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Clinical use of conventional reference intervals in the frail elderly
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Finspång, Primary Health Care in Finspång.
Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Linköping University, Faculty of Health Sciences.
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2015 (English)In: Journal of Evaluation In Clinical Practice, ISSN 1356-1294, E-ISSN 1365-2753, Vol. 21, no 2, p. 229-235Article in journal (Refereed) Published
Abstract [en]

Rationale, aims and objectives

Reference intervals provided by the laboratory are commonly established by measuring samples from apparently healthy subjects in the ages 18–65 years, excluding elderly individuals with chronic diseases and medication. The aim of our study was to establish whether current reference intervals for immune parameters and chemical biomarkers are valid for older individuals including those with chronic diseases, so-called frail elderly.

Methods

Data from our cohort of 138 non-infected nursing home residents (NHR), mean age 86.8 years, range 80–98, were compared with raw data, as basis for the development of reference intervals, obtained from reference populations, like blood donors (IgA, IgG, IgM, C3 and C4) and from the Nordic Reference Interval Project (NORIP) (alanine aminotransferase, albumin, aspartate aminotransferase, creatinine, gamma-glutamyl transferase, lactate dehydrogenase, phosphate, sodium and urea). Immune parameters were measured by nephelometry and in NORIP the measurements were performed by means of different routine methods, in more than 100 laboratories.

Results

Only nine individuals (7%) of NHR were found to be free from chronic disease. C3, C4 (P < 0.001) and IgG levels (P < 0.05) were higher, while IgM levels (P < 0.001) were lower in NHR compared with reference blood donors. Levels of alanine aminotransferase, phosphate (P < 0.001), albumin (P < 0.05) and sodium (P < 0.01) were lower while creatinine and urea levels were higher (P < 0.001) in NHR compared with NORIP subjects.

Conclusion

Comparing laboratory results from elderly people with conventional reference intervals can be misleading or even dangerous, as normal conditions may appear pathological, or vice versa and thus lead to unnecessary or even harmful treatment.

Place, publisher, year, edition, pages
2015. Vol. 21, no 2, p. 229-235
Keywords [en]
ageing; biomarker; clinical practice; nursing home resident
National Category
Other Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-117172DOI: 10.1111/jep.12294ISI: 000351871200009PubMedID: 25494854OAI: oai:DiVA.org:liu-117172DiVA, id: diva2:806663
Available from: 2015-04-21 Created: 2015-04-21 Last updated: 2019-09-09
In thesis
1. Circulating levels and assessment of clinical laboratory analytes, in >80-year-old, apparently healthy, moderately healthy, and frail individuals
Open this publication in new window or tab >>Circulating levels and assessment of clinical laboratory analytes, in >80-year-old, apparently healthy, moderately healthy, and frail individuals
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Blood samples are often used to investigate the possible presence of disease and to make treatment decisions. In the interpretation of the results, comparison either with previous values from the same individual or with a set of appropriate group-based reference intervals are used. Current reference intervals for common laboratory analytes are often based on measurements from apparently healthy persons aged 18–65 years. Age is accompanied by a general decline in organ functions and it is difficult to determine whether a change in levels of laboratory analytes in an elderly individual can be attributed to age alone, independent of environmental or disease processes. Frailty can be seen as a consequence of age-related multifactorial deterioration – physical, cognitive and sensory – resulting in vulnerability and lack of adaptability to internal stressors such as infection or new medication and/or external stressors such as fall at home. Consensus about the definition of “frail” and “frailty” is missing, both nationally and internationally, the question arises whether different definitions of “frailty” affect the interpretation of analytes when comparing different groups of elderly.

The overarching aim of the thesis was to interpret and assess circulating levels of some clinical laboratory analytes in relation to conventional reference values in ≥80-year-old, “apparently healthy”, “moderately healthy”, and “frail” individuals.

 Data originated from other studies, in which blood samples were collected from individuals ≥80-year-old. Comparisons in Paper I of levels of some laboratory analytes, from 138 nursing home residents (NHRs), was made with blood from reference populations, both blood donor and the NORIP study. The results indicated differences for some immunological (complement factor 3 and 4, immunoglobulin G and M) and chemical analytes (alanine aminotransferase (ALT), phosphate, albumin, sodium, creatinine and urea), but no differences in levels occurred for aspartate aminotransferase (AST), gamma-glutamyltransferase (γ-GT) or lactate dehydrogenase (LDH). It was unclear whether the differences were due to differences in age between the elderly and the reference populations or whether the elderly individuals had chronic diseases and were on medication. In Paper II, 569 individuals elderly individuals ≥80 years old were classified as “healthy”, “moderately healthy”, and “frail”, based on diseases, medications and physical and cognitive abilities. Statistical differences between the groups were found for the investigated analytes; albumin, ALT, AST, creatinine and γ-GT. In Paper IV, individuals from Paper II (n=569) were divided into two groups and thereafter divided into “apparently healthy”, “moderately healthy”, and “frail”. One group was subdivided into “apparently healthy”, “moderately healthy” and “frail” based on physical and cognitive abilities and the other group was divided based on the frailty index (FI). There was no statistical difference found between “apparently healthy” and “moderately healthy" groups, regardless of classification model used. Among “frail” individuals, differences in levels occurred for three out of the five investigated analytes: ALT, creatinine and g-GT, with lower levels occurring when the FI classification model was used. No differences in levels occurred for albumin or AST in “frail” individuals, regardless of classification model used. The aim of Paper III was to study whether 1-year changes in complete blood count (CBC) (including haemoglobin (Hb), red blood cell (RBC), erythrocyte volume fraction (EVF), mean corpuscular volume (MCV), mean corpuscular Hb concentration (MCHC), white blood cell (WBC) and platelet count (PLT)), C-reactive protein (CRP) and interleukin (IL)-1β, IL-1RA, IL-6, IL-8 and IL-10 are associated with survival in elderly NHRs aged >80 years. Elevated levels of CRP and IL-8 during 1-year follow-up were associated with reduced length of survival in elderly NHRs. Based on the present thesis it is clear that there is need for reference intervals that consider both age and health status in elderly individuals. A reasonable conclusion when interpreting levels of analytes in elderly individuals with disease or frailty is that individual evaluation based on the individual’s previous levels, is recommended.

Abstract [sv]

Blodprover används ofta för att undersöka ev förekomst av sjukdomar och för att fatta behandlingsbeslut. Vid tolkningen av resultaten används jämförelse antingen med tidigare värden från samma individ eller med en uppsättning lämpliga gruppbaserade referensintervall. Nuvarande referensintervall för vanliga laboratorieanalyter baseras ofta på mätningar från tillsynes friska personer i åldern 18–65 år. Åldern åtföljs av en allmän nedgång i organfunktioner och det är svårt att avgöra om en ev förändring av nivåerna av laboratorieanalyterna kan enbart beror på skillnaden i ålder, oberoende av miljö- eller sjukdomsprocesser. Skörhet kan ses som en konsekvens av åldersrelaterad multifaktoriell försämring - fysisk, kognitiv och sensorisk - vilket resulterar i sårbarhet och brist på anpassningsförmåga till interna stressfaktorer som infektion eller ny medicinering och/eller yttre stressorer, såsom att ramla hemma. Konsensus om definitionen av "skörhet" saknas, både nationellt och internationellt och frågan uppstod om olika definitioner av "skörhet" påverkar tolkningar och referensintervall för laboratorieanalyter, när man jämför olika grupper av äldre individer.

Det övergripande syftet med avhandlingen var att tolka och bedöma cirkulerande nivåer för några kliniska laboratorieanalyser i förhållande till gällande referensvärden hos ≥80-åriga, ”hälsosamma”, ”måttligt friska” och ”sköra” individer.

Data kommer från andra studier, inom vilka blodprov samlades, alla från individer ≥80 år. Jämförelser i studie I gjordes mellan blodprover från 138 individer i särskilt boende, med blodprover från referenspopulationer, både blodgivare och från NORIP-studien. Resultaten visade skillnader för vissa immunologiska (komplementfaktor 3 och 4) och kemiska analyser (alaninaminotransferas (Alat), fosfat, albumin, natrium, kreatinin och urea), men inte alla (aspartataminotransferas (Asat), gamma-glytamyltransferas (γ-GT) eller laktatdehydrgenas (LD)). Det var oklart om skillnaderna berodde på skillnader i ålder mellan de äldre och referenspopulationerna eller om de äldre individerna hade kroniska sjukdomar och medicinerade. I studie II klassificerades 569 individer >80 år som ”hälsosamma”, ”måttligt friska” och ”sköra”, baserat på sjukdomar, medicinering och fysiska och kognitiva förmågor. Statistiska skillnader mellan grupperna hittades för de undersökta analyterna: albumin, Alat, Asat, kreatinin och y-GT. I studie IV delades individer från papper II (n = 569) in i två grupper och delades därefter upp i "hälsosamma", "måttligt friska" och "sköra". En grupp delades in i ”hälsosamma”, ”måttligt friska” och ”sköra” baserat på fysiska och kognitiva förmågor och den andra gruppen delades in baserat på skörhetsindex. Det fanns ingen statistisk skillnad mellan ”hälsosamma” och ”måttligt friska” grupperna, oavsett vilken klassificeringsmodell som användes. Bland ”sköra” individer inträffade skillnader i nivåer för tre av de fem undersökta analyterna: Alat, kreatinin och γ-GT, med lägre nivåer där skörhetsindex hade använts som klassificeringsmodell jämfört klassificering baserad på fysiska och kognitiva förmågor. Syftet med studie III var att studera om 1-års förändringar i blodstatusparametrar (hemoglobin (Hb), erytrocytpartikelkoncentration (EPK), erytrocytvolymfraktion (EVF), medelcellvolym (MCV), mean corpuscular Hb concentration (MCHC), leukocytpartikelkoncentration (LPK) och trombocytpartikelkoncentration (TPK)), C-reaktivt protein (CRP) och interleukin (IL)-1β, IL-1Ra, IL-6, IL-8 och IL-10 var associerade med överlevnad hos individer från särskilt boende > 80 år. De mest framträdande resultaten var att förhöjda nivåer av CRP och IL-8 under 1-års uppföljning var förknippade med förkortad överlevnadstid hos äldre från särskilt boende. Baserat på den aktuella avhandlingen är det tydligt att det finns behov av referensintervall som beaktar både ålder och hälsostatus hos äldre individer. En rimlig slutsats när man tolkar nivåer av laboratorieanalyter hos äldre individer med sjukdom eller skörhet är att individuell utvärdering baserad på individens tidigare nivåer rekommenderas.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. p. 53
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1682
National Category
Clinical Laboratory Medicine Geriatrics
Identifiers
urn:nbn:se:liu:diva-160148 (URN)10.3384/diss.diva-160148 (DOI)9789176850763 (ISBN)
Public defence
2019-09-27, Berzeliussalen, Hus 463, Campus US, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2019-09-09 Created: 2019-09-09 Last updated: 2019-09-10Bibliographically approved

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Sund-Levander, MärthaErnerudh, JanTheodorsson, ElvarGrodzinsky, Eva

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