Revisiting PINI Scoring in Light of Recent Biological Advances.

The prognostic inflammatory and nutritional index (PINI) is a simple scoring formula allowing the follow-up of dietary protein restriction and infectious complications affecting critically ill patients hospitalized in medical and surgical wards. The World Health organization (WHO) has recently recommended using the binary CRP (C-reactive protein) and AGP (α1-acid glycoprotein) numerators of the PINI formula in underprivileged inhabitants of developing countries to evaluate their (sub)clinical infectious states making their chronic malnutrition worse. These studies, mainly located in Africa and Asia, demonstrate that children and women enduring the combined effects of infectious burden and (micro)nutrient deprivation (principally retinol and iron) usually manifest persistent refractoriness and slackened recovery throughout dietary rehabilitation. The additive measurement of ALB (albumin) and TTR (transthyretin) composing the denominator of the PINI formula is shown to be helpful in grading the downsizing of lean body mass (LBM), a cornerstone of bodybuilding. The confrontation of these four objective parameters thus allows the quantification of the respective importance of nutritional and inflammatory components of any disease process, taking into account that TTR is the sole plasma protein remaining highly correlated to the fluctuations of LBM. The below review highlights the prevailing roles played by protein nutritional states in the release of plasma retinol to target tissues and to the restoration of iron-deficient anemias.

Plasma transthyretin is a nutritional biomarker in human morbidities.

Transthyretin (TTR) is a small liver-secreted plasma protein that shows close correlations with changes in lean body mass (LBM) during the entire human lifespan and agglomerates the bulk of nitrogen (N)-containing substrates, hence constituting the cornerstone of body building. Amino acids (AAs) dietary restriction causes inhibition of TTR production and impairs the accretion of LBM reserves. Inflammatory disorders result in cytokine-induced abrogation of TTR synthesis and urinary leakage of nitrogenous catabolites. Taken together, the data indicate that malnutrition and inflammation may similarly suppress the production of TTR through distinct and unrelated pathophysiological mechanisms while operating in concert to downsize LBM stores. The hepatic synthesis of TTR integrates both machineries, acting as a marker of reduced LBM resources still available for defense and repair processes. TTR operates as a universal surrogate analyte that allows for the grading of residual LBM capacity to reflect disease burden. Measurement of TTR is a simple, rapid, and inexpensive micro-method that may be reproduced on a daily basis, hence ideally suited for the follow-up of the most intricated clinical situations and as a reliable predictor of any morbidity outcome.

Implications of protein malnutrition and inflammatory disorders in the pathophysiology of Alzheimer's disease.

Lean body mass (LBM) agglomerates the bulk of nitrogen (N)-containing molecules following well-identified age and sex evolutionary patterns best appraised in clinical practice using the serial measurement of plasma transthyretin (TTR). Methionine (Met), the sole essential amino acid bearing a sulfur (S) atom, presides at the initiation of protein synthesis while maintaining stable body tissue S:N molar ratios of approximately 1:14.5. In protein- depleted states, N- and Met-deficiencies operate as limiting factors for LBM protein synthesis and accretion, causing growth retardation and subnormal TTR plasma values. In inflammatory disorders, LBM is subjected to cytokine-induced tissue breakdown reflecting the S:N ratio found in healthy tissues whereas the liver secretion of TTR declines in proportion. Both malnutrition and inflammation are characterized by stepwise LBM downsizing and reduced bioavailability of Met body stores setting in motion molecular mechanisms safeguarding Met homeostasis at the expense of augmented homocysteine (Hcy) values in biological fluids. Divergent TTR and Hcy alterations indicate that rising Hcy values measured in plasma and cerebrospinal fluid should be regarded as the dark side of efficient compensatory processes. As a result, the neuroprotective activities normally exerted by TTR are weakened, whereas the oxidative burden generated by supranormal Hcy concentrations are strengthened. The combination of protein malnutrition and inflammatory disorders of any cause maximizes the risk of incurable neurodegenerative effects.

Plasma Transthyretin as A Biomarker of Sarcopenia in Elderly Subjects.

Skeletal muscle (SM) mass, the chief component of the structural compartment belonging to lean body mass (LBM), undergoes sarcopenia with increasing age. Decreased SM in elderly persons is a naturally occurring process that may be accelerated by acute or chronic nutritional deficiencies and/or inflammatory disorders, declining processes associated with harmful complications. A recently published position paper by European experts has provided an overall survey on the definition and diagnosis of sarcopenia in elderly persons. The present review describes the additional contributory role played by the noninvasive transthyretin (TTR) micromethod. The body mass index (BMI) formula is currently used in clinical studies as a criterion of good health to detect, prevent, and follow up on the downward trend of muscle mass. The recent upsurge of sarcopenic obesity with its multiple subclasses has led to a confused stratification of SM and fat stores, prompting workers to eliminate BMI from screening programs. As a result, investigators are now focusing on indices of protein status that participate in SM growth, maturation, and catabolism that might serve to identify sarcopenia trajectories. Plasma TTR is clearly superior to all other hepatic biomarkers, showing the same evolutionary patterns as those displayed in health and disease by both visceral and structural LBM compartments. As a result, this TTR parameter maintains positive correlations with muscle mass downsizing in elderly persons. The liver synthesis of TTR is downregulated in protein-depleted states and suppressed in cytokine-induced inflammatory disorders. TTR integrates the centrally-mediated regulatory mechanisms governing the balance between protein accretion and protein breakdown, emerging as the ultimate indicator of LBM resources. This review proposes the adoption of a gray zone defined by cut-off values ranging from 200 mg/L to 100 mg/L between which TTR plasma values may fluctuate and predict either the best or the worst outcome. The best outcome occurs when appropriate dietary, medicinal and surgical decisions are undertaken, resuming TTR synthesis which manifests rising trends towards pre-stress levels. The worst occurs when all therapeutic means fail to succeed, leading inevitably to complete exhaustion of LBM and SM metabolic resources with an ensuing fatal outcome. Some patients may remain unresponsive in the middle of the gray area, combining steady clinical states with persistent stagnant TTR values. Using the serial measurement of plasma TTR values, these last patients should be treated with the most aggressive and appropriate therapeutic strategies to ensure the best outcome.

The Retinol Circulating Complex Releases Hormonal Ligands During Acute Stress Disorders.

Intensive care workers actively participate in very hot debates aiming at defining the true metabolic, hormonal and nutritional requirements of critically ill patients, the contributory roles played by thyroid and retinoid ligands being largely underestimated. The present article makes up for redressing the balance on behalf of these last hormonal compounds. The retinol circulating complex is transported in the bloodstream in the form of a trimolecular edifice made up of transthyretin (TTR), retinol-binding protein (RBP) and its retinol ligand. TTR reflects the size of the lean body mass (LBM) and is one of the 3 carrier-proteins of thyroid hormones whereas RBP is the sole conveyor of retinol in human plasma. In acute inflammatory disorders, both TTR and RBP analytes experience abrupt cytokine-induced suppressed hepatic synthesis whose amplitude is dependent on the duration and severity of the inflammatory burden. The steep drop in TTR and RBP plasma values releases thyroxine and retinol ligands in their physiologically active forms, creating free pools estimated to be 10-20 times larger than those described in healthy subjects. The peak endocrine influence is reached on day 4 and the freed ligands undergo instant cellular overconsumption and urinary leakage of unmetabolized fractions. As a result of these transient hyperthyroid and hyperretinoid states, helpful stimulatory and/or inhibitory processes are set in motion, operating as second frontlines fine-tuning the impulses primarily initiated by cytokines. The data explain why preexisting protein malnutrition, as assessed by subnormal LBM and TTR values, impairs the development of appropriate recovery processes in critically ill patients. These findings have survival implications, emphasizing the need for more adapted therapeutic strategies in intensive care units.

Lean Body Mass Harbors Sensing Mechanisms that Allow Safeguarding of Methionine Homeostasis.

Protein-depleted states generate allosteric inhibition of liver cystathionine ß-synthase (CBS), which governs the first enzymatic step of the transsulfuration cascade, resulting in upstream accretion of homocysteine (Hcy) in body fluids. A similar Hcy increase may arise from normal hepatocytes undergoing experimentally-induced impairment of betaine-homocysteine methyltransferase (BHTM) activity or from components of lean body mass (LBM) submitted to any inflammatory disorder. LBM comprises a composite agglomeration of extrarenal tissues characterized by naturally occurring BHTM inactivity. As a result of cellular injury, LBM releases high concentrations of Hcy into the extracellular space, contrasting with the disruption of normal remethylation pathways. Hyperhomocysteinemia acts as a biomarker, reflecting the severity of insult and operating as an alarm signal. Elevated Hcy levels constitute a precursor pool recognized by a CBS coding region that reacts to meet increased methionine requirements in LBM tissues, using its enhanced production in hepatocytes. Preservation of methionine homeostasis benefits from its high metabolic priority and survival value.

Plasma Transthyretin as a Biomarker of Lean Body Mass and Catabolic States.

Plasma transthyretin (TTR) is a plasma protein secreted by the liver that circulates bound to retinol-binding protein 4 (RBP4) and its retinol ligand. TTR is the sole plasma protein that reveals from birth to old age evolutionary patterns that are closely superimposable to those of lean body mass (LBM) and thus works as the best surrogate analyte of LBM. Any alteration in energy-to-protein balance impairs the accretion of LBM reserves and causes early depression of TTR production. In acute inflammatory states, cytokines induce urinary leakage of nitrogenous catabolites, deplete LBM stores, and cause an abrupt decrease in TTR and RBP4 concentrations. As a result, thyroxine and retinol ligands are released in free form, creating a second frontline that strengthens that primarily initiated by cytokines. Malnutrition and inflammation thus keep in check TTR and RBP4 secretion by using distinct and unrelated physiologic pathways, but they operate in concert to downregulate LBM stores. The biomarker complex integrates these opposite mechanisms at any time and thereby constitutes an ideally suited tool to determine residual LBM resources still available for metabolic responses, hence predicting outcomes of the most interwoven disease conditions.

Downsizing of lean body mass is a key determinant of Alzheimer's disease.

Lean body mass (LBM) encompasses all metabolically active organs distributed into visceral and structural tissue compartments and collecting the bulk of N and K stores of the human body. Transthyretin (TTR) is a plasma protein mainly secreted by the liver within a trimolecular TTR-RBP-retinol complex revealing from birth to old age strikingly similar evolutionary patterns with LBM in health and disease. TTR is also synthesized by the choroid plexus along distinct regulatory pathways. Chronic dietary methionine (Met) deprivation or cytokine-induced inflammatory disorders generates LBM downsizing following differentiated physiopathological processes. Met-restricted regimens downregulate the transsulfuration cascade causing upstream elevation of homocysteine (Hcy) safeguarding Met homeostasis and downstream drop of hydrogen sulfide (H2S) impairing anti-oxidative capacities. Elderly persons constitute a vulnerable population group exposed to increasing Hcy burden and declining H2S protection, notably in plant-eating communities or in the course of inflammatory illnesses. Appropriate correction of defective protein status and eradication of inflammatory processes may restore an appropriate LBM size allowing the hepatic production of the retinol circulating complex to resume, in contrast with the refractory choroidal TTR secretory process. As a result of improved health status, augmented concentrations of plasma-derived TTR and retinol may reach the cerebrospinal fluid and dismantle senile amyloid plaques, contributing to the prevention or the delay of the onset of neurodegenerative events in elderly subjects at risk of Alzheimer's disease.

Nutritional essentiality of sulfur in health and disease.

Sulfur is the seventh most abundant element measurable in the human body and is supplied mainly by the intake of methionine (Met), an indispensable amino acid found in plant and animal proteins. Met controls the initiation of protein synthesis, governs major metabolic and catalytic activities, and may undergo reversible redox processes safeguarding protein integrity. Withdrawal of Met from customary diets causes the greatest downsizing of lean body mass following either unachieved replenishment (malnutrition) or excessive losses (inflammation). These physiopathologically unrelated morbidities nevertheless stimulate comparable remethylation reactions from homocysteine, indicating that Met homeostasis benefits from high metabolic priority. Inhibition of cystathionine-ß-synthase activity causes the upstream sequestration of homocysteine and the downstream drop in cysteine and glutathione. Consequently, the enzymatic production of hydrogen sulfide and the nonenzymatic reduction of elemental sulfur to hydrogen sulfide are impaired. Sulfur operates as cofactor of several enzymes critically involved in the regulation of oxidative processes. A combination of malnutrition and nutritional deprivation of sulfur maximizes the risk of cardiovascular disorders and stroke, constituting a novel clinical entity that threatens plant-eating population groups.

Vegetarianism produces subclinical malnutrition, hyperhomocysteinemia and atherogenesis.

OBJECTIVE: To explain why vegetarian subjects develop morbidity and mortality from cardiovascular diseases unrelated to vitamin B status and Framingham criteria. METHODS: A study of 24 rural male subjects 18 to 30 y old and 15 urban male controls was conducted in the Sahel region of Chad. Food consumption was determined from a dietary questionnaire, and overall health status was assessed by body weight, body mass index, serum albumin, plasma transthyretin, urinary nitrogen, and creatinine. Plasma lipids, vitamins B6, B9 and B12, homocysteine, and related sulfur amino acids were measured as selected cardiovascular disease risk factors. RESULTS: Body weight, body mass index, blood, and urinary markers of protein status were significantly lower, with an estimated 10% decrease of lean body mass in the study group compared with urban controls. Neither lipid fractions nor plasma levels of vitamins B6, B9, and B12 were significantly different between the two groups. Although the mean consumption of sulfur amino acids (10.4 mg·kg(-1)·d(-1)) by rural subjects was significantly below the recommended dietary allowances (13 mg·kg(-1)·d(-1)), plasma methionine values were similar in the two groups. In contrast, homocysteine concentration was significantly increased (18.6 µmol/L, P < 0.001), and the levels of cysteine and glutathione were significantly decreased in the study group, demonstrating inhibition of the trans-sulfuration pathway. The strong negative correlation (r = -0.71) between transthyretin and homocysteine implicated lean body mass as a critical determinant of hyperhomocysteinemia. CONCLUSION: The low dietary intake of protein and sulfur amino acids by a plant-eating population leads to subclinical protein malnutrition, explaining the origin of hyperhomocysteinemia and the increased vulnerability of these vegetarian subjects to cardiovascular diseases.

The nutritional relationship linking sulfur to nitrogen in living organisms.

Nitrogen (N) and sulfur (S) coexist in the biosphere as free elements or in the form of simple inorganic NO3- and SO4(2-) oxyanions, which must be reduced before undergoing anabolic processes leading to the production of methionine (Met) and other S-containing molecules. Both N and S pathways are tightly regulated in plant tissues so as to maintain S:N ratios ranging from 1:20 to 1:35. As a result, plant products do not adequately fulfill human tissue requirements, whose mean S:N ratios amount to 1:14.5. The evolutionary patterns of total body N (TBN) and of total body S (TBS) offer from birth to death sex- and age-related specificities well identified by the serial measurement of plasma transthyretin (TTR). Met is regarded as the most limiting of all indispensable amino acids (IAAs) because of its participation in a myriad of molecular, structural, and metabolic activities of survival importance. Met homeostasis is regulated by subtle competitive interactions between transsulfuration and remethylation pathways of homocysteine (Hcy) and by the actual level of TBN reserves working as a direct sensor of cystathionine-beta-synthase activity. Under steady-state conditions, the dietary intake of SO4(2-) is essentially equal to total sulfaturia. The recommended dietary allowances for both S-containing AAs allotted to replace the minimal obligatory losses resulting from endogenous catabolism is largely covered by Western customary diets. By contrast, strict vegans and low-income populations living in plant-eating countries incur the risk of chronic N and Met dietary deficiencies causing undesirable hyperhomocysteinemia best explained by the downsizing of their TBN resources and documented by declining TTR plasma values.

The essentiality of sulfur is closely related to nitrogen metabolism: a clue to hyperhomocysteinaemia.

N and S metabolisms are closely interwoven throughout both the plant and animal kingdoms. The essentiality of S relates to its participation in the structure of S-containing amino acids (SAA), to its inclusion in many sulfonated molecules, and to a myriad of metabolic and catalytic reactions of vital importance. Methionine (Met) is the indispensable SAA supplied by food proteins and its plasma homeostasis is achieved via a number of highly efficient regulatory mechanisms. In all conditions characterised by a negative body protein balance such as in dietary restriction or cytokine-induced hypercatabolic losses, N and S endogenous pools manifest parallel tissue depletion rates. Adaptive conservation of N and S body stores is reached by a functional restraint of the trans-sulfuration cascade, through the depression of cystathionine beta-synthase activity. As a result, upstream accumulation of homocysteine favours its re-methylation conversion to Met which helps maintain metabolic pathways of survival value. In addition to the measurement of vitamin indices, that of plasma transthyretin, a sensitive marker of protein nutritional status, is proposed to identify the fluctuations of the total body N component accountable for the alterations of homocysteine concentrations in body fluids.

Subclinical protein malnutrition is a determinant of hyperhomocysteinemia.

OBJECTIVES: Hyperhomocysteinemia is regarded as a public health problem of increasing importance likely to contribute to vascular disorders and premature mortality. Folate, cobalamin, pyridoxine, and riboflavin dietary deficiencies are currently regarded as causative factors. However, several investigations have indicated that the theory of vitamin B deprivation provides only a partial explanation for the observed abnormalities of sulfur-containing amino acids. We investigated the potential contributory role played by protein malnutrition. METHODS: For that purpose, three cohorts of 20 adult patients presenting stage I, II, and III goiter underwent careful medical history, dietary inquiry, and clinical examination. Their overall health and nutrition states were assessed with classic anthropometry, measurement of vitamin B blood parameters, visceral protein markers, essential amino acids, total homocysteine, and cystathionine. RESULTS: The concentrations of transthyretin, seven essential amino acids, and cystathionine progressively decreased as the thyroid gland increased. Methionine was the sole essential amino acid whose values did not change; total homocysteine was unique in that increased levels correlated negatively with transthyretin values. Taken together, the data point to a progressive deterioration of protein nutrition status impairing the transsulfuration pathway and is best explained by an acquired defect of cystathionine-beta-synthase activity. CONCLUSIONS: Hyperhomocysteinemia may arise from the shrinking of endogenous nitrogen pools as a result of decreased protein intake or stress-induced increased losses. Raised total homocysteine may result from the attempt of the malnourished and/or stressed body to preserve methionine homeostasis.

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.

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.

The prognostic value of nutritional and inflammatory indices in critically ill patients with acute respiratory failure.

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 alpha1-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.

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.