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Tommy Cederholm
Professor, Klinisk nutrition och metabolism, Folkhälso-och vårdvetenskap, Uppsala Universitet
Överläkare, Geriatriska kliniken, Akademiska sjukhuset, Uppsala
Sjukdoms- vs. svältrelaterad undernäring- malnutrition ur etiologiskt perspektiv
Catabolic trajectories leading to disability & death
Robust
&
Healthy
Cachexia, sarcopenia and frailty are risk
factors for disability and death
†
Kakexi = Sjukdoms-relaterad malnutrition (DRM) med inflammation
- Sjukdom
- Viktförlust >5% s. 12 m
eller
- BMI<20
+ ≥3 av
- Minskad muskelstyrka
- Minskad muskelmassa
- Trötthet
- Anorexi
- CRP/albumin/anemi
Evans et al. Clin Nutr 2008
- Sjukdom
- Viktförlust >5% 3m/10%
och
- BMI<20/22 (<70/>70 år)
eller
- Minskad muskelmassa
- CRP/albumin
ESPEN Consensus. Clin Nutr 2015
Current challenges
The nutrition community needs
- clinically relevant aetiology-baseddiagnoses of malnutrition
(to be used for the ICD and other classificationsystems)
- diagnostic criteria for malnutrition
Etiology-based defintionsGeneral mechanisms underlying
malnutrition/undernutrition
• Food deprivation/starvation
– due to poverty, natural disaster; floodings, droughts
• Catabolic disease with inflammation and anorexia
• Disease with non-inflammatory reasons for reducedfood intake or absorption
Todays diagnostic procedures of malnutrition don’ttake aetiology into consideration
Malnutrition diagnoses tree
ESPEN Consensus Statement 2016
At risk for malnutrition
Malnutrition/Undernutrition
Disease-related malnutrition (DRM) with inflammation
Acute disease- or injury-related malnutrition
Chronic DRM with inflammation
Cancer cachexia and other disease-specific cachexia
Disease-related malnutrition (DRM) without inflammation
Malnutrition/Undernutrition without disease
Socioeconomic or psychologic related
malnutrition
Hunger-related malnutrition
Risk screening
Basic diagnosis
Etiology-based
diagnoses
ESPEN Guidelines on Definitions and Terminology
Cederholm et al. Clin Nutr 2016;e-pub
Malnutrition diagnoses tree
ESPEN Consensus Statement 2016
At risk for malnutrition
Malnutrition/Undernutrition
Disease-related malnutrition (DRM) with inflammation
Acute disease- or injury-related malnutrition
Chronic DRM with inflammation
Cancer cachexia and other disease-specific cachexia
Disease-related malnutrition (DRM) without inflammation
Malnutrition/Undernutrition without disease
Socioeconomic or psychologic related
malnutrition
Hunger-related malnutrition
Risk screening
Basic diagnosis
Etiology-based
diagnoses
ESPEN Guidelines on Definitions and Terminology
Cederholm et al. Clin Nutr 2016;e-pub
ESPEN membership ballot >300 votes:
53% malnutrition
47% undernutrition
More consideration is needed
Malnutrition or undernutrition?
ESPEN Consensus Statement 2016
At risk for malnutrition
Malnutrition/Undernutrition
Disease-related malnutrition (DRM) with inflammation
Acute disease- or injury-related malnutrition
Chronic DRM with inflammation
Cancer cachexia and other disease-specific cachexia
Disease-related malnutrition (DRM) without inflammation
Malnutrition/Undernutrition without disease
Socioeconomic or psychologic related
malnutrition
Hunger-related malnutrition
Risk screening
Basic diagnosis
Etiology-based
diagnoses
Malnutrition related to- Cancer- COPD- Congestive heart failue- Infections- Trauma- ICU
Malnutrition diagnoses tree
ESPEN Guidelines on Definitions and Terminology
Cederholm et al. Clin Nutr 2016;e-pub
0
10
20
30
40
50
60
70
COPD/PEM COPD Controls
S-T
NF
(p
g/m
l)
Di Francia Am J Respir Crit Care Med 1994;150:1453-5
(16)
(14)
p<0.05
Inflammation och kakexi/KOL
Inflammation
Insulin resistenceNeuropeptid Y↓
Leptin↑Ubiquitin-proteasom↑
Lipoprotein lipase
Anorexia Proteolysis Lipolysis
Hormon sensitive lipase↑
Cathepsin↑
Disease/trauma/aging
Cachexia → Sarcopenia
nucleus
proteasome
protein
ubiquitine
Amino acids
- alanine
- glutamine
insulin
+-
TNFa
IL-1b
+
gluconeogenesis
gut
immune system
Inflammation och muskelnedbrytning
Oliff 1987
Insulin
resistance
Sarkopeni
Muskel...
• ~40% av kroppsvikten
• ~20% av muskeln är protein
• 50-75% av kroppens protein
• Rörlighet
• Styrka
• Aminosyrapool
• Glukosreglering
• Energiomsättning
• Endokrina funktioner
• ....
Weight as predictor of COPD mortality
Survival (%)
0
20
40
60
80
100
12 24 36 48
Months
BMI>29
BMI 24-29
BMI 20-24
BMI <20
400 COPD-patients, >65 y
4 y follow-up
Independent mortality predictors;
• BMI <24 (obesity paradox)
• Age
• PaO2
• PaCO2, FEV1, sex
Schols et al. Am J Respir Crit Care Med 1998;157:1791-7
Kardiell kakexi
Definition: >6% viktförlust s. 6 mån
Prevalens: 12-15% (NYHA II-IV)
Incidens: 10%/år
Anker et al. Clin Nutr 2006;25:311
Myrianthefs et al. Cytokine 2007
Anker et al. Lancet 2003;361:1077-83
Kardiell kakexi - mortalitet
Cederholm et al. Clin Nutr 2016;e-pub
ESPEN Consensus Statement 2016
At risk for malnutrition
Malnutrition/Undernutrition
Disease-related malnutrition (DRM) with inflammation
Acute disease- or injury-related malnutrition
Chronic DRM with inflammation
Cancer cachexia and other disease-specific cachexia
Disease-related malnutrition (DRM) without inflammation
Malnutrition/Undernutrition without disease
Socioeconomic or psychologic related
malnutrition
Hunger-related malnutrition
Risk screening
Basic diagnosis
Etiology-based
diagnoses
Malnutrition related to- Stroke, Parkinson- Dementia- Anorexia nervosa- Depression- Malabsorption
- Coeliac disease- Short bowel syndrome
Malnutrition diagnoses tree
ESPEN Guidelines on Definitions and Terminology
ESPEN Consensus Statement 2016
At risk for malnutrition
Malnutrition/Undernutrition
Disease-related malnutrition (DRM) with inflammation
Acute disease- or injury-related malnutrition
Chronic DRM with inflammation
Cancer cachexia and other disease-specific cachexia
Disease-related malnutrition (DRM) without inflammation
Malnutrition/Undernutrition without disease
Socioeconomic or psychologic related
malnutrition
Hunger-related malnutrition
Risk screening
Basic diagnosis
Etiology-based
diagnoses
Malnutrition diagnoses tree
ESPEN Guidelines on Definitions and Terminology
Cederholm et al. Clin Nutr 2016;e-pub
Kroppsviktens relation till funktion och överlevnad hos hemmaboende äldre
~13.000 >65 år
7 års uppföljning
Optimal funktion vid BMI ~25
Högst överlevnad vid BMI ~25-30
Sämst överlevnad vid BMI <22
Al Snih S et al. Arch Intern Med 2007;167:774-80
Bra funktion
Överlevnad
”Obesity paradox”
!
BMI<22
MAIDS –malnutrition associated immune deficiency syndrome
Infections
Cell mediated immunity↓
– T lymphocytopenia
– CD4/CD8 ratio↓
• Humoral immunity↓
– Ig-prod↓→Vaccination↓
• Granulocyte dysfunction
– Chemotaxis↓
– Oxygen radicalproduction↓
Mentala effekter av svält
• Depression
• Apati
• Irritabilitet
• Social tillbakadragenhet
0
50
100
0 6 9 15
Mån
Dep
ress
ions
skala
Svält 0-6 Refeeding 6-15
Keys A. The Biology of Human Starvation 1950
34 unga män, 1500 kcal/dag 6 mån,
förlorade 25% av kv
The nutrition care process needs to assure a diagnostic procedure• Screening/risk evaluationnutritional risk• Assessment for treatment• Treatment• Monitoring
Next challenge: Define diagnostic criteriafor malnutrition/undernutrition
Next challenge: Define diagnostic criteria for malnutrition/undernutrition
The nutrition care process needs to assure a diagnostic procedure• Screening/risk evaluationnutritional risk• Assessment for diagnosis and treatment• Diagnosis• Treatment• Monitoring
”…elements important in operationalism of malnutrition were involuntary weight loss, body mass index, and no nutritional intake”
Conclusion: This study shows that there is no full agreement among experts on the elements defining malnutrition. The results of this study may fuel the discussion within the nutritional societies, which will most ideally lead to an international consensus on a definition and operationalism of malnutrition.
ESPEN initiative 2012-2015 Diagnostic criteria for malnutrition
to be
• used by physicians in daily clinical practice;
• simple; i.e. minimum no. of items
– compare Obesity = BMI >30 kg/m2
• adopted by the International Classificationof Diseases (ICD-10/11)
Cederholm et al. Clin Nutr 2015;34:335-40.
• Weight loss
• Reduced food intake
• Reduced appetite
• Low BMI
• Reduced lean mass
• Reduced fat mass
• Inflammation
• Subjective evaluation
• Functional measures
ESPEN initiative 2012-2015What is the core of malnutrition?Nutrition indicators considered
ESPEN Working Group:Tommy Cederholm, Ingvar Bosaeus, Rocco Barazzoni, Juergen Bauer, Andre Van Gossum, Stanislaw Klek, Maurizio Muscaritoli, Ibolya Nyulasi, Johann Ochenga, Stéphane Schneider, Marian de van der Schueren, Pierre Singer
ESPEN suggestion for diagnostic criteria for malnutrition
Step 2. Diagnosis is confirmed by
• BMI <18.5 kg/m2
or
• Weight loss >10% (indefinite time)/>5% last 3 mo
combined with either
• BMI <20 (<70 y)/<22 (>70 y) or
• FFMI <15 and 17 kg/m2 in women and men, respect.
Step 1. Risk screening by a validated instrument , e.g. NRS-2002, MUST, MNA(-SF), SNAQ, ...i.e. BMI, Weight loss, Reduced food intake, Disease severity
Cederholm et al. Clin Nutr 2015;34:335-40.
ESPEN Poll - 304 ”votes”
Criteria
26%
Result: ~70% ≥ 8/10 agreementConclusion: ”Strong support”
1=strongly disagree,2-9= ....10=strongly agree
1
5
8
10
Problems and issues raised that should be considered
• Too restrictive cut-offs
– Low prevalence figures less reimbursement
• How to handle weight loss/malnutrition in obesepatients?
• Low access to body composition measurement techniques
• Lack of criteria indicating pathophysiology
• Ethnicity/adapted cut-offs
Potential solutions from on-going discussions within the ESPEN community
Introduction of a grading system?
– At risk for malnutrition (not for ICD)
For ICD
–Malnutrition stage 1
–Malnutrition stage 2
Grading of malnutrition
• At risk for malnutrition (by any validated screening tool)
– The diagnosis of malnutrition is only considered after screening positive
• Malnutrition stage 1– Weight loss (unintentional, 5/10%) and
– Any etiology; e.g. food intake↓, catabolic disease, malabsorption and
– BMI >20/22 kg/m2 or
– FFM > lower cutoff/culture relevant (FFMI >15/17); BC, muscle function
• Malnutrition stage 2 (similar to ESPEN Diagnostic Criteria 2015)
– Weight loss (unintentional, 5/10%) and
– Any etiology; e.g. food intake↓, catabolic disease, malabsorption and
– BMI < 20/22 kg/m2 or
– FFM < lower cutoff/culture relevant (FFMI >15/17); BC, muscle function
On-going process since 2016The Global Leadership Initiative on Malnutrition*
(GLIM)Diagnosis and diagnostic criteria of malnutrition
*Working Group created with 5-7 delegates from each continental PEN- society: ESPEN, ASPEN, FELANPE and PENSA- A CORE Working Group with 2 delegates each is also created
Energi- och proteintillägg halverade dödligheten hos utskrivna sjukhuspatienter – The Nourish Study
• 652 undernärda sjukhuspat, >65 år
• Hjärtsvikt, KOL, AMI, pneumoni
• RCT: 350 kcal, 20 g prot, 160 IU D-vitamin, 1,5 g HMB x2/placebo
• 90 dagars behandling
Slutsats:
Halverad dödlighet efter 3 månaders behandling med kosttillägg; från ~10% till ~5%
Deutz et al. Clin Nutr 2016;35:18-26
Metaanalys av proteinrika näringstillskott
• 36 RCT, 3790 patienter (1/3 gamla, 1/3 höftfrakturer)
• Observationstid 3 mån
• Högprotein-ONS (>20E%)
• Färre
• Komplikationer
• Återinläggningar
• Förbättrad
• Vikt
• Greppstyrka
Cawood. Aging Res Rev 2012
ONS and re-admission –a meta-analysis
• 6 studies (n=852) qualified to be part of the meta-analyses
• 23% re-adm by ONS vs 33% in controls (p<0.001)
Conclusion: ONS reducedre-admissions by ~40%
Stratton et al. Aging Res Rev 2013
Ghrelin-agonist, lungcancer och lean body mass
495 patienter med små-cellig lungcancer och anorexi-kakexi.
Ghrelin-agonist under 12 veckor. DXA/lean body mass (kg). Handgreppsstyrka.
• LBM↑
• HGS
• Symptom
Temel et al. Lancet Oncol 2016;17:519-31
Sammanfattning
• Sjukdomsrelaterad malnutrition med inflammation– Cancer, KOL, hjärtsvikt, ….
• Sjukdomsrelaterad malnutrition utan inflammation– Stroke, Parkinson, demens, depression, ….
• Diagnoskriterier för malnutrition?– ESPEN: Viktförlust, BMI, Fettfri massa/muskel, etiologi,
– GLIM: Viktförlust, …?
• DRM är behandlingsbart– Mat, träning, läkemedel
• Att behandla DRM är kostnadseffektivt