pérdidade peso enla poblaciónadulta mayor · pérdidade peso enla poblaciónadulta mayor dra....

Pérdida de peso en la población adultamayor

Dra. Isabel Barrientos CalvoMédico Geriatra y Gerontóloga

Nutriología Clínica

www.nutrigeriatria.wordpress.com

Guía de la charla

• Cambios durante el envejecimiento con repercusión en el peso • Epidemiología de la pérdida de peso• Causas • Abordaje diagnóstico• Perlas en el abordaje terapéutico


Cambios durante el envejecimientoCognitivoEmocional

Visión

Cambios orales

êmasa muscular

êFunción

Enfermedad crónica Polifarmacia

Problemas sociales

Mayor riesgowww.nutrigeriatria.wordpress.com

Cambios durante el envejecimiento

• Masa magra disminuye 0.3 kg/a tercera década• Ganancia de masa grasa …65-70 años• El pico del peso usualmente 60 años, con disminuciones de 0,1-0,2 kg/a después

de los 70 años 1

• Gasto energéCco en reposo disminuye, principalmente por el descenso de MLG 2

1. Am Fam Physician. 2014;89(9):718-7222. Clin Nutr. 2018 Jun 18. pii: S0261-5614(18)30210-3

70 años 80 años

1-2 kg



• Variaciones en la ingesta dietética:• Pérdida de apetito: 20% en PAM

con RN 1

• 42% no consumen proteínas origen animal

• 7% consumen menos de 2 comidas/día

• Edentulismo• 45% nacional• Con RN, 50% edéntulos• 22% prótesis desajustadas

Barrientos Calvo, Isabel. Rev. costarric. salud pública [online]. 2014, vol.23, n.1, pp. 39-43.www.nutrigeriatria.wordpress.com


Curr Opin Clin Nutr Metab Care 2013, 16:27 – 32

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

importance of vision as a sensation playing a rolein appetite [18]. Buffet dining and the use of snackcarts and ice-cream parlors have also improved foodintake. With aging, changes in food preferencesand choices appear to be influenced more by socialforces than by sensory changes [19].

THE GASTROINTESTINAL TRACT ANDSATIATIONThe involvement of the gastrointestinal tract inproducing satiation involves antral stretch, the rateof gastric emptying, the release of gastrointestinalhormones, and feedback to the central nervoussystem, through the ascending fibers of the centralnervous system. Older persons have a delay ingastric emptying when they ingest large meals[20]. This delay in gastric emptying is associatedwith an increase in satiation in older compared toyounger persons. In addition, aging is associatedwith a decrease in fundal compliance leading tomore rapid antral filling and increased centralstretch [21]. This decrease in fundal compliance isdue to a decrease in fundal relaxation to nitric oxidewith aging [22]. When the stomach is bypassedby utilizing an intraduodenal tube, food has lessof a satiating effect in older persons [4]. Liquidsare rapidly emptied from the stomach withoutproducing significant antral stretch. For this reason,it has been demonstrated that oral liquid supple-ments given at least an hour before the meal resultin greater food intake in older persons [23].

Animal studies have suggested that gastro-intestinal hormones have a greater satiation effectin older animals [24&]. In older humans, cholecysto-kinin (CCK) levels have been found to be elevatedat baseline and after a meal compared to levelsfound in younger individuals [25,26]. The elevationof CCK has not been found in all studies [27]. It hasbeen suggested that this is dependent on the volumeof food ingested. CCK infusion has a greater satiationeffect in older than in younger persons [25].

Glucagon-like peptide 1 (GLP-1) is a potentanorexic hormone that also slows gastric emptying

[28,29]. A high fat meal that produced moresatiation in older persons also increased GLP-1levels more than those in younger persons [30].Other gastrointestinal hormones that producesatiation still need to be studied to provide com-parisons between the effects on satiation in youngand old persons.

Ghrelin is a gastrointestinal hormone that isproduced from the fundus of the stomach. It releasesgrowth hormone from the pituitary and it stimu-lates feeding by activating nitric oxide synthasein the hypothalamus [31]. A number of studieshave examined the effect of aging on ghrelin.In general, these studies suggest a small decreasein ghrelin levels in older compared to youngerpersons [32,33]. The active ghrelin (acetylated)levels tend to be lower than deacetylated ghrelinin older persons [34]. The recovery of ghrelin follow-ing a meal is less pronounced in older comparedto younger persons [25]. The expected increasedghrelin levels in malnourished older persons arenot present [33,34], although they also show lesssuppression following a preload [26].

The different responses of the gastrointestinaltract to food in aging are summarized in Fig. 1.Overall, these effects lead to greater satiation byincreasing antral stretch, increasing the satiationhormones CCK and GLP-1, and decreasing the levelsof the orexigenic hormone, ghrelin. These findingsstrongly support that changes in the gastrointestinalresponse to food play a role in producing thephysiological anorexia of aging [35&].

ADIPOKINES AND APPETITEWith aging, there tends to be an increase in adi-posity. This leads to an increase in tumor necrosisfactor alpha and other proinflammatory cytokines.

KEY POINTS

! Peripheral gastrointestinal hormones (cholecystokin,glucagon-like peptide, and ghrelin) play a key role inthe pathogenesis of the anorexia of aging.

! Depression is the major cause of pathological anorexiain older persons.

! SNAQ should be used to screen for anorexia inolder persons.

Decreasedfood intake

Antral stretchGlucagon-like peptide 1

Fundal compliance

Nitric oxide

Ghrelin

Cholecystokinin

FIGURE 1. The changes in the gastrointestinal tract withaging that lead to the physiological anorexia of aging.

Ageing: biology and nutrition

28 www.co-clinicalnutrition.com Volume 16 ! Number 1 ! January 2013


Pérdida de peso no intencional• 5% en 3 meses• 10% en 6 meses (5% en 12 meses en personasindependientes de la comunidad)

• ESPEN: ó una reducción del IMC (<20kg/m2) o de la masa muscular

Clin Nutr. 2018 Jun 18. pii: S0261-5614(18)30210-3

Peso usual 55 kg Dic 2018Peso actual 52 kg = PP 6%


Epidemiología

• Pérdida de peso no intencional: 15%-20% 1• Pérdida de peso en comorbilidades (EPOC) : 10-20%2,3

• Guadalupe y Alajuelita: 5%-6% 4

1. Am Fam Physician. 2014;89(9):718-7222.The Lancet Respiratory Medicine. 2016. 4 ( 9): 675

3.Lancet Respir Med 2016; 4: 911–24 4. Barrientos Calvo, Isabel. Rev. costarric. salud pública [online]. 2014, vol.23, n.1, pp. 39-43.

MalnutriciónPérdida de masa grasa

Pérdida de masa muscularPérdida de densidad ósea


https://www.sciencedirect.com/science/journal/22132600

Causas de pérdida de peso

• Se pueden dividir en 3 grupos:

• Físicas u Orgánicos

• Psíquicas: 9% - 24%

• Sociales

Malignidad 19% a 36%


Por qué ocurre la pérdida peso?

CÁNCER

ANOREXIA

INFLAMACIÓN


Anorexia

• 15%- 30% PAM de la comunidad4

• 30% de mujeres AM, y 25% a hombres adultos mayores1

• Hogares de residencia larga 31% (27% H y 34% M)4

• Hospitalizados 31.5% (26.7% H y 33.3% M) 4

• 20 % de la población estudiada en un área de salud primer nivel (Guadalupe)3

• 25% de casos no se idenLfica la causa 2

1. JAMDA 14 (2013) 119e124 2. JAMDA (2017)18(5): 449–450

3. Rev Costarr Salud Pública 2014; 23: 39- 43Maturitas 74 (2013) 293–302


Por qué ocurre la pérdida peso?Anorexia

potentiated.41 Ghrelin produces its effects by stimulatingnitric oxide synthase.42 The ghrelin agonist, GHRP-2, hasbeen shown to increase food intake in persons withanorexia nervosa.43 Lactate, which is elevated in manycancers, has a direct inhibitory effect on methylmalonylcoenzyme A.16

Sarcopenia is defined as the decline in function due to theloss of muscle mass.44,45 There are multiple causes ofsarcopenia.46 The age-related anorexia decreases musclemass, and this can be aggravated by low grade productionof inflammatory cytokines in chronic disease.6,47

Persons with the anorexia of ageing are at risk ofdeveloping severe anorexia when exposed to high levelsof inflammatory cytokines as occurs in the anorexia–cachexia syndrome.48–50 Persons with illnesses are apt todevelop depression with an increase in the anorecticneurotransmitters, serotonin and corticotrophin-releasingfactor.37,38

The data presented here support the concept that theanorexia of ageing is a major risk factor for older personsdeveloping sarcopenia and/or cachexia. In addition, weightloss together with sarcopenia are major causes of the

physical frailty syndrome.51–54 For these reasons, westrongly recommend regularly monitoring and treating nu-tritional abnormalities in older persons.55–58 When anorexiais associated with weight loss, the appropriate nutritionalsupplement is a leucine-enriched essential amino acidmixture.59,60 Drugs such as dronabinol and megestrol ace-tate have a small effect in increasing food intake.61,62 Otherdrugs are under development to increase food intakeand/or decrease muscle wasting.63

Acknowledgements

The authors certify that they comply with the ethical guide-lines for authorship and publishing of the Journal of Cachexia,Sarcopenia and Muscle.64

Conflict of interestThe author has no conflict of interest regarding this work.

Figure 1 Simplified diagram of factors involved in the pathogenesis of the anorexia of ageing. CRF, corticotrophin releasing hormone; NPY, neuropep-tide Y; MSH, melanocyte-stimulating hormone; CCK, cholecystokinin.

524 Editorial

Journal of Cachexia, Sarcopenia and Muscle 2017; 8: 523–526DOI: 10.1002/jcsm.12192

Journal of Cachexia, Sarcopenia and Muscle 2017; 8: 523–526

Fármacos


Anorexia y Mortalidad

The Journal of Nutrition, Health & Aging. 16(1): 2012

82

The Journal of Nutrition, Health & Aging©Volume 16, Number 1, 2012

ANOREXIA AND MORTALITY IN ELDERLY

Figure 1Survival curves of study participants according to anorexia atbaseline assessment. Survival curves differed significantly at

the log-rank test (p<0.001)

Figure 2Survival curves of study participants according to anorexia atbaseline assessment and weight loss (more or equal 5% duringthe last month or more or equal 10% during the last six months

before the baseline assessment). Survival curves differedsignificantly at the log-rank test (p<0.001)

Discussion

The evaluation of the impact of anorexia and weight loss onsurvival among elderly subjects is an important and intricateissue. In the present study, we explored the association ofanorexia and weight loss in a large sample of community-dwelling subjects aged 65 years or older. Our findings showthat anorexia exerts an important influence on mortality in olderadults living in the community, independently of age, weightloss and other clinical and functional variables. In particular,after adjusting for several potential confounders, such as livingalone, physical and cognitive disability, behavior problems,urinary incontinence, pressure ulcer, hearing impairment,congestive heart failure, hypertension, depression, diabetes,renal failure, and cancer, anorexia emerged as a strong riskfactor for death, independently of functional disability and

multimorbidity.Anorexia is clinically defined as the reduction and/or loss of

appetite (3, 6, 22). Unlike anorexia nervosa, anorexia of aging(i.e. disease-related) is a rather common symptom, andfrequently accompanies chronic diseases (22, 23). Anorexia is amultifactorial health condition correlated with multiplecausations that occurs when the accumulated effects ofimpairments in multiple systems make an older person morevulnerable. The major risk factors of anorexia are the ageingprocess itself, biological changes, behavioural factors, socialand environmental conditions, many acute and chronic diseasesand treatments (24, 25).

Anorexia is frequently under-diagnosed and maysignificantly contribute to the nutritional deterioration ofcachexia, if not properly treated either pharmacologically orwith oral nutritional supplementation (6, 26, 27). Numerousclinical consequences are correlated to anorexia: impairedwound healing, impaired immune response to infections,hypoalbuminemia, decreased coagulation capacity, reduced gutfunction, intestinal bacterial translocation, muscle wasting,decreased function of respiratory muscles (28).

Furthermore, anorexia is highly predictive of incidentdisability, poor quality of life and all-cause mortality (3, 20,29). In particular, as our results suggest, even though worseresults have been observed when anorexia is associated withsignificant weight loss, anorexia per se is an importantmortality risk factor. In fact, the anorexia not accompanied byweight loss confers increased risk for mortality, too. The resultsof our study are also supported by those of a large surveyconducted in European hospitals, which showed that reducedfood intake is an independent negative prognostic factor for 30-day in-hospital mortality, more robust than weight loss (19). Itis possible to hypothesize that in the early stage, the anorexiadoesn't determine an evident status of malnutrition (i.e.significant weight loss) but it determines selective nutritionallacks (i.e. deficit of vitamins and/or micronutrients). Severalstudies have demonstrated the negative role of selectivemalnutrition on functional outcomes and survival amongelderly subjects (30, 31).

In this respect, it is important to highlight that nutritionremains important throughout life. Some studies havedocumented that a “good” diet helps both in reducing the riskof diseases and in managing the diseases’ signs and symptoms(10, 26). This contributes to a better quality of life, enablingolder people to maintain their independence and physicalperformance. On the other hand, poor nutrition and anorexia ofaging can prolong recovery from acute illnesses, increase therate of institutionalization, expand the costs of health care, leadto a poorer quality of life and higher morality (3, 19, 20).

Some methodological issues should be taken into account inthe interpretation of results. Anorexia makes a majorcontribution to multimorbidity, such as anemia, malnutrition,osteoporosis, and dementia. On the other hand, severe andchronic diseases may be associated with anorexia. In thisrespect, we cannot completely exclude that this reverse

82

The Journal of Nutrition, Health & Aging©Volume 16, Number 1, 2012

ANOREXIA AND MORTALITY IN ELDERLY

Figure 1Survival curves of study participants according to anorexia atbaseline assessment. Survival curves differed significantly at

the log-rank test (p<0.001)

Figure 2Survival curves of study participants according to anorexia atbaseline assessment and weight loss (more or equal 5% duringthe last month or more or equal 10% during the last six months

before the baseline assessment). Survival curves differedsignificantly at the log-rank test (p<0.001)

Discussion

The evaluation of the impact of anorexia and weight loss onsurvival among elderly subjects is an important and intricateissue. In the present study, we explored the association ofanorexia and weight loss in a large sample of community-dwelling subjects aged 65 years or older. Our findings showthat anorexia exerts an important influence on mortality in olderadults living in the community, independently of age, weightloss and other clinical and functional variables. In particular,after adjusting for several potential confounders, such as livingalone, physical and cognitive disability, behavior problems,urinary incontinence, pressure ulcer, hearing impairment,congestive heart failure, hypertension, depression, diabetes,renal failure, and cancer, anorexia emerged as a strong riskfactor for death, independently of functional disability and

multimorbidity.Anorexia is clinically defined as the reduction and/or loss of

appetite (3, 6, 22). Unlike anorexia nervosa, anorexia of aging(i.e. disease-related) is a rather common symptom, andfrequently accompanies chronic diseases (22, 23). Anorexia is amultifactorial health condition correlated with multiplecausations that occurs when the accumulated effects ofimpairments in multiple systems make an older person morevulnerable. The major risk factors of anorexia are the ageingprocess itself, biological changes, behavioural factors, socialand environmental conditions, many acute and chronic diseasesand treatments (24, 25).

Anorexia is frequently under-diagnosed and maysignificantly contribute to the nutritional deterioration ofcachexia, if not properly treated either pharmacologically orwith oral nutritional supplementation (6, 26, 27). Numerousclinical consequences are correlated to anorexia: impairedwound healing, impaired immune response to infections,hypoalbuminemia, decreased coagulation capacity, reduced gutfunction, intestinal bacterial translocation, muscle wasting,decreased function of respiratory muscles (28).

Furthermore, anorexia is highly predictive of incidentdisability, poor quality of life and all-cause mortality (3, 20,29). In particular, as our results suggest, even though worseresults have been observed when anorexia is associated withsignificant weight loss, anorexia per se is an importantmortality risk factor. In fact, the anorexia not accompanied byweight loss confers increased risk for mortality, too. The resultsof our study are also supported by those of a large surveyconducted in European hospitals, which showed that reducedfood intake is an independent negative prognostic factor for 30-day in-hospital mortality, more robust than weight loss (19). Itis possible to hypothesize that in the early stage, the anorexiadoesn't determine an evident status of malnutrition (i.e.significant weight loss) but it determines selective nutritionallacks (i.e. deficit of vitamins and/or micronutrients). Severalstudies have demonstrated the negative role of selectivemalnutrition on functional outcomes and survival amongelderly subjects (30, 31).

In this respect, it is important to highlight that nutritionremains important throughout life. Some studies havedocumented that a “good” diet helps both in reducing the riskof diseases and in managing the diseases’ signs and symptoms(10, 26). This contributes to a better quality of life, enablingolder people to maintain their independence and physicalperformance. On the other hand, poor nutrition and anorexia ofaging can prolong recovery from acute illnesses, increase therate of institutionalization, expand the costs of health care, leadto a poorer quality of life and higher morality (3, 19, 20).

Some methodological issues should be taken into account inthe interpretation of results. Anorexia makes a majorcontribution to multimorbidity, such as anemia, malnutrition,osteoporosis, and dementia. On the other hand, severe andchronic diseases may be associated with anorexia. In thisrespect, we cannot completely exclude that this reverse

Predictor independiente de morbilidad y mortalidad

N = 2787 (744 con anorexia)60% mujeresDe la comunidad


Nature Reviews | Cancer

Loss of skeletal muscle mass and function

Tumourburden

n ammatorymediators

Alterations inprotein and amino acid metabolism

↑Apoptosis ↓Regeneration

↑ roteolysis ↓Protein

synt esis ↓AA transport ↑BCAA

oxidation

a b

PI3K

AKT

mTOR

↓ rotein synt esis

SMAD2

FOXO

PGC1αFOXO

MAFBX MURF1

↓IGF1 ACTRIIA/BMyostatin PIFR yto ine

receptor

IKK

Proteindegradation

Proteasome

Muscle wasting

uto a y

Caspases

Apoptosis↑UCPs

↓ ate o synt esis

PNF-κB

NF-κB

NF-κB

IκB

p38

JAK

Nucleus

PIF

Mitoc on rion

IGF1R

yto ine

that is mediated by the activation of the ubiquitin-dependent proteasome path-way41. However, intact myofibrillar pro-teins seem to be degraded by mechanisms upstream of the ubiquitin–proteasome pathway to allow for the release of myo-filaments from the myofibrils and the subsequent ubiquitylation and proteasome-dependent degradation of myofilaments. One such mechanism seems to be the calpain-dependent cleavage of myofilaments and proteins that anchor myofilaments to the Z disc42,43. Another mechanism that is involved in protein degradation is autophagy44. However, although blockade of the ubiquitin-dependent proteolytic system (for example, using the proteasome inhibitor bortezomib) has been shown to preserve muscle45, the blockade of autophagy during development results in muscle weakness and myofiber disorders46.

Many intracellular signals are involved in protein turnover and, therefore, in the wasting process47 (FIG. 2b). Thus, inflam-matory cytokines that are secreted by either immune cells or tumours directly induce signalling pathways that upregulate

enzymes inducing skeletal muscle protein turnover. On the one hand, pro-inflamma-tory and pro-cachectic cytokines such as TNFα or interleukin-1 (IL-1) are involved in two established pathways, the nuclear factor-κB (NF-κB) pathway and the p38 MAPK pathway. These mediators induce an upregulation of the expression of the key E3 ligases — muscle RING finger-containing protein 1 (MURF1; also known as TRIM63) and muscle atrophy F-box protein (MAFBX; also known as atrogin 1 and FBXO32) — which mediate structural muscle protein breakdown and inhibition of protein synthesis48. MURF1 is responsi-ble for facilitating the ubiquitylation of the thick filament of the sarcomere49 , as well as other thick filament components50. Thus, NF-κB inhibition results in a significant decrease in tumour-induced muscle loss, at least in experimental animals, in part, by blocking the upregulation of MURF1 (REFS 51,52). In addition to proteolysis, an impaired regenerative capacity of myogenic cells may also be involved in muscle wasting in cancer. Thus, paired box 7 (PAX7) — a protein involved in

muscle regeneration — also participates in the decreased regenerative capacity and response to NF-κB53.

In contrast to the pathways related to muscle atrophy are the ones that involve muscle hypertrophy. Understanding how muscles can reach hypertrophy not only contributes to the understanding of muscle development but also may provide clues for the design of anabolic therapies for skeletal muscle. Thus, insulin-like growth factor 1 (IGF1) signalling is perhaps the best- characterized mechanism for inducing hypertrophy. IGF1 activates insulin receptor substrate 1 (IRS1)–PI3K–AKT54 signalling (FIG. 2b), and AKT induces protein synthe-sis by blocking the repression of mTOR. Moreover, AKT also phosphorylates the forkhead (FOXO) family of transcription factors. These have a key role in inducing transcriptional upregulation of MURF1 and MAFBX55. These transcription factors seem to be essential, as IGF1–AKT-mediated FOXO phosphorylation — followed by inhi-bition of FOXO transport to the nucleus — is sufficient to block the upregulation of the E3 ligases that participate in muscle proteolysis.

Figure 2 | Skeletal muscle wasting during cachexia. a | Alterations in metabolic pathways, apoptosis and regeneration. Muscle wasting involves alterations in protein and amino acid (AA) metabolism, together with acti-vation of apoptosis and decreased regeneration. All of these alterations are linked with inflammation. b | Intracellular signals that participate in skeletal muscle wasting. Many intracellular signals are activated (shown in purple) by inflammatory mediators (such as cytokines and myostatin) and tumour-derived factors (such as proteolysis-inducing factor (PIF)). Basically, cytokines and PIF increase protein degradation via nuclear factor-κB (NF-κB) by activating forkhead (FOXO) family transcription factors; this allows for the increased transcription of genes encoding ubiquitin ligases (muscle atrophy F-box protein (MAFBX) and muscle RING finger- containin rotein M )) t at are in ol e in t e roteolysis

of myofibrillar proteins. The same mediators (PIF and cytokines) can also activate the p38 and Janus kinase (JAK) MAPK cascades leading to increased caspase activity and, thus, apoptosis. Insulin-like growth factor 1 (IGF1) nor-mally promotes protein synthesis via AKT and mTOR; a decrease (shown in blue) in IGF1 during muscle wasting suppresses protein synthesis. Myostatin can also decrease protein synthesis (through AKT via SMAD2) and activate both protein degradation (via FOXOs) and apoptosis — through the MAPK cascade. Overexpression of peroxisome-proliferator-activated receptor-γ co-activator 1α (PGC1α) causes increased respiration and expression of genes linked to mitochondrial uncoupling and energy expenditure (such as uncou lin roteins s)) acti in rece tor ty e BCAA, branched-chain AA; IGF1R, IGF1 receptor; IκB, inhibitor of NF-κB; IKK, IκB kinase; P, phosphorylation; PIFR, PIF receptor.

PERSPECT IVES

756 | NOVEMBER 2014 | VOLUME 14 www.nature.com/reviews/cancer

© 2014 Macmillan Publishers Limited. All rights reserved

Nature Reviews | Cancer

Adiposetissue

TAGs

Glycerol

Glycerol

Glycerol

NEFA

NEFA

NEFA

Lactate

Lactate Lactate

LiverTumour

Alanine

Alanine

Alanine

Glutamine Glutamine

Glutamine

Protein degradation

Skeletalmuscle

Cori cycle

Glucose Glucose Glucose

Pyruvate

Membrane lipids

Krebs cycle

Proteinsynthesis

+

+

+Pyruvate

shown that this is the case in mice bear-ing cachectic Lewis lung tumours24. Third, in addition to uncoupling, there are other important abnormalities in skeletal muscle mitochondria that occur in cancer patients, such as decreased oxidative capa city25 ,26 , dis-rupted protein synthesis27, changes in mem-brane fluidity25 and oxidatively modified mitochondrial proteins28; all of these result in impaired mitochondrial function.

Some of the above-mentioned alterations could well be attributed to an increased pro-duction of peroxisome-proliferator-activated receptor-γ co-activator 1α (PGC1α), which has been observed in skeletal muscle of mice bearing the Lewis lung carcinoma29. Indeed, this protein seems to have a major role in regulating mitochondrial biogenesis by upregulating nuclear respiratory fac-tors and the mitochondrial transcription

factor A (TFAM)30. In addition, cytokines such as tumour necrosis factor-α (TNFα; generated as a consequence of high tumour burden) activate p38 MAPK, which results in stabilization and activation of PGC1α31. Overexpression of PGC1α causes increased respiration and expression of genes linked to mitochondrial uncoupling and energy expenditure32.

Both mitochondria and sarcoplasmic reticulum (SR) share a key role in muscu-lar function. Thus, Ca2+ released from SR stimulates mitochondrial ATP production contributing to increased energy demand during muscle contraction, a process known as excitation–contraction coupling; whereas functionally intact mitochondria inhibit undesired localized SR Ca2+ release by con-trolling the local redox environment of the calcium release units33. Thus, bidirectional

SR–mitochondrial communication pro-vides a powerful local control mechanism for integrating Ca2+ release and reuptake and ATP utilization during muscle con-traction with ATP production and skeletal muscle bioenergetics34. During cachexia, an increase in the activity of SR Ca2+ pumps (SERCA) occurs35 ; these pumps promote energy inefficiency as they consume ATP associated with Ca2+ export to the cytosol and generate Ca2+ overload. In addition, the gene expression of mitofusin 2 (Mfn2) is increased in skeletal muscle of rats during cancer cachexia36. MFN2 is a mitochondrial protein that is involved in the regulation of mitochondrial morphology. In addi-tion, MFN2 is related to the interactions between SR and mitochondria — it teth-ers SR to mitochondria — which control interorganellar Ca2+ signalling; MFN2 also has a key role in SR morphology. Moreover, the SR–mitochondrial connection that is promoted by MFN2 predisposes mitochon-dria to Ca2+-overloading, eventually lead-ing to apoptosis by excessive Ca2+ transfer. Furthermore, it is known that PGC1α participates in the stimulation of MFN2 expression under various conditions characterized by enhanced energy expenditure36. Hence, in cachexia the overexpression of PGC1α can activate MFN2 expression, thus leading to a Ca2+ deregulation, which is intimately associated with muscle wasting.

Muscle wasting and atrophyCancer cachexia is invariably associ-ated with muscle wasting and atrophy. Loss of myofibrillar proteins in muscle cells37 (BOX 1) is of key relevance in cancer cachexia, as it results in muscle weakness and fatigue. In fact, skeletal muscle loss is a very powerful prognostic factor, independ-ent of the actual body weight loss38. Many metabolic alterations are responsible for the loss of muscle mass39. Thus, abnormali-ties in protein (synthesis and degradation) and amino acid metabolism (transport and branched-chain amino acid oxidation) are seen in the cachectic muscle (FIG. 2a). Furthermore, an increase in apoptosis and an impaired capacity for regeneration contributes to muscle wasting. All of these alterations clearly contribute to the negative nitrogen balance observed in the skeletal muscle of cancer patients. In fact, in addi-tion to tumour burden, some of these alterations may be a consequence of cancer treatment — mainly chemotherapy40. The pathway that seems to be most involved in the wasting process is protein degradation

Figure 1 | Main metabolic adaptations associated with tumour burden. During tumour growth, substantial metabolic alterations take place in cancer patients. Thus, protein degradation is stimulated in skeletal muscle, which results in a massive amino acid efflux to the circulation. Therefore, a flow of nitrogen (mainly in the form of alanine) from skeletal muscle reaches the liver, where this amino acid is used to sustain gluconeogenesis and also the synthesis of acute-phase proteins. Glutamine is also exported from the muscle and used mainly in the tumour as a nitrogen donor for the synthesis of both protein and DNA. The tumour, depending on the availability of glucose, can also oxidize some glu-tamine. Adipose tissue mass is reduced owing to the activation of lipases, which participate in the lipolytic breakdown of triacylglycerols (TAGs), which produces both non-essential fatty acids (NEFAs) and glycerol. Glycerol can also be used to sustain liver gluconeogenesis while the NEFAs are used by the tumour mass, albeit at very low levels. Instead, tumour cells use huge amounts of glucose and thereby generate lactate, which is then exported to the circulation. The liver also uses lactate as a gluconeogenic substrate, partly to compensate for the acidosis associated with lactate production. The recycling of lactate constitutes a ‘Cori cycle’ (shown in purple) between the liver and the tumour, which is linked with high energetic inefficiency, as the conversion of glucose into lactate by the tumour generates much less ATP than the amount required to produce glucose from lactate. Circled “+” symbols indicate pathways that are activated during cachexia.

PERSPECT IVES

NATURE REVIEWS | CANCER VOLUME 14 | NOVEMBER 2014 | 755

© 2014 Macmillan Publishers Limited. All rights reserved

Nat Rev Cancer. 2014 Nov;14(11):754-62

Por qué ocurre la pérdida peso?Cáncer

FML

Factores tumorales

Pérdida de peso acelerada


Riesgo nutricional según tratamiento

462 M. M. Marín Caro y cols.Nutr Hosp. 2008;23(5):458-468

Resultados

El 83% de los pacientes recibía un tipo de tratamientode intención curativa. El 44% recibía quimioterapia, el24% radioterapia, ambos tratamientos el 21%, ninguno11%. Un 28% de los pacientes recibió una tipo de qui-mioterapia de bajo riesgo, y un 37% de riesgo medio.

El 68% recibió otros tratamientos concomitantes:42% antieméticos, 37% analgésicos, un 20% estimu-lantes del apetito, 19,5% protectores gástricos, 16%vitaminas y/o minerales, 10% corticoides, 9% psico-fármacos, 6% anti-estreñimiento, 4% antidiarreicos.

En relación a la clasificación por el método de laVGS-GP el 36% correspondieron al grupo A y tenía

un estado nutricional adecuado, un 50% en el grupoB y tenían un riesgo de malnutrición o malnutriciónmoderada y un 14% C, con malnutrición severa. Enel grupo A, el 58% son mujeres, y 42% hombres; enel grupo B: 63% hombres y 37% mujeres; en elgrupo C: 56% hombres y 44% mujeres (figs. 7, 8, 9,10 y 11).

Analizando las dificultades encontradas en la ali-mentación, un 68% tenía algún tipo de dificultad. Deellas, un 42,5% tuvo falta de apetito, el 40% náuseas,35% estreñimiento, 31% plenitud gástrica, 27%vómitos, 21% disfagia, 21% depresión, 19% dolor, el16% refirió olores desagradables, el 16% problemasdentales, el 13% refiere que los alimentos no tienen

Fig. 3.—Grupo deriesgo nutricional enfunción de la locali-zación tumoral (To-mado del grupo detrabajo de nutricióny cáncer de la SEN-BA. Gómez-Candelay cols., 2003)1.

Fig. 4.—Riesgo nutricional de lospacientes oncológicos en funciónde su tratamiento quimioterápico(Tomado del grupo de trabajo denutrición y cáncer de la SENBA.Gómez-Candela y cols., 2003)1.


Por qué ocurre la pérdida peso?Inflamación

• Inflamación: CLIP• IL-1• IL-6• TNF-alfa

Journal of Cachexia, Sarcopenia and Muscle 2017; 8: 523–526www.nutrigeriatria.wordpress.com

www.nutrigeriatria.wordpress.comwound or postsurgical healing, and delayed recovery fromillness.32,34,35 Frailty and theweakness that followsmuscle loss lead tohigher risk of falls, fractures,30 physical disability,29 need for institu-tional care,29 reduced quality of life,36 and heightened mortality.29,33

Early identification of frailty risk provides the opportunity to pro-vide interventions and avoid or delay disability as well as enhancerecovery.

Loss of muscle associated with disease, injury, disuse, or agingsignificantly increases the cost of health care.34,49,50 Results of a recentstudy showed that older adults (mean age=70 years) who were veryfrail spent (Euro) 1917 more on total health costs in an interval of 3months than did those who were not frail.51 In the United States, thedirect cost of cachexia/sarcopenia to health care was reported to be1.5% of annual total health care expenses.50 Such costs arise from theincreased rate of hospitalization, incidence of complications, lengthsof stay, and likelihood of readmission.52,53 In the face of an agingpopulation, the importance of identifying, preventing, and treatingmuscle loss cannot be overstated.

Detection and Treatment of Muscle Loss

Who Is at Risk of Muscle Atrophy, and How Do We Identify It?

Screening is crucial for predicting risk, and proper, timely inter-vention can reduce or eliminate the ensuing muscle mass and meta-bolic atrophy, substantially affecting morbidity, mortality, and cost.Special attention should be paid to the main risk categories: peoplewho are malnourished or at risk of malnutrition for any reason33,54;frail adults, especially the very old; people who become decondi-tioned and lose muscle due to age- and disability-related physicalinactivity35; those with diseases or conditions with inflammatorycomponents, such as chronic heart failure,55 chronic or acute kidneydisease,56 cancer,57e59 severe infection and sepsis,60 insulin resis-tance/diabetes,61 intensive care uniteacquired weakness,25 andwound/surgical recovery.34

Reaching an accurate diagnosis of age- or disease-related muscleatrophy is difficult, and a number of criteria have been proposed buthave not yet assessed in the clinical setting.14 Nonetheless, specificcriteria and measures can be used to diagnose sarcopenia orcachexia.13,27,62,63 Sarcopenia can be diagnosed when a patient hasmuscle mass that is at least 2 SDs below the relevant population meanand also presents with a low gait (walking) speed. In addition, low

muscle strength and general physical performance may be taken intoconsideration.14 Cachexia can be diagnosed when at least 5% of bodyweight is lost within 12 months in the presence of underlying illness,and 3 of the following criteria are also met: decreased musclestrength, increased fatigue, anorexia, low fat-free mass index,abnormal biochemistry, increased inflammatory markers C-reactiveprotein (>5.0 mg/L) or IL-6 (>4.0 pg/mL), anemia (<12 g/dL), or lowserum albumin (<3.2 g/dL).

Recent research into themolecular adaptations associated with thedevelopment of or that result from muscle atrophy and metabolicdepletion may lead to the identification of biomarkers and, therefore,improvements in early detection (Table 2). A variety of signalingpathways known to positively influence muscle growth (bonemorphogenetic proteins, brain-derived neurotrophic factors, folli-statin, and irisin), as well as those known to negatively regulatemuscle growth (transforming growth factor b, myostatin, activins, andgrowth and differentiation factor-15) and factors associated withmuscle function and dysfunction (C-terminal agrin fragment andskeletal muscle specific troponin T) may emerge as biomarkers formuscle atrophy in aging and disease.64 To date, there is no universallyrecognized biomarker for muscle atrophy, but recent research in thefield suggests that the combination of several biomarkers may facili-tate the adequate diagnosis of muscle atrophy. Identification of suchbiomarkers and their incorporation into validated testing instrumentsshould allow early identification of muscle atrophy (improving prog-nosis, and likely reducing cost to health care systems), but may alsoprovide exciting targets for the development of new medications.

Nutritional Strategies for Maintaining and Rebuilding Muscle

Treatment of patients at risk can prevent or delay onset of muscleatrophy, or even target rebuilding of muscle when muscle atrophy isalready evident (Figure 4).65 As a first step, treatment must provideadequate energy so that muscle proteins and their constituent aminoacids are spared as an energy source. In addition, high protein intake isvital to treatment of muscle atrophy or for delaying its onset.7,66e69 Itshould be noted that the range of protein needs can vary widely frompatient to patient. Because muscle mass may decrease or remain thesame (based largely on how much protein synthesis outpaces proteindegradation), the most direct way to prevent muscle loss is to ensure

Fig. 4. Treatments for sarcopenia. It is currently recommended that patients at risk ofor suffering from sarcopenia consume a diet high in protein, engage in resistanceexercise, and take supplements of the leucine metabolite HMB.

Fig. 3. Complications of lean body mass (muscle) loss.

J.M. Argilés et al. / JAMDA 17 (2016) 789e796 793

DA

Incrementa riesgo de infeccionesDisminuye la cicatrizaciónDebilidad muscularIncremento el riesgo de muerte

Consecuencias de la pérdida de peso no intencional

AnorexiaFactores de riesgocompartidos Fragilidad Discapacidad

SARCOPENIA

Nutrients 2013, 5, 4126-4133 www.nutrigeriatria.wordpress.com

Malnutrición

Estancias Hospitalarias prolongadas

Readmisiones

Mortalidad

Problemas de cicatrización

MAYORES COSTOS SANITARIOS

Cereda E, et al., NutriConal status in older persons according to healthcare seEng: A systemaCc review and meta-analysis of prevalence data using MNA®, Clinical NutriCon (2016), hSp://dx.doi.org/10.1016/j.clnu.2016.03.008 www.nutrigeriatria.wordpress.com

Abordaje

• 1. Iden(ficar los pacientes con Pérdida de peso

• 2. Evaluar el riesgo nutricional asociado a la pérdida de peso

• 3. Estudios concomitantes

• 4. Establecer pauta terapéu(ca


Abordaje

• 1. Identificar los pacientes con Pérdida de peso• Evolución de la pérdida de peso• Cantidad de kg perdidos

• Si no hay historial de pesos: cambios en la talla de la ropa


Abordaje3. Estudios concomitantes

Medicine. 2014;11(62):3720-4 3723

Fig. 1. Fig. 1. Algoritmo diagnóstico del síndrome constitucional en el paciente mayor. Modificada de Bouras EP, et al12.

PROTOCOLOS DE PRÁCTICA ASISTENCIAL

Pruebas de laboratorioComo hemograma, bioquímica general (glucosa, urea, fun-ción renal, hepática, iones, lactatodeshidrogenasa [LDH], albúmina y proteínas), calcio y fósforo, función tiroidea, HbA1c, B12 y folatos, velocidad de sedimentación globular (VSG), proteína C reactiva (PCR), sangre oculta en heces y un examen de orina.

Pruebas de imagenComo radiografía de tórax y una ecografía abdominal que nos puede dar una información valiosa (visualización del re-troperitoneo, páncreas, hígado y vía biliar, riñones).

Probablemente se requieran más estudios complementa-rios en función de los resultados de este conjunto de pruebas básicas.

Si a pesar de una valoración inicial integral del paciente

pular y pelviana, de la piel y del tacto rectal, junto con la exploración cardiaca, pulmonar, abdominal y neurológica que de forma reglada debemos realizar17.

Pruebas complementarias

En los pacientes con datos clínicos positivos de la historia y del examen físico, las pruebas complementarias deben ir di-rigidas según el diagnóstico etiológico de sospecha, reeva-luando al paciente con los resultados de las mismas por si requiriera alguna exploración adicional.

Si a través de la historia clínica y de la exploración física no se obtienen datos orientativos, se debería realizar una ba-tería inicial de pruebas, incluyendo las que enumeramos a continuación2,7,12,13.

Posible neoplasia Posible patología digestiva

Posible infección Posible proceso inflamatorio

Si no se encuentra una etiología, reevaluar en 1 – 6 meses

Posible problema psicosocial

Estudio diagnóstico dirigido en función de los resultados de la historia clínica, examen físico y pruebas complementarias

Pruebas complementarias*��.$�� – Hemograma – Glucosa, urea, creatinina, electrolitos , calcio, fósforo��)�� )��##%�� $�� 0"�� #$�.��$$�� – VSG o PCR*��'�"��#��*�� #��%�$��!��*�� #��.��$/#�'

Exploración física

Historia clínica detallada +

Revisión de sistemas, historia dietética, antecedentes médicos patológicos, aspectos psicológicos y afectivos, hábitos sociales, tratamiento habitual

¿Cumple criterios diagnósticos?

�� #�$"�� /�$��.��#"��$�$%��$��"�(#

Labs normales Cada 3 meses


Abordaje4. Establecer pauta terapéutica

• TRATAR LA CAUSA DE LA PÉRDIDA DE PESO

• Nutricionalmente:• Consistencia de la dieta• Asistencia de la dieta• Acompañamiento en la alimentación• Suplementos nutricionales


Abordaje4. Establecer pauta terapéu4caSuplementos nutricionales

• Proteínas• 1.0-1.2 g/ kg /d Basal • 1.2-1.5 g/kg /d en enfermedad• 2.0 g/kg/d malnutrición o enfermedad severa

1. Clin Nutr. 2018 Jun 18. pii: S0261-5614(18)30210-3www.nutrigeriatria.wordpress.com

Abordaje

4. Establecer pauta terapéu4caSuplementos nutricionales (so)

• Objetivo: Proveer calorías extra y mejorar el aporte calórico• 30 kcal/kg/d (ajustado al estado nutricional, nivel de actividad, estado deenfermedad e IMC) (B)1

• NUNCA reemplazar tiempos principales de comidas por SO

• Inicialmente suplementos líquidos: Permite un vaciamiento gástricomás rápido, 2 h previo tiempos de alimentación

• El uso de suplementos orales han demostrado mejorar el estado nutricional 2

1. Clin Nutr. 2018 Jun 18. pii: S0261-5614(18)30210-32. Maturitas 76 (2013) 296–302



• Suplementos orales1

• Forma• Líquidos• Polvo• Pudín

• Tipos• Normo proteicos o hiperproteicos (> 20%)

• Densidad energéDca• 1-3 kcal/ml

1. Clin Nutr. 2018 Jun 18. pii: S0261-5614(18)30210-3www.nutrigeriatria.wordpress.com


• ESPEN 1• Ante pérdida de peso y malnutrición: Aportar por medio de suplementación

oral 400 kcal con 30% de E como proteína (30 g de proteína)

1. Clin Nutr. 2018 Jun 18. pii: S0261-5614(18)30210-3

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

(e.g. megesterol acetate) [48]. In contrast, a meta-analysisconducted by Colomer et al. [49] has shown that supple-mentation mainly with EPA (1.5–2.0 g/ day) would leadto benefits at a biochemical, clinical and functional level.European guidelines for enteral nutrition claim thatin the light of studies performed to date, it is impossibleto draw any firm conclusions or recommend withcertainty supplementation with v3 fatty acids in orderto counteract the anorexia-cachexia syndrome. Moreover,there is no clear evidence that such supplementation canlead to increased survival in cancer patients. In addition,it is clear that the efficacy of oral supplementation withEPA and DHA strictly depends on patient compliance,which is in turn affected by the low palatability ofpreparations currently available in the market [13,21].In our experience, a retrospective analysis of patientswith head and neck cancer has shown that earlyand intensive nutritional intervention (with standardnutritional formulas) can improve tolerance to combinedchemoradiotherapy treatment, thus reducing the lengthof hospital stay while minimizing weight loss andinterruption of treatment due to toxicity [50!!]. A retro-spective analysis of a similar group of patients undergoingoral supplementation with ONS with the addition ofv3 fatty acids (1.5 g/day), who were also ensured therequired calorie and nutritional intake, would appear toshow that this intervention leads to improved toleranceto treatments, further reducing the days lost due toradiation therapy toxicity (Figs. 2 and 3) (PaccagnellaA, unpublished data). A larger number of studies will berequired, however, to confirm, or otherwise, the effectof these products in a clinical or prognostic context.Nevertheless, for the purposes of our study, in additionto combined nutritional treatment, much attentionwas given to monitoring the patient, who was seenabout once a week while undergoing chemoradiotherapytreatment.

Glutamine and cancerGlutamine is an amino acid used as a source of energy andnitrogen by rapidly dividing cells. For this reason, cancerpatients, who require an increased amount of this aminoacid, can be affected by deficiency, which may lead tochanges in their immune status, the integrity of theintestinal mucous membrane and protein-energy metab-olism, contributing to cancer cachexia [51,52]. In-vitroand in-vivo studies have shown how enteral and parent-eral supplementation with glutamine is well tolerated andfree from complications. It improves the metabolism andthe clinical condition of the patient without increasingcancer growth. In adequate doses, it appears to supportthe efficacy of chemoradiotherapy treatment, thus redu-cing toxicity of the tissues (mucositis). Furthermore, itseems to positively influence outcomes especially inpatients undergoing bone marrow transplantation [53!].Consequently, it appears that glutamine can be used forthe metabolic treatment of cancer, and is potentiallyeffective as a nutraceutical for improving the outcomesof cancer patients.

Branched amino acids and cancerBranched amino acids (BCAAs) are rationally used asregulators of protein synthesis and degradation, and as asource of energy for the muscles and other tissues. More-over, they are precursors of glutamine and alanine. Theiruse in cancer patients is supported by short-term studiesmainly conducted on patients with hepatocellular carci-noma undergoing hepatectomy or chemoembolization. Inthe first place, it seems that oral supplementation withBCAA reduces the length of hospital stay and allows amore rapid recovery of liver function; in the second place,it appears to lead to a reduction in morbidity and animprovement in the quality of life. In either case, how-ever, no significant difference in mortality is evidentcompared to the control groups [54–57].

ArginineWith regard to perioperative supplementation, we knowthat European guidelines have already recognized thebenefits achieved with immuno-modulating formulas forperioperative treatment in cancer patients undergoingsurgery of the neck and abdomen. It was shown that thisleads to reduced length of hospital stay and a decreasein postoperative complications. In addition, in bothmalnourished patients and normally nourished patientsundergoing gastrectomy for gastric cancer, a reducedincidence of complications related to the healingof surgical wounds and infections was demonstrated[29,58,59]. A recent randomized study performed onmalnourished patients with cancer of the head and neck,undergoing enteral supplementation with a mixtureenriched with arginine, has shown a significant increasein long-term survival compared to the control group,

Nutritional intervention to improve treatment tolerance Paccagnella et al. 327

Figure 2 Percentage weight loss during chemoradiotherapytreatment

−20

−18

−16

−14

−12

−10

−8

−6

−4

−2

0During RT-CT End RT-CT 30 Days later

Weightloss (%)

Nutraceutical nutritionalintervention

Standard nutritionintervention

Control group

Los SO no mejoran la mortalidad o la función/desmpeño físico

~ 1–3 kg en 1 a 3 meses


Opciones de tratamiento

• Fármacos en casos de caquexia (anorexia asociado a enfermedad)• Ninguno tiene evidencia robusta para recomendar su uso

.

Clin Geriatr Med. 2017 Aug;33(3):315-323www.nutrigeriatria.wordpress.com

https://www.ncbi.nlm.nih.gov/pubmed/28689565

Fármacos

• Análogos de Ghrelina (anamorelin, GHRP-2): • Incrementa el ape>to

• Acetato de Megestrol: hormona sinté>ca (progestágeno) • Indicada en el tratamiento de pérdida de ape>to asociado con pérdida de

peso en pacientes HIV posi>vos y/o cáncer.• De las más estudiadas, sus efectos adversos limitan uso

Journal of Cachexia, Sarcopenia and Muscle 2017; 8: 523–526Curr Opin Clin Nutr Metab Care 2013, 16:27 – 32

Maturitas 74 (2013) 293–302 www.nutrigeriatria.wordpress.com

Fármacos

• Dronabinol forma sinté/ca de delta-9-tetrahydrocannabinol, componente natural de la planta Cannabis sa/va.• Aprovada para pacientes con pérdida de peso y SIDA• Como an/hemé/co en pacientes con cáncer

• Inhibidores de CCK (loxiglumida o dexloxiglumida)• Aún en fase experimental



Fármacos

• Cor$costeroides• Incremento de peso secundario a retención de líquido y aumento de peso.

• Hormona de crecimiento• Ganancia de peso, sin mejoría en fuerza.

• Esteroides anabólicos (testosterona y oxandrolona) • Efectos adversos, cardiovasculares y falla hepá$ca

• Metoclopramida• Saciedad temprana/efectos extrapiramidales



Para concluir…


Adulto Mayor Nutricionalmente vulnerable por la pérdida de peso

Reserva física reducida

Contribuye a:Complicaciones médicasEstancias hospitalariasAdmisiones a hogares Limita la respuesta

ante estresores

Curr Nutr Rep. 2015 June ; 4(2): 176–184

Preguntar siempre por pérdida de peso


Gracias por su atención

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