Volume 40, Issue 12

As introduction to the First International Congress on Transthyretin in Health and Disease, this lecture traces the origin of the subject from the discovery in the 1950s that a serum protein migrating ahead of albumin in an electrical field binds the thyroid hormone, thyroxine. Early work defined the molecular and biological properties of thyroxine-binding prealbumin (TBPA). Its tetrameric structure, first recognized from a polymorphism in monkeys, was later elaborated by crystallographic studies, and the very different affinity of its two identical thyroxine-binding sites was explained by an allosteric effect upon occupation of the first site. The far higher concentration of TBPA in cerebrospinal fluid compared to blood was explained by the discovery, 30 years later, that TBPA is synthesized by cells of the choroid plexus, and its rapid turnover in the body made TBPA a convenient marker of malnutrition and chronic disease. Late in the 1960s it was learned that TBPA also carries vitamin A in the circulation by interacting with retinol-binding protein (RBP). TBPA then was renamed transthyretin (TTR), in recognition of its dual transport function, and it was shown that retinol-RBP-TTR interactions are mutually enhancing. Investigation of the molecular genetics of TTR began in 1980 and a large number of inherited variants were discovered in the ensuing years. Some affect thyroxine and/or RBP binding but the majority are associated with familial amyloidotic polyneuropathy. Seizing on this discovery, structural biologists are now investigating why mutated TTR changes from a compact, soluble molecule into a fibrillar, insoluble polymer, and how this pathological transformation might be prevented.

Thyroid hormones are evolutionarily old signal molecules, which can partition between compartments by partitioning into lipid membranes. The role of thyroid hormone distributor proteins is to ensure that sufficient thyroid hormone remains in the bloodstream. Of particular interest is the role of transthyretin, synthesised by the liver and secreted into the blood. In this review, three hypotheses are presented, suggesting the selection pressures leading to the onset of transthyretin synthesis in the liver during evolution. A thyroid hormone distribution network would be a selection advantage over a single protein performing this function. Similarly to the situation in eutherians, hepatic transthyretin synthesis in marsupials is under negative acute phase regulation. The overall three-dimensional structure of transthyretin did not change appreciably during vertebrate evolution. The region of the primary sequence which evolved most was the N-terminal region of the subunit. The N-termini of transthyretin changed from longer and more hydrophobic in reptiles/birds, to shorter and more hydrophilic in eutherians. These changes are correlated with a change in preference from binding of triiodothyronine, to binding thyroxine. As the rest of the molecule had not changed significantly during vertebrate evolution, the gene coding for transthyretin must have evolved prior to the divergence of the vertebrates from the non-vertebrates. Five open reading frames in the genomes of C. elegans (2), S. dublin , S. pombe and E. coli were identified. The protein products are predicted to form tetramers similar to transthyretins. Two possible functions of these proteins are suggested.

Choroid plexus has the highest concentration of transthyretin (TTR) mRNA in the body, 4.4 μg TTR mRNA/g wet weight tissue, compared with 0.39 μg in the liver. The proportion of TTR to total protein synthesis in choroid plexus is 12%. All newly synthesized TTR is secreted towards the ventricles. Net transfer of T4 occurs only towards the ventricle and depends on ongoing protein synthesis. Thyroxine-binding globulin (TBG), TTR and albumin form a “buffering” system for plasma [T4] because of their overlapping affinities and on/off rates for L-thyroxine (T4)-binding. The individual components of this network determining T4 distribution are functionally highly redundant. Absence of TBG (humans), or TTR (mice), or albumin (humans, rats) is not associated with hypothyroidism. Natural selection is based on small, inheritable alterations improving function. The study of these alterations can identify function. TTR genes were cloned and sequenced for a large number of vertebrate species. Systematic, stepwise changes during evolution occurred only in the N-terminal region, which became shorter and more hydrophilic. Simultaneously, a change in function occurred: TTR affinities for T4 are higher in mammals than in reptiles and birds. L-triiodothyronine (T3) affinities show the opposite trend. This favors site-specific regulation of thyroid hormones by tissue-specific deiodinases in the brain.

The retinol/retinol-binding protein/transthyretin complex, that carries and delivers hydrophobic retinol molecules to target cells, is assembled in the hepatocyte endoplasmic reticulum. In this paper, we review data related to events that lead to the formation of this complex, including transthyretin oligomerization and retinol-binding protein secretion. Our studies on transthyretin oligomerization have demonstrated that cleavage of signal peptide and the environment of endoplasmic reticulum influence transthyretin oligomerization. In vitro , mutated transthyretin without signal sequence fails to form dimers, while wild-type transthyretin is translocated into the microsomes where it forms dimers and small amounts of tetramers. In vivo , tetramers were detected in HepG2 cells but not in transfected Cos cells, suggesting that tissue-specific factors affect tetramer stability. In vitamin A deficiency, retinol-binding protein secretion is blocked and the protein accumulates in the endoplasmic reticulum, from where it is promptly released after retinol repletion. We use MMH cells to identify factors involved in complex formation, retention and secretion, the crucial steps to understand the molecular mechanisms underlying vitamin A homeostasis. In parallel, studies on vitamin A transport in fish are in progress; retinolbinding protein and transthyretin have already been characterized in different fish species.

Transthyretin (TTR) is a 55 kDa protein responsible for the transport of thyroid hormones and retinol in human serum. Misfolded forms of the protein are implicated in the amyloid diseases familial amyloidotic polyneuropathy and senile systemic amyloidosis. Its folding properties and stabilization by ligands are of current interest due to their importance in understanding and combating these diseases. To assist in such studies we developed a method for the solid phase synthesis of the monomeric unit of a TTR analogue and its folding to form a functional 55 kDa tetramer. The monomeric unit of the protein was chemically synthesized in three parts, comprising amino acid residues 1–51, 54–99 and 102–127, and ligated using chemoselective thioether ligation chemistry. The synthetic protein was folded and assembled to a tetrameric structure in the presence of the TTR's native ligand, thyroxine, as shown by gel filtration chromatography, native gel electrophoresis, TTR antibody recognition and thyroid hormone binding. In the current study the solution structure of the first of these fragment peptides, TTR(1–51) is examined to determine its intrinsic propensity to form β-sheet structure, potentially involved in amyloid fibril formation by TTR. Despite the presence of extensive β-structure in the native form of the protein, the N-terminal fragment adopts an essentially random coil conformation in solution.

Transthyretin (TTR), formerly called prealbumin, one of the transporters of the hormone thyroxine and retinolbinding protein (RBP), the specific carrier of vitamin A, forms, under physiological conditions, a macromolecular complex that prevents glomerular filtration of the low-molecular-weight RBP in the kidneys. This paper describes briefly the three-dimensional structure of the two proteins as determined by X-ray diffraction analysis of single crystals and that of the complex that the two molecules form in plasma and discusses the noncrystallographic evidence that supports the model of the macromolecular complex.

Structure-activity data show that many pharmacological agents are strong competitive inhibitors for thyroxine (T4) binding to transthyretin (TTR) and that this competition can interfere with their normal pharmacological actions. TTR is a tetrameric serum protein responsible for the transport of 20% of the circulating T4 in man, while in lower vertebrates such as rats it is the only carrier. The sequence of rat TTR is 85% homologous to the human protein. Crystallographic analyses of ligand co-crystal complexes of human and rat TTR have been studied to understand the molecular basis for binding selectivity of competitor binding to TTR. Analysis of TTR crystal complexes with several classes of competitors (hormone metabolites, flavonoids, fluorescent probes, analgesics and cardiac agents) revealed multiple modes of binding with both forward and reverse ligand binding orientations. These ligands also have different binding positions along the length of the channel with the smallest ligands located deeper within the hormone domain. Data for the human TTR complex with the bromoflavone EMD21388 incubated at different times revealed variable binding positions and occupancies dependent upon incubation time. Comparison of the structures of T4 thyroacetic acid in complex with both human and rat TTR revealed forward and reverse binding, but also showed different modes of binding in the rat compared to the human complex. These data highlight the importance of hydrogen bonding with Lys-15 and Ser-117 and provide insight into ligand binding affinity and negative cooperativity.

Relatively little is known about thyroid hormone-binding proteins in fish and, until recently, the thyroid hormones (THs), thyroxine (T 4 ) and triiodothyronine (T 3 ), had only been found in fish plasma bound to albumin and lipoproteins. Recently, transthyretin (TTR) was cloned in a teleost fish, the sea bream (sb); it is composed of 130 amino acids and shares 47–54% sequence similarity with other vertebrate TTR and binds preferentially T 3 . Homology modelling of sbTTR based upon the crystallographic structure of TTR in human, rat and chicken reveals similar monomer-monomer and dimer-dimer interfaces and a conserved tetrameric structure. In sbTTR, a single amino acid substitution in the thyroid hormone binding site (Ser 117 in human by Thr in sea bream) may explain the higher affinity of this tetramer for T 3 rather than T 4 . The principal site of production of TTR in the sea bream is the liver but transcripts are also present in the intestine, brain, skin, heart, skeletal muscle, kidney, testis, gills and pituitary (in descending order of abundance). The function of TTR in fish remains to be studied but we have recently carried out studies which suggest it may be involved in TH balance during food shortage.

We investigated the effects of medical, industrial and agricultural chemicals on 3,3′,5-L-[ 125 I]triiodothyronine ([ 125 I]T 3 ) binding to purified recombinant Xenopus laevis ( X. laevis ) transthyretin (xTTR), a plasma thyroid hormone-binding protein, and to the ligand-binding domain of thyroid hormone receptor-β (xTR LBD). xTTR derived from X. laevis serum had about 80 times higher affinity for T 3 than for L-thyroxine. The xTTR's relative affinities for diethylstilbestrol, pentachlorophenol and ioxynil were 10 −1 - to 10 −2 -fold less than that for T 3 . However, all chemicals investigated had either a weak or no influence on [ 125 I]T 3 binding to xTR LBD. The concentration of diethylstilbestrol, the most potent chemical, required for 50% inhibition of [ 125 I]T 3 binding to xTR LBD was 10 4 times greater than that of unlabeled T 3 . These results indicate the existence of several chemicals that interact with xTTR but not with xTR LBD.

Familial amyloid polyneuropathy (FAP) was once considered to be a disease peculiar to endemic areas, but it is now recognized that FAP kindreds exist in worldwide places. The amyloid precursor of FAP is a variant form of transthyretin (TTR) with one amino acid substitution, which is ascribed to a mutation of TTR gene. Corresponding to the variety of the clinical phenotypes of FAP, more than 80 mutations have been identified as causative gene abnormality in this disease. Since the vast majority of TTR in serum is produced in the liver, liver transplantation has become widely accepted as a valuable treatment for FAP.

Mutations in transthyretin (TTR) are the most common cause of autosomal dominant systemic amyloidosis. To date, more than 80 TTR mutations have been associated with amyloidosis in humans. A high prevalence of some mutations like Val122Ile which is identified in 3% of African Americans indicates the necessity of thorough investigation of patients suspected of having, or to be at risk of developing, TTR amyloidosis. Laboratory tests available for evaluation of TTR amyloidosis include both DNA and protein assays. In the case of a known mutation DNA analysis is realized by restriction fragment length polymorphism (RFLP), polymerase chain reaction-induced mutation restriction analysis (PCR-IMRA), single strand confirmation polymorpism (SSCP) or nucleotide sequencing. SSCP, PCR-non-isotopic RNAse cleavage assay (NIRCA) or nucleotide sequencing are used to identify an unknown mutation. At the protein level, two techniques are used, isoelectric focusing and mass spectrometry, in both cases (known or unknown mutation). The identification of a previously unknown mutation requires a combination of clinical, pathological and molecular studies.

We have expressed transthyretin (TTR) mutants which have significantly destabilised tetramers that aggregate into amyloid fibrils via a series of intermediates. We used atomic force microscopy to follow the morphology of aggregates during fibril formation. Initially, amorphous aggregates are formed that subsequently mature into fibrillar structures. This observation is interpreted as an optimisation of β-strand registers. The rate of aggregation and maturation is highly temperature-dependent suggesting that entropic forces significantly contribute to stability. In addition, we identified a correlation between the presence of early formed aggregates of TTR and cytotoxicity. The toxic response was mediated via an apoptotic mechanism. The fact that early formed amorphous aggregates, but not more mature fibrils, exert a toxic response suggests that the rate of fibril formation may be a critical parameter. We propose that a slow rate of aggregation facilitates an increased concentration of a toxic intermediate.

The history of prealbumin dates back to the early forties and may be divided into three parts, based on a chronological and functional approach. The first part–the discovery and the identification of prealbumin–was essentially based on classical protein chemistry methods. The second–the demonstration of prealbumin as a thyroid hormone-binding protein (thyroxine-binding prealbumin)–has greatly benefited from isotopic techniques. The third one–establishing prealbumin as a nutritional marker–was a result of field studies on nutrition. The discovery of the role of prealbumin in retinol binding led to a change in its name, prealbumin becoming transthyretin. Finally, structural studies and mutation analysis of transthyretin in patients with amyloid neuropathy have opened a new area of research.

Protein malnutrition in humans and other animals is consistently associated with a decreased concentration of circulating serum albumin, transthyretin (TTR), and insulin-like growth factor-I (IGF-I). The molecular mechanisms for regulation of the three polypeptides by dietary protein remain to be completely elucidated. The abundance of albumin, TTR and IGF-I mRNA is decreased in liver of juvenile rats consuming insufficient amounts of protein. Moreover, protein restriction specifically decreases the abundance of albumin and TTR nuclear transcripts, indicating that the reduction in mRNA levels for these two genes is caused at least partly by a decrease in gene transcription. Expression of several other genes transcribed at a high level in the liver is also decreased under conditions of dietary protein restriction, suggesting that the level/functional activity of liver-enriched transcription factor(s) might be decreased under these conditions. Limitation of cultured hepatoma cells for a single amino acid also selectively decreases the mRNA levels of several genes with liver-enriched expression, including albumin and TTR. The decrease in albumin mRNA is caused partly by decreased albumin gene transcription and partly by destabilization of albumin mRNA.

Total body nitrogen (TBN) is mainly sequestered within the metabolically active lean body mass, in close relationship with total body potassium (TBK). TBN and TBK of growing children manifest superimposed accretion rates, display a sexual difference at the onset of adolescence and during adulthood, thereafter decreasing in elderly subjects. Plasma transthyretin (TTR) follows a comparable profile from birth to death in healthy individuals. Uncomplicated proteinenergy malnutrition primarily affects the activity of nitrogen metabolic pool, reducing protein syntheses to levels compatible with survival. This adaptive response is well identified by declining TTR concentrations. In various stressful conditions, in vivo responses are characterized by upregulation in injured regions and with muscle proteolysis exceeding protein synthesis, resulting in a net body negative nitrogen balance. Again, this evolutionary pattern mirrors that of plasma TTR. Attenuation of stress and/or introduction of nutritional rehabilitation allows restoration to normal of both TBN and TTR values that follow parallel slopes. Despite distinct etiopathogenic mechanisms, TTR concentrations appear to reflect the loss or gain of TBN in body pools and they predict later outcome in malnutrition and in conditions of acute and/or chronic inflammation.

Thyroid hormones are essential for normal mammalian development and for normal metabolism. Thyroxine (T 4 ) is the principal product synthesized by the thyroid follicles, and triiodothyronine (T 3 ), the biologically active hormone, derives mainly from tissue T 4 deiodination. More than 99% of the circulating hormone is bound to plasma proteins, mainly to thyroxine-binding globulin, transthyretin and albumin in man, and to transthyretin and albumin in rodents. The role of plasma proteins in the transport of hormones to target tissues has, for a long time, been controversial. The liver and the choroid plexus are the major sites of transthyretin synthesis, tissues from which transthyretin is secreted into the blood and the cerebrospinal fluid, respectively. Transthyretin has been proposed to mediate thyroid hormone transfer into the tissues, particularly into the brain across the choroid-plexus-cerebrospinal fluid barrier. Studies in a transthyretinnull mice strain have shown conclusively that transthyretin is not indespensable for thyroid hormones' entry into the brain and other tissues, nor for the maintenance of an euthyroid status. An euthyroid status is also observed in man totally deprived of thyroxine-binding globulin and in rats without albumin. Taken together, these results exclude dependence of thyroid hormone homeostasis on any major plasma carrier per se . This evidence agrees with the free hormone hypothesis which states that the biologically significant fraction, that is taken up by the tissues, is the free circulating hormone.

The molar ratio of retinol-binding protein to transthyretin (RBP:TTR) has been proposed as an indirect method to assess vitamin A status in children with inflammation. Neither reference values nor appropriate cut-off point are available for adults. RBP, TTR and retinol were determined in plasma from 100 healthy adults and 31 low-risk surgical patients with no inflammatory response. RBP:TTR percentile distribution from 99 healthy adults with plasma retinol ≥0.7 μmol/l was: 2.5th = 0.24; 5th = 0.31; 10th = 0.32; 25th = 0.41; 50th = 0.47; 75th = 0.54; 90th = 0.67; 95th = 0.78 and 97.5th = 0.81. In order to define a cut-off point, receiver operating characteristic (ROC) curve was constructed, using plasma retinol as gold standard. ROC curve was based on data from the 131 studied subjects, 11 of whom (8.4%) were classified as deficient on the basis of plasma retinol <0.7 μmol/l. According to ROC curve criteria, RBP:TTR ratio was considered a good test, the area under the curve being 0.822, p<0.001. A cut-off-point of ≤0.37 is proposed to detect vitamin A deficiency in adults, since it allows reaching high sensitivity (81.8%), specificity (79.2%) and predictive value (79.4%). The proposed cut-off point falls between 13th and 14th percentiles.

The National Kidney Foundation K/DOQI Guidelines state that, “Serum prealbumin is a valid and clinically useful measure of protein-energy nutritional status in maintenance dialysis (MD) patients.” Prealbumin, also known as serum transthyretin (TTR), was not recommended as a nutritional parameter of the same usefulness as the serum albumin. This decision was made, in part, because published research at that time suggested that serum TTR was not a more sensitive index of nutritional status than serum albumin and there was much more clinical and research experience with serum albumin as a nutritional and inflammatory marker. Evidence, including more recently published research data, which is reviewed in this paper has led to the following conclusions by the current authors: 1) In MD patients either protein-energy malnutrition or inflammation can lead to a reduction in serum TTR concentrations. 2) Hence, in MD patients, serum TTR concentrations can be used as a measure of both nutritional and inflammatory status. 3) Serum TTR concentrations are typically increased in MD patients. 4) In maintenance hemodialysis (MHD) patients, serum TTR is a risk factor for mortality that is somewhat independent of serum albumin. 5) Current epidemiological evidence suggests that a serum TTR value of 25 or 30 mg/dl or greater is associated with increased survival and, hence, is desirable in MHD patients. 6) MHD patients with serum TTR levels less than 25–30 mg/dl should be evaluated for protein-energy malnutrition and inflammation.

Chronic renal failure is responsible for an increase in serum concentrations of transthyretin. Elevated serum transthyretin during renal insufficiency is secondary to the lack of retinol-binding protein degradation in renal tubules and to the subsequent increase in the fraction of transthyretin bound to retinol-binding protein. In both hemodialysis and peritoneal dialysis patients, serum transthyretin was demonstrated to be a reliable marker of nutritional status, exhibiting significant relationships with energy and protein intakes as well as with fat stores and lean body mass. Serum transthyretin levels less than 300 mg/l were shown to be associated with an increased risk of morbidity and mortality in dialysis patients. The predictive value of transthyretin was shown to be independent of serum albumin. Regular measurements of both serum albumin and transthyretin make it possible to detect patients whose prognosis is compromised by malnutrition and in whom an active nutritional therapy must be undertaken. Simultaneous measurements of inflammatory markers such as serum C-reactive protein are required to evaluate the role of inflammation in serum albumin and transthyretin variations. These low-cost protein parameters should be incorporated in the regular assessment of dialysis patients and measured every 1 to 3 months.

Malnutrition may develop in acute pancreatitis (AP), accompanied by hypermetabolism and high nutritional requirements, and in chronic pancreatitis (CP). We measured the incidence of protein malnutrition in AP and CP by comparing different serum biomarkers of protein metabolism and inflammation. Thirty-five patients with acute (27 moderate, 8 severe), and 35 with chronic, pancreatitis were enrolled in the study. Serum transthyretin, albumin, transferrin and C-reactive protein (CRP) concentrations were measured in AP at admission, after 1 and 2 weeks of jejunal feeding, and in patients with CP at follow-up. In AP, at admission the transthyretin level was low in 74%, transferrin in 48%, and albumin in 29% of patients. In severe pancreatitis, transthyretin levels were significantly lower than in moderate forms (7.5±2.43 vs. 14.39±6.8 mg/dl, p<0.005). Transthyretin levels increased significantly after 2 weeks of jejunal feeding (p<0.05). In CP, transthyretin levels were decreased in 37%, transferrin in 27%, and albumin in 12% of patients. We found significantly lower transthyretin levels in alcohol-related CP than in other forms (18.5±8.3 vs. 30.2±5.7, p<0.01). Transthyretin correlated positively with albumin and transferrin and negatively with CRP. Transthyretin seems to be a sensitive biomarker of protein status and metabolic stress. Monitoring nutritional status through measurement of serum proteins is important for optimal treatment of AP and CP.

Transthyretin has been proposed as a nutritional index to screen for malnutrition and monitor the metabolic response to dietary intervention. In the presence of inflammation, circulating transthyretin levels drop regardless of optimal caloric intake. In this case, due to its rapid turnover, the pattern of transthyretin, monitored by means of repeated measures, could indicate the metabolic status (catabolism vs. anabolism). The aim of this review is to investigate the possible role of transthyretin as a nutritional parameter in organ transplantation. The literature on nutritional assessment in transplantation was reviewed and all the data regarding circulating transthyretin levels were analyzed. It appears that, on the one hand, the transthyretin level reflects closely dietary manipulations; on the other hand, it is affected by the inflammatory status. Consequently, interpretation could be difficult during the acute phase immediately after the transplant. Moreover, the role of transthyretin in monitoring the hepatic synthetic function in liver transplant is discussed. In conclusion, transthyretin is a reliable indicator of nutritional status in transplant candidates and potentially useful in the post-transplant phase if the inflammatory status is taken into account.

Undernutrition is a frequent complication of evolutive and chronic HIV (human immunodeficiency virus) infection characterized by bodyweight loss and changes in body composition. The Centers for Disease Control and Prevention define AIDS wasting as involuntary loss of more than 10% of body weight, plus more than 30 days of either diarrhea, or weakness and fever. Wasting syndrome has been considered as a case definition of the AIDS disease since 1987. Wasting syndrome is clearly linked to disease progression and death. Despite the progress under the era of highly active antiretroviral therapy (HAART), wasting is still a problem for people with AIDS. A small part of the weight lost is fat. More important is the loss of “lean body mass”, which is mostly muscle. Body composition changes during HIV infection are different from those observed in food deprivation. Under the era of HAART, a HIV-associated adipose redistribution syndrome (HARS) was described that associates subcutaneous lipoatrophy and abdominal obesity linked to various metabolic disorders. Several factors contribute to wasting syndrome. Not only low food intake and poor nutrient absorption, but mainly altered metabolism (increased resting energy expenditure) and specific disturbances in protein turnover, which is also increased. Nutritional evaluation of HIV-infected patients should include the measurement of body composition and analysis of nutritional parameters, including albumin, transthyretin and C-reactive protein. Transthyretin seems to be particularly useful to follow the recovery period of malnutrition.

The clinical usefulness of C-reactive protein (CRP) and of transthyretin (TTR) for the early diagnosis and follow-up of infection after an open fracture was prospectively investigated (cohort A). It was complemented by a retrospective study of trauma patients admitted to an intensive care unit (cohort B). Serial determinations of serum CRP and TTR concentrations were first performed in uninfected patients from cohort A to define a reference profile during the early postoperative period. It showed a concomitant increase in CRP and decrease in TTR concentrations, followed by progressive return to initial values in patients free from bacterial infection. Variations of the CRP/TTR ratio were analyzed. Recovery phase was defined by an exponential evolution of the two plasma proteins and of their ratio value. The CRP and TTR concentrations were independent of sex and severity of the trauma. In the case of postoperative infection, patients of cohort A revealed amplified CRP and TTR responses usually preceding the occurrence of clinical signs. During successful antibiotic therapy, their recovery response became superimposable to that of the reference group. The same profiles were recorded in cohort B patients admitted with lower limb fractures or various types of trauma. This suggests that observations made on cohort A can be extrapolated to other trauma patients. We recommend that serial measurements of CRP and TTR and of their ratio should be performed every 2 days to appropriately follow-up these patients.

In critically ill patients suffering from acute respiratory failure, weaning from ventilatory assistance is a key survival factor in intensive care units (ICU). The aim of this study was to provide deeper insight into laboratory methods allowing improved monitoring of that critical period. Eighty-three ICU patients (mean age 63.9 years), classified according to the Second Acute Physiology and Chronic Health Evaluation criteria, were submitted to mechanical ventilation, antibiotherapy and nutritional support. Weaning attempts required degressive pressure support ventilation. The biological status of the patients was assessed by the serial measurement of inflammatory (C-reactive protein and α 1 -acid glycoprotein) and of nutritional (albumin and transthyretin) indicators whose aggregation yields a prognostic inflammatory and nutritional index (PINI). Statistical analyses compared ventilatory and biological data recorded on admission and at the time of extubation. Results showed that vital capacity and plasma concentrations of albumin and transthyretin rose, whereas rapid shallow breathing index, C-reactive protein and PINI values declined during the tested period. Persistent low transthyretin concentrations were predictive of lethality while increased values were associated with improved ventilatory performances. The PINI scoring formula worked as an independent predictor of the weaning trial outcome. The study underlined the value of the PINI system for the successful management of the weaning procedure.

Serum transthyretin is an ideal marker for monitoring patients who are malnourished or have metabolic consequences of acute stress injury because it has a short half-life, it measures the level of metabolic deficit, the response to nutritional metabolic support, and because it is a prognostic indicator. Mounting clinical evidence indicates that the use of transthyretin to assess and monitor a patient's nutritional status results in improved treatment outcomes and lower overall healthcare costs.

In this study the impact of malnutrition on hospitalized patients and the value of using transthyretin level as a screening test for malnutrition were evaluated. One hundred and forty seven consecutive patients admitted through the emergency department were included in the study. The primary outcome measures were length of stay in hospital, in-hospital mortality, and nutritional supplementation in patients with malnutrition. A cost analysis of screening with transthyretin was also performed. In 24% of the patients in the study malnutrition was diagnosed (transthyretin level < 160 mg/l), however, by determination of the albumin level (< 35 g/l) only 50% of these patients could be identified. The length of stay and mortality were 16±18 days and 17%, respectively, in patients with malnutrition, compared to 8±12 days and 4% in patients without malnutrition (p < 0.0002 and p < 0.02, respectively). Only 42% of patients with malnutrition received nutritional supplementation. Cost analysis of screening with transthyretin level projected a saving of $414 per patient screened. We conclude that malnutrition is underdiagnosed in current clinical practice and is associated with poor outcomes. Transthyretin is a biochemical marker that could be used as a cost-effective screening test to identify patients with malnutrition who may benefit from nutritional supplementation.

Early assessment of protein calorie malnutrition (PCM) can improve the outcome for hospitalized patients by allowing the initiation of nutrition support if required. In addition, monitoring nutritional status during the hospital stay can identify a decline in or improvement of PCM so that alterations to treatment regimens can be made if needed. The visceral protein albumin is the traditional laboratory indicator of PCM. In the past decade another protein has been lauded as a superior marker that can be used in conjunction. We undertook several studies to test the effectiveness of TTR as an aid in nutritional assessment. We found TTR to be a sensitive measure of nutritional status, allowing for earlier assessment and intervention, thus reducing length of stay and other hospital associated costs. Based on these findings, our hospital generated and implemented a multidisciplinary nutrition care program. Transthyretin is an integral portion of this program; levels are determined on admission and repeated twice weekly until discharge.

Despite substantial evidence of the crucial role protein calorie malnutrition (PCM) plays in the occurrence of complications, increased length of stay, and cost of care in hospitalized populations, no standard approach for screening and monitoring the nutritional status of patients initially and throughout admission currently exists. Recognizing that there is a growing public and professional recognition of the importance of malnutrition, a large patient population (30–55%) at risk for PCM, and an even larger population experiencing declining nutritional status during hospitalization, this study examined the feasibility of a full-scale study to assess the value of two biochemical markers, transthyretin and albumin, for detecting and monitoring PCM in hospitalized patients. It was demonstrated that these two markers do provide important information predictive of outcomes for those they identify at risk for PCM. The patients who entered the study with or developed low transthyretin and albumin experienced poorer health outcomes and higher costs of care. Their discharge occurred in an early phase of recovery, with significant implications for after-discharge care. The full-scale study must consider severity of illness and other confounders during randomization and, preferably, be conducted in institutions that currently do not use transthyretin for nutrition assessment.