Observations with regard to the National Kidney Foundation K/DOQI clinical practice guidelines concerning serum transthyretin in chronic renal failure.

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.     

Metabolism and clinical interest of serum transthyretin (prealbumin) in dialysis patients.

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.     

Significance of transthyretin in protein metabolism.

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 protein-energy 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.     

Is serum transthyretin a reliable marker of nutritional status in patients with end-stage renal disease?

ObjectiveTo test the value of serum transthyretin (TTR) concentration as a nutritional marker in renal patients.MethodsThe study included 115 renal patients, out of which 35 are on conservative treatment, 50 on hemodialysis and 30 renal transplant recipients, and 31 healthy control subjects. Serum TTR, albumin, transferrin, C-reactive protein (CRP) and α1 anti trypsine (AAT) were assessed by immunoturbidimetry, and vitamin A by HPLC. Linear regression models were applied to test the association between serum TTR and body mass index (BMI).ResultsSerum TTR concentrations were normal, but serum vitamin A, CRP and AAT concentrations were significantly higher in patients. In renal patients, serum TTR was positively and independently related to BMI and was significantly lower in malnourished than well-nourished patients (367 ± 91 vs. 417 ± 130 mg/L; p = 0.05). The risk of serum TTR < 300 mg/L was higher in malnourished patients [OR, 4.82 (1.78–13.2); p = 0.001].ConclusionSerum TTR concentrations were at normal range in renal patients despite evidence of malnutrition and inflammation. However, they were related to BMI and were significantly lowered in malnourished patients. Thus, serum TTR would reflect nutritional status in renal patients. However, the cutoff of malnutrition should be raised to 300 mg/L.     

Protein status in pancreatitis--transthyretin is a sensitive biomarker of malnutrition in acute and chronic pancreatitis.

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 CPthan 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 as a marker to predict outcome in critically ill patients

BackgroundA determination of serum Transthyretin (TTR, Prealbumin) level is an objective method of assessing protein catabolic loss of severely ill patients and numerous studies have shown that TTR levels correlate with patient outcomes of non-critically ill patients. We evaluated whether TTR level correlates with the prevalence of PEM in the ICU and evaluated serum TTR level as an indicator of the effectiveness of nutrition support and the prognosis in critically ill patients.MethodsWe studied PEM prevalence in 118 patients admitted to a community hospital's medical intensive care unit and the association between TTR, low albumin (ALB) concentration and high-risk disease (HRD), i.e., sepsis, inability to take in oral nutrients, etc. Serum TTR was measured on the day of admission, day 3 and day 7 of their ICU stay. APACHE II and SOFA score was assessed on the day of admission and the nutritional status and nutritional requirement was assessed for their entire ICU stay. Patients were divided into three groups based on initial TTR level and the outcome analysis was performed for APACHE II score, SOFA score, ICU length of stay, hospital length of stay, and mortality.ResultsTTR showed excellent concordance with patients classified with PEM or at high malnutrition risk, and followed for 7 days, it is a measure of the metabolic burden. TTR levels decline from day 1 to day 7 in spite of providing nutritional support. Patients were classified in 3 categories with respect to the level of TTR: more than 170 mg/L, twenty-five patients (group 3); 100–170 mg/L, forty-eight patients (group 2); less than 100 mg/L, forty-five patients (group 1). TTR level correlated with ICU length of stay, hospital length of stay, and APACHE II score, and predicts mortality.ConclusionsTTR identified patients at highest risk for metabolic losses associated with stress hypermetabolism as serum TTR levels did not respond early to nutrition support because of the delayed return to anabolic status. It is particularly helpful in removing interpretation bias, and it is an excellent measure of the systemic inflammatory response concurrent with a preexisting state of chronic inanition.     

Assessment of nutritional status in organ transplant: is transthyretin a reliable indicator?

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.     

C-reactive protein to transthyretin ratio for the early diagnosis and follow-up of postoperative infection.

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 othertrauma 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.     

血清瘦素、肿瘤坏死因子α及白细胞介素6与慢性阻塞性肺疾病缓解期患者营养不良的相关性

目的探讨血清瘦素(leptin)、肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6)与慢性阻塞性肺病(chronicobstructive pulmonary disease,COPD)缓解期患者营养状况的关系。方法测定50例COPD缓解期男性患者(营养不良组25例、非营养不良组25例)及25例正常人的leptin、TNF-α、IL-6水平和理想体质量百分比(NBM%)、体质量指数(BMI)、三头肌皮褶厚度(TSF)、上臂肌围(AMC)、血清白蛋白(ALB)等营养学指标,并分析leptin、TNF-α、IL-6水平与营养学指标的相关性。结果 COPD营养不良组TNF-α及IL-6水平均明显高于COPD非营养不良组(P<0.01)。COPD营养不良组leptin水平明显低于COPD非营养不良组,(4.74±0.92)μg/L vs(6.96±0.75)μg/L(P<0.01)。3组血清leptin浓度与NBM、BMI、TSF、AMC等营养学指标均有明显正相关(P<0.01)。COPD营养不良组血清TNF-α浓度与NBM、BMI正相关性(P<0.05),与余各指标均无相关性。3组血清IL-6浓度与营养学指标、leptin及TNF-α均无相关性。结论 leptin与COPD缓解期患者营养学指标有明显相关性。     

Low levels of plasma proteins: malnutrition or inflammation?

Levels of several plasma proteins, including albumin, transferrin, and transthyretin (prealbumin), have been proposed as markers for protein energy malnutrition. However, many other factors, especially inflammatory disease and drug or hormone therapy, affect levels of these proteins. These factors probably account for the majority of low levels of transthyretin. Levels of albumin and other proteins may be helpful in determining increased risk of morbidity and mortality, but better markers are needed for diagnosis of protein energy malnutrition per se.     

Dysprealbuminemic hyperthyroxinemia in a patient with hyperthyroid graves disease

Rare mutant forms of circulating albumin and prealbumin [transthyretin (TTR)] have increased binding affinity for thyroxine (T4). Patients with these variant plasma proteins, as a result of inherited mutations or as a paraneoplastic phenomenon, typically present with increased serum total T4 and, by some assay methodologies, an increased free T4 as well. Although these individuals are, in fact, euthyroid, nonspecific symptoms may lead to inappropriate treatment for hyperthyroidism. We present a 34-year-old woman in whom a mutant form of TTR with increased T4 binding affinity and coexisting Graves disease was present. Subsequent 131I therapy led to development of postablative hypothyroidism, which was obscured by her higher serum free T4 concentration. Circulating thyroid-binding globulin (TBG), albumin, and TTR concentrations were all within their respective reference limits. A T4-binding protein panel confirmed that TTR-bound T4 was significantly increased, whereas TBG- and albumin-bound T4 was normal, indicating that this patient had euthyroid dysprealbuminemic hyperthyroxinemia, which had been masked by the initial presentation of hyperthyroidism. These findings indicate that hypothyroidism can be masked by coexisting euthyroid dysprealbuminemic hyperthyroxinemia.     

The role of visceral protein markers in protein calorie malnutrition.

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.     

Transthyretin from discovery to now.

As introduction to the First International Congress on Transthyretin in Health and Disease, this lecture traces the origin of the subjectfrom 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.     

探讨鉴别诊断肺癌与肺感染患者的生物标志物

目的:探讨肺癌与肺感染患者之间生化成分含量以及蛋白组学变化,用于筛选诊断恶性胸腔积液的生物标志物。方法:(1)分别测定肺癌和肺感染患者血清和胸腔积液总蛋白、白蛋白、甘油三酯等10项生化成分含量,进一步比较两组之间各项指标的胸腔积液与血清的比值。(2)基质辅助激光电离飞行时间质谱(MALDI-TOF-MS)分析TTR蛋白化学修饰。结果:(1)肺癌患者血清中CHO、ApoA-1、TTR蛋白含量明显高于肺感染患者;而肺感染患者胸腔积液中ADA的活性高于肺癌患者。(2)计算个体胸腔积液与血清生化成分含量比值,肺癌患者TTR蛋白比例显著高于肺感染患者,ADA减低,与血清变化趋势相同,但更加明显。(3)肺癌患者及肺感染患者血清TTR蛋白均出现3种修饰类型,而肺癌患者胸腔积液中cysgly-TTR明显增高。结论:联合分析胸腔积液与血清TTR蛋白的比值和化学修饰,可能有助于鉴别诊断肺癌与肺感染。     

Biochemical indices to evaluate nutritional support for malignant disease

Malignant diseases are often complicated by malnutrition, and nutritional support is often indicated. Nutritional support should be evaluated primarily by improved clinical outcome. During nutritional support as artificial nutrition, monitoring is of paramount importance.

Several biochemical markers are frequently used to monitor nutritional status. Most widely used are serum levels of albumin, transferrin, and transthyretin which are subnormal in malnutrition. Unfortunately, monitoring nutritional support by biochemical indices in malignant disease is complicated by the pathophysiology of cancer related malnutrition. Systemic inflammation is central in this context as it perturbs most of the traditional biochemical indices, and is inversely correlated to survival. In addition, systemic inflammation explains variations in body composition. Thus, the most important biochemical index to be measured in malignant disease is the assessment of systemic inflammatory response, preferably by high-resolution CRP, and if normal, common biochemical indices such as albumin, transferrin or transthyretin might be used. Preferentially, indices with high turnover should be used. IGF-1 is an index well suited for assessing nutrition support in conventional malnutrition, but its use in malignant disease is still unproved. If APPR is prevalent, methods detecting changes in body composition, performance or physical activity might offer better options to evaluate nutritional support.     

Presence of a plasma transthyretin (prealbumin) variant in familial amyloidotic polyneuropathy in a kindred of Greek origin

Human plasma transthyretin (TTR, a protein formerly called prealbumin) is known to be associated with familial amyloidotic polyneuropathy (FAP) of autosomal inheritance. A variant TTR with a methionine-for-valine substitution at position 30 has been described as the major protein component of amyloid in Portuguese and Japanese patients with FAP and in patients of Swedish ancestry with FAP. In these patients, TTR(Met30) also circulates in relatively low concentration in the plasma. TTR variants having substitutions in other positions have also been reported in a patient of Jewish origin with FAP. We now report studies on TTR from an FAP kindred of Greek ancestry. By peptide mapping analysis, plasma TTR from the propositus was compared with TTR from a Portuguese patient with FAP. TTR(Met30) was found to circulate in the blood plasma of the Greek propositus. By use of a recently developed immunoblotting technique, this variant TTR was also detected in some of the relatives of the propositus. Future studies of this mutant gene among ethnically different FAP populations might contribute to an understanding of selection and persistence of the mutation.     

Outcomes of continuous process improvement of a nutritional care program incorporating TTR measurement.

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.     

Usefulness of data on albumin and prealbumin concentrations in determining effectiveness of nutritional support

In this ongoing study, albumin and prealbumin (transthyretin) changes were compared in 40 patients managed with enteral and (or) parental support with attainment of caloric/protein goals. The concentration of prealbumin in serum changed rapidly and more accurately reflected current nutritional status of these patients than did that of albumin. We determined concentrations of albumin and prealbumin that reflected significant improvement in nutritional status, using Rudolph's approach based on Shannon information measures. Reference values for albumin and prealbumin in the treatment populations were 25 g/L and 107 mg/L, respectively. A prealbumin concentration of 135 mg/L or greater reflected a return to stable status.     

Mechanisms of molecular recognition: crystal structure analysis of human and rat transthyretin inhibitor complexes.

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.