Serum Transthyretin Research Articles

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.

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.

Transthyretin: its response to malnutrition and stress injury. clinical usefulness and economic implications.

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.

Nutritional regulation of visceral markers in rat liver and cultured hepatoma cells.

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.

Serum transthyretin monomer in patients with familial amyloid polyneuropathy

Although dissociation of the transthyretin (TTR) tetramer is suspected of being the first step in amyloid fibril formation in hereditary TTR amyloidosis, including familial amyloid polyneuropathy (FAP), the TTR monomer has never been examined in vivo. Therefore, we analyzed the TTR monomer in the serum of FAP patients and normal individuals. Free TTR monomer was detected in both groups using gel filtration chromatography and immunoblotting. Both the mean concentration of free TTR monomer and the total serum TTR were significantly lower in FAP patients than in normal individuals. Moreover, in FAP patients, mass spectrometry showed that the variant TTR monomer was markedly decreased compared with the wild-type TTR monomer. These findings suggest that the free variant TTR monomer is unstable in serum, and that it aggregates in deposits in various organs or is adsorbed by preexisting amyloid fibrils before it is degraded.

Detection by Mass Spectrometry of Highly Increased Amount of S- Sulfonated Transthyretin in Serum from a Patient with Molybdenum Cofactor Deficiency

Serum transthyretin has several isoforms, most of which are caused by disulfide linkage with cysteine residue at position 10. We found an ion peak 80 D larger than unmodified transthyretin by electrospray ionization mass spectrometry and assigned it to S-sulfonated transthyretin. The peak height was <2% of total transthyretin in control sera from more than 200 individuals including infants. Transthyretin from a patient with molybdenum cofactor deficiency was analyzed, and the peak was prominent, higher than 85% of total transthyretin. In patients with this disease, the presence of elevated levels of sulfite leads to the formation of S-sulfonated cysteine. The peak can be used as a diagnostic marker for molybdenum cofactor deficiency, although more sera from patients with this disease should be tested.

Standardized thigh muscle area measured by computed axial tomography as an alternate muscle mass index for nutritional assessment of hemodialysis patients

Quantification of muscle mass, which represents the largest protein pool in the body, is important for nutritional assessment but is difficult to achieve with conventional methods in hemodialysis patients. We measured the cross-sectional area of the thigh occupied by muscle by using computed tomography and compared this with other muscle mass indicators. Thigh muscle area (TMA) was examined and correlated with creatinine production and various nutritional indexes in 163 patients undergoing hemodialysis. Where appropriate, TMA was expressed relative to bone area in the thigh (TBA) to avoid the influence of body size. TMA was highly correlated with creatinine production as measured in the spent dialysate (r = 0.85, P < 0.001), indicating that TMA substantially reflects total-body muscle mass. TMA standardized for TBA was negatively correlated with age and positively correlated with other nutritional indicators including body weight, body mass index, serum albumin, serum transthyretin, and protein catabolic rate. Multiple regression analysis revealed that of these variables, age, serum albumin, and protein catabolic rate independently predicted TMA standardized for TBA. By using correlations with various nutritional indicators, we concluded that patients with a value <10.0 for TMA standardized for TBA were likely to be malnourished whereas those with a value >13.0 were likely to be well nourished. These results indicate that TMA standardized for TBA, measured by computed tomography, is a reliable indicator of muscle mass that could be used for nutritional assessment of hemodialysis patients.

Niveles de transtirretina en suero y en líquido cefalorraquídeo apoyan la hipótesis nutrio-vírica de la neuropatía epidémica cubana

Transthyretin is considered an excellent marker for monitoring nutritional status in serum. In cerebrospinal fluid it is synthesized by chroroid plexus. Cuban epidemic neuropathy is an emergent disease with a hypothetically viral and nutritional origin. To know the behavior of this transport molecule in serum and cerebrospinal fluid in patients with Cuban epidemic neuropathy. Serum and cerebrospinal fluid was quantified in 11 patients with Cuban epidemic neuropathy, eight patients suffering from other neuropathies and 15 patients with Down's syndrome and 10 patients with Alzheimer's disease. Serum transthyretin was diminished in patients with Cuban epidemic neuropathy, other neuropathies and Alzheimer's disease. Down's syndrome patients had significantly higher transthyretin levels in comparison with Cuban epidemic neuropathy and Alzheimer's disease. Cerebrospinal fluid transthyretin was significantly increased in patients with Cuban epidemic neuropathy in comparison with the normal values and with Alzheimer's disease patients whose values were settled below the normal values. The decrement of serum transthyretin in Cuban epidemic neuropathy indicates malnutrition and its higher levels in cerebrospinal fluid also indicate a viral infection. These findings support the nutrio-viral hypothesis of the disease.

A Novel Compound Heterozygote (FAP ATTR Arg104His/ATTR Val30Met) with High Serum Transthyretin (TTR) and Retinol Binding Protein (RBP) Levels

A 64-year-old Japanese male suffering from very slowly progressive amyloidosis was studied by immunohistopathologic, mass spectrometric, and molecular genetic methods. After confirming the immunoreactivity of transthyretin (TTR) in the amyloid deposits using an anti-TTR polyclonal antibody, matrix-assisted laser desorption ionization/time-of-flight–mass spectrometry (MALDI/TOF–MS) was employed to look for the presence of variant TTR(s) in the serum. Two variant forms of TTR, one with a molecular weight 32 Da greater and another with a molecular weight 19 Da less than that of normal TTR encoded by the two respective alleles, were detected in this patient. Direct sequence analysis confirmed the presence of a double substitution: one at codon 30 from GTG (Val) to ATG (Met) and the other at codon 104 from CGC (Arg) to CAC (His) in the two alleles. MALDI/TOF–MS of the parents of the proband revealed that his father was a heterozygote of ATTR Arg104His and his mother was a heterozygote of ATTR Val30Met. The total TTR and retinol binding protein (RBP) concentrations in the serum samples of the proband were very high compared with those of FAP ATTR Val30Met patients and control subjects. We report here a new compound heterozygote in the TTR gene with familial amyloidotic polyneuropathy (FAP).

Salivary indicators of protein nutritional status in the elderly

Protein-energy malnutrition (PEM) is a serious nutritional problem in hospitalized elderly patients. Serum albumin, transthyretin (prealbumin), and total protein have been used as biochemical indicators of protein nutritional status, but taking blood from the elderly is difficult and invasive. We therefore assessed the possibility of using saliva or urine as noninvasive materials to estimate serum concentrations of albumin, transthyretin and total protein. Blood, saliva and urine were collected from 32 hospitalized elderly (aged 68–97 y) and the correlation between the concentrations of albumin, transthyretin and total protein in serum and those in saliva or urine were evaluated. There was no correlation among them, but the concentrations of albumin and transthyretin adjusted for the concentration of IgG in saliva were significantly correlated with the concentrations of albumin and transthyretin in serum (albumin: R 2 = 0.308, p = 0.0010, transthyretin: R 2 = 0.433, p < 0.001 by log linear regression analysis). This study suggests the possible usefulness of the concentrations of proteins in the fluids for evaluating protein nutritional status in the elderly. Further studies on the method of adjustment of protein concentrations in saliva and the adaptability to other populations will confirm the results of this study.

Validation of serum transthyretin (prealbumin) as a nutritional parameter in hemodialysis patients

Objective: To evaluate the use of serum transthyretin (TTR) as a valid indicator of nutritional status in the hemodialysis patient and to validate the correlation of low-serum (TTR) levels with established nutrition assessment parameters. Design: Prospective, cohort, correlation analysis. Setting: Free-standing outpatient dialysis center. Patients: Fifty-one stable, chronic hemodialysis patients meeting the following selection criteria: (1) received thrice weekly hemodialysis treatments for greater than 3 months, (2) absence of impaired hepatic function, (3) absence of chronic infection, inflammatory syndromes, or infections in the 3 months before the study, (4) not taking corticosteroids, and (5) willing to participate in the study as evidenced by signing of an informed consent. Intervention: Serum TTR, albumin, blood urea nitrogen, creatinine, cholesterol, postdialysis weight and body mass index were measured monthly for 6 consecutive months. Normalized protein catabolic rate and KT V were measured monthly for 3 consecutive months. Main outcome measures: Nutrition and biochemical indices. Results: The overall mean TTR level was 32 mg/dL ± 7 for the 6-month study period. Thirty-six percent of patients had mean TTR levels less than 30 mg/dL. TTR levels less than 30 mg/dL correlated significantly with urine outputs greater than 240 mL/24 hours, predialysis blood urea nitrogen < 18 mmol/L (<50 mg/dL), and normalized protein catabolic rate less than 0.8 g/kg/d ( P<.05). A significant correlation was found between TTR and creatinine, albumin and loss of dry body weight ( P<.05). Mean TTR levels less than 30 mg/dL were found in 33% of subjects with mean albumin levels greater than 35 g/L (>3.5 g/dL) and in 19% with mean albumin levels greater than 40 g/L (>4.0 g/dL). TTR levels were consistently lower in diabetics for all 6 months (statistically significant in 2 out of 6 months). Conclusion: Measuring serial serum TTR levels in hemodialysis patients is a reliable method for identifying patients in need of nutrition intervention.

Specificity of indexes of malnutrition when applied to apparently healthy people: the effect of age

Protein-energy malnutrition is thought to be widespread in hospitalized patients. However, the specificity of indexes used to assess malnutrition is uncertain. We therefore assessed the rate of false-positive diagnoses of malnutrition when biochemical-anthropometric indexes were applied to healthy subjects. Nutritional status was assessed in 175 healthy blood donors (aged 44.2 +/- 13.4 y) and in 34 highly fit elderly volunteers (aged 74.7 +/- 3.6 y) participating in the Nijmegen Four Days Walking March. We investigated both the Nutritional Risk Index [(1.489 x albumin) + (41.7 x present/usual weight)] and the Maastricht Index [20.68-(0.24 x albumin, g/L)-(19.21 x serum transthyretin, g/L)-(1.86 x lymphocytes, 10(6)/L)-(0.04 x ideal weight)]. We found previously that 52-64% of nonsurgical hospitalized patients were malnourished according to these indexes. In the present study, 1.9% of the 209 volunteers had apparent malnutrition according to the Nutritional Risk Index and 3.8% according to the Maastricht Index. The prevalence of apparent malnutrition in the elderly volunteers was 5.9% and 20.6%, respectively. The rate of false-positive diagnoses was acceptably low in those aged < 70 y with both the Nutritional Risk Index and the Maastricht Index; therefore, the use of these indexes will not cause a clinically significant increase in the prevalence of malnutrition because patients who are not malnourished are included. The high percentage of spurious malnutrition in the elderly limits the use of the Maastricht Index to subjects aged < 70 y.

Sequential changes of inflammatory and nutritional markers in patients with community-acquired pneumonia

Hansson L-O, Hedlund JU, Örtqvist ÅB. Sequential changes of inflammatory and nutritional markers in patients with community-acquired pneumonia. Scand J Clin Lab Invest 1997; 57: 111-118.The aim of the present study was to describe the long-term sequential changes of the acute phase proteins and of commonly used so-called nutritional markers in patients with community-acquired pneumonia (CAP), and to calculate the normalization rate of serum C-reactive protein (CRP), defined as the time for a 50% decrease, during the initial treatment of these patients. The long-term sequential changes of inflammatory and nutritional markers in patients with CAP have not been previously well-documented. However, in the diagnostic work-up of patients with suspected infectious diseases CRP levels are often used nowadays. Serum albumin, transthyretin (prealbumin), and transferrin together with serum iron, have often been used as “nutritional markers” in patients. We therefore studied the long-term changes of these parameters in patients with CAP, as these markers also are influenced by inflammatory reactions, in pneumonia for example. All the patients within the age range 50-85 years, with the exception of immunocompromised patients, who were admitted with CAP to the Department of Infectious Diseases at Danderyd Hospital during a 12-month period (January 1992-January 1993), were reviewed for inclusion in a prospective study of the long-term sequential changes of inflammatory and nutritional markers in CAP patients. A total of 97 patients (50 men) with a mean age of 69.6 years were included in the study. Blood samples were drawn on admission, during the hospitalization period, and at the follow-up visits. Serum CRP, α1antitrypsin, haptoglobin and orosomucoid (α1acid glycoprotein) were used as acute phase proteins. However, albumin, transthyretin, and transferrin together with serum iron and percentage transferrin saturation were also included. Of all the parameters studied, CRP showed the greatest variation, already having the highest values at admission. CRP also showed, together with iron, the earliest response to recovery in the patients. The median time for a 50% decrease of CRP was 3.3 days for the patients (n=73) with more than two CRP values measured during the first nine days. Transthyretin responded faster to patient recovery than did albumin. CRP showed the greatest amplitude of changes and together with iron and percentage saturation of transferrin it also showed the earliest response to recovery in patients with CAP. This indicates that CRP is the best of the parameters studied for use in diagnostic work-up and in follow up.

A new family with hyperthyroxinemia caused by transthyretin Val109 misdiagnosed as thyrotoxicosis and resistance to thyroid hormone--a clinical research center study.

Serum transthyretin (TTR) is a protein of liver origin that under normal conditions transports approximately 20% T4. Missense mutations of the TTR gene produce familial amyloidotic polyneuropathy and rarely, euthyroid hyperthyroxinemia (EHT). Of the 3 TTR variants so far identified with increased affinity for T4, Ser6, Thr109, and Met119, only TTR-Thr109 has high enough affinity for T4 to produce consistent hyperthyroxinemia in the heterozygous individuals. Because the mutation GCC-->ACC in codon 109 results in the loss of one Bso FI site in exon 4 of the TTR gene, the use of this enzyme was suggested to screen for TR-Thr109 in subjects with EHT. We investigated a family with dominantly inherited EHT, in which two of eight affected members received ablative thyroid treatment for presumed thyrotoxicosis, and one was misdiagnosed as having resistance to thyroid hormone. All affected individuals had serum reverse T3 concentrations above normal and average T4 50% above the mean of unaffected relatives. Total T3 and TSH levels were within the normal range. Although loss of the Bso FI site in one allele of the two TTR suggested the presence of Thr109, gene sequencing revealed a different mutation in the same codon (GCC-->GTC) producing TTR-Val109. T4-binding to TTR-Val109 was compared to that of the normal TTR-Ala109 and the formerly identified variant TTR-Thr109. Association constants were 1.3, 9.5, and 13.6 X 10(7) M-1 for TTR-Ala109, Val109, and Thr109, respectively. Thus, for equally expressed mutant and normal allele and 20% of serum T4 bound to TTR, the calculated mean serum T4 concentration of heterozygotes for TTR-Val109 should be 50% above the normal mean; the observed value being 55%. These results are in agreement with the observations based on the crystallographic structure of TTR-Thr109 indicating that the extra atoms in Val as in Thr, which are absent in the Ala of the wild type TTR, widen the ligand binding site.

Serum osteocalcin regulation in protein-energy malnourished children.

To evaluate bone turnover changes occurring during protein-energy malnutrition, serum osteocalcin, a marker of bone formation, has been studied in healthy control, stunted, and severely malnourished (kwashiorkor and marasmus) Senegalese children. Serum osteocalcin levels were dramatically reduced in stunted, kwashiorkor, and marasmic children compared with control children. In addition serum osteocalcin levels of control children living in Senegal were lower (-46%) than those of African children living in France. Interestingly, serum osteocalcin level was not related to its major known regulators (1 alpha,25-dihydroxycholecalciferol, 25-hydroxycholecalciferol, and PTH) nor to stunting, but was related to serum transthyretin and thyroid hormones concentrations. These data suggest that serum osteocalcin level is related to protein-energy status and that bone formation was affected in apparently healthy and in malnourished Senegalese children. Serum osteocalcin could be a potent tool in the study of the alterations of bone formation in malnutrition.

Purification and Characterization of Amyloid-Related Transthyretin Associated with Familial Amyloidotic Cardiomyopathy

Analysis of amyloid fibril material associated with familial amyloidotic cardiomyopathy revealed that it contains a mixture of transthyretin-related polypeptides. The major protein band in SDS/polyacrylamide gel corresponding to a molecular mass of 14.5 kDa, consists of transthyretin fragments starting at positions 46, 49 and 59, the latter not previously identified, and one blocked fragment derived from the N-terminal part of transthyretin. In reverse-phase HPLC, the major fragment recovered was that starting at Thr49, indicating a trypsin-like cleavage (Lys at position 48). Two minor bands, corresponding to 17 kDa and 35 kDa, contained proteins with blocked N-termini, and migrated as monomeric and dimeric transthyretin, respectively. A 13-kDa protein band was found to contain transthyretin with a ragged N-terminus, mainly starting at positions 2 and 5. Three more bands, corresponding to 10, 25 and 29 kDa, consist of transthyretin molecules with blocked N-termini and most likely of aggregates of truncated molecules. A point mutation of amyloid transthyretin was identified at position 111 (Met instead of Leu in normal serum transthyretin) which confirms the mutation found for Danish siblings with familial amyloidotic cardiomyopathy. However, the presence of a non-variant amyloid transthyretin was also observed, indicating that the Danish kindred is heterozygous with respect to this point mutation. Isoelectric focusing of the amyloid fibril material resolved multiple protein bands ranging over pH 4.5-6.5, confirming heterogeneities. Methanol extraction of the cardiac amyloid fibril material prior to the purification steps reveals a methanol-soluble substance amounting to about 10% (by mass dry material) of the amyloid fibril material. A yellow substance in this fraction shows absorbance maxima (270, 280 and 430 nm) similar to those observed for transthyretin in normal serum. Gas chromatography/mass spectrometry of the methanol extract revealed the presence of saturated fatty acids (C14:0, C16:0 and C18:0 in the corresponding ratio 2:8:5) and polyunsaturated fatty acids (C16:1, C18:1, C18:2 and C20:4 in the corresponding ratio of 1:2:1:1) as further constituents of the amyloid fibril material.

Purification and Characterization of Amyloid‐Related Transthyretin Associated with Familial Amyloidotic Cardiomyopathy

Analysis of amyloid fibril material associated with familial amyloidotic cardiomyopathy revealed that it contains a mixture of transthyretin‐related polypeptides. The major protein band in SDS/polyacrylamide gel corresponding to a molecular mass of 14.5 kDa, consists of transthyretin fragments starting at positions 46, 49 and 59, the latter not previously identified, and one blocked fragment derived from the N‐terminal part of transthyretin. In reverse‐phase HPLC, the major fragment recovered was that starting at Thr49, indicating a trypsin‐like cleavage (Lys at position 48). Two minor bands, corresponding to 17 kDa and 35 kDa, contained proteins with blocked N‐termini, and migrated as monomeric and dimeric transthyretin, respectively. A 13‐kDa protein band was found to contain transthyretin with a ragged N‐terminus, mainly starting at positions 2 and 5. Three more bands, corresponding to 10, 25 and 29 kDa, consist of transthyretin molecules with blocked N‐termini and most likely of aggregates of truncated molecules.A point mutation of amyloid transthyretin was identified at position 111 (Met instead of Leu in normal serum transthyretin) which confirms the mutation found for Danish siblings with familial amyloidotic cardiomyopathy. However, the presence of a non‐variant amyloid transthyretin was also observed, indicating that the Danish kindred is heterozygous with respect to this point mutation. Isoelectric focusing of the amyloid fibril material resolved multiple protein bands ranging over pH4.5–6.5, confirming heterogeneities.Methanol extraction of the cardiac amyloid fibril material prior to the purification steps reveals a methanol‐soluble substance amounting to about 10% (by mass dry material) of the amyloid fibril material. A yellow substance in this fraction shows absorbance maxima (270, 280 and 430 nm) similar to those observed for transthyretin in normal serum. Gas chromatography/mass spectrometry of the methanol extract revealed the presence of saturated fatty acids (C14:0, C16:0 and C18:0 in the corresponding ratio 2:8:5) and polyunsaturated fatty acids (C16:1, C18:1, C18:2 and C20:4 in the corresponding ratio of 1:2:1:1) as further constituents of the amyloid fibril material.

Transport of Serum Transthyretin into Chicken Oocytes: A RECEPTOR-MEDIATED MECHANISM

Transthyretin (TTR) is involved in the transport of thyroid hormones and, due to its interaction with serum retinol-binding protein, also of vitamin A. The importance of both ligands in vertebrate embryonic development has prompted us to investigate the molecular details of TTR transport function in a powerful germ cell system, the rapidly growing chicken oocytes. Yolk TTR is derived from the circulatory system, since biotinylated TTR was recovered by immunoaffinity chromatography of yolk obtained from a hen previously infused with in vitro biotinylated chicken serum proteins. In concordance with the intraoocytic localization in an endosomal compartment, ligand blotting and chemical cross-linking experiments revealed the presence of a approximately 115-kDa TTR-binding oocyte membrane protein. This putative TTR receptor was not detected in chicken ovarian granulosa cells or embryonic fibroblasts and was different from the previously described oocyte-specific receptor for two estrogen-induced chicken serum lipoproteins, vitellogenin and very low density lipoprotein (Barber, D. L., Sanders, E. J., Aebersold, R., and Schneider, W. J. (1991) J. Biol. Chem. 266, 18761-18770). Furthermore, in contrast to the serum levels of the yolk precursor lipoproteins, those of TTR were not significantly changed by estrogen; thus, TTR represents a newly defined, estrogen-independent class of yolk precursor proteins. These data strongly suggest that oocytic TTR is derived from the circulation, where it is a constitutive component, and deposited into yolk as a result of endocytosis mediated by a specific receptor.

Clinical Associations of an Increased Transthyretin Band in Routine Serum and Urine Protein Electrophoresis

The 9697 electrophoretograms performed over an 8 year period were reviewed to identify the frequency and clinical associations of the finding of a prominent transthyretin band in serum or urine, the concentration of which was equal to or greater than a 64 mg/dL protein calibrator. All samples were electrophoresed at a constant 90 V using agarose gels with a barbital buffer pH 8.6 and Ponceau S staining. Reference calibrators were used as standards to identify increased transthyretin bands and the patients' clinical records were subsequently reviewed. High values were found in 46 patients' sera and a further nine patients' urines representing 0.57% of the total workload. Renal impairment was present in 58% of cases including those with chronic renal failure, the nephrotic syndrome and paraproteinaemia. The high levels were not persistent in three myeloma cases where there was a recovery in renal function following chemotherapy. In some nephrotics, a high urine transthyretin may be secondary to a general hepatic albumin and transport protein synthesis response to severe proteinuria. Why the serum transthyretin was elevated in many other cases remains unclear.

Serum osteocalcin concentrations in protein and/or energy restricted rats

The effects of protein and/or energy deficiency on serum osteocalcin concentrations were studied in growing rats. Animals were fed a high or a low protein diet (respectively 22 and 6% casein) either ad libitum or restricted (60%). After four weeks, serum osteocalcin concentrations were significantly decreased by imposed energy restriction. However, they were not affected by protein deficiency, although growth was similarly reduced in both cases. By comparison, serum transthyretin concentrations were decreased by protein and/or energy deficiency, and they were significantly correlated with serum osteocalcin concentrations. These results suggest that serum osteocalcin concentrations are not a reflection of bone growth in protein and energy restricted rats, but are related to energy availability.