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KEYWORDS
Vitamin D;
Arterial stiffness;
Chronic fatigue;
Randomised
controlled trial
Abstract Background and aims: Low 25-hydroxyvitamin D levels are common in patients with
chronic fatigue syndrome; such patients also manifest impaired vascular health. We tested
whether high-dose intermittent oral vitamin D therapy improved markers of vascular health
and fatigue in patients with chronic fatigue syndrome.
Methods and results: Parallel-group, double-blind, randomised placebo-controlled trial. Patients
with chronic fatigue syndrome according to the Fukuda (1994) and Canadian (2003) criteria were
randomised to receive 100,000 units oral vitamin D3 or matching placebo every 2 months for 6
months. The primary outcome was arterial stiffness measured using carotid-femoral pulse wave
velocity at 6 months. Secondary outcomes included ow-mediated dilatation of the brachial artery, blood pressure, cholesterol, insulin resistance, markers of inammation and oxidative
stress, and the Piper Fatigue scale.
As many as 50 participants were randomised; mean age 49 (SD 13) years, mean baseline pulse
wave velocity 7.8 m/s (SD 2.3), mean baseline ofce blood pressure 128/78 (18/12) mmHg and
mean baseline 25-hydroxyvitamin D level 46 (18) nmol/L. 25-hydroxyvitamin D levels increased
by 22 nmol/L at 6 months in the treatment group relative to placebo. There was no effect of treatment on pulse wave velocity at 6 months (adjusted treatment effect 0.0 m/s; 95% CI 0.6 to 0.6;
p Z 0.93). No improvement was seen in other vascular and metabolic outcomes, or in the Piper
Fatigue scale at 6 months (adjusted treatment effect 0.2 points; 95% CI 0.8 to 1.2; p Z 0.73).
Conclusion: High-dose oral vitamin D3 did not improve markers of vascular health or fatigue in
patients with chronic fatigue syndrome.
Trial registration: www.controlled-trials.com, ISRCTN59927814.
2014 Elsevier B.V. All rights reserved.
Introduction
Chronic fatigue syndrome/Myalgic encephalomyelitis
(CFS/ME) is a poorly-understood syndrome characterised
by extreme tiredness, and activity limitation in the
absence of other diagnoses that might explain the symptom complex. Vigorous debate continues as to both the
causes of the syndrome and the most effective approach to
therapy. Recent evidence suggests that a range of markers
of vascular health are impaired in patients with CFS/ME,
including arterial stiffness and endothelial function [1,2];
ventricular function and cardiac output are also reduced
[3]. Whether this is due to the disease state itself or to
deconditioning from low activity levels is unclear. Such
impairments might provide a causal contribution to the
288
tonometry using the validated SphygmoCor pulse waveform analysis system (AtCor Medical) [14]. Augmentation
index e a ratio of the pressure increase to pulse pressure
normalised for a heart rate of 75 beats per minute
(AIx@75) e was calculated from the central aortic pulse
wave by the internal Sphygmocor algorithm. Pulse wave
velocity in metres/second was derived by recording the
pressure waveform at the femoral & carotid artery and
comparing time of arrival with time of the ECG R-wave. If a
measurement could not be obtained at the femoral artery
the radial artery was used as an alternative site to capture
the carotid to radial pulse wave velocity. The coefcient of
variation (within-person test variability) for PWV in our
laboratory is 6.3%
Blood pressure
Blood pressure was measured in the supine position using
an automatic sphygmomanometer (Omron M6, OMRON
Healthcare Europe, Hoofddorp, Netherlands). Three readings were taken and the mean blood pressure was calculated from the second and third readings.
Endothelial function
Flow mediated dilation (FMD) of the brachial artery was
measured according to standard guidelines [15]. In brief,
the diameter of the brachial artery was measured in
longitudinal section using a 5e8 MHz linear array
transducer (Acuson Sequoia 512, Siemens Medical Solutions, Berkshire, UK). Images were recorded for 1 min at
baseline before inating a sphygmomanometer cuff,
placed around the forearm, to 50 mm above systolic
pressure or to a minimum of 200 mmHg for 5 min. After
cuff release brachial artery images were recorded for a
further 2 min. Images were stored in the DICOM (Digital
Imaging and Communications in Medicine) le format
and analysed using the dedicated edge detection software Vascular Tools Brachial Analyser (Medical Imaging
Applications LLC, Coralville, USA). Once a stable baseline
had been re-established the change in brachial artery
diameter was measured in response to sublingual
administration of 0.4 mg of glyceryl trinitrate (GTN, Lipha
Pharmaceuticals Ltd, West Drayton, UK), an endotheliumindependent vasodilator. The coefcient of variation
(within-person test variability) for FMD in our laboratory
is 10.9%.
Metabolic and inammatory markers
Blood was sampled from the antecubital fossa after
minimal venous occlusion using size 21 gauge buttery
cannula, and blood was allowed to ow freely. The blood
was collected into BD Vacutainer SST Tubes (BD Diagnostics, USA) for serum preparation. The serum tubes
were centrifuged for 15 min at 1300g. The serum was
removed and placed into various aliquots before being
stored at 20 C for vitamin D analysis and 70 C for all
other blood tests. High sensitivity enzyme linked
289
290
Results
64 potential participants were given information on the
trial, of whom 50 were randomised into the trial between
August 2011 and March 2012. Participant ow through the
trial is shown in Fig. 1. Baseline details of participants are
shown in Table 1. The group allocated to placebo differed
in a number of important ways from the intervention
group; the placebo group had higher baseline blood
pressure, worse endothelial function, stiffer arteries, worse
symptoms and higher levels of inammation and oxidative
stress than the intervention group. One participant in each
group had malabsorption syndrome (from celiac disease in
the treatment group, and from an enteroenterostomy in
the placebo group).
Tables 2e5 show the main trial results. Further
adjustment for baseline systolic blood pressure, baseline
25OHD level, baseline total cholesterol and baseline CRP
was performed for endothelial function and arterial stiffness measures; no signicant treatment effects were seen
after these further adjustments (FMD adjusted treatment
effect at 6 months 0.1% [95% CI 2.01.9] p Z 0.93; PWV
Figure 1
291
Vitamin D
group (n Z 25)
Placebo
group
(n Z 25)
48.1 (12.0)
7 (28)
4 (16)
28.8 (7.9)
50.7 (13.1)
5 (20)
6 (24)
29.8 (5.4)
0.47
0.51
0.73
0.60
1 (4)
1 (4)
1 (4)
3 (12)
1.0
0.61
3 (12)
1 (4)
0.61
2
0
4
2
4
3
5
4
(8)
(6)
(20)
[4]
0.67
0.12
0.71
0.04
68 (12)
71 (10)
0.30
2.27 (0.06)
2.31 (0.08)
0.05
44 (15)
48 (20)
0.44
48 (17)
43 (19)
0.36
6.0 (2.6)
125 (17)
5.0 (2.0)
132 (18)
0.15
0.16
76 (10)
81 (12)
0.14
70 (11)
70 (9)
0.85
5.2 (1.2)
5.7 (1.3)
0.17
3.2 (0.9)
3.6 (1.2)
0.19
1.5 (0.5)
1.2 (0.3)
0.07
1.2 (0.7)
2.0 (0.8)
0.002
2.6 (3.0)
7.7 (3.1)
2.2 (3.7)
6.5 (2.9)
0.78
0.17
7.3 (2.6)
8.3 (1.9)
0.13
16 (13)
27 (10)
0.001
0.6 (3.2)
2.7 (4.6)
0.04
1.6 (0.8)
1.5 (0.7)
2.5 (1.8)
1.9 (0.8)
0.05
0.09
389 (99)
473 (143)
0.04
2128 (407)
6.6 (1.8)
7.4 (1.6)
6.3 (1.9)
5.1 (1.5)
6.3 (1.6)
1815 (480)
8.0 (1.3)
7.8 (1.6)
7.5 (1.5)
6.1 (1.4)
7.3 (1.2)
0.03
0.006
0.45
0.02
0.04
0.02
(4)
(0)
(16)
[4]
292
Pulse wave
velocity (m/s)
Augmentation
index (%)
Systolic blood
pressure (mmHg)
Diastolic blood
pressure (mmHg)
Pulse (beats/min)
FMD (%)
2
6
2
6
2
6
2
6
2
6
2
6
mths
mths
mths
mths
mths
mths
mths
mths
mths
mths
mths
mths
Vitamin D (SD)
Placebo (SD)
Adjusted treatment
effect (95% CI)a
7.2
6.9
15
15
123
124
76
75
74
74
7.4
7.4
8.5
8.1
25
25
130
133
83
82
76
73
6.1
6.9
0.2
0.0
2
1
2
2
5
2
3
1
0.9
0.1
0.44
0.93
0.16
0.60
0.59
0.55
0.04
0.34
0.40
0.78
0.17
0.93
(2.5)
(2.4)
(12)
(12)
(17)
(17)
(8)
(9)
(12)
(13)
(2.6)
(2.5)
(1.7)
(1.4)
(9)
(10)
(16)
(15)
(9)
(10)
(14)
(11)
(2.8)
(3.4)
(0.7e0.3)
(0.6e0.6)
(1e6)
(4e6)
(10e6)
(10e5)
(9e0)
(7e2)
(9e4)
(5e6)
(0.4e2.2)
(1.6e1.7)
25OHD (nmol/L)
1,25OHD (pmol/L)
Adjusted serum
calcium (mmol/L)
PTH (pmol/L)
2
6
2
6
2
6
2
6
mths
mths
mths
mths
mths
mths
mths
mths
Vitamin D (SD)
Placebo (SD)
Adjusted treatment
effect (95% CI)a
55
64
53
56
2.30
2.31
7.0
5.8
44
44
36
35
2.29
2.30
6.4
7.8
15
22
14
18
0.03
0.04
0.4
2.4
0.001
0.001
0.003
0.008
0.23
0.10
0.72
0.006
(18)
(21)
(19)
(22)
(0.09)
(0.07)
(5.9)
(3.2)
(21)
(22)
(17)
(24)
(0.08)
(0.09)
(3.3)
(4.6)
(7e22)
(10e34)
(5e23)
(5e31)
(0.02e0.08)
(0.01e0.09)
(1.9e2.8)
(4.1 to 0.7)
group of patients studied in this trial were carefully phenotyped to ensure that they met both the Fukuda and the
Canadian criteria for diagnosis of CFS/ME. 25OHD levels
were raised by the intervention. The study duration was
2
6
2
6
2
6
2
6
2
6
2
6
2
6
2
6
6
6
mths
mths
mths
mths
mths
mths
mths
mths
mths
mths
mths
mths
mths
mths
mths
mths
mths
mths
5.1 (1.3)
4.8 (1.1)
2.9 (0.9)
2.8 (0.8)
1.4 (0.5)
1.3 (0.4)
1.4 (0.9)
1.4 (0.8)
1.1 [3.2]
1.9 [2.9]
0.7 [8.3]
0.9 [5.8]
2.4 (1.8)
2.4 (1.9)
1.7 (0.8)
1.5 (0.6)
377 (134)
2046 (349)
5.5 (1.1)
5.7 (1.2)
3.4 (1.1)
3.6 (1.2)
1.2 (0.3)
1.3 (0.3)
2.1 (1.0)
1.9 (0.9)
3.9 [5.4]
2.2 [4.2]
2.1 [9.4]
1.8 [2.8]
2.7 (1.9)
2.1 (1.1)
1.9 (0.8)
2.1 (1.2)
448 (72)
2113 (579)
0.0
0.3
0.1
0.2
0.0
0.1
0.0
0.2
2.7
0.3
0.0
0.4
0.2
0.7
0.2
0.3
32
146
0.82
0.10
0.55
0.31
0.72
0.14
0.90
0.31
0.09
0.75
0.98
0.60
0.66
0.11
0.06
0.28
0.30
0.37
(0.3e0.4)
(0.8e0.1)
(0.4e0.2)
(0.6ee0.2)
(0.1e0.1)
(0.2e0.0)
(0.4e0.5)
(0.2e0.5)
(5.8e0.4)
(2.4e1.7)
(4.0e4.0)
(1.1e1.9)
(0.7e1.1)
(0.2e1.6)
(0.4e0.0)
(0.8e0.3)
(93e29)
(471e179)
LDL, low density lipoprotein; HDL, high density lipoprotein; HOMA-IR, homeostasis model assessment e insulin resistance; IL-6, interleukin 6;
TNF, tumour necrosis factor; d-ROMS, derivatives of Reactive Oxygen Metabolites; BAP, biological antioxidant potential.
a
Adjusted for baseline outcome measure values.
293
Placebo
(SD)
Adjusted
treatment
effect (95% CI)a
0.1 (1.1e1.3)
0.3 (0.6e1.3)
0.1 (1.2e1.0)
0.1 (0.8e1.0)
0.2 (0.8e1.2)
0.88
0.48
0.85
0.85
0.73
0.4 (0.9e1.8)
1.0 (2.6e0.5)
0.53
0.18
Acknowledgements
randomisation; this, together with the small size of the
trial, makes interpretation of the results more difcult. Our
trial was conducted in a single centre, on an overwhelmingly white, adult cohort; thus the results cannot
necessarily be generalised to patients from other ethnic
groups, children or other geographic areas. Alternative
scales for measuring fatigue (e.g. the Krupp Fatigue
Severity Scale) may provide better sensitivity and face
validity in CFS [26,27].
It is reassuring that no excess of adverse events was
seen in the treatment group. An aetiological hypothesis
that has been proposed previously suggests that low
vitamin D levels are a host response to infection by unknown microbes [28], and further suggests that vitamin D
supplementation could worsen the chronic infection by
suppressing the host response to such an infection. We
found no evidence of worsening symptoms over the six
month study follow up to support this hypothesis,
although our study was not designed to examine longterm outcomes or any rebound effects after cessation of
therapy. Although we did not nd evidence of benet on
the selected vascular markers studied in this trial, it is of
interest that PTH levels were signicantly lower in the
vitamin D group by six months. PTH may have vasculotoxic
effects independent of low 25OHD levels [29], and such
effects may be manifest in ways that we did not measure
in this trial, for example by promoting left ventricular
hypertrophy [30].
Infection
Musculoskeletal
Gastrointestinal
Dermatological
Cardiovascular
New cancer
Hypercalcemia
Ureteric colic
Other
Total:
Deaths
Hospitalisations
Vitamin D
Placebo
14
2
6
0
1
2
0
0
8
33
0
1
9
2
12
1
2
0
0
0
13
39
0
0
294
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