【Abstract】Background Frailty-related issue is increasingly
prominent with the acceleration of aging in China.However, domestic research on
frailty is still in its infancy characterized by non-objective diagnosis basis,
unclear pathogenesis and imperfect interventions.Objective To investigate the correlation of
25-hydroxyvitamin D and interleukin-6 with frailty in elderly patients with
chronic disease in the stable phase，so
asto explore objective diagnostic basis and new interventions for frailty. Methods A total of 152 inpatients （≥ 60 years old） with chronic disease in the
stable phase were recruited from Department of Geriatrics，the First People's Hospital of
Yunnan Province（hereinafter referred
to as “the department of the hospital”）
from November 2020 to April 2021. Clinic and laboratory data were collected.
Comprehensive geriatric assessment was conducted via an internet-based platform
of the Comprehensive Geriatric Assessment（inpatient
version） developed by the
department of the hospital，among which frailty
was assessed by the Chinese version of Fried Frailty Phenotype，a component of the assessment
scale. Results Among the 152
patients，47（30.9%） had no frailty，51（33.6%） had pre-frailty and 54（35.6%） had frailty. According to the
binary Logistic regression analysis，disability〔OR=6.162，95%CI（1.091，34.789），P=0.039〕， 25-hydroxyvitamin D〔OR=0.901，95%CI（0.825，0.985），P=0.022〕 and interleukin-6〔OR=1.103，95%CI（1.012，1.201），P=0.025〕 were influencing factors for
frailty in elderly patients with chronic disease in the stable phase. Conclusion Sufficient 25-hydroxyvitamin D may be
associated with decreased risk of frailty and elevated interleukin-6 may be
associated with increased risk of frailty in elderly patients with chronic
disease in the stable phase. So these two indicators may be potential targets
for predicting and treating frailty.
【Key words】 Frailty；Aged；Chronic disease；25-hydroxy-vitamin D；Vitamin D；Interleukin-6
【Chinese Library Classification
Number】R 151.1 【Document Identification Code】A
1.Introduction
Frailty is a special
state in which the physical functions of the elderly gradually decline. It is
characterized by weakened muscle strength and endurance, decreased
physiological functions, increased vulnerability, decreased anti-stress ability
with subsequent adverse consequences such as falls, disability, cognitive
impairment, mental abnormalities, and even death[1][2].
To identify high-risk older adults, Fried et al.[3]roposed
the use of a clinical phenotype to characterize frailty, which consisted of
five body components, including decreased muscle strength, reduced walking
speed, fatigue, reduced physical activity and unconscious weight loss. These
criteria are now widely used in clinical research for the diagnosis of frailty.
With the aging of the
Chinese population, the problem of frailty in old age is increasingly serious.
However, frailty specific diagnosis is not objective, the pathogenesis is not
clear, and the intervention is not sound, indicating that the current research
on this matter is yet in its infancy. Although there are previous studies that
have explored the possibility of symptoms related to the geriatric syndrome,
such as cognitive function, daily activity ability, anxiety and depression and
others, to diagnose frailty more confidently and precisely, data on the
correlation between 25- hydroxyvitamin D (25(OH)D), interleukin (IL)-6 and frailty
in elderly are still missing. Therefore, we aim to explore the correlation
between senile frailty and 25(OH)D and IL-6, so asto lay a foundation for the
objective diagnosis and intervention of senile frailty in the future.
2 Objects and Methods
2.1 Research objects
152 patients at the age of 60
years and above, diagnosed with a chronic disease in the stable phase were
recruited at the Department of Geriatrics, the First People's Hospital of
Yunnan Province, China. The inclusion criteria were as follows: 1) previously
hospitalized patients with no new disease, aged ≥ 60 years without new disease,
2) patients with no communication barriers and able to cooperate in the
comprehensive geriatric assessment (CGA), and 3) patients who were voluntarily
participating in the study and have signed the informed consent. The applied
exclusion criteria were: 1) elderly people who have been supplemented with
Vitamin D and anti-inflammatory drugs in the past one month, 2) patients, who
were diagnosed with acute infectious diseases recently, 3) patients with
serious physical and/or mental diseases with communication barriers, who were
unable to complete the Fried scale assessment, 4) patients who were bedridden
or unstable for a long time and 5) patientswho had insufficient information on
the evaluation scale or laboratory data.
This study was implemented after
approval of the Medical Ethics Committee of the First People's Hospital of
Yunnan Province (No. KHLL2021-KY034).
2.2 Data
Collection
2.2.1 General information
Patients’ general information, including age,
gender, height, body mass, body mass index (BMI), educational level, allergyhistory,
vision or hearing loss, presence or absence of dentures, marital status, eating
habits, sleep time, sleep aids supplementation, current smoking (referring to
smoking in the last 30 days before the survey), current drinking (referring to
the alcohol consumption in the last 30 days before the survey) were collected.
2.2.2
Comprehensive Geriatric Assessment (CGA)
The internet-based
platform of the Comprehensive Geriatric Assessment (inpatient version) is a
software independently developed by the Department of Geriatrics, First
People's Hospital of Yunnan Province, China and was applied in the current
study. It consists of several national general assessment scales and has
certain intelligence. The calculated scores and evaluation results were given
automatically according to each assessment option following the criteria and
reference scope formulated by various general scales. The researchers collected
patients’ data through a WeChat mini-program or computer, and Excel forms were
automatically generated for data summary later. The assessors were
geriatricians who have received the "Comprehensive Geriatric Assessment
System" software training. The assessment included mainly nutritional
status assessment and the Micronutrient Assessment Scale (MNA-SF) was used.
Values ≥ 24 were considered as indicators of good nutrition, betwen17 and 24
were designated as potential malnutrition, while between 0 and 17 were
classified as malnutrition. The cognitive function assessment was according to
the Simple Mental State Examination Scale (MMSE), where values between 0 and 9
were classified as a severe impairment, between 10 and 20 - as moderate
impairment, between 21 and 26 were classified as mild impairment, while scores
between 27 and 30 were designated as cognitive normal functions. Evaluation of
anxiety and depression followed the Geriatric Depression Scale (GDS-15), where
scores ≥ 6 indicated anxiety and depression. Evaluation of depression following
the Self-rating Depression Scale (SDS) was used and the T scores <50
indicated no presence of depression, whereas T ≥ 50 was classified as a
depressive mental state. The evaluation of anxiety was according to the
Self-rating Anxiety Scale (SAS), where scores <50 indicated lack of anxiety,
while equal and above 50 was categorized as anxiety. Daily living ability
assessment was according to the basic Living activity ability (BADL) scale,
where scores between 91 and 100 were indicators of good daily living function,
between 61 and 90 were regarded as mild functional impairment, between 41 and
60 was labeled as moderate functional impairment, between 21 and 40 were
considered as severe functional impairment, whereas patients with scores
between 0 and 20 were grouped as completely disabled. Instrumental living
ability assessment was according to the Instrumental Ability of Daily Living
(IADL) scale was used to assess whether patients were able to go shopping, go
out for activities, cook food, maintain household chores and wash clothes.
Those who need assistance in 3 or more of these criteria were considered
disabled. The sleep status assessment was done according to the Assens Insomnia
Scale (AIS), where scores between 0 and 3 indicated good sleep, between 4 and 6
spoke for potential insomnia, whereas between 7 and 24 indicated insomnia. Fall
risk assessment was according to the Morse Fall Risk Assessment Scale, where
scores between 0 and 24 classified the patients at low risk of fall, between 25
and 44 categorized the patients at moderate risk, whereas scores equal and
above ≥ 45 categorized the elderly people at severe risk. The balance function
evaluation was agreeing with the Tinetti balance and gait scale, where scores
less than 15 indicated the risk of falling, between 15 and 24 designated
balance dysfunction, whereas scores ≥ 24 indicated good physical function. The
visual simulation method was used for pain evaluation. Scores equal to 0
indicated lack of pain, between 1 and 3 designated mild pain, between 4 and 6
showed the presence of moderate pain, whereas between 7 and 10 indicated
presence of severe pain. The evaluation of urinary incontinence was in harmony
with the Incontinence Questionnaire Simple Form (ICI-Q-SF), where scores equal
to 0 classified the patients into the group of asymptomaticurinary
incontinence, between 1 and 7 determined the elderly people with mildurinary
incontinence, between 8 and 14 indicated moderateurinary incontinence, whereas
the scores between 15 and 21 indicated that the patients had severe urinary
incontinence. Constipation was assessed using the Roma = 3 \* ROMAN III Scale (≥2). Other parameters that were taken into account included falls
(within the last 1 year), the number of chronic diseases, the coexistence of
multiple diseases (≥ 2 diseases), multiple medications (≥ 5 oral medications),
the number of medications and others. All these allowed to assess and diagnose
frailty and evaluating scores are presented in Table 1.
Table
1
Contents of the Chinese version of Fried method for evaluation and
classification of frailty among elderly people
|
variable
|
Overall
(n=288)
|
Non-Frailty(n=87)
|
Pre-Frailty(n=93)
|
Frailty(n=108)
|
χ2(F) value
|
P value
|
|
age a(years)
|
|
|
|
|
67.501
|
<0.001**
|
|
<75
years old
|
111(38.5)
|
50(67.8)
|
37(39.8)
|
15(13.9)
|
|
|
|
≥75,<85
years old
|
92(31.9)
|
24(27.6)
|
35(37.6)
|
33(30.6)
|
|
|
|
≥85
years old
|
82(29.5)
|
4(4.6)
|
21(22.6)
|
60(55.6)
|
|
|
|
gender b
|
|
|
|
|
1.527
|
0.466
|
|
male
|
173(60.1)
|
48(55.2)
|
56(60.2)
|
69(63.9)
|
|
|
|
Female
|
115(39.9)
|
39(44.8)
|
37(39.8)
|
39(36.1)
|
|
|
|
BMI a,mean ± SD
|
23.28±4.14
|
23.63±3.41
|
23.42±5.54
|
22.87±3.15
|
0.897
|
0.409
|
|
Education level b
|
|
|
|
|
7.599
|
0.269
|
|
illiteracy
|
12(4.2)
|
1(1.1)
|
6(6.5)
|
5(4.6)
|
|
|
|
primary
school
|
155(53.8)
|
51(58.6)
|
44(47.3)
|
60(55.6)
|
|
|
|
Middle
school
|
66(29.9)
|
15(17.2)
|
26(28.0)
|
25(23.1)
|
|
|
|
College
degree and above
|
55(19.1)
|
20(23.0)
|
17(18.3)
|
18(16.7)
|
|
|
|
Vision condition b
|
|
|
|
|
9.617
|
0.008*
|
|
normal
|
87(30.2)
|
24(27.6)
|
39(41.9)
|
24(22.2)
|
|
|
|
decline
|
201(69.8)
|
63(72.4)
|
54(58.1)
|
84(77.8)
|
|
|
|
Hearing condition b
|
|
|
|
|
20.417
|
<0.001**
|
|
normal
|
115(39.9)
|
48(55.2)
|
41(44.1)
|
26(24.1)
|
|
|
|
decline
|
173(60.1)
|
39(44.8)
|
52(55.9)
|
82(75.9)
|
|
|
|
marital status b
|
|
|
|
|
4.667
|
0.097
|
|
Married
|
222(77.1)
|
72(82.8)
|
74(79.6)
|
76(70.4)
|
|
|
|
Divorced/Widowed
|
66(22.9)
|
15(17.2)
|
19(20.4)
|
32(29.6)
|
|
|
|
Eating habits b
|
|
|
|
|
2.114
|
0.347
|
|
Light
diet mainly
|
248(86.1)
|
71(81.6)
|
82(88.2)
|
95(88.0)
|
|
|
|
Mainly
salty and greasy diet
|
40(13.9)
|
16(18.4)
|
11(11.8)
|
13(12.0)
|
|
|
|
sleeping time(h) a ,mean ± SD
|
|
6.74±1.69
|
7.08±1.78
|
7.19±2.09
|
1.459
|
0.234
|
|
Smoking status b
|
|
|
|
|
1.363
|
0.506
|
|
Not
currently smoking
|
224(77.8)
|
65(74.7)
|
76(81.7)
|
83(76.9)
|
|
|
|
Current smoking
|
64(22.2)
|
22(25.3)
|
17(18.3)
|
25(23.1)
|
|
|
|
Drinking situation b
|
|
|
|
|
3.529
|
0.171
|
|
Not
currently drinking
|
242(84.0)
|
68(78.2)
|
82(88.2)
|
92(85.2)
|
|
|
|
Current drinking
|
46(16.0)
|
19(21.8)
|
11(11.8)
|
16(14.8)
|
|
|
|
Number of chronic diseases (species) a,mean ± SD
|
7.72±3.39
|
6.70±3.59
|
7.46±3.45
|
8.75±4.23
|
7.297
|
0.001*
|
|
Polypharmacy(kind) b
|
|
|
|
|
14.734
|
0.001*
|
|
No
Polypharmacy
|
103(35.8)
|
44(50.6)
|
33(35.5)
|
26(24.1)
|
|
|
|
There are Polypharmacy (≥5 species)
|
185(64.2)
|
43(49.4)
|
60(64.5)
|
82(75.9)
|
|
|
Note:
The lack of compliance with any of the items listed in Table 1 indicated a lack
of frailty. The compliance with 1 and/or 2 items indicated a pre-frailty
condition, while the compliance with 3 items was firmly diagnosed as frailty;
IPAQ = International Physical Activity Scale
2.2.3 Laboratory examination
30 ml of fasting venous blood was collected from the
hospitalized elderly patients from 6:00 to 8:00 am and sent to the clinical
laboratory of our hospital for testing. The automatic analyzer Xiang Instrument
L1550 was used for blood samples analyse. The blood was centrifuged at 3 500
r/min for 5 min. The detected parameters included the white blood cells (WBC)
and red blood cells count (RBC), haemoglobin (Hb), platelets (PLT) and
neutrophils count (NEUT), as well as the C-reactive protein (CRP). The
aspartate (AST) and alanine aminotransferase (ALT) were detected by the rate
method. Triacylglycerols (TG) were detected by the deionization glycerol
method, the total protein (TP) was detected by the biuret method, albumin (ALB)
was detected by the bromocresol green method, while the total cholesterol (TC)
was detected by the cholesterol oxidase method. High density (HDL) and
low-density lipoproteins (LDL) were detected by the elimination method. Blood
sodium (Na+), blood potassium (K+) and blood chlorine (Cl-)
were detected by the ion-selective electrode method. Creatinine (Cr) and
glycosylated haemoglobin (HbA1c) were assayed by enzyme reactions. Urea
nitrogen (BUN) was assayed by the urease UV rate method. Uric acid (UA) was
assayed by enzyme calorimetry. Blood calcium (Ca2+) was assessed by
the arsenazo ⅲ method. The Hexokinase method was used for assessing the amount
of fasting blood glucose. Fructosamine was detected by the tetrazolium blue
method. Thyroid-stimulating hormone (TSH), triiodothyronine (T3),
thyroid hormone (T4), free triiodothyronine (FT3), free thyroid
hormone (FT4), ferritin, vitamin B12, folic acid, 25(OH)D,
estradiol, testosterone, homocysteine (Hcy), fasting insulin (FINS) were
detected by electrochemiluminescence. Activated partial thrombin time (APTT),
prothrombin time (PT), thrombin time (TT) and D-dimer (DD2) were
detected by the magnetic bead method or by immunoturbidimetry. Tumour necrosis
factor (TNF), IL-10, IL-6, IL-12P70, IL-1 and IL-8 were detected by
chemiluminescence.
2.2.4 Data quality control
To assure the gathered data quality all assessment
physicians passed the training programme for assessment of the Comprehensive
Geriatric Assessment System Software Platform (Inpatient version). All
incomplete or inconsistent data were regarded as invalid data and thus excluded
from the study.
2.3 Statistical Methods
SPSS 23.0 software was used for statistical
analysis. The measurement data (
3 Results
152
elderly patients were included in the study, among them, 47 (30.9%) had no
frailty, 51 (33.6%) had early frailty and 54 (35.6%) had frailty.
3.1
Comparison of general data and geriatric syndrome of patients with
different degrees of frailty
There
were no significant differences in gender, height, body mass, BMI, education
level, food or
drug allergy, denture, marital status, eating habits, sleep time, use of
sleeping supplementation, current smoking and alcohol consumption, present
anxiety, fall, pain, urinary incontinence, constipation and multiple diseases
among patients with different degrees of frailty (P > 0.05). There
were statistically significant differences in age, visual impairment, hearing
impairment, nutritional status, cognitive function, presence of anxiety and
depression, presence of anxiety, daily living ability, disability, sleep
status, fall risk, balance function, number of chronic diseases, multiple
medications, number of medications（P <0.05).
These data are shown in Table 2.
Table 2 Comparison of clinical data and geriatric syndromes in participants by level of
frailty
|
frailty degree
|
no frailty (n=47)
|
pre-frailty（n=51）
|
frailty (n=54)
|
χ2(F) value
|
P value
|
|
Age (±s, years)
|
74.45±8.035
|
80.29±8.81
|
85.17±7.06
|
22.678a
|
<0.001
|
|
Gender〔n(%)〕
|
|
|
|
1.263
|
0.532
|
|
male
|
25（53.2）
|
32（62.7）
|
34（63.0）
|
|
|
|
female
|
22（46.8）
|
19（37.3）
|
20（37.0）
|
|
|
|
height(±s,m)
|
1.60±0.88
|
1.61±0.06
|
1.62±0.08
|
0.815a
|
0.444
|
|
Body mass(±s,kg)
|
59.57±11.15
|
58.52±10.63
|
60.60±10.30
|
0.494
|
0.611
|
|
BMI（ ±s，kg/m2）
|
24.47±2.69
|
24.17±1.90
|
23.84±2.21
|
0.959a
|
0.385
|
|
Education level〔n(%)〕
|
|
|
|
13.692
|
0.090
|
|
illiteracy
|
0（0.0）
|
2（3.9）
|
4（7.4）
|
|
|
|
primary school
|
17（36.2）
|
13（25.5）
|
18（33.3）
|
|
|
|
junior high school
|
20（42.6）
|
13（25.5）
|
13（24.1）
|
|
|
|
high school
|
5（10.6）
|
15（29.4）
|
9（16.7）
|
|
|
|
College degree and
above
|
5（10.6）
|
8（15.7）
|
10（18.5）
|
|
|
|
Food or medicineHistory of allergies〔N(%)〕
|
11（23.4）
|
13（25.5）
|
10（18.5）
|
0.776
|
0.678
|
|
Vision loss〔N(%)〕
|
30（63.8）
|
31（60.8）
|
44（81.5）
|
6.138
|
0.046
|
|
Hearing loss〔N(%)〕
|
25（53.2）
|
31（60.8）
|
44（81.5）
|
9.790
|
0.007
|
|
Have false teeth〔n（%）〕
|
25（53.2）
|
25（49.0）
|
33（61.1）
|
1.602
|
0.449
|
|
Divorced/Widowed
|
8（17.0）
|
13（25.5）
|
16（29.6）
|
2.224
|
0.329
|
|
Eating habits〔n(%)〕
|
|
|
|
0.035
|
0.983
|
|
Light diet
|
40（85.1）
|
44（86.3）
|
46（85.2）
|
|
|
|
Greasy diet
|
7（14.9）
|
7（13.7）
|
8（14.8）
|
|
|
|
sleeping time(±s,h/d)
|
6.55±1.84
|
7.18±2.17
|
7.22±1.81
|
1.794a
|
0.170
|
|
TakeSleeping aids〔N(%)〕
|
8（17.0）
|
9（17.6）
|
11（20.4）
|
0.218
|
0.897
|
|
Current smoking〔N(%)〕
|
13（27.7）
|
12（23.5）
|
17（31.5）
|
0.829
|
0.661
|
|
Current drinking〔 N (%)
|
9（19.1）
|
10（19.6）
|
11（20.4）
|
0.024
|
0.988
|
|
Nutritional status〔n(%)〕
|
|
|
|
30.644
|
<0.001
|
|
Good nutrition
|
29（61.7）
|
23（45.1）
|
13（24.1）
|
|
|
|
Potential malnutrition
|
16（34.0）
|
26（51.0）
|
23（42.6）
|
|
|
|
Severe malnutrition
|
2（4.3）
|
2（3.9）
|
18（33.3）
|
|
|
|
Cognitive function〔n(%)〕
|
|
|
|
51.111
|
<0.001
|
|
Good cognitive
function
|
33（70.2）
|
21（41.2）
|
13（8.6）
|
|
|
|
Mild cognitive impairment
|
13（27.7）
|
24（47.1）
|
13（24.1）
|
|
|
|
Moderate cognitive impairment
|
1（2.1）
|
6（11.8）
|
18（33.3）
|
|
|
|
Severe cognitive impairment
|
0（0.0）
|
0.（0.0）
|
10（18.5）
|
|
|
|
Anxiety and depression
〔N(%)〕
|
19（40.4）
|
35（68.6）
|
43（79.6）
|
17.495
|
<0.001
|
|
Existence suppression
Depression〔N(%)〕
|
18（38.3）
|
36（70.6）
|
42（77.8）
|
18.654
|
<0.001
|
|
ExistenceWorry state〔N(%)〕
|
2（4.3）
|
3（5.9）
|
5（9.3）
|
1.084
|
0.581
|
|
Ability of daily living [n (%)]
|
|
|
|
87.800
|
<0.001
|
|
Good daily function
|
40（85.1）
|
21（41.2）
|
3（5.5）
|
|
|
|
Mild dysfunction
|
5（10.6）
|
22（43.1）
|
19（35.2）
|
|
|
|
Moderate dysfunction
|
2（4.3）
|
6（11.8）
|
7（13.0）
|
|
|
|
Severe dysfunction
|
0（0.0）
|
2（3.9）
|
25（46.3）
|
|
|
|
Disability〔N(%)〕
|
9（19.1）
|
26（51.0）
|
48（90.6）
|
51.821
|
<0.001
|
|
Sleep condition〔n(%)〕
|
|
|
|
12.017
|
0.017
|
|
Sleep well
|
29（61.7）
|
18（35.3）
|
16（29.6）
|
|
|
|
Potential insomnia
|
7（14.9）
|
11（21.6）
|
14（25.9）
|
|
|
|
Insomnia
|
11（23.4）
|
22（43.1）
|
24（44.4）
|
|
|
|
Nearly 1 yearFall〔n（%）〕
|
7（14.9）
|
9（17.6）
|
5（9.3）
|
1.616
|
0.446
|
|
Risk of falling [n(%)]
|
|
|
|
9.603
|
0.048
|
|
Low risk
|
39（83.0）
|
37（72.5）
|
31（57.4）
|
|
|
|
Moderate risk
|
6（12.8）
|
6（11.8）
|
11（20.4）
|
|
|
|
Severe risk
|
2（4.3）
|
8（15.7）
|
12（22.2）
|
|
|
|
Balance function〔n(%)〕
|
|
|
|
16.314
|
0.003
|
|
Function well
|
28（59.6）
|
19（37.3）
|
15（27.8）
|
|
|
|
Balance disorder
|
11（23.4）
|
23（45.1）
|
18（33.3）
|
|
|
|
Risk of falling
|
8（17.0）
|
9（17.6）
|
21（38.9）
|
|
|
|
Have pain〔N(%)〕
|
26（56.5）
|
29（56.9）
|
32（59.3）
|
0.094
|
0.954
|
|
Urinary incontinence〔N(%)〕
|
3（6.4）
|
9（17.6）
|
10（18.5）
|
3.614
|
0.164
|
|
constipate〔N(%)〕
|
11（23.4）
|
14（27.5）
|
16（29.6）
|
0.503
|
0.778
|
|
Number of chronic diseases
(±s, kind)
|
4.87±2.29
|
5.86±2.12
|
6.39±2.80
|
4.985a
|
0.008
|
|
Multiple diseases coexist
〔N(%)〕
|
45（95.7）
|
51（100.0）
|
52（96.3）
|
2.104
|
0.349
|
|
Multi-drug〔N(%)〕
|
24（51.1）
|
38（74.5）
|
36（66.7）
|
6.046
|
0.049
|
|
Number of medications(±s, kind)
|
5.15±2.53
|
6.22±2.82
|
6.81±3.35
|
3.987
|
0.021
|
Note:
Pain = mild pain + moderate pain + severe pain; urinary incontinence = mild
urinary incontinence + moderate urinary incontinence + severe urinary
incontinence; a represents F value; BMI = body mass index
3.2 Comparison of the laboratory examination
indexes of the elderly patients with different degrees of frailty
There were no significant differences in the WBC,
RBC, PLT, NEUT, CRP, AST, TG, TP, TC, HDL, LDL, K+, Cr, HbA1c, BUN, UA, Ca2+, fasting
blood glucose, glucosamine, TSH, T3, T4, FT3,
FT4, ferritin, vitamin B12, folic acid, testosterone,
FINS, TT, TNF, IL-10, IL-12P70, IL-1 among the studied patients with different
degrees of frailty (P>0.05). Statistically significant differences were
found in the Hb, ALT, ALB, Na+, Cl-, (25(OH)D,
estradiol, Hcy,, APTT, PT, DD2,
IL-6 and IL-8 (P<0.05). These parameters and interactions are shown
in Table 3.
Table 3 Comparison of the
laboratory indicators in the elderly participants by the level of frailty
|
frailty degree
|
no frailty (n=47)
|
pre-frailty（n=51）
|
frailty (n=54)
|
Z( F ) value
|
P value
|
|
WBC 〔M（P25，P75），
×109 /L〕
|
6.82（5.26，7.76）
|
6.16（4.89，7.22）
|
5.93（5.07，7.26）
|
1.520
|
0.285
|
|
RBC〔M（P25，P75），
×1012/L〕
|
4.34（3.99，4.64）
|
4.39（4.07，4.71）
|
4.10（3.44，4.59）
|
8.158
|
0.077
|
|
Hb（g/L）
|
132.43±24.84
|
137.43±17.65
|
121.44±27.33
|
6.276
|
0.002
|
|
PLT〔M（P25，P75），
×109 /L〕
|
210.00（168.00，248.00）
|
194.00（151.00，235.00）
|
180.50（137.00，224.25）
|
4.028
|
0.329
|
|
NEUT〔M（P25，P75），
×109 /L〕
|
4.54（2.74，5.35）
|
3.81（2.95，4.71）
|
4.09（2.95，4.96）
|
1.487
|
0.084
|
|
CRP〔M（P25，P75）， mg/L〕
|
2.35（0.50，20.75）
|
3.04（1.31，11.42）
|
11.17（2.67，28.05）
|
8.650
|
0.056
|
|
AST〔M（P25，P75）， U/L〕
|
20.00（15.00，27.00）
|
19.00（15.00，24.00）
|
18.50（15.00，26.00）
|
0.419
|
0.770
|
|
ALT 〔M（P25，P75）,U/L〕
|
14.00（10.00，25.00）
|
16.00（10.00，20.00）
|
12.00（8.00，19.00）
|
4.242
|
0.030
|
|
TG 〔M（P25，P75）,mmol/L〕
|
1.18（0.85，1.84）
|
1.25（0.85，1.96）
|
1.10（0.74，1.61）
|
2.263
|
0.439
|
|
TP（g/L）
|
64.28±7.07
|
63.48±6.60
|
63.72±9.38
|
0.133
|
0.875
|
|
ALB（g/L）
|
37.20±4.96
|
36.50±4.14
|
34.18±3.52
|
7.250
|
0.001
|
|
TC（mmol/L）
|
4.16±1.25
|
4.11±1.00
|
3.87±1.05
|
1.040
|
0.356
|
|
HDL（mmol/L）
|
1.08±0.37
|
1.05±0.28
|
1.00±0.28
|
0.803
|
0.450
|
|
LDL（mmol/L）
|
2.51±1.00
|
2.43±0.79
|
2.28±0.87
|
0.936
|
0.395
|
|
Na+（mmol/L）
|
139.34±2.96
|
139.51±2.87
|
137.33±4.02
|
6.844
|
0.001
|
|
K+（mmol/L）
|
3.96±0.47
|
4.00±0.45
|
3.97±0.49
|
0.034
|
0.966
|
|
Cl-〔M（P25，P75），
mmol/L〕
|
108.00（106.00，110.00）
|
107.00（105.00，110.00）
|
106.00（102.75，108.00）
|
9.637
|
0.003
|
|
Cr〔M（P25，P75）,μmol/L〕
|
72.00（60.00，90.00）
|
77.00（63.00，95.00）
|
83.00（67.50，114.00）
|
5.176
|
0.147
|
|
HbA1c〔M（P25，P75），%〕
|
6.25（5.82，7.75）
|
6.31（5.81，7.74）
|
6.02（5.57，6.82）
|
4.246
|
0.160
|
|
BUN〔M（P25，P75），μmol/L〕
|
6.40（4.90，8.70）
|
6.80（4.90，8.90）
|
7.85（5.68，10.10）
|
3.946
|
0.225
|
|
UA〔M（P25，P75）μmol/L〕
|
362.00（285.00，425.00）
|
396.00（339.00，457.00）
|
346.00（261.25，504.75）
|
4.083
|
0.069
|
|
Ca2+〔M（P25，P75），mmol/L〕
|
2.19（2.09，2.28）
|
2.19（2.10，2.26）
|
2.18（2.10，2.24）
|
0.486
|
0.875
|
|
Fasting blood glucose〔M（P25，P75）, mmol/L]
|
5.40（4.60，6.80）
|
4.90（4.40，6.60）
|
4.85（4.20，6.00）
|
3.010
|
0.140
|
|
Fructosamin〔M（P25，P75）,μmol/L]
|
1.60（1.46，1.76）
|
1.55（1.44，1.66）
|
1.54（1.37，1.70）
|
1.231
|
0.786
|
|
TSH〔M（P25，P75），mU/L〕
|
2.83（1.49，4.38）
|
2.73（1.50，4.51）
|
2.28（1.30，4.51）
|
0.231
|
0.544
|
|
T3〔M（P25，P75），nmol/L〕
|
1.04（0.81，1.30）
|
0.95（0.80，1.28）
|
0.96（0.72，1.16）
|
2.450
|
0.277
|
|
T4〔M（P25，P75）nmol/L〕
|
76.33（66.67，80.07）
|
76.33（65.58，90.15）
|
72.55（64.11，83.71）
|
0.809
|
0.781
|
|
FT3〔M（P25，P75），pmol/L〕
|
4.37（3.92，4.97）
|
4.29（3.41，4.77）
|
4.17（3.16，4.70）
|
3.854
|
0.776
|
|
FT4〔M（P25，P75），pmol/L〕
|
12.41（10.88，14.53）
|
12.25（9.92，14.72）
|
13.23（11.67，15.14）
|
2.435
|
0.238
|
|
APTT（s）
|
36.01±4.19
|
37.51±4.44
|
39.29±5.53
|
5.943
|
0.003
|
|
PT〔M（P25，P75），s〕
|
12.80（12.20，13.40）
|
12.90（12.40，13.50）
|
13.30（12.78，14.18）
|
12.309
|
0.010
|
|
TT〔M（P25，P75），s〕
|
18.10（17.20，18.80）
|
18.30（17.60，19.20）
|
18.00（17.18，18.70）
|
2.184
|
0.668
|
|
DD2(ug/ml)
|
1.18（0.90，2.11）
|
1.33（1.00，2.06）
|
2.00（1.29，4.39）
|
16.137
|
0.009
|
|
Ferritin〔M（P25，P75）, ng/ml〕
|
237.07（181.59，418.50）
|
225.96（95.43，378，26）
|
224.03（106.48，480.20）
|
1.025
|
0.676
|
|
Vitamin B12〔M（P25，P75）, pmol/L〕
|
297.00（225.00，498.77）
|
344.00（224.00，462.00）
|
394.50（260.25，924.50）
|
5.727
|
0.654
|
|
Folic acid 〔M（P25，P75）,nmol/L〕
|
15.50（9.80，22.80）
|
15.50（9.60，24.80）
|
12.70（7.68，28.25）
|
0.733
|
0.325
|
|
25（OH）D（μg/L）
|
22.72±9.69
|
19.60±9.42
|
17.14±6.59
|
5.282
|
0.006
|
|
Estradiol
(Pmol/L)
|
111.61±53.60
|
125.17±62.47
|
149.60±52.97
|
5.919
|
0.003
|
|
Testosterone (nmol/L)
|
1.86（0.51，13.24）
|
2.84（0.54，15.20）
|
4.77（0.57，13.51）
|
0.162
|
0.776
|
|
Hcy〔M（P25，P75），μmol/L〕
|
14.40（11.90，17.95）
|
16.80（14.20，19.10）
|
17.95（15.00，23.63）
|
7.705
|
0.015
|
|
FINS〔M（P25， P75），U/L〕
|
6.92（4.94，11.52）
|
6.06（3.90，9.04）
|
6.77（4.16，8.62）
|
2.150
|
0.600
|
|
TNF〔M（P25，P75），ng/L〕
|
5.98（4.18，12.87）
|
6.32（4.18，13.20）
|
6.15（5.20，10.39）
|
0.597
|
0.832
|
|
IL-10〔M（P25，P75），ng/L〕
|
4.33（3.48，5.38）
|
4.75（3.70，6.30）
|
4.92（3.68，6.46）
|
3.196
|
0.147
|
|
IL-6〔M（P25，P75）,ng/L〕
|
12.61（5.95，18.37）
|
20.88（7.82，34.01）
|
25.29（17.21，46.79）
|
31.520
|
<0.001
|
|
IL-12P70〔M（P25， P75），ng/L〕
|
5.22（3.57，5.92）
|
4.99（2.04，5.80）
|
5.56（4.64，6.32）
|
4.078
|
0.165
|
|
IL-1ß〔M（P25，P75），ng/L〕
|
4.65（3.64，7.59）
|
4.93（3.45，8.02）
|
4.65（3.91，7.22）
|
0.408
|
0.873
|
|
IL-8〔M（P25，P75），ng/L〕
|
19.46（12.77，38.93）
|
41.67（18.53，90.28）
|
25.65（14.64，60.40）
|
8.685
|
0.008
|
Note:
WBC=white blood cell count, RBC=red blood cell count, Hb=hemoglobin,
PLT=platelet count, NEUT=neutrophil fraction, CRP=C reactive protein,
AST=aspartate aminotransferase, ALT=alanine aminotransferase,
TG=triacylglycerol, TP=total protein, ALB=albumin, TC=total cholesterol,
HDL=high-density lipoprotein, LDL=low-density lipoprotein, Na+=serum
sodium, K+=serum potassium, Cl-= blood chlorine, Cr=
creatinine, HbA1c= glycosylated hemoglobin, BUN= urea nitrogen, UA= uric acid,
Ca2+=blood calcium, TSH= thyroid stimulating hormone, T3=
triiodothyronine, T4= thyroid hormone, FT3= Free triiodothyronine,
FT4 = free thyroid hormone, 25 (OH) D = 25 hydroxyvitamin D, Hcy =
homocysteine, FINS = fasting insulin, APTT = activated partial thromboplastin
time, PT = coagulation proenzyme time, TT = thrombin time, DD2 =
D-dimer, TNF = tumor necrosis factor, IL = interleukin; a represents F value
3.3 Binary Logistic regression analysis
Taking frailty of elderly patients with stable chronic diseases
as a dependent variable, where 1 indicated lack of frailty and 2 designated
pre-frailty and frailty, all variables with statistically significant
differences (P<0.05) demonstrated in Tables 1 and 2 were taken as
independent variables. These included the age (assigned: measured value),
vision (where 0 was normal and 1 was decreased), hearing (where 0 was normal
and 1 was accepted as decreased), nutritional status (where 0 indicated good
nutrition, 1 - potential malnutrition and 2 - malnutrition), cognitive function
(where 0 was normal cognition and 1 was cognitive impairment), anxiety and
depression states (where 0 was accepted as no anxiety and depression state,
whereas 1 was classified with anxiety and depression state, depression state
(where 0 indicated no depression state, whereas 1 indicated presence of such),
daily living ability (where 0 was indicative of good daily life function, while
1signified dysfunction of daily life), disability (where 0 indicated not
disabled and 1 - complete disability), sleep status (with 0 equal to good
sleep, 1equal to potential insomnia, whereas 2 represented insomnia), risk of
fall (where 0 indicated low risk, 1- moderate risk, while 2 indicated severe
risk), balance function (where 0 stood for good physical function, 1 for
balance dysfunction, whereas 2 indicated risk of fall), number of chronic
diseases (measured value), multiple medications (where 0 indicated none and 1
indicated presence), number of medications (measured value), Hb (measured
value), ALT (measured value), ALB (measured value), Na+ (measured value), Cl-
(measured value), 25- (OH) D (measured value), estradiol (measured value), Hcy
(measured value), APTT (measured value), PT (measured value), DD2 (measured
value), IL-6 (measured value), IL-8 (measured value). Binary Logistic
regression analysis showed that the disability, 25-(OH)D and IL-6 were the
independent influencing factors in elderly patients with stable chronic
diseases (P<0.05), as shown in Table 4.
Table 4 Binary logistic
regression analysis of frailty in elderly patients with chronic disease
|
variable
|
β
|
SE
|
Wald x2 value
|
P value
|
OR（95%CI）
|
|
Disability
|
1.818
|
0.883
|
4.240
|
0.039
|
6.162（1.091，34.789）
|
|
25-（OH）D
|
-0.104
|
0.045
|
5.238
|
0.022
|
0.901（0.825，0.985）
|
|
IL-6
|
0.098
|
0.044
|
5.008
|
0.025
|
1.103(1.012,1.201)
|
4 Discussion
4.1 Occurrence of senile frailty and independent
related factors
Our results showed
that the overall incidence of frailty in the studied hospitalized elderly
patients was 35.6% (54/152), which was similar to the results of Lai Xiaoxing et al.[4],
Wei Yin et al.[5]and
others[6],
where the estimated incidence rate was 31.3%, 34.4% and 35.4%, respectively,
which was higher than that estimated one by Wang Wanwan et al.[7],
whose calculations showed an incidence of the frailty of 25.1%. Interestingly,
these estimations were lower than that by Jin Qiulu et al.[8],
who found that the frailty rate of elderly patients (≥ 80 years old) was 41.6%.
These differences in the prevalence and incidence rate of frailty among elderly
people may be due to different assessment tools, age, and study subjects.However,overall,
the prevalence of frailty in China is not optimistic.Considering that is often
followed by a variety of adverse consequences[1-2], early screening,
prevention and intervention can greatly reduce the prevalence and
hospitalization rate of elderly people with frailty.
Other authors’ studies
in the United States, Mexico, Australia and other countries have shown that
Vitamin D (25(OH)D) is an independent factor affecting frailty[9][11].
In addition, another analysis involving that 20 355 subjects from 13 studies
demonstrated a significant inverse relationship between the 25(OH)D levels in
patients’ blood results and increased frailty severity (following Fried's
phenotypic definition) in both the original analysis and sensitivity analysis[12].
The results of our study are consistent with those of the above. However,
according to a cross-sectional study of community women aged ≥ 75 years in
Belgium, there no relationship between low vitamin D levels and lower limb
muscle strength and grip strength was estimated[13].
The reason for this variance may be that the study from Belgium only targeted
community women ≥ 75 years. Moreover, the levels of 25(OH)D in the blood are
influenced by multiple factors, such as gender, age, geography and others,
therefore these results may be somewhat limited.
According to multiple other meta-analyses, frailty
and early frailty were associated with higher levels of CRP and IL-6[14][15].
This was confirmed by a recent meta-analysis of 23 910 older adults, where the
authors proved that frailty and pre-frailty were associated with higher levels
of inflammatory factors, especially CRP and IL-6[16].
Our research results were similar to the above studies. Although CRP was not an
independent risk factor for frailty in our study, the single factor comparison
was still statistically significant (P<0.05). The reason for this difference
may be that the sample size of this study, which we understand that is
relatively small. Second, the subjects were elderly patients with stable
chronic diseases, and CRP was an acute phase reactant[17],
therefore it was possible to rise under a variety of pathophysiological
conditions. Therefore, this non-specific inflammatory marker was not considered
as necessarily related to frailty[18].
4.2 25(OH)D, IL-6 and senile frailty are
interrelated in elderly patients
25(OH)D is the major circulating metabolite of
Vitamin D which is a globally recognized marker reflecting the Vitamin D
status. Vitamin D deficiency is often associated with muscle weakness[19].
Vitamin D receptors (VDRs) are distributed in multiple target organs such as
skin and muscles[20].VDRs
act as nuclear receptor-mediated gene effects. VDRs bind to (1,25-(OH)2D) to induce the proliferation and
differentiation of muscle fiber, and also affect the synthesis of related
proteins. On the other hand, VDRs can also activate signal transduction
pathways that can induce MAP kinase and phospholipase C through non-nuclear
receptor-mediated non-genetic effects, so that a large number of calcium ions
can rapidly flow into cells and affect muscle contraction[21][22].
Therefore, the possible mechanisms of 25(OH)D deficiency leading to frailty are
due to affected muscle strength, resulting in decreased grip strength [23][24] and because of reduced development of muscle cells, ultimately leading to
unconscious weight loss[25].
In addition, Vitamin D deficiency can also cause osteolysis secondary to
hyperparathyroidism, leading to osteoporosis and even fracture, which can
aggravate the progression of frailty and osteoporosis, leading to disability
and other adverse events.
IL-6 levels increase
with age[14],
and high IL-6 can be used as a predictor of both the occurrence of sarcopenia
and the adverse outcomes of frailty and sarcopenia, such as disability,
functional decline and even death[26].
IL-6 can inhibit TNF-α and IL-1β and induce the production of CRP, fibrinogen
and other acute-phase reactants[14],
it can also indirectly reduce growth hormone (GH) and insulin-like growth
factor 1 (IGF-1) levels, reduce protein synthesis and lead to sarcopenia. In
addition, increased serum IL-6 and CRP levels were also associated with
decreased grip strength[27].
The study of Maet al.[28]included
130 elderly patients and showed that IL-6 was negatively correlated with the
strength and gait speed of the frailty elderly. IL-6 levels were also inversely
associated with exercise tolerance in older adults after adjustment for age and
gender. Therefore, we suggested that IL-6 could be applied as a biomarker for
functional decline and frailty.
All the above studies
suggest that high IL-6 levels are associated with senile frailty, and Vitamin D
deficiency may be involved in inflammation and immune system activation[29].
Moreover, data are suggesting that Vitamin D supplementation reduced the levels
of IL-6 in peripheral blood, inhibiting the production of IL-6 by peripheral
blood monocytes, macrophages and T cells[30][31],
and thus upregulating the expression of anti-inflammatory factors (such as
IL-10) and inflammatory suppressor molecules[32].
4.3
Vitamin D supplementation as an intervention for reducing senile frailty
Some relevant epidemiological studies suggested that
Vitamin D had a potential role in maintaining and improving muscle strength,
function and physical performance, thus maintaining the independence of elderly
people[33].
Other authors’ results demonstrated that the combined supplementation of
elderly people with calcium and Vitamin D reduced the incidence of fractures
and the risk of falls among them[34][36].
In addition, a randomized controlled trial of 5,615 participants showed only a
slight improvement in the overall muscle strength after baseline Vitamin D
supplementation[37].
Some data show that Vitamin D supplementation in elderly people may take longer
or larger doses are needed before its beneficial effect on the muscles is
present[38],
to slow the progression of frailty[39].
Nonetheless, Cummingset al.[40]confirmed
that the high-dose Vitamin D supplementation increased the risk of falls.
Therefore, the ideal supplementation threshold for Vitamin D is a major
question that needs special attention. According to the American Institute of
Medicine, concentrations of 25(OH)D above 50 nmol/L are fully sufficient for
human needs [41],
while the American Endocrine Society sets the sufficient threshold above 72.5
nmol/L, the insufficiency threshold between 52.5 and 72.5 nmol/L, while the
deficiency threshold is set at daily uptake concentrations less than 50 nmol/L[42].
Thus it can be seen that the dose critical value of vitamin D supplementation
in the intervention of senile frailty needs further investigation.
5 Conclusion
The detected
prevalence of senile frailty in hospitalized patients is not optimistic at all
and is a burden to the medical and social systems in China. Therefore, the
early screening, diagnosis and intervention of frailty are particularly
essential. In this study, 25(OH)D and IL-6 were found to be independently
correlated with frailty in elderly patients with stable chronic diseases. This
indicates that 25(OH)D played as a protective factor of frailty in elderly
patients with stable chronic diseases, while IL-6 was a risk factor. Therefore,
25(OH)D and IL-6 are expected to be predictors or objective biological
indicators for the diagnosis of frailty in elderly patients with stable chronic
diseases. In addition, Vitamin D supplementation may help prevent or delay
senile frailty, though its dosage needs to be further discussed.
The innovativeness of this study can be summarized
as follows:
1. The mobile software platform was successfully
used to replace the traditional paper version for the evaluation of the senile
frailty and related symptoms, which greatly reduced data collection time and
statistical errors, thus increasing the reliability of the data.
2. The study of the senile frailty from the direction
of the objective biomarkers in haematology and the mechanism of their action
was described, which covered the lack of domestic research in this area.
3. This study proposed that 25-hydroxyvitamin D and
interleukin-6 may be predictive or diagnostic factors of frailty in elderly
patients with stable chronic diseases. Moreover, the hypothesis that Vitamin D
supplementation of elderly patients may be a potential target for interventions
is raised.
Like any other study, ours has some limitations too.
The study was cross-sectional with a small sample size, which could not
directly explore the causal relationship between the 25-hydroxyvitamin D,
interleukin-6 and frailty. Second. it was a single-centre study with certain
regional limitations. Finally, the subjects of this study were hospitalized
elderly patients with stable chronic diseases, which could not represent the
whole elderly population.
Author contribution: Dai Jingrong was
responsible for the conception and design of the paper, the analysis and interpretation
of the results, as well as the writing of the paper; Li Yan carried out
the implementation and feasibility analysis of the research and was responsible
for the quality control and review of the paper. Data collection was done by Li Jie, He Xu and Li Yang; He Xu and Li Yang, whosorted out and input data; Li
Jie conducted the statistical processing and revised the paper; Dai Jingrong and Li Yan were responsible for the supervision and management of
the article.
No conflict of
interest is declared.
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