However, many of these clinical studies used HMB as a component of combination treatment with glutamine, arginine, leucine, higher dietary protein and/or vitamins, which limits the assessment of the efficacy of HMB alone. Epidemiology
Accurate epidemiological data on the prevalence of cachexia is lacking due to changing diagnostic criteria and under-identification of people with the disorder. It is estimated that cachexia from any disease is estimated to affect more than 5 million people in the United States. The prevalence of cachexia is growing and estimated at 1% of the population. The prevalence is lower in Asia but due to the larger population, represents a similar burden. Cachexia is also a significant problem in South America and Africa.The most frequent causes of cachexia in the United States by population prevalence are: 1) chronic obstructive pulmonary disease (COPD), 2) heart failure, 3) cancer cachexia, 4) chronic kidney disease. The prevalence of cachexia ranges from 15 to 60% among people with cancer, increasing to an estimated 80% in terminal cancer. This wide range is attributed to differences in cachexia definition, variability in cancer populations, and timing of diagnosis. Although the prevalence of cachexia among people with COPD or heart failure is lower (estimated 5% to 20%), the large number of people with these conditions dramatically increases the total cachexia burden.Cachexia contributes to significant loss of function and healthcare utilization. Estimates using the National Inpatient Sample in the United States suggest that cachexia accounted for 177,640 hospital stays in 2016.
Mechanism
The exact mechanism in which these diseases cause cachexia is poorly understood, and likely is multifactorial with multiple disease pathways involved. Inflammatory cytokines appear to play a central role including tumor necrosis factor (TNF) (which is also nicknamed cachexin or cachectin), interferon gamma and interleukin 6. TNF has been shown to have a direct catabolic effect on skeletal muscle and adipose tissue through the ubiquitin proteasome pathway. This mechanism involves the formation of reactive oxygen species leading to upregulation of the transcription factor NF-κB. NF-κB is a known regulator of the genes that encode cytokines and cytokine receptors. The increased production of cytokines induces proteolysis and breakdown of myofibrillar proteins. Systemic inflammation also causes reduced protein synthesis through inhibition of the Akt/mTOR pathway.Although many different tissues and cell types may be responsible for the increase in circulating cytokines, evidence indicates tumors themselves are an important source of factors that may promote cachexia in cancer. Tumor-derived molecules such as lipid mobilizing factor, proteolysis-inducing factor, and mitochondrial uncoupling proteins may induce protein degradation and contribute to cachexia. Uncontrolled inflammation in cachexia can lead to an elevated resting metabolic rate, further increasing the demands for protein and energy sources.There is also evidence of alteration in feeding control loops in cachexia. High levels of leptin, a hormone secreted by adipocytes, block the release of neuropeptide Y, which is the most potent feeding-stimulatory peptide in the hypothalamic orexigenic network, leading to decreased energy intake despite the high metabolic demand for nutrients.