional intervention. Barbe et al. [69] stated also that transthyretin concentrations in the majority of anorectic patients did not differ from those in control subjects, even in the presence of severe cachexia, but increased after weight gain. On the other hand, Gendall et al. [70] found lower concentrations of TTR in women with bulimia nervosa. These contradictory data indicate that further studies are needed to determine the effect of the aforementioned generalized malnutrition states on the values of transthyretin.

#### **7.2. Disease marker**

As transthyretin (prealbumin) belongs to negative acute phase proteins, its serum concentrations may be affected by many disease conditions, including trauma, inflammatory diseases, infections or malignancy (**Table 1**). Patients with severe sepsis or multiple injuries often have very low concentrations of TTR, related to severe acute phase response [71]. Studies have suggested that TTR may be a sensitive marker for the diagnosis of patients with liver cell damage, liver cirrhosis or hepatocellular carcinoma, reflecting the impaired liver synthetic function [72, 73]. Hutchinson et al. [74] and Yasmin et al. [75] found significantly lower concentrations of TTR in various types of chronic liver diseases when compared with controls with no impairment of liver functions. Moreover, Liu et al. [72] reported significantly lower TTR values in patients who died compared to survivors suggesting its role in predicting the prognosis of patients with decompensated liver cirrhosis.

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.

Transthyretin may be used as important diagnostic tool for various disease conditions in humans, but is more often used as an indicator of malnutrition [62]. Several studies have shown a correlation between the concentrations of TTR and nutritional status [63, 64]. According to Ingenbleek and Young [14], low TTR concentrations are associated with inadequate protein calorie consumption or malnutrition. However, TTR may not serve as a reliable nutritional marker in patients with high concentrations of C-reactive protein (CRP), because of the activation of inflammatory responses [65]. This may complicate the use of TTR as an indicator of nutritional status, since inflammatory processes can lead to the decrease of serum TTR concentrations (negative acute phase protein) [66]. The CRP/TTR ratio may be a useful index in these cases to differentiate inflammatory states from protein malnutrition [67]. Very high ratios (>20) are indicative of acute phase response rather than protein malnutrition, while mild inflammatory processes may be accompanied by approximately a 10-fold increase in the concentrations of CRP and in CRP/TTR index values [6]. However, an inflam-

Surprisingly, extreme cases of starvation, including anorexia nervosa, have not been associated with a decrease of TTR concentrations. Nova et al. [68] reported normal values of transthyretin in patients with anorexia nervosa, which were comparable to values found in controls and did not differ after nutritional intervention. Barbe et al. [69] stated also that transthyretin concentrations in the majority of anorectic patients did not differ from those in control subjects, even in the presence of severe cachexia, but increased after weight gain. On the other hand, Gendall et al. [70] found lower concentrations of TTR in women with bulimia nervosa. These contradictory data indicate that further studies are needed to determine the effect of the

As transthyretin (prealbumin) belongs to negative acute phase proteins, its serum concentrations may be affected by many disease conditions, including trauma, inflammatory diseases, infections or malignancy (**Table 1**). Patients with severe sepsis or multiple injuries often have very low concentrations of TTR, related to severe acute phase response [71]. Studies have suggested that TTR may be a sensitive marker for the diagnosis of patients with liver cell damage, liver cirrhosis or hepatocellular carcinoma, reflecting the impaired liver synthetic function [72, 73]. Hutchinson et al. [74] and Yasmin et al. [75] found significantly lower concentrations of TTR in various types of chronic liver diseases when compared with controls with no impairment of liver functions. Moreover, Liu et al. [72] reported significantly lower

aforementioned generalized malnutrition states on the values of transthyretin.

**7. The usefulness of transthyretin in the human clinical practice**

matory and nutrition index in animals was not yet established.

**7.1. Nutritional marker**

56 Pathophysiology - Altered Physiological States

**7.2. Disease marker**

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

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 hypothyroidism the TTR values were within the normal range.

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 to the gastrointestinal losses.


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

Increased serum concentrations of transthyretin are typically associated with chronic renal failure, presumably due to the decreased tubular uptake and degradation of RBP [82]. Cano [83] stated also that chronic renal failure may result in an increase of serum TTR concentrations, but these elevated TTR values during renal insufficiency are secondary to the lack of RBP degradation in renal tubules and to the subsequent increase in TTR. The concentrations of TTR may rise also during corticosteroid therapy and administration of anabolic steroids, as well as in patients using anti-inflammatory agents [6, 84]. Young et al. [85] found increased concentrations of TTR in ill-surgical patients receiving anabolic steroids, which may enhance amino acid and water uptake by tissues and increase the utilization of fat. Increased TTR concentrations may be seen in acute alcohol intoxication, caused by the leakage of proteins from damaged hepatic cells [86]. Transthyretin was shown to be upregulated also in Hodgkin´s lymphoma and pancreatic cancer [11, 87].

dodecyl-polyacrylamide gel electrophoresis with subsequent Western blot analysis [98]. Piechotta et al. [99] investigated the serum concentrations of TTR in dogs with nonthyroidal illness (including neoplasia, allergy, cardiac disease, gastrointestinal disease, parasitism and hepatic disease) and low T4 concentrations compared with those in healthy dogs and dogs with primary hypothyroidism. They found significantly decreased serum concentrations of TTR in dogs with nonthyroidal illness (24.8 mg/L) compared with its concentration in hypothyroid dogs (41.1 mg/L). On the other hand, significant differences in TTR values were not found between hypothyroid and healthy dogs, or between dogs with nonthyroidal illness and healthy dogs. In the study presented by Raila et al. [100], low concentration of TTR was found in a young dog with chronic renal failure, probably caused by its increased urinary excretion. Changes in the serum concentrations of TTR were observed also in rats during proteinenergy malnutrition [62]. The mean value of transthyretin in healthy pig serum obtained by Campbell et al. [54] was 302 ± 8 mg/L, but following *Streptococcus suis* type 2 infection the concentrations markedly decreased. In horses, transthyretin was identified using immunodiffusion technique, but the study was performed many years ago [101]. Establishing a quantitative method, such as an enzyme immunoassay, to measure the concentrations of TTR may be useful also in horses. In cattle, there are very little published reports about the usefulness of transthyretin in the diagnosis of diseases. Our preliminary results suggest lower concentrations of TTR in diarrhoic calves at the age of 1 month compared with healthy animals at the same age. Similarly, *Mycobacterium avium paratuberculosis* seropositive cows showed lower TTR values than those obtained in healthy cattle (unpublished data). Chang et al. [102] have isolated and sequenced transthyretin not only in humans and other mammalian species but also in birds, including emu, chicken, ostrich and pigeon. This study showed that TTR has greater than 98% homology and has a very similar binding pattern across species. However, additional studies should be done to determine the effect of various diseases on the serum

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

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

59

Presented data suggest that transthyretin may contribute to the evaluation of health state and diagnosis of some diseases also in animals. Changes in serum concentrations of TTR may be indicative of inadequate nutrient intake and may serve as an additional diagnostic tool for clinicians in the evaluation of some pathological conditions. It may be used as an integral part of the overall health assessment or in hospitalized animals to evaluate their nutritional status during the treatment and recovery. Low serum TTR concentrations may be considered a sign

This work was supported by Scientific Grant Agency of Ministry of Education SR Nos.

of increased risk of malnutrition, requiring further nutritional assessment.

concentrations of TTR in animals.

**9. Conclusions**

**Acknowledgement**

1/0154/15 and 1/0486/17.

#### **7.3. Prognostic indicator**

Several studies evaluated the significance of TTR as a prognostic biomarker and suggested that low concentrations may be associated with poor prognosis [88, 89]. Transthyretin was found as a prognostic factor for treatment outcomes and/or nutritional status of colon, oesophagus, ovarian and lung cancers [90–92]. In these studies, the concentrations of TTR correlated with response to treatment and clinical outcomes. Ho et al. [93] reported that low values of TTR may serve as prognostic factor for overall survival in cancer patients. However, the interpretation of its values in patients with systemic inflammatory response may be challenging. In these conditions, further clinical assessments and laboratory assays may be helpful, including markers of inflammation such as C-reactive protein, erythrocyte sedimentation rate or white blood cell number.

According to Cheng et al. [94], TTR has also been identified as a significant predictor of clinical outcomes after surgical intervention. Therefore, it may be used as part of the blood screening completed before surgery to determine pre-surgery health. Low TTR values before surgery may be associated with an increased risk of complications, including infections or pneumonia. Devakonda et al. [88] reported that surgery patients with low preoperative TTR values had significantly longer hospital duration of stay and longer intensive care unit duration of stay. Moreover, low concentrations of transthyretin were associated with higher rates of infectious complications, mortality and other surgical complications [95, 96].
