Under Appreciated Issues in the Treatment of Chronic Illness – Muscle/Dietary Protein Update Part – II

In part I of this series I presented a review of the fascinating paper by Argiles et al (1) that presented compelling information that loss of muscle mass during illness, both acute and chronic, is more than just a mechanical issue where the only concerns are movement and pain.  Rather loss of muscle mass is also a systemic issue where virtually every key metabolic function, from the GI tract to the cardiovascular system, is affected.  In part II of this series I would like to focus on a well-known therapeutic intervention that has been extensively documented to optimize muscle mass and function.  This intervention is commonly known as exercise, either in the form of aerobic movement, increasing the force of gravity on muscle (weight bearing exercise), or both.  However, does the term “exercise” limit our thinking in terms of how these interventions actually create benefit both locally to the muscle and systemically to general health?  In my opinion, the answer is yes.  Therefore, I would like to expand this discussion to consider not only exercise but any intervention that stimulates muscle.  By doing this, therapies such as chiropractic, massage, and electrostimulation will also be included in the discussion.

However, my intent is not to present evidence that these therapeutic modalities are beneficial.  We are all well aware of that through extensive research, anecdotal evidence, and clinical experience, so there is no need to belabor the point from a direct efficacy standpoint.  What I would like to address is why these modalities have clinical benefit, particularly when they are combined with optimal diet generally and optimization of protein intake specifically.  For, beyond the fact that they seem to make muscles larger and more functional, do we really know what they do?  I would suggest that, even though extensive evidence makes it clear that exercise and other forms of muscle stimulation are of clinical benefit, we know they surprisingly little about why they are effective.  Why is it important to know the biochemistry and physiology of the positive impact of muscle stimulation?  As I hope to demonstrate, this understanding will help us better appreciate how muscle functions to improve general systemic health, particularly in chronically ill patients who do not respond to our usual dietary and supplemental interventions.

Before I delve into my review of the papers that consider the biochemistry and physiology of muscle movement and stimulation, I would like to discuss a big picture concept.  It is important to note that muscle movement/stimulation is, for lack of a better term, the “stimulating hormone” of muscle.  What do I mean by this?  We all know, for example, that substances from various endocrine glands such as the thyroid and adrenal, are induced by various stimulating hormones such as TSH and ACTH.  For muscle, the various substances produced by muscle that have profound metabolic and physiologic impacts are stimulated to be produced by muscle movement and other forms of muscle stimulation, i.e., chiropractic adjustments, massage, and, of course, exercise.

With the above in mind, I would now like to review a paper that discusses a major family of substances produced by muscle upon stimulation that have a major impact on physiology and metabolism: myokines.


In “The role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases” by Brandt and Pederson (2), these vastly under-appreciated metabolic modifiers produced by muscle are discussed in detail.  To begin my review of this paper, though, I would like to highlight a quote that does not discuss the specific nature of myokines but instead discusses why they are important.  As you will see, this quote tells us what we already know, that chronic inflammation is a major foundational issue for virtually all chronic illness:

“…inflammation is directly involved in the pathogenesis of insulin resistance, atherosclerosis, neurodegeneration, and tumour growth.  Therefore, the finding that type 2 diabetes, cardiovascular diseases, Alzheimer’s disease and cancer is associated with chronic inflammation suggests that inflammatory mechanisms contribute as causative factors in the development of these disorders.”

Of course, all of us are also well aware that exercise has a powerful anti-inflammatory effect.  One of the major reasons for this is the production within muscle of a family of cytokines called “myokines.”  In response to this I suspect you may wonder how the cytokines of the muscle could be anti-inflammatory because it is well known that most cytokines are pro-inflammatory.  As you will see, myokines are a distinctly different and unusual set of cytokines with significant anti-inflammatory properties.  In the quote that follows, Brandt and Pedersen (2) discuss muscle as an endocrine organ and the idea that muscle contractions are the stimulating factor for production of its endocrine output, myokines:

“In line with the acceptance of adipose tissue as an endocrine organ, we came up with the innovative idea that also skeletal muscle be viewed as an endocrine organ.  We have suggested that cytokines and other peptides that are produced, expressed, and released by muscle fibres and exert paracrine or endocrine effects should be classified as ‘myokines’.  This paradigm provides a conceptual basis explaining the multiple consequences of physically inactive lifestyle.  If the endocrine and paracrine functions of the muscle are not stimulated through contractions, this will cause dysfunction of several organs and tissues of the body as well as an increased risk of cardiovascular disease, cancer, and dementia.”

What specific myokines are produced by muscle?  As you will see, they have names that have been traditionally associated by many with pro-inflammatory cytokines:

“Today, it appears that skeletal muscle has the capacity to express several myokines.  The list includes IL-6, IL-8, IL-15, brain derived neurotrophic factor (BDNF), and leukemia inhibitory factor (LIF).”

What follows are comments by the authors on several of the myokines mentioned in the above quote.


Of all those myokines mentioned in the above quote, the authors go on to discuss what they consider the most important myokine, IL-6:

“The prototype myokine, IL-6, appears to be able to mediate metabolic effects as well as anti-inflammatory effects.  IL-6 was the first identified and to date the most studied myokine.”

Of all the myokines, why has IL-6 generated the bulk of the interest?

“Identification of IL-6 production by skeletal muscle during physical activity generated renewed interest in the metabolic role of IL-6 because it created a paradox.  On one hand, IL-6 is markedly produced and released in the post exercise period when insulin action is enhanced but, on the other hand, IL-6 has also been associated with obesity and reduced insulin action.”

Which effect tends to predominate with the release of exercise induced IL-6 from muscle, Brandt and Pedersen (2) suggest it is the insulin-sensitizing, anti-inflammatory effect:

“…we showed that rhIL-6 infusion as well as exercise inhibited the endotoxin-induced increase in circulating levels of TNF-α in healthy humans.”

The authors go on to note that, whereas IL-6 released by monocytes and macrophages has a pro-inflammatory effect, the IL-6 released by muscle acts in an opposite manner:

“…when IL-6 is signaling in monocytes or macrophages, it creates a pro-inflammatory response, whereas IL-6 activation and signaling in muscle is totally independent of a preceding TNF-response or NFκB activation.”

(NFκB is a potent pro-inflammatory factor.)

Finally, IL-6 from muscle has been demonstrated to exert actions associated with insulin sensitivity:

“IL-6 may also work in an endocrine fashion to increase hepatic glucose production during exercise or lipolysis in adipose tissue…”


In the following quotes Brandt and Pedersen (2) point out that the myokine IL-15 has major anabolic properties.

“IL-15 is expressed in human skeletal muscle, and has been identified as an anabolic factor in muscle growth, and appears to play a role in lipid metabolism.  Recently, we demonstrated that IL-15 mRNA levels were upregulated in human skeletal muscle following a bout of strength training, suggesting that IL-15 may be accumulated within muscle as a consequence of regular training.”

It also appears that IL-15 from muscle has a major positive impact on fat metabolism:

“Interestingly, a negative association exists between plasma IL-15 concentration and trunk fat mass.  In support of the human data, we found a decrease in visceral fat mass, but not subcutaneous fat mass, when IL-15 was overexpressed in murine muscle.  Quinn et al. found that elevated circulating levels of IL-15 resulted in significant reductions in body fat and increased bone mineral content, without appreciably affecting lean body mass or levels of other cytokines.  These findings lend support to the idea that muscle-expressed IL-15 may be involved in the regulation of visceral fat mass.”

Brain-derived neurotrophic factor (BDNF)

What is the evidence that BDNF, which is usually considered to be a factor produced in the nervous system, is produced in muscle as the result of exercise, making it a myokine?  Brandt and Pedersen (2) state:

“We studied whether skeletal muscle would produce BDNF in response to exercise.  It was found that BDNF mRNA and protein expression was increased in human skeletal muscle after exercise; however, muscle-derived BDNF appeared not be released into the circulation.”

It is also important to note that BDNF from muscle is increased with non-exercise mediated stimulation:

“In addition, BDNF mRNA and protein expression was increased in muscle cells that were electrically stimulated.”

These findings led the authors to conclude:

“Thus, we have been able to identify BDNF as a novel contraction-induced muscle cell-derived protein that may increase fat oxidation in skeletal muscle…”


“BDNF appears to be a myokine that works in an autocrine or paracrine fashion with strong effects on peripheral metabolism, including fat oxidation with a subsequent effect on the size of adipose tissue.”

With the above in mind, could BDNF produced in muscle due to muscle activity or stimulation have a positive effect on neurologic function?  Brandt and Pedersen (2) answer this question with the following comments on the positive impact BNDF has on neurologic function in a variety of neurologic imbalance conditions:

 “BDNF is recognized as playing a key role in regulating survival, growth, and maintenance of neurons, and BDNF plays a role in learning and memory.  Hippocampal samples from Alzheimer’s disease donors show decreased BDNF expression and individuals with Alzheimer’s disease have low plasma levels of BDNF.  Also, patients with major depression have lower levels of serum BDNF than normal control subjects.  Other studies suggest that plasma BDNF is a biomarker of impaired memory and general cognitive function in ageing women and a low circulating BDNF level was recently shown to be an independent and robust biomarker of mortality risk in old women.  Interestingly, we found low levels of circulating BDNF also in individuals with both obesity and type 2 diabetes.  Thus, BDNF is low in people with Alzheimer’s disease, major depression, impaired cognitive function, CVD, type 2 diabetes, and obesity.”

With all the above in mind, what can be concluded about the biochemical and physiologic impact on human metabolism seen with muscle exercise or stimulation?  To answer this question, consider these concluding remarks from the abstract of the Brandt and Pedersen (2) paper:

“Contracting skeletal muscles release myokines with endocrine effects, mediating direct anti-inflammatory effects, and/or specific effects on visceral fat.  Other myokines work locally within the muscle and exert their effects on signaling pathways involved in fat oxidation and glucose uptake.  By mediating anti-inflammatory effects in the muscle itself, myokines may also counteract TNF-driven insulin resistance.  In conclusion, exercise-induced myokines appear to be involved in mediating both systemic as well as local anti-inflammatory effects.”

Indeed, muscle is so much more than just a mechanical device to get us from here to there.


With the above in mind, it would logically follow that prolonged lack of muscle movement and stimulation, which we all know takes a significant toll mechanically on muscle, would also take a significant toll biochemically and physiologically.  To what degree is this biochemical and physiologic toll?  This question has been answered by studying hospitalized, critically ill patients, as seen in the study I am about to review, “Exploring the potential effectiveness of combining optimal nutrition with electrical stimulation to maintain muscle health in critical illness: A narrative review” by Parry et al (3).  Interestingly, as you will see, even though it may not be apparent at first glance, studying the massive loss of muscle mass and function seen with the critical care situation is very applicable to the sedentary behavior seen with many of our chronically ill patients, especially those who are middle-aged and older.  The suboptimal biochemistry and physiology observed with long-term lack of significant movement in the critically ill patient is virtually the same as we see in our sedentary chronically ill patients.  The only difference is a matter of degree.  Therefore, a paper that focuses on muscle biochemistry and physiology in the critically ill is highly significant to our situation.

However, as you hopefully can infer from the title of this paper, there are other very clinically significant reasons why I chose to present this paper to you.  For not only does it define the problem, it addresses a solution in terms of the incredible healing power that occurs when optimal nutrition is combined with optimal muscle stimulation.  There is, though, still one additional reason why I am so impressed with this paper.  We all know that one of our most difficult challenges in dealing with the sedentary, chronically ill patient is gaining compliance with movement and exercise recommendations.  As this paper by Parry et al (3) demonstrates, while movement is optimal, it is not necessary to improve movement-mediated muscle function.  In fact, any form of stimulation may have a positive impact.  While the paper focuses on electrical stimulation, I feel it is safe to hypothesize that other forms of muscle stimulation such as chiropractic, osteopathic, massage, and physical therapy can also have similar effects.

This paper begins by discussing the prevalence of loss of muscle mass with sickness and its impact physiologically.  Even though much of this information was discussed in part I of this series in my review of the Argiles et al (1) paper, I feel it bears repeating both due to its importance and the fact it has been grossly under appreciated by both the functional medicine and clinical nutrition communities.

Why has loss of muscle mass and function and its downstream adverse effects on quality of life become more prevalent?  One reason is that the modern medical community is doing a much better job of helping very sick people to stay alive.  Parry et al (3) state:

“There is a growing population of survivors of critical illness, with almost 90% of patients surviving the initial insult of critical illness.  However, approximately 50% of survivors may develop intensive care unit-acquired weakness (ICU-AW) and suffer ongoing significant morbidity in terms of physical cognitive, and psychological health.”

What is ICU-AW more specifically?  As you will see from the quote below, it is what we see with more and more patients who present to us after experiencing significant illness and have been stabilized from a mortality standpoint, very often with the use of a surgical procedure or one or more medications.  They invariably do not have a defined illness.  Rather they just don’t feel good in terms of muscular function:

“ICU-AW refers to clinically detectable global muscle weakness that develops as a result of no specific etiology other than being critically unwell.”

What does this “unwell” muscle look like?  Parry et al (3) continue:

“Individuals may have evidence of myopathy, polyneuropathy, and/or significant muscle atrophy.”

Most importantly, it has a massive impact on quality of life, which can last for years:

“ICU-AW contributes to significant impairments in physical functioning and decreased health-related quality of life (HRQoL), which persist years after hospital discharge.”

As we all know, this long-term loss of quality of life after a significant sickness episode, for which many allopathic practitioners have no good solutions, is one of the most common reasons today’s chronically ill patients contact us.  While much of what we already do in terms of improving diet, dealing with food sensitivities, addressing GI dysfunction, and detoxification is very helpful for these patients, more and more often long-term outcomes are not all that we or the patients would prefer.  As I have been suggesting and will continue to suggest with the following quotes, one major roadblock to getting to the next level of improvement in quality of life may be suboptimal muscle health.  The next quote I would like to feature from the Parry et al (3) specifically defines muscle health:

“Muscle health can be characterized as a composite of muscle quantity (measured as muscle mass, muscle cross-sectional area, etc.) as well as muscle quality (physical and metabolic function of skeletal muscle).”

Of course, traditionally it has been assumed that improved nutrition would provide all the answers to loss of muscle health.  The next quote makes it clear that this is not true:

“Marked catabolism occurs during critical illness, and hence protein in particular may assist in reducing at least some of the muscle wasting experienced in the ICU setting.”

However, as I have been suggesting, improved nutrition often does not work as well as we would like.  Why?  As you will see, much of the problem is that sick tissues often have difficulty utilizing what has been delivered in terms of quality nutrition:

“However, the delivery of nutrition does not equate directly to utilization of energy in critical illness.  In other words, although one may be providing nutrition support to ICU patients, patients’ tissues may develop resistance to sufficiently taking up nutrients from enteral or parenteral feeds to meet their energy demands.”

Why?  Two reasons.  Patient variability plus the complexity of mitochondrial dysfunction:

“Critically ill patients demonstrate a vast heterogeneity in energy needs as well as magnitude in mitochondrial dysfunction and dysregulated fat oxidation that unfavorably influence energy generation in skeletal muscle.”

What is the answer?  Not to dismiss the idea of supplementation and good nutrition as suggested by many of our critics when desired outcomes do not occur but to maintain good nutrition and supplementation and add the type of muscle stimulation that comes with an understanding of why movement and stimulation of muscle is so important:

“As such, we need to better understand the metabolic energy demands of exercise in critically ill patients to understand its bioenergetic implications and ultimately reduce muscle wasting and improve functional recovery.”

More information on the nature of muscle wasting with sickness

Even though there is some overlap with the information provided in part I of this series, I would next like to feature quotes from the Parry et al (3) paper that address the specifics of muscle wasting with significant illness.  The first quote addresses the fact that muscle can go through significant changes based on the nature of muscle stimulation, which plays a major role in determining outcomes:

“Skeletal muscle is a highly plastic and adaptive tissue, which responds to changes in mechanical loading and is one of the largest tissue groups in the human body.  Skeletal muscle is an integral tissue in predicting clinical, physical, and metabolic outcomes.”

Next, as I have mentioned, low muscle mass is extremely common with sickness and, as noted in the last sentence of the following quote, does not tend to resolve by itself after the patient has moved beyond the acute phase of their illness:

“Low muscle mass is reported in 20%-70% of ICU patients at the time of ICU admission, and a further 30% reduction in quadriceps muscle mass may occur within 10 days of an ICU admission.  Remarkably, low muscle mass is also reported up to 6 and 12 months following ICU discharge.”

The next quote emphasizes what was discussed in part I of this series about the tremendous adverse metabolic impact of loss of muscle mass and function:

“Skeletal muscle atrophy is associated with morbidity, increased hospital length of stay (LOS), and mortality.  Lower limb muscle mass is commonly associated with strength, suggesting that reduction in muscle mass may also contribute to poorer physical performance, and these functional deficits may persist years following ICU discharge.  Muscle atrophy has been linked to elevated tumor necrosis factor-α and interleukin-6 concentrations, and these have been further associated with increased risk of infection in older adults.  Given that skeletal muscle comprises >75% of glucose disposal, it is anticipated that glucose and fat dysregulation may occur.  For example, muscle atrophy as a result of acute immobility has been associated with impaired glucose tolerance, impaired glucose uptake, and reduced fat oxidation.”

In the following quote immobilization and other factors that contribute to loss of muscle mass and function are addressed:

“There are multifaceted factors that lead to skeletal muscle atrophy in critically ill patients, including prolonged bed rest, catabolic signaling (including proinflammation and insulin resistance), and undernourishment via low caloric and protein intakes.  Insufficient caloric intake generally compromises protein intake, leading to reduced protein synthesis.  Amino acids provide the substrate for protein synthesis; thus, reduced intake may lead to reduced protein synthesis.”

The next quote discusses the impact of the combination of lack of movement and insulin resistance on the creation of an issue I have discussed many times in these newsletters as well as my lectures: anabolic resistance.  What is anabolic resistance?  It is the reduced ability of muscle to take up amino acids for the creation of new muscle tissue:

“…in the presence of reduced activity and insulin resistance, it is likely that critically ill patients also exhibit anabolic resistance, which is the reduced ability of the muscle to take up and use amino acids for protein synthesis.”

If that were not enough, because other key organ systems needed for recovery, such as the immune system, also require increased protein, muscle breakdown will be further exacerbated to provide amino acids for these key systems:

“To compensate for the body’s high protein needs during critical illness, skeletal muscle degradation is enhanced to provide amino acids for the synthesis of other proteins that may be needed for immune function, for example, resulting in muscle atrophy.”

The next quote addresses one of the major issues seen with our patients, sedentary behavior:

“…bed rest, independent of illness, can result in muscle loss.  Reduced blood flow is related to reduced delivery of amino acids to skeletal muscle.”

In turn, the potent combination of sedentary behavior and sickness can lead to massive muscle loss:

“Given the extent of bed rest combined with accelerated catabolic processes in a critically ill patient, reduced delivery of amino acids to skeletal muscle would likely contribute extensively to muscle wasting.”

Still another change that occurs with muscle when sedentary behavior and sickness co-exist is fatty infiltration into muscle:

“Loss of muscle quality may be evidenced with infiltration of fat into skeletal muscle, which would likely impair muscle glucose and fat metabolism.”

Finally, with all the above changes in muscle, it should not be surprising that optimal electrical conductivity of muscle is impaired:

“Skeletal muscle relies on proper regulation of the electrical excitability for adequate muscle contraction.  Lower activation of voltage-gated Na+ channels can reduce membrane excitability, which leads to attenuated muscle contraction and consequently muscle weakness.  This acute neuropathy is reported to be reversible – not degenerative – and may be related to electrolyte abnormalities during critical illness.  Although this neuropathic mechanism may be acute, the consequential muscle atrophy that results may be longer term.”

Before continuing, please note again the phrase “electrolyte abnormalities” in the above quote.  If you have been wondering if there is a point of intersection between the two metabolic issues I have been focusing on intensively over the last few months – protein and electrolyte (especially potassium) physiology, I hope this review makes it readily apparent.  Both are needed to optimize one of the most important, most underappreciated factors that contribute to poor quality of life in ailing patients, suboptimal muscle mass and function.

However, as I have been emphasizing in this newsletter, still one other factor is needed besides optimal protein and electrolyte metabolism to optimize muscle physiology: movement or stimulation.  With this in mind, I would now like to present quotes from the Parry et al (3) paper that discuss this.  First, consider the following:

“Targeted rehabilitative approaches that require muscle contraction to preserve muscle mass or recovery from muscle atrophy would be essential to regaining proper neural processes in rehabilitation of muscle strength.”

Unfortunately, as we all know, patient-directed volitional movement is often not an option for many ailing individuals.  Therefore, at least initially, as noted in the following quote, we need to find methods of stimulating muscle that does not require patient directed activity:

“…given the unstable condition of many critically ill patients, we need to consider a continuum of exercise interventions that may begin with cost effective and feasible strategies in which participation is nonvolitional in nature and then progresses to functional activities that require voluntary contraction as patient alertness and ability to engage improve.”

Of course, as I have been suggesting, chiropractic, osteopathic, massage, and physical therapies certainly fulfill the above requirements.  However, the intervention discussed by Parry et al (3) is electrical stimulation:

“Skeletal muscle can be artificially stimulated to induce a visible and palpable muscle contraction in the absence of volitional control using 2 different methodologies:

1.       Neuromuscular electrical stimulation (NMES), which often involves stimulation of isolated muscle groups in a nonfunctional manner (i.e., stimulated in supine).

2.       Functional electrical stimulation (FES), which generally involves stimulation of multiple muscle groups while undertaking a combined functional activity such as bedside cycling.  The muscles are artificially stimulated to contract at the point in range at which volitional activation would occur during the functional activity.  For example, during knee extension while cycling the quadriceps muscle would be stimulated to contract, and on knee flexion the hamstrings would be activated.  This alternating muscle recruitment potentially may enable longer time for contraction to be sustained prior to reaching a point of fatigue.”


As I mentioned in the beginning of my review of the Parry et al (3) paper, while the paper focuses therapeutically on the importance of muscle stimulation in improving quality of life in ailing individuals, it also places major emphasis on nutrition in the form of increased protein intake.  What follows are some quotes on this important therapeutic intervention.  While the authors do not go into detail on specific patient management in terms of protein intake, they make it unmistakably clear the importance of increased protein intake in combination with exercise:

“Protein delivery is considered vital for muscle maintenance in both health and disease.”


“A number of observational studies show an association between greater protein delivery and improved clinical outcomes, including mortality and time to discharge from ICU alive.”


“…Biolo et al showed amino acid transport after exercise is 30%-100% greater than following rest, and this may be related to exercise-induced nutrient-stimulated vasodilation.”


As someone who focuses on the value of nutrition in optimizing health, I have tended to focus on many nutritional factors over the years.  Lately, as you have seen, I have felt that I can best contribute to the clinical nutrition community and the health of chronically ill patients in general by focusing on nutritional issues that have been heavily emphasized by researchers but, for reasons I have  yet to fully understand, have been largely ignored both by the public and the nutritional and functional medicine community.  One is fluid and electrolytes, particularly potassium, and the other is protein.  However, when it comes to discussing muscle health, a major underappreciated issue for all clinicians, not just nutritional practitioners, we need to have a better appreciation of still another greatly misunderstood therapeutic intervention: movement and stimulation, which, for muscle, appears to be an essential stimulating factor, just as important as TSH is to the thyroid and ACTH is to the adrenals.

Of course, we have heard about the benefits of exercise for years.  However, it is my opinion that, to truly maximize the benefits of exercise, we need to fully understand exactly what exercise does, not just mechanically, but biochemically and physiologically.  It is my hope that this review has addressed this need.  Finally, with this increased understanding comes the need to fully recognize and appreciate that, for many if not most patients, optimal, volitional exercise is not a practical option.  Fortunately, as noted by the Parry et al (3) paper, there are other ways of stimulating optimal muscle mechanics, biochemistry, and physiology besides patient-directed movement.  In turn, with this reality in mind, it is long past due that we remove interventions such as chiropractic, osteopathic, massage and physical therapies from the optional, somewhat fringe “B list” patient care modalities list to the “A list” of those that are absolutely essential for maximizing quality of life for the acute or chronic, seriously ill patient.

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.

Moss Nutrition Report #284 – 03/01/2019 – PDF Version



  1. Argiles JM et alInter-tissue communication in cancer cachexia. Nat Rev Endocrinol. 2019;15:9-20.
  2. Brandt C & Pedersen BKThe role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases. J Biomed Biotech. 2010;2010.
  3. Parry SM et alExploring the potential effectiveness of combining optimal nutrition with electrical stimulation to maintain muscle health in critical illness: A narrative review. Nutr Clin Practice. 2018;33(6):772-89.