Under Appreciated Issues in the Treatment of Chronic Illness - Muscle/Dietary Protein Update Part 1
Expanding the awareness that all practitioners should include muscle assessment and treatment as part of the diagnostic and treatment repertoire for every chronically ill patient.
01/01/2019 - Moss Nutrition Report #283
UNDER APPRECIATED ISSUES IN THE TREATMENT OF CHRONIC ILLNESS - MUSCLE/DIETARY PROTEIN UPDATE PART I - INTRODUCTION
Upon finishing part III of my metabolic acidosis/potassium series that appeared in the November 2018 Moss Nutrition Report, I had every intention of writing part IV for January of 2019. However, as the time came to write part IV, I decided that, while there is still a large volume of research on this issue that I will be reviewing in future newsletters in this series, I needed to take a break from this subject for a short period of time. Why? During the last few months a literal avalanche of research on another grossly underappreciated issue in the treatment of chronic illness, loss of muscle mass and the need for increased protein intake, has been published. Some of these papers, in particular the two I am about to review in this and the next newsletter, are, to me, so compelling and so desperately relevant to the needs of today's ever-growing volume of aging chronically ailing patients, that I felt, in good conscience, I could not delay writing about them until I had finished the metabolic acidosis/potassium series. Therefore, to start the new year, I want to re-emphasize the need to consider muscle mass and increased protein need for literally every chronically ill patient, particularly those who are aged 50 years and older.
Interestingly, both of these papers focus on health conditions that most of us rarely encounter in routine clinical practice - cancer cachexia and critical illness. Why are these papers important to us in our treatment of the chronically ill? As I have mentioned in many past newsletters, a large body of research has made it clear that, from a biochemical and metabolic standpoint, all illness, whether it be chronic or acute, is fundamentally the same. All generally share key metabolic issues such as chronic inflammation, GI dysfunction, suboptimal insulin metabolism, stress hormone imbalances, etc. The only difference is a matter of degree where the cachectic and critical care patients demonstrate a higher level of dysfunction and imbalance than our usual, chronically ill patients. With this reality in mind, I hope you agree that the two papers I am about to review not only provide valuable information about the true nature of the various metabolic dysfunctions that underlie your patients' chief complaints but excellent insights on how to re-establish optimal health even in some of your most challenging patient presentations.
THE IMPACT OF MUSCLE LOSS ON WHOLE BODY BIOCHEMISTRY AND PHYSIOLOGY
As I have discussed repeatedly over the years in various newsletters and presentations, loss of muscle mass and function is almost universal in every chronically ill patient, particularly in those aged 50 years or older. The paper I am about to review considers an advanced form of muscle loss generally seen in cancer patients, cachexia. As I review this paper, though, please keep in mind that cachexia is merely an advanced form of muscle loss that we see in our average, chronically ill patient every day.
The paper, "Inter-tissue communication in cancer cachexia" by Argiles et al (1) begins by providing a sobering statement about the massive, whole-body impact of muscle loss during illness:
"Even though the cachectic condition severely affects skeletal muscle, a tissue that accounts for ~40% of total body weight, it represents a multi-organ syndrome that involves tissues and organs such as white adipose tissue, brown adipose tissue, bone, brain, liver, gut and heart. Indeed, evidence suggests that non-muscle tissues and organs, as well as tumour tissues, secrete soluble factors that act on skeletal muscle to promote wasting."
Therefore, as this quote suggests, there is a complex interaction between muscle and non-muscle tissue where adverse effects can occur in both directions.
The next few quotes discuss cancer cachexia specifically. While they may not apply to many of you, they will be quite significant for the many readers who do regularly address the needs of cancer patients:
"Cachexia, which is associated with cancer and other systemic diseases, is a multi-organ syndrome characterized by systemic inflammation and at least 5% body weight loss due to extensive skeletal muscle and adipose tissue wasting. Abnormalities associated with cancer cachexia include alterations in carbohydrate, lipid and protein metabolism, as well as anorexia, insulin resistance and increased muscle protein degradation. A defining characteristic of cachexia is that it cannot be fully reversed by conventional nutritional support and therefore patients develop progressive functional impairment."
Before continuing, please note again the phrase "conventional nutritional support." As I have demonstrated in past newsletters and will demonstrate again when I review the second paper on critical care, poor results seen with nutritional therapies in cachectic patients and other very sick individuals are not a function of patient uniqueness, as suggested by many in the conventional health care community. Rather, poor results are, very often, a function of the poor quality of conventional nutritional support. More on that later.
Argiles et al (1) continue with their description of cachexia:
"Cachexia occurs in the majority of patients with cancer (up to 85% in some tumour types) and is responsible for the death of at least 22% of individuals who have cancer; notably, the degree of cachexia depends on the tumour type and stage. Moreover, cancer treatment, both chemotherapy and radiotherapy, also contribute to the cachectic syndrome. Importantly, the survival of patients with different types of neoplasias depends on the amount of weight loss, with patients who lose <5% of oedema-free body weight over <12 months have increased chances of survival."
This preceding quote brings up two extremely important points. First, for very sick individuals, loss of muscle mass in a great enough volume will have an adverse impact on mortality, not just the usual quality of life issues. The second important point is that traditional medical therapies can often contribute to significant loss of muscle mass.
The next quote is extremely important clinically because it highlights the fact that loss of muscle mass can have an adverse effect on the effectiveness of therapeutic interventions and much more, which is true both for cancer patients and the chronically ill patients we see in our practices:
"The wasting of cardiac and skeletal muscle in patients with cancer who have cachexia not only affects the individual's quality of life, but also the efficacy of anticancer treatment, survival outcomes and medical costs."
Then, of course, there is the issue that I initially mentioned above that loss of muscle mass is not just an issue of skeletal muscle:
"Cachexia, however, is a multi-organ syndrome that, in addition to muscle, affects adipose tissues, the heart, intestine, kidneys and liver. In fact, the final cause of death in patients with cancer who have cachexia is, apart from the tumour (primary or metastasis), either sudden death (heart arrhythmias or hypoventilation), thromboembolic events (platelet aggregation), cardio-renal alterations (kidney dysfunction) or compromised immune function (immunosuppression), which highlights the multi-organ nature of the syndrome."
What is the primary metabolic driver of muscle loss? As you might guess, it is inflammation:
"To fully understand the aetiology of cancer cachexia, it is essential to unravel the mediators that drive communication between skeletal muscle and other tissues. Systemic inflammation is a hallmark of cancer, the inflammatory response being the main driving force behind metabolic alterations present during cancer cachexia."
In the next few sections of the Argiles et al (1) paper individual organ system dysfunctions seen with severe muscle loss are discussed in more detail.
Skeletal muscle wasting
A good place to begin with this discussion is muscle per se. What exactly happens to muscle during the cachectic process? The authors explain:
"Loss of myofibrillar proteins is of key relevance in cancer cachexia as it results in muscle weakness and fatigue. Numerous metabolic alterations are responsible for the loss of muscle mass observed in patients with cachexia. Research has revealed abnormalities in protein synthesis, protein degradation and amino acid metabolism (both transport and branched-chain amino acid oxidation) in the cachectic muscle of patients with cancer. Furthermore, an increase in apoptosis also contributes to muscle wasting. Finally, cachectic muscle also has an impaired capacity for regeneration."
The last statement in the above quote is particularly important. For, due to abnormalities discussed above, there is impaired ability to regenerate, which means that the usual nutritional support will not be effective. Does this mean that we revert to the typical medical dogma that the patient experiencing significant muscle loss is "hopeless" to the point that there is no need to even attempt nutritional interventions? Of course not!! What it means, as I mentioned, when patients experiencing significant muscle loss do not respond to the "usual," the issue is not the patient per se but a lack of understanding by the practitioner for the need for unique and custom formulated nutritional supplementation and lifestyle modifications, as will be demonstrated.
What is the net metabolic impact of all the imbalances mentioned in the above quote? Argiles et al (1) point out:
"All of the aforementioned alterations contribute to the negative nitrogen balance (that is, more nitrogen excreted than nitrogen ingested) observed in the skeletal muscle of patients with cancer."
The liver and muscle loss
As you will see, the most important role of the liver in respect to muscle loss is that it is the main site of inflammatory mediator production. The authors state:
"The liver is a major contributor to cancer-associated inflammation; in addition, the synthesis of structural proteins is decreased in patients with cancer. As cancer progresses, hepatocytes change their pattern of protein synthesis and an increased proportion of synthesized proteins are released as acute-phase proteins."
This reprioritization of protein synthesis in the liver is an incredibly important factor not only in cancer but all chronic illnesses where inflammation is a factor, which is virtually all of them. For, when the liver redirects its efforts towards the production of protein-based inflammatory proteins known as "acute-phase proteins" and away from structural proteins, the reparative and growth capacity of almost all organ systems is impaired, ranging from muscle to bone to the heart to the immune system. In turn, this protein reprioritization in the liver can be a major contributor to virtually any sign or symptom seen in your chronically ill patients and can be a major reason why your intervention that works in most patients did not yield successful results in your most difficult patients.
What, specifically, are these "acute phase" proteins? One you already know - C-reactive protein (CRP). Argiles et al (1) discuss the others:
"This class of proteins include those whose plasma concentrations increase during inflammation (positive acute-phase proteins) such as C-reactive protein (CRP), serum amyloid A (SAA), α1-antitrypsin, fibrinogen, α1-acid glycoprotein, haptoglobulin, α2-macroglobulin, ceruloplasmin and complement factors B and C3. Conversely, plasma concentrations of negative acute-phase proteins decrease in response to inflammation (for example, transferrin and albumin, leading to marked hypoalbuminaemia)."
What is the specific role of these acute-phase proteins and what do they mean clinically? The authors continue:
"CRP seems to be a very important prognostic marker for different types of cancer. In fact, the ratio of albumin:CRP has been used successfully as a prognostic indicator in the Glascow Prognostic Score. CRP also seems to have a role in activating complement factors, phagocytosis and regulation of cell immunity. α1-Acid glycoprotein inhibits platelet aggregation and phagocytosis and might also participate in the spacing of collagen fibres, while haptoglobulin binds to haemoglobin and is related to plasma clearance. α1-Antitrypsin and α2-macroglobulin regulate serine proteases. Ceruloplasmin is thought to be involved in copper transport. SAA acts in synergy with IL-6 and is involved in the activation of muscle proteolysis."
What does all the above mean in terms of muscle form and function during chronic illness? Argiles et al (1) point out:
"...in cancer, opposing patterns of protein metabolism are observed in the liver and skeletal muscle - although protein synthesis is a very active process in the liver, degradation predominates over synthesis in skeletal muscle. This muscular protein degradation is actually what drives nitrogen transfer, in the form of amino acids (particularly alanine), from muscle to liver."
Please note again this quote as it emphasizes what I stated above about one of the major metabolic reasons your patient looks and feel so awful during chronic illness. During chronic illness chronic inflammation redirects amino acids away from skeletal muscle and towards the liver for the purpose of producing more inflammation-inducing acute-phase proteins such as CRP. Therefore, your chronically ill, chronically inflamed patients get into a feed-forward proinflammatory loop where chronic inflammation begets more inflammation, continually sacrificing muscle tissue for the purpose of producing more acute-phase proteins in the liver.
The next quote from the Argiles et al paper (1) provides information as to why your chronically ill patients lack energy and are so fatigued:
"The liver might also have a role in energy imbalance in cachexia. During cancer cachexia, cardiolipin phospholipid composition and accumulation in liver mitochondria is associated with energy wasting, in the form of a reduction in the efficiency of oxidative phosphorylation."
Why does cardiolipin accumulate? As you can probably guess by now, the reason is inflammation:
"...cardiolipin is activated by tumour necrosis factor (TNF), a cytokine that seems to have a key role in cancer cachexia."
Gut dysfunction and muscle loss
We all know that gut dysfunction is virtually a given with chronic illness patients. As you will see from the next quote, this problem can be compounded by allopathic medical interventions often used with chronically ill patients:
"Gut barrier dysfunction is often observed during the course of cancer, partly due to the effects of radiotherapy and/or chemotherapy. This syndrome results from a breakdown and leakage of the gut epithelial barrier, which leads to systemic inflammation resulting from the entry of either bacterial cell wall components (endotoxin of lipopolysaccharide) or intact bacteria into the circulation."
The net effect of the above is breakdown of the tight junctions of the intestinal lining, leading to "leaky gut":
"Decreases in tight junction proteins such as ZO1 and occluding increases permeability of the gut and allows large molecules such as lipopolysaccharide to enter the lymphatic circulation. In addition, gut barrier dysfunction is also associated with malabsorption of nutrients, diarrhea and other complications that contribute to the negative energy balance in patients with cancer."
Therefore, with the above in mind, when your chronically ill patients complain of long-term fatigue and lack of energy, do not forget to evaluate a link with gut dysfunction.
What happens with gut microflora during chronic illness? Argiles et al (1) suggest:
"In experimental models of cancer cachexia, the numbers of bacteria in the gut decrease. Interestingly, a symbiotic approach (which includes the administration of exogenous bacteria) restores intestinal homeostasis and prolongs survival in leukaemic mice with wasting."
Gut microflora and muscle loss
The authors go on to discuss a grossly underappreciated relationship in clinical nutrition and functional medicine practice - the relationship between gut microflora and loss of muscle mass and function:
"The existence of a gut microbiota-skeletal muscle axis has also been reported. The gut microbiota generates metabolites that can reach skeletal muscle and influence energy expenditure in the muscle cells. For instance, the gut microbiota influences amino acid bioavailability, participates in the release of various metabolites (such as bile acids) and modulates the production of pro-inflammatory cytokines; all of these factors could potentially influence muscle metabolism. Other compounds released by intestinal bacteria, including lipopolysaccharide, flagellin, and peptidoglycan, can stimulate Toll-like receptors in skeletal muscle, which are associated with cachexia. NF-κB is a major downstream target of the Toll-like receptors, and muscle specific activation of this transcription factor causes muscle wasting."
Adipose tissue and muscle loss
As we all well know, for most chronically ill patients muscle loss is accompanied by gain in fat mass, known as "sarcopenic obesity." However, in many chronically ill patients, and cancer patients in particular, both loss of muscle and adipose tissue can occur simultaneously. Therefore, with chronically ill patients who are losing muscle mass, it is possible that we can see either fat gain or loss. Concerning patients who are losing fat and muscle concurrently, is there a relationship between the two? Argiles et al (1) provide an answer to this question:
"The possible link between adipose tissue lipolysis and skeletal muscle wasting was proposed in a study that concluded that the breakdown of fat precedes that of skeletal muscle proteins."
Therefore, for those chronically ill patients who are experiencing weight loss and appear to be happy about it because, at long last, they are getting rid of unwanted fat mass, they need to be educated that, unless they begin a program of lifestyle modifications and supplementation to maintain or increase muscle mass, loss of muscle mass and function will be soon to follow.
What about the many patients who are gaining weight during chronic illness? As I just suggested, it is very possible that loss of muscle mass is occurring in conjunction with the fat gain. However, the problem does not end there. As levels of adipose tissue increase, adipose cells will start to infiltrate muscle to also cause loss of functional capacity in addition to loss of mass. Argiles et al (1) point out:
"The infiltration of adipose tissue cells into skeletal muscle tissue also seems to contribute to muscle wasting. One group reported a correlation between the increased presence of intramyocellular lipid droplets (which are a manifestation of adipose tissue cell infiltration in muscle tissue) in the rectus abdominis muscle of patients with cancer and body weight loss."
Cardiovascular dysfunction and muscle loss
As I mentioned in the beginning of this newsletter, contrary to the opinion of many, loss of muscle mass and function in chronically ill patients is not limited to skeletal muscle. Loss of protein in other key muscles can occur. Specifically, it has been documented that key muscles involved in cardiovascular function can be affected in chronically ill patients. In particular, muscle in the heart and diaphragm can be adversely impacted. The authors state:
"The cause of death in patients with cancer is often associated with pulmonary incapacity or cardiac arrest resulting from the loss of either diaphragm or cardiac protein. The loss of these two protein types is directly linked with muscle wasting resulting from the cachectic syndrome. Indeed, patients with cancer often experience severe cardiac abnormalities - individuals often present with symptoms that are clinical indicators of chronic heart failure, including fatigue, shortness of breath, and impaired exercise tolerance."
What is the main metabolic driver of loss of cardiac function in these patients? As you might expect from the above text, the answer is inflammation:
"Inflammatory cytokines are the main drivers of cancer-associated heart failure."
Furthermore, as you might expect, oxidative stress is also a factor:
"In addition to inflammatory cytokines, oxidative stress resulting from the combination of chemotherapy, chronic inflammation and deficient antioxidant consumption further contributes to heart failure."
Loss of appetite and muscle loss
Classically, family members and even treating physicians have assumed that loss of muscle mass in chronically ill patients was purely an issue of not eating enough food, primarily due to loss of appetite. Of course, as was noted above, the primary issue is not lack of food ingestion but inflammation. However, loss of appetite is still a factor. What is the cause of this loss of appetite? Ironically, it is the same cause of all the other issues discussed so far - inflammation. Argiles et al (1) comment:
"Following the publication of a study involving 1,853 patients with cancer that found no common genetic causes for appetite loss, it became clear that increases in the concentrations of circulating cytokines and tumour-released mediators, as well as neuroendocrine changes (such as hypothalamic inflammation), are the key signals that regulate appetite suppression in cancer cachexia."
The authors go on to discuss hypothalamic inflammation in more detail:
"Hypothalamic inflammation is linked to the systemic inflammatory response, which is primarily mediated by pro-inflammatory cytokines, but inflammation within the hypothalamus alone has been shown to profoundly alter the activity of hypothalamic nuclei, which are involved in the regulation of energy homeostasis."
With the above in mind, the authors conclude:
"Thus, the hypothalamic inflammatory response underlies the anorexia that is very often present in patients with cancer."
Of course, whenever we consider hypothalamic activity we are reminded of the hypothalamic-pituitary-adrenal (HPA) axis, which in involved in cortisol production. Where does cortisol come into play in the scenario I have been describing? Argiles et al (1) comment:
"...activation of the hypothalamic-pituitary-adrenal axis by IL-1β results in the release of glucocorticoids that stimulate skeletal muscle protein degradation. Research also suggests that the hypothalamus might contribute to muscle wasting via neuronal output through the melanocortin system."
The relationship between bone and muscle loss
With all of our focus on bone health over the last several decades I always find it interesting that many in the health care community are so focused on bone health that they forget what they learned in first year college anatomy classes - it is the musculoskeletal system where bone and muscle health are intimately interlinked. Therefore, it should come as no surprise that, when muscle loss occurs during chronic illness, bone loss is inevitable. The authors state:
"...it is becoming clear that physiological and molecular mechanisms mediate a link between bone and muscle wasting. Concomitant bone and muscle loss and dysfunction (osteosarcopenia or sarco-osteoporosis) is observed in many patients with cancer. Indeed, bone loss is a characteristic feature of cancer cachexia, which is dependent on tumour type, burden and stage."
What may be a key diagnostic feature of the above? It should come as no surprise that it is hypercalcemia:
"Interestingly, in patients with cancer, hypercalcaemia is independently associated with reduced survival."
Argiles et al (1) go to make an extremely important point about the relationship between bone and muscle that is often underappreciated or ignored by clinicians. It is often thought that the only way muscle can affect bone health is through the mechanical pull of muscle on bone. While this is certainly true, there is more to the muscle-bone relationship:
"It is now recognized that skeletal muscle can regulate bone mass in a number of ways, not just via mechanical loading. A study in a syngeneic mouse model of osteolytic cancer in bone reported that skeletal muscle weakness is associated with the oxidation of ryanodine receptor 1 (RYR1). During normal muscle contraction, RYR1 is activated, which leads to the release of calcium from the sarcoplasmic reticulum and muscle contraction."
What happens with RYR1 during chronic illness?
"...the pathological oxidation of RYR1 that is observed in cancer cachexia leads to calcium channel leakage and muscle weakness."
Possible therapeutic interventions
Argiles et al (1) end their paper with a discussion on possible therapeutic options. Contrary to what you might expect in a paper such as this, while pharmaceutical treatment is mentioned, diet, supplements, and exercise are emphasized:
"...consensus is growing that future positive treatment for the syndrome should have a multifactorial nature. A combination of nutrition, nutraceuticals, drugs and a moderate degree of programmed exercise might provide the best approach."
Furthermore, the authors should be given credit for recommending a functional medicine intervention that you and I employ in many if not most patients:
"...we might be able to use inter-organ cancer metabolism to design novel therapeutic approaches. For instance, the gut microbiota has been proposed as a new therapeutic target for muscle wasting."
Of course, a key tenet of the functional medicine approach is reduction of inflammation, the primary driver of virtually all that I have described above. The authors agree:
"Similarly to targeting inter-organ cancer metabolism, manipulating the machinery of liver's acute-phase protein response might be a good strategy. Targeting this hepatic pathway might be successful as there is a clear negative correlation between certain acute-phase proteins, particularly CRP, and survival in different types of human cancer."
Some final thoughts from Argiles et al (1)
Argiles et al (1) end this fine paper with a summation that focuses on their most important point - that muscle mass in chronic illness is more than just an issue of loss of muscle mass. In fact, loss of muscle mass is merely an outward, more visible, "canary in the mineshaft" manifestation of a true systemic disorder that must be regarded as such if true understanding and effective improvement of quality of life through optimization of muscle mass is to be attained:
"Since the 1980s, research in cancer cachexia has focused on body weight, before progressing to focus on body composition and then finally on skeletal muscle. This progression is justified as human skeletal muscle represents ~40% of body weight. However, we now know that, in addition to being a systemic disorder, cancer cachexia is a multi-organ syndrome affecting many types of cells, including adipose tissues, heart, bone, liver, gastrointestinal tract, and brain. Mediators released by non-muscle tissues might actually be directly responsible for the activation of the main metabolic alterations present during cancer cachexia. The implications of this are relevant as the discovery of new therapeutic approaches can benefit from this knowledge."
Fortunately, for many if not most of you, taking a whole body, inter-organ approach to ailments that most allopathic practitioners and all too many in the alternative medicine community consider to be isolated, individual body-part issues is nothing new. For, this whole-body approach has been a key tenet of the functional medicine approach for years. However, as the title of this newsletter suggests, it is my opinion that many in functional medicine who adhere to the whole body, metabolic approach to caring for chronically ill patients still do not, for reasons that I do not entirely understand, include optimization of muscle mass and function in their whole-body approach. Hopefully this review of a truly outstanding paper will help expand the awareness of more functional medicine practitioners to include muscle assessment and treatment as part of the diagnostic and treatment repertoire for every chronically ill patient.
In part II of this series on current research on muscle and chronic illness I will explore a fascinating paper that considers novel ways of combining muscle stimulation and nutritional treatment for those patients who are unable to engage in effective muscle stimulation.
1. Argiles JM et al. Inter-tissue communication in cancer cachexia. Nat Rev Endocrinol. 2019;15:9-20.