Volume 1 (2010)

Number 1 / September 2010

      Page 1 - 5

Stephan von Haehling, Stefan D. Anker

Cachexia as a major underestimated and unmet medical need: facts and numbersCachexia is a serious, however underestimated and underrecognised medical consequence of malignant cancer, chronic heart failure (CHF), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), cystic fibrosis, rheumatoid arthritis, Alzheimer's disease, infectious diseases, and many other chronic illnesses. The prevalence of cachexia is high, ranging from 5% to 15% in CHF or COPD to 60% to 80% in advanced cancer. By population prevalence, the most frequent cachexia subtypes are in order: COPD cachexia, cardiac cachexia (in CHF), cancer cachexia, and CKD cachexia. In industrialized countries (North America, Europe, Japan), the overall prevalence of cachexia (due to any disease) is growing and currently about 1%, i.e., about nine million patients. The relative prevalence of cachexia is somewhat less in Asia, but is a growing problem there as well. In absolute terms, cachexia is, in Asia (due to the larger population), as least as big a problem as in the Western world. Cachexia is also a big medical problem in South America and Africa, but data are scarce. A consensus statement recently proposed to diagnose cachexia in chronic diseases when there is weight loss exceeding 5% within the previous 3–12 months combined with symptoms characteristic for cachexia (e.g., fatigue), loss of skeletal muscle and biochemical abnormalities (e.g., anemia or inflammation). Treatment approaches using anabolics, anti-catabolic therapies, appetite stimulants, and nutritional interventions are under development. A more thorough understanding of the pathophysiology of cachexia development and progression is needed that likely will lead to combination therapies being developed. These efforts are greatly needed as presence of cachexia is always associated with high-mortality and poor-symptom status and dismal quality of life. It is thought that in cancer, more than 30% of patients die due to cachexia and more than 50% of patients with cancer die with cachexia being present. In other chronic illnesses, one can estimate that up to 30% of patients die with some degree of cachexia being present. Mortality rates of patients with cachexia range from 10% to 15% per year (COPD), to 20% to 30% per year (CHF, CKD) to 80% in cancer.

von Haehling S, Anker SD. Cachexia as a major underestimated and unmet medical need: facts and numbers. J Cachexia Sarcopenia Muscle 2010;1:1–5.

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      Page 7 - 8

Stephan von Haehling, John E. Morley, Andrew J. S. Coats, Stefan D. Anker

Ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and MuscleThe principles of ethical authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle (JCSM) are:
1. all authors listed on the manuscript have approved its submission and publication as provided to JCSM;
2. no person who has a right to be recognized as author has been omitted from the list of authors;
3. each author has made an independent material contribution to the work submitted for publication;
4. the submitted work is original and is neither under consideration elsewhere nor has it been published previously in whole or in part other than in abstract form;
5. all original research work is approved by the relevant bodies such as institutional review boards or ethics committees;
6. all conflicts of interest, financial or otherwise, that may affect the authors' ability to present data objectively have been duly declared in the manuscript;
7. the manuscript in its published form will be maintained on the servers of JCSM as a valid publication only as long as all statements in the guidelines on ethical publishing remain true;
8. if any of the aforementioned statements ceases to be true, the authors have a duty to notify the editors of JCSM as soon as possible so that the information available online can be updated and/or the manuscript can be withdrawn

von Haehling S, Morley JE, Coats AJ, Anker SD. Ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle. J Cachexia Sarcopenia Muscle 2010;1: 7-8.

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      Page 9 - 21

Karsten Lenk, Gerhard Schuler, Volker Adams

Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise trainingSkeletal muscle is the most abundant tissue in the human body, and the maintenance of its mass is essential to ensure basic function as locomotion, strength and respiration. The decision to synthesize or to break down skeletal muscle proteins is regulated by a network of signaling pathways that transmit external stimuli to intracellular factors regulating gene transcription. The tightly regulated balance of muscle protein breakdown and synthesis is disturbed in several distinct myopathies, but also in two pathologies: sarcopenia and cachexia. In recent years, it became evident that in these two muscle wasting disorders specific regulating molecules are increased in expression (e.g. members of the ubiquitin–proteasome system, myostatin, apoptosis inducing factors), whereas other factors (e.g. insulin-like growth factor 1) are down-regulated. So far, not many treatment options to fight the muscle loss are available. One of the most promising approaches is exercise training that, due to its multifactorial effects, can act on several signaling pathways. Therefore, this review will concentrate on specific alterations discussed in the current literature that are present in the skeletal muscle of both muscle wasting disorders. In addition, we will focus on exercise training as an intervention strategy.

Lenk K, Schuler G, Adams V. Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training. J Cachexia Sarcopenia Muscle 2010;1:9-21.

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      Page 23 - 33

Pontus M. A. Siren, Matti J. Siren

Systemic zinc redistribution and dyshomeostasis in cancer cachexiaCachexia affects up to two thirds of all cancer patients and is a significant cause of morbidity and mortality. It is a complex metabolic syndrome associated with the underlying illness and characterized by loss of skeletal muscle tissue with or without loss of fat mass. Cachexia’s other prominent clinical symptoms include anorexia, systemic inflammation, pediatric growth failure, and hypogonadism. The relationship between the symptoms of cancer cachexia and the underlying illness is unclear, and there is an urgent need for a better understanding of the pathophysiology of this syndrome. Normal Zn metabolism is often disrupted in cancer patients, but the possible effects of systemic Zn dyshomeostasis in cachexia have not been investigated. We propose that the acute phase response can mediate Zn redistribution and accumulation in skeletal muscle tissue and contribute to the activation of the ubiquitin–proteasome pathway that regulates protein catabolism. This chronic redistribution deprives Zn from other tissues and organs and compromises critical physiological functions in the body. The cardinal symptoms of Zn deficiency are anorexia, systemic inflammation, growth failure in children, and hypogonadism. These symptoms also prominently characterize cancer cachexia suggesting that the role of systemic Zn dyshomeostasis in cachexia should be investigated.

Siren PM, Siren MJ. Systemic zinc redistribution and dyshomeostasis in cancer cachexia. J Cachexia Sarcopenia Muscle 2010;1:23-33.

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      Page 35 - 42

Piotr Rozentryt, Stephan von Haehling, Mitja Lainscak, Jolanta U. Nowak, Kamyar Kalantar-Zadeh, et al.

The effects of a high-caloric protein-rich oral nutritional supplement in patients with chronic heart failure and
cachexia on quality of life, body composition, and inflammation markers: a randomized, double-blind pilot study
The prevalence of cardiac cachexia in chronic heart failure is approximately 5% to 15% and 18-month mortality rates can reach 50%. Treatment with angiotensin-converting enzyme inhibitors and beta-blockers may confer some benefit but no proven therapy exists. We tested the effects of an oral nutritional supplement in cachectic patients with heart failure. This was a prospective, randomized, double-blind, placebo-controlled pilot study which randomized 29 patients to a high-caloric (600 kcal) high-protein (20 g) oral nutritional supplement or placebo for a duration of 6 weeks in addition to the patients’ usual food intake. At baseline, 6 weeks, and 18 weeks, we measured body weight, quality of life, body composition, heart function, laboratory parameters, and exercise performance. Edema-free body weight increased in 19 of 20 patients receiving intervention at 6 weeks and in 17 of 19 patients at 18 weeks with an average weight gain of 2.0 ± 1.7 kg (3.1 ± 2.4%, p = 0.0001) and 2.3 ± 3.1 kg (3.6 ± 4.7%, p = 0.007) at 6 and 18 weeks, respectively. Most of the weight gain was fat tissue with an absolute gain of 1.5 ± 1.7 kg (p = 0.003) and 1.6 ± 2.7 kg (p = 0.008). A significant improvement in quality of life and decrease in serum levels of tumor necrosis factor-α were observed (p < 0.05 for both). We demonstrated the feasibility of oral nutritional supplement in cachectic patients with heart failure and significant clinical benefit in terms of body size and body composition, laboratory parameters, and quality of life (www.clinicaltrials.gov identifier NCT00654719).
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Rozentryt P, von Haehling S, Lainscak M, Nowak JU, Kalantar-Zadeh K, Polonski L, Anker SD. The effects of a high-caloric protein-rich oral nutritional supplement in patients with chronic heart failure and cachexia on quality of life, body composition, and inflammation markers: a randomized, double-blind pilot study. J Cachexia Sarcopenia Muscle 2010;1:35-42.

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      Page 43 - 128

Abstracts of the 5th Cachexia Conference, Barcelona, Spain, December 5–8, 2009Abstracts of the 5th Cachexia Conference, Barcelona, Spain, December 5–8, 2009

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Number 2 / Dezember 2010

      Page 129 - 133

Stephan von Haehling, John E. Morley, Stefan D. Anker

An overview of sarcopenia: facts and numbers on prevalence and clinical impactHuman muscle undergoes constant changes. After about age 50, muscle mass decreases at an annual rate of 1–2%. Muscle strength declines by 1.5% between ages 50 and 60 and by 3% thereafter. The reasons for these changes include denervation of motor units and a net conversion of fast type II muscle fibers into slow type I fibers with resulting loss in muscle power necessary for activities of daily living. In addition, lipids are deposited in the muscle, but these changes do not usually lead to a loss in body weight. Once muscle mass in elderly subjects falls below 2 standard deviations of the mean of a young control cohort and the gait speed falls below 0.8 m/s, a clinical diagnosis of sarcopenia can be reached. Assessment of muscle strength using tests such as the short physical performance battery test, the timed get-up-and-go test, or the stair climb power test may also be helpful in establishing the diagnosis. Sarcopenia is one of the four main reasons for loss of muscle mass. On average, it is estimated that 5–13% of elderly people aged 60–70 years are affected by sarcopenia. The numbers increase to 11–50% for those aged 80 or above. Sarcopenia may lead to frailty, but not all patients with sarcopenia are frail—sarcopenia is about twice as common as frailty. Several studies have shown that the risk of falls is significantly elevated in subjects with reduced muscle strength. Treatment of sarcopenia remains challenging, but promising results have been obtained using progressive resistance training, testosterone, estrogens, growth hormone, vitamin D, and angiotensin-converting enzyme inhibitors. Interesting nutritional interventions include high-caloric nutritional supplements and essential amino acids that support muscle fiber synthesis.

von Haehling S, Morley JE, Anker SD. An overview of sarcopenia: facts and numbers on prevalence and clinical impact. J Cachexia Sarcopenia Muscle 2010;2:129-133.

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      Page 135 - 145

Theodore P. Braun, Daniel L. Marks

Pathophysiology and treatment of inflammatory anorexia in chronic diseaseDecreased appetite and involuntary weight loss are common occurrences in chronic disease and have a negative impact on both quality of life and eventual mortality. Weight loss in chronic disease comes from both fat and lean mass, and is known as cachexia. Both alterations in appetite and body weight loss occur in a wide variety of diseases, including cancer, heart failure, renal failure, chronic obstructive pulmonary disease and HIV. An increase in circulating inflammatory cytokines has been implicated as a uniting pathogenic mechanism of cachexia and associated anorexia. One of the targets of inflammatory mediators is the central nervous system, and in particular feeding centers in the hypothalamus located in the ventral diencephalon. Current research has begun to elucidate the mechanisms by which inflammation reaches the hypothalamus, and the neural substrates underlying inflammatory anorexia. Research into these neural mechanisms has suggested new therapeutic possibilities, which have produced promising results in preclinical and clinical trials. This review will discuss inflammatory signaling in the hypothalamus that mediates anorexia, and the opportunities for therapeutic intervention that these mechanisms present.

Braun TP, Marks DL. Pathophysiology and treatment of inflammatory anorexia in chronic disease. J Cachexia Sarcopenia Muscle 2010;2:135-145.

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      Page 147 - 157

Joerg C. Schefold, Jeffrey Bierbrauer, Steffen Weber-Carstens

Intensive care unit—acquired weakness (ICUAW) and muscle wasting in critically ill patients with severe sepsis and septic shockSepsis presents a major health care problem and remains one of the leading causes of death within the intensive care unit (ICU). Therapeutic approaches against severe sepsis and septic shock focus on early identification. Adequate source control, administration of antibiotics, preload optimization by fluid resuscitation and further hemodynamic stabilisation using vasopressors whenever appropriate are considered pivotal within the early—golden—hours of sepsis. However, organ dysfunction develops frequently in and represents a significant comorbidity of sepsis. A considerable amount of patients with sepsis will show signs of severe muscle wasting and/or ICU-acquired weakness (ICUAW), which describes a frequently observed complication in critically ill patients and refers to clinically weak ICU patients in whom there is no plausible aetiology other than critical illness. Some authors consider ICUAW as neuromuscular organ failure, caused by dysfunction of the motor unit, which consists of peripheral nerve, neuromuscular junction and skeletal muscle fibre. Electrophysiologic and/or biopsy studies facilitate further subclassification of ICUAW as critical illness myopathy, critical illness polyneuropathy or critical illness myoneuropathy, their combination. ICUAW may protract weaning from mechanical ventilation and impede rehabilitation measures, resulting in increased morbidity and mortality. This review provides an insight on the available literature on sepsis-mediated muscle wasting, ICUAW and their potential pathomechanisms.

Schefold JC, Bierbrauer J, Weber-Carstens S. Intensive care unit-acquired weakness (ICUAW) and muscle wasting in critically ill patients with severe sepsis and septic shock. J Cachexia Sarcopenia Muscle 2010;2:147-157.

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      Page 159 - 167

Timo D. Müller, Diego Perez-Tilve, Jenny Tong, Paul T. Pfluger, Matthias H. Tschöp

Ghrelin and its potential in the treatment of eating/wasting disorders and cachexiaThe gastrointestinal “hunger” hormone ghrelin is the only known circulating peripheral molecule with the ability to decrease body fat utilization and to increase body weight gain. Accordingly, due to ghrelin’s effects to promote food intake while decreasing energy expenditure ghrelin may offer potential as a drug for treatment of eating/wasting disorders and cachexia. Therapeutic potential of ghrelin and ghrelin analogues to promote food intake and body weight gain was recently indicated in several clinical studies. The recent discovery of the ghrelin O-acyltransferase as the key enzyme responsible for ghrelin acylation has further deepened our understanding of ghrelin activation, thereby paving the way for more efficient targeting of the ghrelin pathway. Here, we summarize the current knowledge pertaining to the potential of the endogenous ghrelin system as a drug target for the treatment of eating/wasting disorders and cachexia.

Müller TD, Perez-Tilve D, Tong J, Pfluger PT, Tschöp MH. Ghrelin and its potential in the treatment of eating/wasting disorders and cachexia. J Cachexia Sarcopenia Muscle 2010;2:159-167.

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      Page 169 - 176

Takashi Akamizu, Kenji Kangawa

Ghrelin for cachexiaGhrelin, a natural ligand for the growth hormone (GH)-secretagogue receptor, is primarily produced in the stomach. Administration of ghrelin stimulates food intake and GH secretion in both animals and humans. Ghrelin is the only circulating hormone known to stimulate appetite in humans. As GH is an anabolic hormone, protein stores are spared at the expense of fat during conditions of caloric restriction. Ghrelin also inhibits the production of anorectic proinflammatory cytokines. Thus, ghrelin exhibits anti-cachectic actions via both GH-dependent and -independent mechanisms. Several studies are evaluating the efficacy of ghrelin in the treatment of cachexia caused by a variety of diseases, including congestive heart failure, chronic obstructive pulmonary disease, cancer, and end-stage renal disease. These studies will hopefully lead to the development of novel clinical applications for ghrelin in the future. These studies have also facilitated a better understanding of the molecular basis of the anti-catabolic effects of ghrelin. This review summarizes the recent advances in this area of research

Akamizu T, Kangawa K. Ghrelin for cachexia. J Cachexia Sarcopenia Muscle 2010;2:169-176.

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      Page 177 - 185

Robert D. Kilgour, Antonio Vigano, Barbara Trutschnigg, Laura Hornby, Enriqueta Lucar, et al.

Cancer-related fatigue: the impact of skeletal muscle mass and strength in patients with advanced cancerBackground 
Although exertional fatigue is directly and negatively related to skeletal muscle mass and strength, it is currently unknown if these variables are associated with cancer-related fatigue (CRF). Therefore, the purpose of this study was to determine if CRF is associated with measures of appendicular lean muscle mass and strength in advanced cancer patients (ACP).
Methods and results 
Eighty-four patients (48 men, 36 women aged 61.6 ± 13.2 year) newly diagnosed (?6 months) with inoperable (Stages III–IV) gastrointestinal or non-small cell lung cancer participated in this study. All patients completed the Brief Fatigue Inventory (BFI). Handgrip (HGS) and quadriceps (QS) strength were assessed using isometric and isokinetic dynamometry, respectively. Skeletal muscle mass index (SMMI) was calculated from the appendicular lean mass measured via dual-energy X-ray absorptiometry divided by body height squared. Univariate analysis showed BFI to be significantly associated with body mass index, weight loss, anemia, hypoalbuminemia, activity level, pain, depression, and sarcopenia along with SMMI, HGS, and QS. HGS (r = -0.34; p = 0.018), QS (r = -0.39; p = 0.024), and SMMI (r = -0.60; p
Conclusion
These results suggest that in ACP, CRF is related to muscle mass and strength, which may provide targets for future interventions.

Kilgour RD, Vigano A, Trutschnigg B, Hornby L,  Lucar E, Bacon SL, Morais JA. Cancer-related fatigue: the impact of skeletal muscle mass and strength in patients with advanced cancer. J Cachexia Sarcopenia Muscle 2010;2:177-185.

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      Page 187 - 194

Stephan von Haehling, Mitja Lainscak, Wolfram Doehner, Piotr Ponikowski, Giuseppe Rosano, et al.

Diabetes mellitus, cachexia and obesity in heart failure: rationale and design of the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF)Background
Chronic heart failure (CHF) is increasing in prevalence. Patients with CHF usually have co-morbid conditions, but these have been subjected to little research and consequently there is a paucity of guidance on how to manage them. Obesity and diabetes mellitus are common antecedents of CHF and often complicate management and influence outcome. Cachexia is an ominous and often missed sign in patients with CHF.
Methods
This manuscript describes the rationale and the design of Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF), a prospective, multicentre, multinational, longitudinal, pathophysiological evaluation study, which is being conducted in 11 centres across six countries in the European Union and in Russia. We aim to recruit >1,600 patients with CHF due to various common aetiologies, irrespective of left ventricular ejection fraction, and with or without co-morbidities at study entry. In addition, >300 patients with type 2 diabetes mellitus without CHF and >150 healthy subjects will serve as control groups. Participants will be systematically investigated at annual intervals for up to 48 months. Additional investigations focusing on cellular and subcellular mechanisms, adipose and skeletal muscle tissue, and in endothelial progenitor cells will be performed in selected subgroups.
Conclusion
SICA-HF will provide insights into common co-morbidities in CHF with a specific emphasis on diabetes mellitus and body mass. This will provide a more thorough pathophysiological understanding of the complexity of CHF that will help develop therapies tailored to manage specific co-morbidities.

von Haehling S, Lainscak M, Doehner W, Ponikowski P, Rosano G, Jordan J, Rozentryt P, Rauchhaus M, Karpov R, Tkachuk V, Parfyonova Y, Zaritskey AY, Shlyakhto EV, Cleland JG, Anker SD. Diabetes mellitus, cachexia and obesity in heart failure: rationale and design of the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF). J Cachexia Sarcopenia Muscle 2010;2:187-194.

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