Tryptophan metabolism and kynurenine metabolites in cancer: systemic nutritional and metabolic implications.

PURPOSE OF REVIEW: To describe the role of Tryptophan (Trp) metabolism and Kynurenine (Kyn) metabolites in nutritional and metabolic changes in cancer. RECENT FINDINGS: Trp is in part utilized for protein and neurotransmitters biosynthesis, but more than 95% is implicated in Kyn pathways. In this molecular cascade, metabolites are produced with distinct biological activities regulating the immune response and neurotransmission with potential implications in malnutrition/cachexia during cancer. Immune dysfunction is a phenomenon occurring during cancer and malnutrition. Kyn metabolites regulate lymphocytes activity and recent data in animals showed that the inhibition of indoleamine-2,3-dioxygenase (IDO) via 1-methyl-tryptophan determines partial amelioration of inflammation, but no positive effects on the preservation of muscularity were observed. Kynurenines seem to contribute to muscle catabolism via NAD+ biosynthesis and ROS generation. Trp metabolism via the serotonin biosynthesis is involved in appetite control in cancer. Moreover, kynurenines have a role in determining fatigue in conditions associated with inflammation. SUMMARY: Trp metabolism has implications in immune and energy balance in cancer. The modulation of Trp and kynurenines have impact on central nervous system mechanisms, including appetite, fatigue, and muscle wasting/cachexia. Research focusing on these clinical implications will open new scenario for therapeutic interventions aimed at counteracting nutritional derangements in cancer.

Metabolic and histomorphological changes of adipose tissue in cachexia.

PURPOSE OF REVIEW: To describe the role of the main changes occurring in adipose tissue during cachexia and how these affects patient's outcomes, with a specific focus on cancer. RECENT FINDINGS: In cachexia, the changes within the adipose tissue have been recently described as the presence of inflammatory infiltration (T-lymphocytes and macrophages), enhanced fibrosis, and the occurrence of beige adipocytes (i.e., browning). The latter one is a process driving cachexia enhancing thermogenesis, primarily via modulation of uncoupling protein 1. Also, increased lipolysis of white adipose tissue, especially in cancer, via higher expression of hormone sensible and adipose tissue triglyceride lipases, was detected in experimental models and in human adipose tissue. Other systemic metabolic alterations occur in association with changes in adiposity, including insulin resistance and increased inflammation, all conditions associated with a worse outcome. Moreover, these profound metabolic alterations were shown to be implicated in several consequences, including extreme and progressive unvoluntary body weight loss. SUMMARY: Alterations in adiposity occur early during cachexia. Adipose tissue atrophy, as well as metabolic changes of white adipose tissues were observed to be pivotal in cachexia, and to be implicated in several clinical complications and poor prognosis.Further research is necessary to clarify the mechanisms underlying the loss of adiposity and therefore to identify novel therapeutic options to counteract this phenomenon in cachexia.

Liquid Biopsy for Cancer Cachexia: Focus on Muscle-Derived microRNAs.

Cancer cachexia displays a complex nature in which systemic inflammation, impaired energy metabolism, loss of muscle and adipose tissues result in unintentional body weight loss. Cachectic patients have a poor prognosis and the presence of cachexia reduces the tolerability of chemo/radio-therapy treatments and it is frequently the primary cause of death in advanced cancer patients. Early detection of this condition could make treatments more effective. However, early diagnostic biomarkers of cachexia are currently lacking. In recent years, although solid biopsy still remains the "gold standard" for diagnosis of cancer, liquid biopsy is gaining increasing interest as a source of easily accessible potential biomarkers. Moreover, the growing interest in circulating microRNAs (miRNAs), has made these molecules attractive for the diagnosis of several diseases, including cancer. Some muscle-derived circulating miRNA might play a pivotal role in the onset/progression of cancer cachexia. This topic is of great interest since circulating miRNAs might be easily detectable by means of liquid biopsies and might allow an early diagnosis of this syndrome. We here summarize the current knowledge on circulating muscular miRNAs involved in muscle atrophy, since they might represent easily accessible and promising biomarkers of cachexia.

Association between change in serum bicarbonate and change in thyroid hormone levels in patients receiving conventional or more frequent maintenance haemodialysis.

AIM: Correction of metabolic acidosis in patients with chronic kidney disease has been associated with improvement in thyroid function. We examined whether changes in bicarbonate were associated with changes in thyroid function in patients with end-stage renal disease receiving conventional or more frequent haemodialysis. METHODS: In the Frequent Hemodialysis Network Trials, the relationship between changes in serum bicarbonate, free triiodothyronine (FT3) and free thyroxine (FT4) was examined among 147 and 48 patients with endogenous thyroid function who received conventional (3×/week) or more frequent (6×/week) haemodialysis (Daily Trial) or who received conventional or more frequent nocturnal haemodialysis (Nocturnal Trial). Equilibrated normalized protein catabolic rate (enPCR) was examined to account for nutritional factors affecting both acid load and thyroid function. RESULTS: Increasing dialysis frequency was associated with increased bicarbonate level. Baseline bicarbonate level was not associated with baseline FT3 and FT4. Change in bicarbonate level was not associated with changes in FT3 and FT4 in the Daily Trial nor for FT4 in the Nocturnal Trial (r ≤ 0.14, P > 0.21). While, a significant correlation between change in serum bicarbonate and change in FT3 (r = 0.44, P = 0.02) was observed in the Nocturnal Trial; findings were no longer significant after adjusting for change in enPCR (r = 0.37, P = 0.08). For participants with baseline bicarbonate <23 mmol/L, no association between change in bicarbonate and change in thyroid indices were seen in the Daily Trial; for the Nocturnal Trial, findings were also not significant for change in FT3 and the association between change in bicarbonate and change in FT4 (r = 0.54, P = 0.03) was no longer significant after adjusting for enPCR (r = 0.45, P = 0.11). CONCLUSION: Changes in bicarbonate were not associated with changes in thyroid hormone levels after adjusting for enPCR, as a marker of nutritional status. Future studies should examine whether improvement in acid base status improves thyroid function in haemodialysis patients with evidence of thyroid hypofunction.

Foods and their components promoting gastrointestinal cancer.

PURPOSE OF REVIEW: Cancer represents one of the most feared diseases. Despite an increasing number of available scientific data, most people remain unaware of those basic dietary and healthy lifestyle measures, which might reduce their risk to develop cancer. Environmental factors, diet, and lifestyle play a crucial role in the development of several different neoplastic diseases, particularly gastrointestinal cancer. In this article, we aimed at focusing on foods and their components able to increase gastrointestinal cancer risk. RECENT FINDINGS: During the last few years, major emphasis has been addressed on the relation between red meat and gastrointestinal cancer. Many potential mechanisms linked red meat consumption and cancer risk, including heterocyclic amines, polycyclic aromatic hydrocarbons, N-nitroso compounds, and heme iron. Other chemical substances, contaminating food, such as acrylamide, showed gastrointestinal carcinogenic properties. SUMMARY: Correct diet and lifestyle are clinically relevant strategies in preventing gastrointestinal cancer. In the fight against cancer, nutritional educative intervention programs are necessary to spread the knowledge on healthy eating and appropriate nutrition to reduce cancer risk.

Validating Appetite Assessment Tools Among Patients Receiving Hemodialysis.

OBJECTIVE: To test the performance of appetite assessment tools among patients receiving hemodialysis (HD). DESIGN: Cross-sectional. SUBJECTS: Two hundred twenty-one patients receiving HD enrolled in seven dialysis facilities in Northern California. INTERVENTION: We assessed 5 appetite assessment tools (self-assessment of appetite, subjective assessment of appetite, visual analog scale [VAS], Functional Assessment of Anorexia/Cachexia Therapy [FAACT] score, and the Anorexia Questionnaire [AQ]). MAIN OUTCOME MEASURES: Reported food intake, normalized protein catabolic rate, and change in body weight were used as criterion measures, and we assessed associations among the appetite tools and biomarkers associated with nutrition and inflammation. Patients were asked to report their appetite and the percentage of food eaten (from 0% to 100%) during the last meal compared to usual intake. RESULTS: Fifty-eight (26%) patients reported food intake ≤ 50% (defined as poor appetite). The prevalence of anorexia was 12% by self-assessment of appetite, 6% by subjective assessment of appetite, 24% by VAS, 17% by FAACT score, and 12% by AQ. All the tools were significantly associated with food intake ≤ 50% (P < .001), except self-assessment of appetite. The FAACT score and the VAS had the strongest association with food intake ≤ 50% (C-statistic 0.80 and 0.76). Patients with food intake ≤ 50% reported weight loss more frequently than patients without low intake (36% vs 22%) and weight gain less frequently (19% vs 35%; P = .03). Normalized protein catabolic rate was lower among anorexic patients based on the VAS (1.1 ± 0.3 vs 1.2 ± 0.3, P = .03). Ln interleukin-6 correlated inversely with food intake (P = .03), but neither interleukin-6 nor C-reactive protein correlated with any of the appetite tools. Furthermore, only the self-assessment of appetite was significantly associated with serum albumin (P = .02), prealbumin (P = .02) and adiponectin concentrations (P = .03). CONCLUSIONS: Alternative appetite assessment tools yielded widely different estimates of the prevalence of anorexia in HD. When considering self-reported food intake as the criterion standard for anorexia, the FAACT score and VAS discriminated patients reasonably well.

The Role of Docosahexaenoic Acid (DHA) in the Control of Obesity and Metabolic Derangements in Breast Cancer.

Obesity represents a major under-recognized preventable risk factor for cancer development and recurrence, including breast cancer (BC). Healthy diet and correct lifestyle play crucial role for the treatment of obesity and for the prevention of BC. Obesity is significantly prevalent in western countries and it contributes to almost 50% of BC in older women. Mechanisms underlying obesity, such as inflammation and insulin resistance, are also involved in BC development. Fatty acids are among the most extensively studied dietary factors, whose changes appear to be closely related with BC risk. Alterations of specific ω-3 polyunsaturated fatty acids (PUFAs), particularly low basal docosahexaenoic acid (DHA) levels, appear to be important in increasing cancer risk and its relapse, influencing its progression and prognosis and affecting the response to treatments. On the other hand, DHA supplementation increases the response to anticancer therapies and reduces the undesired side effects of anticancer therapies. Experimental and clinical evidence shows that higher fish consumption or intake of DHA reduces BC cell growth and its relapse risk. Controversy exists on the potential anticancer effects of marine ω-3 PUFAs and especially DHA, and larger clinical trials appear mandatory to clarify these aspects. The present review article is aimed at exploring the capacity of DHA in controlling obesity-related inflammation and in reducing insulin resistance in BC development, progression, and response to therapies.

Contribution of Neuroinflammation to the Pathogenesis of Cancer Cachexia.

Inflammation characterizes the course of acute and chronic diseases and is largely responsible for the metabolic and behavioral changes occurring during the clinical journey of patients. Robust data indicate that, during cancer, functional modifications within brain areas regulating energy homeostasis contribute to the onset of anorexia, reduced food intake, and increased catabolism of muscle mass and adipose tissue. In particular, functional changes are associated with increased hypothalamic concentration of proinflammatory cytokines, which suggests that neuroinflammation may represent the adaptive response of the brain to peripheral challenges, including tumor growth. Within this conceptual framework, the vagus nerve appears to be involved in conveying alert signals to the hypothalamus, whereas hypothalamic serotonin appears to contribute to triggering catabolic signals.

Ghrelin: from discovery to cancer cachexia therapy.

PURPOSE OF REVIEW: Despite the high prevalence of cancer cachexia, a condition that negatively impacts patients' prognosis and quality of life, effective therapies are still lacking. Ghrelin is a peptide hormone involved in anabolic and homeostatic functions, whose mechanisms of action are still only partially clarified, but with promising positive effects in cancer cachexia. Recently, the therapeutic administration of ghrelin in cancer has been shown to counteract loss of body mass and function, including muscle, and we specifically focus on this novel evidence. RECENT FINDINGS: Recent research aimed at developing new pharmacological therapies to prevent muscle wasting has used ghrelin and molecules acting as synthetic ghrelin receptor agonists with different modalities of administration and with high selectivity for specific targeted tissues. Positive effects of these therapies were described in cancer cachexia and chemotherapy-induced muscle wasting. New insights into the mechanisms of action of ghrelin revealed how its pleiotropic effects should be ascribed both to systemic anti-inflammation effect and to muscle-specific action through the activation of the antiatrophic molecular cascade. SUMMARY: Growing interest arises from the identification of ghrelin as a valid and well tolerated therapeutic option to counteract structural and functional wasting derived from tumour growth.

Muscularity and adiposity are differently associated with inflammatory and nutritional biomarkers among patients on hemodialysis and peritoneal dialysis.

PURPOSE: Nutritional alterations are prevalent in patients undergoing hemodialysis (HD) and peritoneal dialysis (PD). We aimed at evaluating whether body composition parameters in HD vs PD are differently associated with nutritional and inflammatory biomarkers. METHODS: Body composition was assessed by bioimpedance analysis. Neutrophil to lymphocyte ratio (NLR), serum albumin and C-reactive protein were used as nutritional and inflammatory biomarkers. Multivariable linear regression analysis was used to determine association(s) of body composition parameters with biomarkers. RESULTS: We enrolled a total of 108 patients, 58 on HD and 50 on PD. Fat free mass percent was higher in HD patients than PD (p = 0.006) and higher extracellular water (ECW)/intracellular water (ICW) in HD compared to PD patients (p = 0.023), as well as fat mass index was greater in PD than HD (p = 0.004). In HD patients, albumin positively correlated with fat free mass (r = 0.42; p = 0.001) and ICW/h2 (r = 0.31; p = 0.02). In PD, NLR positively correlated with fat mass (r = 0.36; p = 0.01), fat mass index (r = 0.37; p = 0.01) and ECW (r = 0.41; p = 0.005), and negatively correlated with fat free mass percent (r = -0.30; p = 0.04) and ICW percent (r = -0.34; p = 0.02). By linear regression analysis, in HD fat free mass index was associated with albumin and the absence of diabetes. In PD, the association of fat free mass index was present with NLR. Regarding adiposity, in HD we found no association of ECW/ICW with NLR and CRP, whereas in PD the ECW/ICW was associated with NLR. CONCLUSION: Inflammation drives body composition changes with differences according to the type of dialysis, as expressed by the modulation of some circulating biomarkers.

EXPRESS: Liver Fibrosis Prediction Models in a Population of Latina and White Women.

Point of care tools to assess advanced liver fibrosis, including the NFS, BARD, FIB-4, and APRI, are of major interest due to their non-invasive nature. However, these tools have not been investigated extensively in the Latina population. Given that the highest rate of NAFLD in Latinos and the most severe presentation of NAFLD is more common in women, we hypothesize that ethnicity may play a role in predicting liver fibrosis, particularly in women.We determined whether ethnicity alone or in association with other parameters can predict the severity of fibrosis in women with NAFLD when included in four tools. We retrospectively included 562 Latina and 133 White Caucasian women with history of NAFLD. Associations between ethnicity and liver fibrosis severity using the four cirrhosis predictor models were studied using backward selection multinomial logistic regression.Latina women compared to White showed lower BMI (p<0.001), higher HbA1c (p<0.001), lower prevalence of bariatric surgery (p<0.001), lower likelihood to smoke (p=0.003), and higher prevalence of chronic kidney disease (CKD) stages 3-5 (p=0.01). Some clinical variables were associated with fibrosis but not univocally in each tool. We did not find differences in the outcome of the four models when holding all other factors and examining ethnicity alone between Latina and White women.Although we did not include data on liver histology, this is the first study examining the role of ethnicity in predicting severity of fibrosis using established non-invasive scores and documenting no association between Latina ethnicity and severity of fibrosis in women with NAFLD.

Bioimpedance-assessed muscle wasting and its relation to nutritional intake during the first week of ICU: a pre-planned secondary analysis of Nutriti Study.

BACKGROUND: Muscle mass evaluation in ICU is crucial since its loss is related with long term complications, including physical impairment. However, quantifying muscle wasting with available bedside tools (ultrasound and bioimpedance analysis) must be more primarily understood. Bioimpedance analysis (BIA) provides estimates of muscle mass and phase angle (PA). The primary aim of this study was to evaluate muscle mass changes with bioimpedance analysis during the first 7 days after ICU admission. Secondary aims searched for correlations between muscular loss and caloric and protein debt. METHODS: Patients with an expected ICU-stay ≥ 72 h and the need for artificial nutritional support were evaluated for study inclusion. BIA evaluation of muscle mass and phase angle were performed at ICU admission and after 7 days. Considering the difference between ideal caloric and protein targets, with adequate nutritional macronutrients delivered, we calculated the caloric and protein debt. We analyzed the potential correlation between caloric and protein debt and changes in muscle mass and phase angle. RESULTS: 72 patients from September 1st to October 30th, 2019 and from August 1st to October 30th, 2021 were included in the final statistical analysis. Median age was 68 [59-77] years, mainly men (72%) admitted due to respiratory failure (25%), and requiring invasive mechanical ventilation for 7 [4-10] days. Median ICU stay was 8 [6-12] days. Bioimpedance data at ICU admission and after 7 days showed that MM and PA resulted significantly reduced after 7 days of critically illness, 34.3 kg vs 30.6 kg (p < 0.0001) and 4.90° vs 4.35° (p = 0.0004) respectively. Mean muscle loss was 3.84 ± 6.7 kg, accounting for 8.4% [1-14] MM reduction. Correlation between caloric debt (r = 0.14, p = 0.13) and protein debt (r = 0.18, p = 0.13) with change in MM was absent. Similarly, no correlation was found between caloric debt (r = -0.057, p = 0.631) and protein debt (r = -0.095, p = 0.424) with changes in PA. CONCLUSIONS: bioimpedance analysis demonstrated that muscle mass and phase angle were significantly lower after 7 days in ICU. The total amount of calories and proteins does not correlate with changes in muscle mass and phase angle.

Assessment of lipolysis biomarkers in adipose tissue of patients with gastrointestinal cancer.

BACKGROUND: Adipose tissue metabolism may be impaired in patients with cancer. In particular, increased lipolysis was described in cancer-promoting adipose tissue atrophy. For this reason, we assessed the expression of the lipolysis-associated genes and proteins in subcutaneous adipose tissue (SAT) of gastrointestinal (GI) cancer patients compared to controls to verify their involvement in cancer, among different types of GI cancers, and in cachexia. METHODS: We considered patients with GI cancer (gastric, pancreatic, and colorectal) at their first diagnosis, with/without cachexia, and controls with benign diseases. We collected SAT and total RNA was extracted and ATGL, HSL, PPARα, and MCP1 were analyzed by qRT-PCR. Western blot was performed to evaluate CGI-58, PLIN1 and PLIN5. RESULTS: We found higher expression of ATGL and HSL in GI cancer patients with respect to controls (p ≤ 0.008) and a trend of increase for PPARα (p = 0.055). We found an upregulation of ATGL in GI cancer patients with cachexia (p = 0.033) and without cachexia (p = 0.017) vs controls. HSL was higher in patients with cachexia (p = 0.020) and without cachexia (p = 0.021), compared to controls. ATGL was upregulated in gastric cancer vs controls (p = 0.014) and higher HSL was found in gastric (p = 0.008) and in pancreatic cancer (p = 0.033) vs controls. At the protein level, we found higher CGI-58 in cancer vs controls (p = 0.019) and in cachectic vs controls (p = 0.029), as well as in gastric cancer vs controls (p = 0.027). CONCLUSION: In our cohort of GI cancer patients, we found a modulation in the expression of genes and proteins involved in lipolysis, and differences were interestingly detected according to cancer type.

Association between serum levels of GDF-15, suPAR, PIVKA-II, sdLDL and clinical outcomes in hospitalized COVID-19 patients.

To quantify the circulating levels of novel serum biomarkers including GDF-15, PIVKA-II, sdLDL, suPAR, and of CRP in hospitalized COVID-19 patients compared with healthy subjects, and to evaluate their association(s) with outcomes in COVID-19. We considered patients with confirmed COVID-19, hospitalized in an Internal Medicine ward. The clinical characteristics were collected, including the number and type of comorbidities. Serum levels of GDF-15, PIVKA-II, suPAR, sdLDL, as well as CRP were measured. As outcomes, we considered Intensive Care Unit (ICU) transfer or death, as well as the length of stay (days) and in-hospital complications. Data were statistically analyzed, as appropriate, and a p value < 0.05 was considered significant. Ninety-three patients and 20 healthy controls were enrolled. COVID-19 patients vs. controls showed higher median levels of GDF-15 (p < 0.0001), PIVKA-II (p < 0.0001) and sdLDL (p = 0.0002), whereas no difference was observed for suPAR. In COVID-19 patients, the most frequent comorbidities were arterial hypertension (62.4%) and cardiovascular disease (30.1%). GDF-15 levels positively correlated with age (r = 0.433, p < 0.0001), and this correlation was confirmed for suPAR (r = 0.308, p = 0.003) and CRP (Rho = 0.40 p < 0.0001), but not for PIVKA-II and sdLDL. Higher GDF-15 levels were associated with a higher number of comorbidities (p = 0.021). The median length of stay was 22 (15; 30) days. During hospitalization, 15 patients (16%) were ICU transferred, and 6 (6.45%) died. GDF-15 serum levels correlated with the length of stay (rho = 0.27 p = 0.010), and were associated with ICU transfer or death (p = 0.003), as well as PIVKA-II (p = 0.038) and CRP (p < 0.001). Moreover, higher GDF-15 and PIVKA-II serum levels were associated with infectious complications (p = 0.008 and p = 0.017, respectively). In this cohort of hospitalized COVID-19 patients, novel inflammatory biomarkers, including GDF-15, suPAR and PIVKA II were associated with some patient's clinical characteristics, complications, and poor outcomes.

Interventions to promote energy balance and cancer survivorship: priorities for research and care.

The growing population of cancer survivors worldwide and the growing epidemics of obesity and physical inactivity have brought increased attention to the role that interventions to promote exercise and a healthy body weight may play in mitigating the chronic and late effects of cancer. In this light, the authors describe the similarities and differences in research and clinical priorities related to energy balance interventions among post-treatment cancer survivors in Europe versus North America. Randomized controlled trials that targeted nutrition, exercise, and weight are reviewed to determine the affect on survivorship outcomes. Interventions focused on improving prognosis or survival are investigated along with the emerging literature on the interventions targeting pathways and mechanisms of prognosis or survival. Current North American and European guidelines for diet, exercise, and weight control among cancer survivors also are investigated along with the implications of the current state of this science for clinical care. Finally, the authors delineate future European and American priorities for research and care involving energy balance among survivors. It is hoped that this dialogue launches an international conversation that will lead to better research and care for all post-treatment cancer survivors.

Omega-3 fatty acids in cancer.

PURPOSE OF REVIEW: Significant achievements have been obtained in cancer treatment, but the clinical relevance of drug approach in daily practice remains questionable due to the high costs, limited efficacy, and negligible influence on quality of life. A new concept is emerging which is based on the early combination of chemotherapy and nutrition therapy. RECENT FINDINGS: Inflammation dictates tumour initiation, progression and growth. Omega-3 fatty acids exert anti-inflammatory effects, and therefore recent studies investigated their role in cancer prevention, in cancer cachexia treatment and in enhancement of antitumour therapies. Limited evidence suggests a role for omega-3 fatty acid supplementation in cancer prevention, but they have been shown to preserve muscle mass and function in cancer patients even during active treatment. During chemotherapy, omega-3 fatty acids may contribute to a reduced inflammatory response, but whether cancer treatment toxicity can be prevented remains to be assessed. Finally, small studies showed that omega-3 fatty acids increase response rate to chemotherapy. SUMMARY: Combination of chemotherapy and omega-3 supplementation appears an effective strategy to enhance the clinical outcome of cancer patients in their curative and palliative clinical trajectory.

Beta-hydroxy-beta-methylbutyrate supplementation in health and disease: a systematic review of randomized trials.

Beta-hydroxy-beta-methylbutyrate (HMB), a metabolite of the branched-chain amino acid leucine, is extensively used by athletes and bodybuilders in order to increase strength, muscle mass and exercise performance. We performed a systematic review of the clinical literature on the effectiveness of HMB supplementation in healthy and pathological conditions (i.e. training programs, aging, acute and chronic diseases, and after bariatric surgery). We reviewed all clinical trials indexed in Medline that tested HMB supplementation as well as all the experimental data regarding HMB intracellular mechanisms of action. Search terms included: randomized controlled trials, controlled clinical trials, single- and double-blind method, HMB, proteolytic pathways, muscle atrophy, cachexia, and training. We found out 13 studies testing HMB in healthy young trained subjects, 11 in healthy young untrained subjects, 9 in patients affected by chronic diseases (i.e. cancer, HIV, chronic obstructive pulmonary disease), and 6 in elderly subjects. The indexed studies support that HMB is effective in preventing exercise-related muscle damage in healthy trained and untrained individuals as well as muscle loss during chronic diseases. Most of the selected studies showed the effectiveness of HMB in preventing exercise-related muscle damage in healthy trained and untrained individuals as well as muscle loss during chronic diseases. The usual dose of 3 g/day may be routinely recommended to maintain or improve muscle mass and function in health and disease. The safety profile of HMB is unequivocal. Further, well-designed clinical studies are needed to confirm effectiveness and mode of action of HMB, particularly in pathological conditions.

MuRF-1 and p-GSK3ß expression in muscle atrophy of cirrhosis.

BACKGROUND: Chronic diseases, including cirrhosis, are often accompanied by protein-energy malnutrition and muscle loss, which in turn negatively affect quality of life, morbidity and mortality. Unlike other chronic conditions, few data are available on the molecular mechanisms underlying muscle wasting in this clinical setting. AIMS: To assess mechanisms of muscle atrophy in patients with cirrhosis. METHODS: Nutritional [subjective global assessment (SGA) and anthropometry] and metabolic assessment was performed in 30 cirrhotic patients awaiting liver transplantation. Rectus abdominis biopsies were obtained intraoperatively in 22 cirrhotic patients and in 10 well-nourished subjects undergoing elective surgery for non-neoplastic disease, as a control group. Total RNA was extracted and mRNA for atrogenes (MuRF-1, Atrogin-1/MAFbx), myostatin (MSTN), GSK3ß and IGF-1 was assayed. RESULTS: A total of 50% of cirrhotic patients were malnourished based on SGA, while 53% were muscle-depleted according to mid-arm muscle area (MAMA<5th percentile). MuRF-1 RNA expression was significantly increased in malnourished cirrhotic patients (SGA-B/C) vs. well-nourished patients (SGA-A) (P = 0.01). The phosphorylation of GSK3ß was up-regulated in cirrhotic patients with hepatocellular carcinoma (HCC) vs. patients without tumour (P < 0.05). CONCLUSIONS: Muscle loss is frequently found in end-stage liver disease patients. Molecular factors pertaining to signalling pathways known to be involved in the regulation of muscle mass are altered during cirrhosis and HCC.

Prealbumin is associated with visceral fat mass in patients receiving hemodialysis.

OBJECTIVE: Albumin and prealbumin are associated with nutritional status and inflammatory status. Each has a residual effect on mortality outcomes when included in regression models that include the other. Prealbumin is increased in the obese mouse model as a consequence of stabilization of prealbumin by retinol binding protein 4 (RBP4) secreted by adipocytes. We carried out this study to establish the contribution of adiposity to prealbumin levels in prevalent patients receiving dialysis and the relationship of prealbumin to RBP4. DESIGN AND METHODS: We determined whether prealbumin was associated with adiposity in patients receiving hemodialysis (HD), controlling for the effects of inflammation and nutrition. We evaluated body composition in 48 prevalent patients receiving HD by magnetic resonance imaging (MRI), measuring total skeletal muscle mass (SM), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and serum albumin, prealbumin, RBP4, and interleukin-6 (IL-6) levels. We used normalized protein catabolic rate (nPCR) to report nutrition and separately analyzed the determinants of albumin and then of prealbumin by multiple stepwise regression. RESULTS: Thirty-two patients were women, 16 patients were diabetic, and median age and body mass index were 54.5 and 27.3 kg/m(2), respectively. Median total adipose tissue (TAT) was 24.3 kg and VAT was 3.25 kg. Prealbumin was positively associated with VAT, nPCR, and RBP4 and was negatively associated with IL-6; r(2) for the model was 0.64. By contrast, albumin was positively associated with nPCR and negatively associated with IL-6 but not with any measure of adiposity (r(2) for the model = 0.2). CONCLUSIONS: Prealbumin, like albumin, is associated with markers of nutrition (nPCR) and inflammation, but unlike albumin, prealbumin levels are positively associated with visceral adiposity.