entry level clinical nutrition part xiii inflammation: the...

Entry Level Clinical Nutrition – Part 13Dr. Jeff Moss

© Dr. Jeff Mosshttp://www.mossnutrition.comhttp://www.FMTown.com

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Entry Level Clinical NutritionEntry Level Clinical NutritionPart XIIIPart XIII

Inflammation:Inflammation:The acute phase response The acute phase response ––

The metabolic foundationThe metabolic foundation

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Jeffrey Moss, DDS, CNS, DACBNJeffrey Moss, DDS, CNS, [email protected]@mossnutrition.com

413413--530530--0858 (cell)0858 (cell)

Quality of life issues are the major concerns more than

ever now.

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Summer of work exposes medical students to system’s ills The NewSummer of work exposes medical students to system s ills, The New York Times, September 9, 2009

“…a tidal wave of chronic illness…”

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Baracos VE. Overview on metabolic adaptation to stress, pp. 1-13.

“An understanding of the nature of stress is f d t l t th ti lfundamental to the rational design of nutrient mixtures to feed patients whose homeostasis has been altered by one or more stressors.”

“All stresses may be presumed to be associated

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with characteristic modifications in the metabolism of lipids, carbohydrates, amino acids, and micronutrients.”



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Bengmark S. Acute and “chronic” phase reaction – a mother of disease, Clin Nutr, Vol. 23, pp. 1256-66, 2004

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Su KP. Biological mechanism of antidepressant effect of omega-3 fatty acids: How does fish oil act as a ‘mind-body interface’? Neurosignals, Vol. 17, pp. 144-152, 2009

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Key metabolic imbalances seen Key metabolic imbalances seen with the acute phase responsewith the acute phase response

• Metabolic acidosisMetabolic acidosis• Loss of lean body mass (sarcopenia)• Insulin resistance• Inflamm-aging (Increased innate immunity

and decreased adaptive immunity)• Suboptimal caloric intake and

carbohydrate:protein ratio (Refeeding

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carbohydrate:protein ratio (Refeeding syndrome)

• Gastrointestinal dysfunction/gut atrophy• Deficiencies of key micronutrients such as

zinc, selenium, and vitamin D



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Underlying hypotheses of Underlying hypotheses of Entry Level Clinical Nutrition:Entry Level Clinical Nutrition:

Chief complaints in chronically ill• Chief complaints in chronically ill patients are not diseases but responses that have gone on too long (Allostatic load).

• The metabolic imbalances that combine

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to form this response have been well defined by critical care nutritionists.

Entry Level Clinical Nutrition:Entry Level Clinical Nutrition:

A new model of functional A new model of functional medicine that incorporates medicine that incorporates

allostatic load and the “chronic” allostatic load and the “chronic”

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acute phase responseacute phase response



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Chronic inflammation, inflammaging, metainflamm.

Key deficiencies or excesses, i.e.,

Calories, macronutrients, B

vitamins, zinc, selenium, iodine,

sleep, psychological

Low calorie intake and excessive

carbohydrate/protein ratio – Refeeding

syndrome

Hyperinsulinemia/Insulin resistance

Sarcopenia/Loss of lean

sleep, psychological and chemical stress, movement against

gravity, weight

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THE CREATION OF THE EXCESSIVE CATABOLIC PHYSIOLOGY “RESPONSE”

pbody mass

Low grade chronic metabolic acidosis/fluid electrolyte imbalance

Gut dysfunction/atrophy

Inflammation:Inflammation:The major driving force behind The major driving force behind

the acute/chronic phase the acute/chronic phase responseresponse

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responseresponse



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Dhabhar FS et al. Effects of stress on immune cell distribution, J Immunol, Vol. 154, pp. 5511-5527, 1995.

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• “We hypothesize that an important function of endocrine mediators released under conditions of acute stress may be to ensure that

i t l k t t iappropriate leukocytes are present in the right place and at the right time to respond to an immune challenge that might be initiated by the stress-inducing agent (e.g., attack by a predator,

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g ( g y pinvasion by a pathogen, etc.).”



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• “The modulation of immune cell distribution by acute stress may be an adaptive response designed to enhance immune vigilance and increase the capacity of the immune system to respond to challenge in y p gimmune compartments (such as the skin and epithelia of the lung, gastrointestinal and urogenital tracts), which serve as major defense barriers for the body.”

• “Thus, endocrine mediators released during

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stress may serve to enhance immune preparedness for potential (or ongoing) immune challenge.”

Yeager MP et al. Glucocorticoid regulation of the inflammatory response to g g y pinjury, Acta Anaesthesiol Scand, Vol. 48, pp. 799-813, 2004.

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Does the quantity of cortisol Does the quantity of cortisol affect inflammation?affect inflammation?

“Low levels of cortisol are identified as“Low levels of cortisol are identified as having ‘preparative’ or ‘permissive’ effects in that they are necessary for the early, immediate response of an organism to an external stressor.”

Yeager MP et al, Glucocorticoid regulation of the inflammatory response to injury, Acta Anaesthesiol Scand, Vol. 48, No. 7, pp. 799-813, 2004 17


“Intermediate levels of cortisol up to the“Intermediate levels of cortisol up to the maximum concentrations seen during unstressed diurnal variations often act to stimulate many defensive responses.”

Yeager MP et al, Glucocorticoid regulation of the inflammatory response to injury, Acta Anaesthesiol Scand, Vol. 48, No. 7, pp. 799-813, 2004. 18



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“Finally high concentrations of GC such“Finally, high concentrations of GC, such as commonly observed during a major stress, are suppressive or anti-inflammatory, and are probably designed to protect an animal from


over-activity of its own inflammatory responses to injury.”

Glucocorticoid Glucocorticoid Regulation of Regulation of

the the Inflammatory Inflammatory Response to Response to

InjuryInjury




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Cortisol, Catecholamines, and Cortisol, Catecholamines, and InflammationInflammation

“It is now clear that HPA and sympathoadrenalIt is now clear that HPA and sympathoadrenal activation occur at multiple levels in the brain and in the periphery and there is considerable cross-talk and feedback occurring between these two systems at every level creating not only complexity but redundancy in processes


only complexity but redundancy in processes that act to stimulate and/or suppress inflammation.”

Bengmark S. Acute and “chronic” phase reaction – a mother of disease, Clin Nutr, Vol. 23, pp. 1256-66, 2004

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Bengmark S. Nutritional modulation of acute- and “chronic”-phase responses, Nutrition, Vol. 17, pp. 489-495, 2001.

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The chronic phase responseThe chronic phase response

“The body’s reaction to physical and• “The body’s reaction to physical and psychological stresses is similar irrespective of the cause: microbial invasion, allergic reaction, surgical operation, trauma, burn, tissue

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ischemia, tissue infarction, strenuous exercise, or childbirth.”



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Chronic phase responseChronic phase response

• “This response which in essence is aThis response, which in essence is a localized acute inflammation with general symptoms, is called the acute phase response (APR).”

• “The common clinical symptoms of an APR are fever, chill, somnolence, and anorexia, which are accompanied by profound changes

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in plasma proteins, lipids, minerals, hormones, cytokines, and cellular components of the blood.”

The chronic phase responseThe chronic phase response

• “A similar inflammatory reaction is seen in patients with subclinical or apparent chronic diseases such as arteriosclerosis, Alzheimer’s disease, cancer, coronary artery disease, diabetes, hepatitis, and rheumatoid arthritis. Elevations in acute-phase proteins cytokines and other signal molecules are

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proteins, cytokines, and other signal molecules are often observed weeks or months before clinically manifest disease.”



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“Although the extent of the changes• “Although the extent of the changes observed differs between an APR and a “chronic”-phase response (CPR), common to both conditions is a general hypermetabolism with higher resting

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energy expenditure.”


• “This hypermetabolism is associated with increased• This hypermetabolism is associated with increased hepatic gluconeogenesis, increased glucose turnover, and decreased muscle glucose uptake; hyperlipidemia, adipose tissue lipolysis, and increased production of non-esterified fatty acids; increased whole-body protein turnover, increased hepatic protein synthesis, and decreased muscle amino acid uptake; insulin resistance; increased

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amino-acid uptake; insulin resistance; increased production of cytokines; increased concentrations of endotoxins in the blood; and elevated concentrations of cataecholamines, cortisol, and glucagon.”



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• “Changes in plasma proteins lipids minerals• Changes in plasma proteins, lipids, minerals, hormones, cytokines, and cellular components of blood are distinctly different in an APR and a CPR.”

• “In an APR the increase in cytokines and acute-phase proteins is instantaneous; very hi h t ti h d ithi f

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high concentrations are reached within a few hours but are often more or less normalized within 10 to 14 d.”

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Bengmark S. Fiber (prebiotics) and probiotics: Prevention of ICU infections and bioecological control and symbiotic treatment, in Cresci G ed., Nutritional Support for the Critically Ill Patient, CRC Press, Boca Raton, 2005, pp. 151-171.



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• “In a CPR cytokines and acute phase• In a CPR cytokines and acute-phase proteins remain not so high but clearly increased concentrations over months and years.”

• “Whereas acute-phase protein production constitutes about 30% of the body’s total

t i th i i APR it tit t

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protein synthesis in an APR, it constitutes only about 5% in a CPR.”

• “An increase in C-reactive protein is prominent is an APR, whereas fibrinogen increases dominate in a CPR.”



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Rodriguez NA et al. Nutrition in burns: Galveston contributions, JPEN, Vol. 35, No. 6, pp. 704-714, November 2011.

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“The primary mediators of the hypermetabolic response postburn

are catecholamines, corticosteroids, and inflammatory cytokines.”

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• “During postburn hypermetabolic response, both glycolytic-gluconeogenic and triglyceride-fatty acid cycling have been reported to increase by 250% and 450%, respectively.”

• “Collectively, these changes increase glycogenolysis, gluconeogenesis, and circulation of glucogenic precursors, which translate into hyperglycemia and

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impaired insulin responsiveness, in turn related to post-receptor insulin resistance.”



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• “Although glucose delivery to peripheral tissues is increased up to 3-fold, glucose oxidation is restricted, leading to elevated fasting glucose.”

• “Increased glucose production is directed, in part, to the burn wound to support the anaerobic metabolism of fibroblasts, endothelial cells, and inflammatory cells.”

• “The end product of anaerobic glucose

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production – lactate – is recycled to the liver to produce more glucose via gluconeogenic pathways.”

“Adequate nutrition support is an effective nonpharmacological

strategy to attenuate these catastrophic metabolic responses.”

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Kushner I and Rzewnicki D. Acute phase response, in Gallin JI and Snyderman R eds., Inflammation: Basic Principles and Clinical Correlates, Third Edition, Lippincott Williams & Wilkins, Philadelphia, PA, 1999, pp. 317-329.

• “The term inflammation refers to the complex, localized responses elicited by a variety of noxious stimuli. In addition to these localized responses, a vast number of distant systemic changes may also occur if the stimulus is severe enough These changes are referred toenough. These changes are referred to collectively as the acute phase response (APR), because attention was first focused on them by the discovery of C-reactive protein (CRP) in the serum of patients in the acute phase of pneumococcal pneumonia. Oswald Avery, in whose laboratory this observation was made in 1930 was excited by this discovery which he

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1930, was excited by this discovery, which he regarded as an important lead to understanding what he termed ‘the chemistry of the host’ – the host response to disease.”



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• “An unfortunate consequence of the use of the term acute phase is that many physicians incorrectly believe that acute phase changes are limitedthat acute phase changes are limited to acute inflammatory states and are not found in chronic inflammation. In fact, the APR persists in many chronic diseases, resulting in what

i ht t b

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might seem to be an oxymoron, a chronic APR.”

• “…investigators whose major focus is on the neuroendocrine aspects of the APR have employed the term stress response, originated by Hans Selye in the 1940s. They define stress as a state of disharmony or threatened homeostasisdisharmony or threatened homeostasis. Many of these investigators have been particularly interested in the changes that are induced by psychological and emotional stimuli and that are mediated by corticotrophin-releasing hormone (CRH) and the autonomic nervous system. As i di t d l t th t f ti li

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indicated later, these types of stimuli may also influence other, nonneuroendocrine components of the APR.”



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• “A large number of changes, distant from inflammatory sites and involving many organ systems, accompany inflammatory states. New APR phenomena continue to be recognized, year after year. In general, these represent the s bstit tion of nethese represent the substitution of new ‘set points’ for the homeostatic mechanisms that normally maintain a constant internal environment during good health. These changes can be categorized as affecting plasma protein synthesis, the neuroendocrine and

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y ,hematologic systems, metabolic processes, intrahepatic constituents, and nonprotein plasma components.”

• “Both increases (positive acute phase proteins) and decreases (negative acute phase proteins) are seen; changes in different proteins occur at different rates and to different degrees.”

• “A few plasma proteins have long been• A few plasma proteins have long been recognized as positive acute phase proteins. Ceruloplasmin and the complement components C3 and C4 exhibit relatively modest positive acute phase behavior (typically an increase of about 50%). Concentrations of haptoglobulin, α1-acid glycoprotein (α1-AGP), α1-protease inhibitor, α1 antichymotrypsin and fibrinogen ordinarily

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α1-antichymotrypsin, and fibrinogen ordinarily increase about twofold to fivefold.”



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• “The two major human acute phase proteins…are CRP and serum amyloid A (SAA). Both are normally present in plasma in only trace p ese t p as a o y t aceamounts but can manifest dramatic increases in rate of synthesis and plasma concentration after stimulation, achieving levels more than 1 000 times normal in some

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than 1,000 times normal in some severely infected persons.”

• “The long-recognized negative acute phase reactants in humans are albumin and transferrin.”

• “Among the neuroendocrine changes are fever (literally a resetting of thefever (literally a resetting of the thermostat), somnolence, anorexia, the ‘sick euthyroid syndrome’, and altered synthesis of many endocrine hormones including CRH, glucagons, insulin, corticotrophin (ACTH), cortisol, adrenal catecholamines growth hormone thyroid

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catecholamines, growth hormone, thyroid stimulating hormone, thyroxin, aldosterone, and arginine vasopressin.”



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Changes in the hematopoietic Changes in the hematopoietic systemsystem

• “Involvement of the hematopoietic• Involvement of the hematopoietic system includes leukocytosis, thrombocytosis, and the ‘anemia of chronic disease’ (better designated the ‘anemia of chronic inflammation’) which is seen in most

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inflammation ), which is seen in most patients with chronic inflammatory states.”

Metabolic ChangesMetabolic Changes

“Osteoporosis appears to belong in• “Osteoporosis appears to belong in this category also, as does the reported increase in blood leptin levels in inflammatory states.”

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Changes in the liverChanges in the liver

• “A very large number of enzymatic• “A very large number of enzymatic, morphologic, and chemical changes occur in the liver, including increases in metallothionein, inducible nitric oxide synthase (iNOS), heme oxygenase, manganese superoxide dismutase,

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manganese superoxide dismutase, hepatocyte growth factor activator, and glutathione.”

Changes in the liverChanges in the liver

“Decreased expression of many“Decreased expression of many members of the cytochrome P450

family is seen, but several others are induced.”

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Changes in plasma nutrient Changes in plasma nutrient statusstatus

“ changes in nonprotein plasma• “…changes in nonprotein plasma constituents include hypozincemia, hypoferremia, hypercupremia, increased retinol, and increased glutathione secondary to increased

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hepatic levels.”

Factors that can induce the acute Factors that can induce the acute phase responsephase response

• “Recognition of an acute phase phenomenonRecognition of an acute phase phenomenon requires in vivo induction by any of a variety of inflammatory stimuli. In humans, stimuli that commonly give rise to the APR include bacterial and, to a lesser extent, viral infection; surgical or other trauma; neoplasm; burn injury; tissue infarction; various immunologically mediated…inflammatory states; strenuous exercise; heatstroke; and childbirth Several

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exercise; heatstroke; and childbirth. Several psychiatric illnesses and psychological stress are associated with acute phase changes, as is chronic fatigue syndrome…”



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Inflammatory factors that can affect the Inflammatory factors that can affect the production of acute phase proteinsproduction of acute phase proteins

• “A number of different cytokines, alone or in aA number of different cytokines, alone or in a network, may influence acute phase protein synthesis. These cytokines are elicited during, and participate in, the inflammatory process. They include IL-6, IL-1, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and transforming growth factor-β (TGF-β). Some of these cytokines are regarded as proinflammatory, while others are regarded as anti-inflammatory Inflammation-

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are regarded as anti-inflammatory. Inflammation-associated cytokines may be produced by many different cells, including monocytes, macrophages, fibroblasts, endothelial cells, T lymphocytes, and epithelial cells, but macrophages and monocytes at inflammatory sites clearly play major roles.”

“Psychological stresses may stimulate IL-6 production through release of 6 p oduct o t oug e ease o

catecholamines.”

“IL-1β, IL-6, and interferons are capable of altering the expression of

a number of hepatic P450

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a number of hepatic P450 cytochromes during inflammatory

states.”



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Acute phase response and fatigueAcute phase response and fatigue

• “IL 1 and TNF α are both• IL-1 and TNF-α are both somnogenic on injection into the lateral cerebral ventricle of rabbits, enhancing non-rapid eye movement (non-REM) sleep while inhibiting REM sleep and presumably directly

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REM sleep, and presumably directly affecting the anterior hypothalamic preoptic area.”

Acute phase response and appetiteAcute phase response and appetite

“Older data suggest that local TNF α• “Older data suggest that local TNF-α production in the brain may also participate in the development of anorexia.”

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Acute phase response and anemiaAcute phase response and anemia

• “The mechanisms responsible for the• “The mechanisms responsible for the anemia of chronic inflammation, although somewhat poorly understood, include decreased proliferation of red cell progenitors and inadequate erythropoietin production, both caused at least in part by

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production, both caused at least in part by inflammation-associated cytokines.”

Acute phase response and Acute phase response and anemiaanemia

• “Another acute phase phenomenon• Another acute phase phenomenon, thrombocytosis, also appears to be caused by IL-6.”

• “Hypoferremia seen during the APR is largely caused by iron sequestration in the reticuloendothelial system. This sequestration appears to result from increased apoferritin t l ti i h i d d b IL 4 d

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translation in macrophages induced by IL-4 and IL-13, with consequent inhibition of iron release.”



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Cachexia/SarcopeniaCachexia/Sarcopenia

• “Cachexia the loss of body mass thatCachexia, the loss of body mass that accompanies chronic inflammatory states and cancer, results from decreases in skeletal muscle, fat tissue, and bone mass. There is considerable evidence that IL-1, IL-6, TNF-α, and IFN-γ all contribute to these processes. Loss of skeletal muscle is caused by the combination of

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muscle is caused by the combination of decreased protein synthesis and increased proteolysis.”

Acute phase response and Acute phase response and lipid metabolismlipid metabolism

• “Lipid metabolism is markedly altered during the• Lipid metabolism is markedly altered during the APR. Loss of fat tissue results, at least in part, from inhibition of lipoprotein lipase production by cytokines. Increases in serum triglycerides, very-low-density lipoproteins, and low-density lipoproteins are seen. Effects on high-density lipoproteins (HDLs) are particularly striking. HDL levels fall during inflammatory states and serum

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levels fall during inflammatory states, and serum amyloid A may largely displace apolipoprotein I (apo A-I) in HDL.”



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The acute phase response and The acute phase response and immunosuppressionimmunosuppression

“IL 10 regarded as an anti• “IL-10, regarded as an anti-inflammatory cytokine, has been implicated in the pathogenesis of postoperative immunosuppression, which is probably also an acute

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phase phenomenon.

The acute phase response and The acute phase response and thyroid functionthyroid function

“Inflammation associated cytokines• “Inflammation-associated cytokines play a major role in the pathogenesis of septic shock and are believed to play a role in the ‘sick euthyroid syndrome.’”

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Acute phase response and Acute phase response and CC--reactive proteinreactive protein

• “CRP…can be regarded as a component of the primitiveCRP…can be regarded as a component of the primitive innate, or natural, immune system. A very large number of binding specificities and biologic effects of CRP are reported, and a major function of CRP is presumed to be ‘proinflammatory,’ related to its ability to specifically bind to phosphocholine and some nuclear components. Through such binding, CRP could recognize some foreign pathogens, as well as both phospholipids and nuclear constituents of damaged or necrotic cells. Further, CRP can activate the complement system when bound to one of it li d d l bi d t h ti ll

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its ligands and can also bind to phagocytic cells, suggesting that it can initiate elimination of targeted cells by interaction with humoral and cellular effector systems of inflammation. This argument is supported by the observation that CRP can induce production of inflammatory cytokines and tissue factor, the main initiator of blood coagulation, by monocytes.”

Acute phase response and Acute phase response and LDL oxidationLDL oxidation

“ ceruloplasmin enhances• “…ceruloplasmin enhances oxidation of low-density lipoproteins.”

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Acute phase responseAcute phase responseand nutrient metabolismand nutrient metabolism

• “Decreases in serum levels of iron• Decreases in serum levels of iron and zinc may have beneficial effects in defense against bacterial infection and in tissue repair. It has been hypothesized that decreased zinc concentrations benefit the host by

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concentrations benefit the host by influencing the production of cytokines.”

Acute phase response andAcute phase response andfever and cortisolfever and cortisol

“Several acute phase changes such• “Several acute phase changes such as fever and hypercortisolemia are presumed to provide a systemic environment appropriate for the adaptive requirements of coping with

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significant tissue injury or infection.”



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Some concluding thoughts from Some concluding thoughts from Kushner and RznewnickiKushner and Rznewnicki

• “In a given patient, the APR represents theIn a given patient, the APR represents the integrated sum of multiple, separately regulated changes induced primarily by inflammation-associated cytokines and influenced by modulators of cytokine function (cytokine inhibitors, soluble receptors, autoantibodies), some endocrine hormones, and other circulating molecules. Although many of these changes commonly occur together clinical experience

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commonly occur together, clinical experience teaches that not all of them occur in all patients, indicating that they must be individually regulated.”


• “For example febrile patients may haveFor example, febrile patients may have normal blood levels of CRP and vice versa, leukocytosis does not always accompany other acute phase phenomena, and instances of discordance between levels of the various acute phase proteins are regularly encountered. These variations may be explained by

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variations may be explained by differences in patterns of specific cytokines or cytokine modulators in the various pathophysiologic states.”



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• “It is widely held that components of• It is widely held that components of the APR influence the inflammatory response or enhance adaptation to noxious stimuli. Although this probably is true most of the time, it is not invariably true The host

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not invariably true. The host response may be either protective or destructive…”

Rodriguez NA et al. Nutrition in burns: Galveston contributions, JPEN, Vol. 35, No. 6, pp. 704-714, November 2011.

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Chronic stress/↑Allostatic load

↑IDO/Sickness behavior

Euthyroid sick syndrome

and gut

Altered macro and micronutrient

↑Body fat

Detox

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Altered macro- and micronutrient metabolism/metabolic acidosis↑S wastingDiet

Supplements

Movement

Sleep

Routine

Mindset/Energy

Pharmaceutical/Herbal

Thank you!!

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