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Surplus vitamin B12 use does not reduce fatigue in patients with Irritable Bowel Syndrome or inflammatory bowel disease: A randomized double-blind placebo-controlled trial
Clinical Nutrition ESPEN xxx (2017) e1ee6
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Randomized Controlled Trial
Surplus vitamin B12 use does not reduce fatigue in patients with Irritable Bowel Syndrome or inflammatory bowel disease: A randomized double-blind placebo-controlled trial Anne-Marie Scholten a, b, 1, Esther Vermeulen a, c, 1, Rosalie A.M. Dhonukshe-Rutten a, Teuni Verhagen a, Angeline Visscher a, Anouk Olivier d, Lilian Timmer d, Ben J.M. Witteman a, e, * a
Department of Human Nutrition, Wageningen University, Wageningen, The Netherlands The Hague University of Applied Sciences, Nutrition and Dietetics, The Hague, The Netherlands c Department of Public Health, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands d The Hogeschool van Amsterdam, University of Applied Sciences, Amsterdam, The Netherlands e Department of Gastroenterology and Hepatology, Gelderse Vallei Hospital, Ede, The Netherlands b
a r t i c l e i n f o
s u m m a r y
Article history: Received 24 November 2016 Accepted 19 October 2017
Objective: In non-conventional care, high doses of vitamin B12 supplementation are used for the treatment of fatigue even in case of normal vitamin B12 blood levels. We performed a randomized placebo controlled trial to investigate the effect of surplus oral vitamin B12 supplementation on fatigue in patients with IBS or IBD. Methods: This randomized double-blind, placebo-controlled trial included 95 out-clinic IBS and IBD patients with deactivating fatigue and normal vitamin B12 blood levels (150 pmol/l) aged 18e65 years. Participants were randomly assigned to receive 1000 mg vitamin B12 daily or a placebo supplement for 8 weeks. The primary outcome measure was fatigue (Checklist Individual Strength (CIS)). In addition, measures of quality of life and depression were examined. Results: No significant difference in scores of the CIS subscale ‘subjective fatigue’ was observed between the intervention group and the control group with changes in scores of 8.1 ± 9.5 and 8.3 ± 10.6 (95% CI 11.65 to 6.71), respectively. The scores on the CIS subscale ‘motivation’ improved with a significant change in scores of 2.2 ± 4.6 (95% CI 4.4 to 0.04). No significantly increased scores were observed for depression or quality of life in the intervention group compared to the control group. Conclusion: This study did not confirm the expected effect of non-conventional surplus vit B12 supplementation on fatigue in IBS or IBD patients. In addition, no positive effect was observed on depression or quality of life. We conclude that surplus treatment with vitamin B12 in IBS and IBD patients suffering from fatigue has no beneficial clinical effect. © 2017 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
Keywords: Vitamin B12 supplementation Fatigue IBS IBD
1. Introduction 1.1. Background Fatigue is a common nonspecific symptom in patients suffering from chronic diseases [1]. Irritable Bowel Syndrome (IBS) is a chronic functional bowel disorder of the gastrointestinal tract. The * Corresponding author. Department of Gastroenterology and Hepatology, Gelderse Vallei Hospital, Postbus 9025, 6710 HN Ede, The Netherlands. E-mail address: [email protected] (B.J.M. Witteman). 1 Shared first co-authorship.
prevalence of IBS is estimated to be 10e20% in the Western population. The percentage of fatigue in IBS patients is up to 60%. One study reports that 14% of the IBS patients is diagnosed with the chronic fatigue syndrome [1]. Inflammatory bowel disease (IBD) involves a chronic inflammatory condition of the digestive tract e.g. Crohn's disease (CD) and ulcerative colitis (UC). The prevalence of IBD in the Netherlands was 57.000 people in 2007 [2]. Seventy percent of patients with IBD suffer from fatigue [3e5]. Two studies report a fatigue prevalence around 40% in IBD patients in remission [3,6]. In IBD patients, fatigue is generally more pronounced in patients with CD than in
https://doi.org/10.1016/j.clnesp.2017.10.004 2405-4577/© 2017 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
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Table 1 Inclusion criteria of the eligible subjects. Eligibility criteria
Definition
IBS
According to the Rome III criteria: Recurrent abdominal pain/discomfort at least 3 days/month in the last 3 months associated with two or more of the following criteria: (1) Improvement with defecation, (2) Onset associated with a change in frequency of stool, (3) Onset associated with a change in form (appearance) of stool. By a histopathologic confirmation 18e65 years old; based on entry date into study * Experience of fatigue for at least 3 months * Elevated or severe fatigue score (27 on the 8item subscale of the CIS) * No use of B12 supplements or B12 injections in last 2 months * No use of iron supplements in last 2 months No subjects who underwent a bowel resection No participation in any kind of therapy that might prevent fatigue No Prednisone therapy Serum vitamin B12 level 150 pmol/l * Male: 8.5e11.0 mmol/l * Female: 7.5e11.0 mmol/l Available
IBD Age Fatigue
Supplement use
Bowel resection Therapy
Vitamin B12 status Haemoglobin levels Signed informed consent
patients with UC. In addition, disease activity and anaemia are positively correlated with fatigue [3]. So, fatigue is an important symptom in IBS and IBD patients and has a negative influence on the clinical outcome. Furthermore, IBS leads to increased health care costs as a result [7]. There are several studies showing that health-related quality of life in IBD and IBS patients is impaired compared to the general population [3,8,9]. Besides fatigue and impaired quality of life, depression and anxiety were present in 22% and 30% of IBS patients, respectively [10]. In IBS patients the presence of anxiety and depression results in more symptoms and a decreased quality of life [11]. Also, in IBD patient's psychological symptoms such as a depressive mood were found in 28% and may affect symptoms in a negative way [12]. Vitamin B12 deficiency is a common cause of fatigue in IBD and is treated with vitamin B12 via oral or parenteral route. In non-conventional care however, high doses (more than 500 ug daily) of vitamin B12 supplementation are used for the treatment of fatigue even in case of normal vitamin B12 blood levels. Yet, to date no scientific evidence for this treatment is available.
who also fulfilled the haemoglobin and serum vitamin B12 criteria were eligible to enter the intervention study. Subjects were recruited over a 1-year period. The study protocol was approved by the Medical Ethics Committee of Wageningen University (approval no: NL31209.081.10). Written consent was obtained from all subjects before the intervention period started. 2.2. Study design The study was conducted as an 8 week, randomized, doubleblind, placebo-controlled trial. Eligible subjects were randomly allocated to receive either tablets containing 1000 mg vitamin B12 (intervention group) or placebo tablets (control group). The intervention period of this study was set on 8 weeks because it was shown earlier that an 8-week period treatment with 1000 mg vitamin B12 was effective in significantly elevating biochemical vitamin B12 levels [13]. The tablets were identical in appearance, smell and taste. Study supplementation was personally delivered to the subjects together with the questionnaires for baseline measurement. Subjects returned the completed questionnaires by mail. Eight weeks after starting the intervention, subjects were asked to complete the same questionnaires. In addition, subjects were asked to maintain their regular diet and physical activity. Randomisation was stratified according to disease (IBS, IBD), gender (male, female), and age (18e29 years, 30e65 years). All study employees and subjects were blinded for the duration of the study to prevent bias. Un-blinding took place after all data was collected. Compliance was checked by tablet registration on a ‘pill calendar’ and by assessing vitamin B12 blood levels before and after the intervention period. 2.3. Sample size To assess the required sample size, a power calculation was performed by using the data from the study from Gielissen et al., 2006 who examined the effect of cognitive behavioural therapy on fatigue [14]. They used the Checklist Individual Strength (CIS) questionnaire and set the clinically relevant difference on 8 points for the CIS subscale ‘Subjective experience of fatigue’. Results of this study showed an even larger decrease of fatigue levels than 8 points. In the present study, we set the clinically relevant difference on 10 points to prove that the effect of vitamin B12 supplementation may be similar to the effect of cognitive behavioural therapy. Therefore, it was calculated that 68 subjects would be a sufficient sample size (power 80%, two-sided, a ¼ 0.05). To account for the probability that 20% of the subjects would not complete the intervention period, the aim was to randomly allocate 80 subjects; 40 subjects per treatment group.
1.2. Objective 2.4. Questionnaires The objective of our study is to determine the effect of surplus high-dose (1000 mg/d) oral vitamin B12 supplementation for 8 weeks on fatigue in IBS and IBD patients with normal serum Haemoglobin (Hb), vitamin B12 levels and C-reactive protein (CRP) blood levels below 10 mg/L.
Questionnaires were sent to the subjects at baseline and at the end of the intervention period to measure fatigue, quality of life and depression (Table 2). 2.5. Fatigue
2. Methods 2.1. Study population In total, 146 out-clinic patients (74% female) diagnosed with IBS or IBD were recruited from a large general hospital (Gelderse Vallei Hospital (GVH), Ede, The Netherlands). Subjects were aged between 18 and 65 years. Patients were recruited during outpatient visits. Subjects that fulfilled the study criteria (Table 1) and signed the informed consent were invited to donate a blood sample. Subjects
To measure fatigue, 3 questionnaires were used; firstly the CIS, which determines subjective fatigue and related behavioural aspects and consists of 20 items with total scores ranging from 20 to 140. Scores between 27 and 35 on the subscale ‘subjective experience of fatigue’ indicate an increased experience of fatigue and scores of 35 or higher indicate severe experience of fatigue [15]. The CIS has been tested in various populations and results have confirmed good internal consistency (Cronbach's a ¼ 0.90), discriminative validity and the sensitivity to change [16]. Secondly,
Please cite this article in press as: Scholten A-M, et al., Surplus vitamin B12 use does not reduce fatigue in patients with Irritable Bowel Syndrome or inflammatory bowel disease: A randomized double-blind placebo-controlled trial, Clinical Nutrition ESPEN (2017), https://doi.org/10.1016/ j.clnesp.2017.10.004
A.-M. Scholten et al. / Clinical Nutrition ESPEN xxx (2017) e1ee6
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Table 2 Overview of questionnaires that patients were asked to complete at baseline and after 8 weeks of intervention. Outcome
Questionnaire
Response format
Score
Fatigue
Checklist Individual Strength (CIS)
7-point Likert scale (20 items) 4 subscales - Subjective fatigue (8 items) - Concentration (5 items) - Motivation (4 items) - Physical activity (3 items) 100 mm horizontal line 5-point Likert scale (40 items) 3 subscales - Cognitive dimension (10 items) - Physical dimension (10 items) - Social dimension (20 items) Likert scale/dichotomous (36 items) 8 subscales - Physical Functioning (10 items) - Social Functioning (10 items) - Role Physical (4 items) - Role emotional (3 items) - Mental Health (5 items) - Energy/Vitality (4 items) - Bodily pain (2 items) - General health (5 items) 5-point Likert scale (26 items) 4 subscales - Physical health (7 items) - Psychological (6 items) - Social relationships (3 items) - Environment (8 items) 4-point Likert scale (20 items) 4-point Likert scale (14 items) 2 subscales - Anxiety (7 items) - Depression (7 items)
Range Range Range Range Range Range Range Range Range Range
20e140 8e56 5e35 4e28 3e21 0e100 0e160 0e40 0e40 0e80
Range Range Range Range Range Range Range Range Range Range Range Range
0e100 (transformed score) 0e100 (transformed score) 0e100 (transformed score) 0e100 (transformed score) 0e100 (transformed score) 0e100 (transformed score) 0e100 (transformed score) 0e100 (transformed score) 4e20 (transformed score) 4e20 (transformed score) 4e20 (transformed score) 4e20 (transformed score)
Visual Analogue Scale (VAS) Fatigue Impact Scale (FIS)
Quality of life
RAND-36 World Health Organisation Quality of Life Assessment-Bref (WHOQOL-BREF)
Depression
Center for Epidemiologic Studies Depression Scale (CES-D) Hospital Anxiety and Depression Scale (HADS)
Range 0e60 (16 ¼ depression) Range 0e21 (8e10 borderline; 11e21 abnormal) Range 0e21 (8e10 borderline; 11e21 abnormal)
the Fatigue Impact Scale (FIS) is a self-report instrument that is developed to understand the impact of fatigue on quality of life and consists of 40 items with total scores ranging from 0 to 160 [17]. The internal consistency has been confirmed (Cronbach's a ¼ 0.93) together with the ability to distinguish between patients groups [17]. Finally, the Visual Analogue Scale (VAS) was used to measure fatigue. This questionnaire is a 100 mm horizontal line with scores ranging from 0 to 100 [18].
Anxiety and Depression Scale (HADS) questionnaire is a self-report questionnaire to indicate depression and anxiety and consists of 14 items with scores ranging from 0 to 21 [22,23]. The internal validity has been confirmed (Cronbach's a ¼ 0.71e0.90) together with the ability to distinguish between the general population, medical outclinic patients and psychiatric patients. Furthermore, using the cutoff point of a score of 8 or higher, the sensitivity and specificity were approximately 80% for both subscales [22].
2.6. Quality of life
2.8. Biochemical analyses
Two questionnaires were used to measure quality of life; The RAND-36 includes one multi-item scale measuring 8 subscales and scores range from 0 to 100. The mean Cronbach's a is 0.84 across different population samples and scores varied significantly between groups with a different disease severity [19]. Secondly, the short form World Health Organisation Quality of Life Assessment (WHOQOL-BREF) is another assessment to measure quality of life which includes 4 domains with scores ranging from 4 to 20 with a mean Cronbach's a of 0.79 [20].
Blood samples were collected from all study subjects at baseline and after the 8-week intervention period and were collected in a 4 ml SST tube to determine serum vitamin B12 levels and haemoglobin. C-reactive protein (CRP) was collected in EDTA tubes. Serum vitamin B12 levels were determined with the Electro Chemi Luminescentie Immuno Assay (ECLIA) on the COBAS 6000 of Roche (Level 340 pmol/l; CV: 2.4%). Serum CRP was measured immunoturbidimetrically on the COBAS 6000 of Roche. Haemoglobin levels were determined with the Sysmex XE-2100 or the XT 2000i (level 7.5 mmol/l; CV: 0.9%).
2.7. Depression 2.9. Statistical analyses To measure depression, two questionnaires were used; the Centre for Epidemiologic Studies Depression (CES-D) questionnaire is a self-report scale designed to measure depressive symptoms in the general population. The scale consists of 20 items divided in 4 domains and total scores range from 0 to 60. A total score of 16 or higher indicates the presence of depressive symptoms [21]. The CES-D has been validated in the general population and the results confirmed good internal consistency (Cronbach's a ¼ 0.79e0.92) with a sensitivity of 100% and a specificity of 88% [21]. The Hospital
Baseline characteristics between the 2 treatment groups were compared with the Student's t test and Chi-square for categorical variables. Levene's test was used to test for equal variances and normal plots were used to assess the normality of the data. Furthermore, compliance between the 2 treatment groups was compared with the Fisher's exact test. Differences in the mean change between the treatment groups were analysed with the independent sample Student's t test. The ManneWhitney U test was
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used when it was not possible to normalise the skewed changes. A P-value <0.05 was considered statistically significant. Due to the sample size and the primary end-points of the study, no distinction was made in the analyses between IBS and IBD patients. All statistical analyses were carried out using SPSS, version 21. 3. Results 3.1. Study population More than 1200 out-clinic patients with IBS or IBD of the GVH patient database were checked and 146 patients were initially selected for our study. In total, 52 potential subjects did not meet the inclusion criteria and were therefore excluded from the study. At baseline, 95 subjects started the intervention period of which 44 subjects were assigned to the intervention group and 51 subjects to the control group. The mean age of the subjects was 41 years and 74% of the total study population was female. No significant differences were observed between the 2 treatment groups in the baseline characteristics (Table 3). Only patients with elevated or severe fatigue were selected for the present study. Fatigue severity was measured with the CIS subscale ‘Subjective experience of fatigue’. The subjects had a mean fatigue severity score of 46.3 ± 7.4 and 94% suffered from severe fatigue at baseline. Compliance was confirmed by a significant increase in vitamin B12 levels of 254 pmol/l (±138 pmol) in the intervention group compared to an increase of 13 pmol/l (±72 pmol) in the placebo group. Changes in haemoglobin levels and CRP levels were not different between the two treatment groups (Table 4). 3.2. Questionnaires Baseline fatigue scores of the three questionnaires (CIS, FIS, VAS) were not significantly different between the two groups (Table 5). No significant difference was observed in the change in total fatigue scores between the two treatment groups after the 8-week intervention period. Both the intervention and the placebo group showed lower scores in all three questionnaires after the intervention period, however not significantly different between the two groups. Except for the CIS subscale ‘motivation’ which showed a significant improvement in the intervention group (2.9 ± 5.6)
Table 3 Baseline characteristics of the subjects by treatment group.
Age (years)a Age category, n (%) 18e29 years 30e65 years Gender, female, n (%) Treatment, n (%) Vitamin B12 BMI (kg/m2)a Serum vitamin B12 (pmol/L) Haemoglobin (mmol/L) CRP (mg/L) Educational level, n (%)b Low Intermediate High Not specified a
IBS (n ¼ 56)
CD (n ¼ 20)
UC (n ¼ 19)
40.3 ± 13.5
42.2 ± 12.5
43.5 ± 13.0
15 (27%) 41 (73%) 48 (86%)
3 (15%) 17 (85%) 14 (70%)
3 (16%) 16 (84%) 8 (42%)
24 (43%) 25.4 ± 4.2 317.5 ± 113.6 8.7 ± 0.69 2.9 ± 4.6
11 (55%) 26.5 ± 5.0 307.2 ± 112.5 8.6 ± 0.54 5.5 ± 8.4
9 (47%) 27.3 ± 3.9 323.0 ± 163.5 8.8 ± 0.60 1.9 ± 2.5
17 (30%) 24 (43%) 15 (27%)
9 (45%) 6 (30%) 5 (25%)
5 5 7 2
(27%) (27%) (37%) (11%)
Mean ± standard deviation (SD). Education; low ¼ elementary and preparatory school, intermediate ¼ secondary school/high school, high ¼ higher education and university, not specified ¼ details of educational level unknown. b
compared to the placebo group (0.6 ± 5.0) after the intervention period with a mean difference of 2.2 (95% CI 4.4 to 0.4), P ¼ 0.046. However, the motivation of the intervention group was higher at baseline compared to the control group, with scores of 18.7 (±5.4) and 15.7 (±5.0), respectively. At baseline, no significant difference was observed in the quality of life score between the intervention and the placebo group. After the intervention period, no significant difference was observed in any of the WHOQOL-BREF domains between the intervention and placebo group. None of the WHOQOL-BREF domains changed with more than 1 point in both groups after the intervention period. In addition, no significant difference was observed in the scores of the RAND-36 questionnaire between the intervention and placebo group after the intervention period. Based on the CESD questionnaire, with a cut-off point of >16, 66% of the subjects experienced depressive symptoms. These cases were not significantly different between both treatment groups. Furthermore, based on the HADS questionnaire, with a cut-off point of 11, 24% of the subjects had ‘abnormal’ depression scores and 78% had ‘abnormal’ anxiety scores. After the intervention period, there were no significantly different changes between the intervention group and the placebo group for any of the depression measures (Table 5). 4. Discussion The present study showed that surplus therapy with 1000 mg vitamin B12 in IBD patients with normal plasma vitamin B12 levels suffering from debilitating fatigue did not significantly improve fatigue scores. Furthermore, no positive effect was observed on depression or quality of life. Only a small improvement was observed on the CIS subscale ‘motivation’ in the intervention group compared to the placebo group. A double-blind cross-over trial performed in patients with fatigue demonstrated a reduction of fatigue after parenteral administration of vitamin B12 injections (5000 mg twice weekly for 2 weeks). The response reached significantly higher scores for general well-being and happiness in the vitamin B12 injection group compared to the placebo group who received a placebo injection twice for two weeks [24]. However, the results of this study are difficult to compare with the present study because fatigue was assessed with other endpoints. Besides, in this study higher vitamin B12 doses were used and the route of administration was different. There was only one study that investigated the effect of cognitive behaviour and evaluated the effect on fatigue. This study showed that cognitive behavioural therapy in adolescents with IBD improved somatic symptoms of depression (including fatigue) irrespective of disease severity or treatment intensification [25]. No observed adverse events were reported in the treatment groups in our study due to the study supplementation. This is consistent with other studies who also did not report adverse effects that were associated with daily oral vitamin B12 intake of 1000 mge2000 mg for a period of 12e16 weeks [13] and 1000 mg for a period of 2e5 years [26]. A major strength of this study is its double blind, randomized, placebo-controlled design. Subjects are considered compliant confirmed by the statistically significant increased serum vitamin B12 levels in the intervention group. Another strength is the validated amount of oral vitamin B12 supplementation that has been demonstrated to be effective in improving serum vitamin B12 blood levels in elderly and is appropriate in daily practise [13]. Furthermore, the wide range of self-report questionnaires used to measure fatigue, quality of life and depression are a strength of this study. An advantage of using self-administered questionnaires is the greater willingness to answer sensitive questions. Furthermore, answers could not be influenced by interactions between interviewer and
Please cite this article in press as: Scholten A-M, et al., Surplus vitamin B12 use does not reduce fatigue in patients with Irritable Bowel Syndrome or inflammatory bowel disease: A randomized double-blind placebo-controlled trial, Clinical Nutrition ESPEN (2017), https://doi.org/10.1016/ j.clnesp.2017.10.004
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Table 4 Blood parameters at baseline, after 8 weeks, and change after 8 weeks of intervention in the vitamin B12 group and placebo group. Marker
Placebo
Vitamin B12 Baseline n ¼ 44
Serum vitamin B12 (pmol/L) Haemoglobin (mmol/L) CRPc (mg/L) a b c
311.0 ± 113.1 8.8 ± 0.7 3.0 ± 5.7
a
8 weeks n ¼ 44 565.2 ± 205.8 8.8 ± 0.7 3.3 ± 5.2
Change b
254.2 ± 138.0 0.0 ± 0.3 0.3 ± 2.8
Baseline n ¼ 51
8 weeks n ¼ 51
Change
318.5 ± 142.5 8.6 ± 0.6 3.5 ± 5.2
331.1 ± 136.3 8.7 ± 0.7 4.2 ± 6.5
12.6 ± 71.6 0.1 ± 0.5 0.7 ± 7.9
Mean ± standard deviation (all such values). Significantly different from placebo, P < 0.001. CRP ¼ C-reactive protein.
Table 5 Scores at baseline, after 8 weeks, and change in scores after 8 weeks of intervention for the vitamin B12 group and placebo group (n ¼ 92). Questionnaire (range)
Fatigue VASa (0e100) Total CISa (20e140) Subjective fatigue (8e56) Concentration (5e35) Motivation [4e28] Physical activity [3e21] Total FISa (0e160) Cognitive Dimension (0e40) Physical Dimension (0e40) Social Dimension (0e60) Quality of life WHOQOL-BREFb Physical health [4e20] Psychological health [4e20] Social relationships [4e20] Environment [4e20] RAND-36b Physical functioning (0e100) Social functioning (0e100) Role physical (0e100) Role emotional (0e100) Mental health (0e100) Energy/vitality (0e100) Bodily pain (0e100) General health (0e100) Depression/Anxiety Total CES-Dc (0e60) HADSc Anxiety (0e21) Depression (0e21) a b c d e
Vitamin B12 (n ¼ 43)
Placebo (n ¼ 49)
Baseline
8 weeks
Change
Baseline
66.1 ± 17.2d 103.2 ± 19.2 47.3 ± 7.2 21.7 ± 7.5 18.7 ± 5.4 15.6 ± 4.5 70.7 ± 27.9 16.7 ± 7.1 20.4 ± 8.2 33.6 ± 15.2
58.6 88.5 39.2 20.1 15.8 13.3 55.9 13.3 15.8 26.8
± ± ± ± ± ± ± ± ± ±
10.8 13.1 13.2 15.1
± ± ± ±
1.7 1.7 2.8 2.0
11.2 13.4 13.2 15.2
64.1 44.9 24.4 54.5 60.1 47.7 41.1 58.9
± ± ± ± ± ± ± ±
20.7 8.7 30.6 42.6 10.0 9.8 26.9 12.9
72.8 44.6 51.7 57.6 62.1 49.6 35.3 59.0
8 weeks
Change
21.8 24.0 10.2 6.9 5.9 4.7 30.3 7.3 8.4 15.7
7.5 ± 20.2 14.8 ± 21.9 8.1 ± 9.5 1.6 ± 6.8 2.9 ± 5.6e 2.1 ± 4.5 14.8 ± 22.1 3.3 ± 5.9 4.6 ± 6.9 6.9 ± 12.4
61.1 96.2 45.5 21.0 15.7 13.9 66.6 16.2 18.9 31.5
± ± ± ± ± ± ± ± ± ±
23.3 16.6 7.4 7.1 5.0 4.6 28.6 8.7 7.9 15.0
51.1 83.2 37.2 17.7 15.2 13.0 54.4 12.6 16.0 25.9
± ± ± ± ± ± ± ± ± ±
22.2 23.6 11.4 7.8 5.2 4.4 25.6 8.1 7.5 12.7
9.2 ± 22.5 12.4 ± 22.3 8.3 ± 10.6 3.0 ± 7.2 0.6 ± 5.0 0.8 ± 4.4 12.1 ± 18.1 3.6 ± 5.6 3.0 ± 6.1 5.6 ± 9.1
± ± ± ±
1.8 1.8 1.8 2.3
0.3 ± 1.3 0.3 ± 1.7 0.1 ± 2.5 0.1 ± 1.6
10.8 13.5 14.1 15.8
± ± ± ±
1.6 1.8 2.4 2.3
11.4 13.7 14.2 15.9
± ± ± ±
2.0 1.7 2.8 2.0
0.6 0.2 0.1 0.0
± ± ± ± ± ± ± ±
18.5 10.9 39.8 42.1 8.6 10.6 24.2 9.2
8.3 ± 15.3 0.3 ± 14.4 27.3 ± 41.8 3.0 ± 40.6 2.1 ± 9.7 2.1 ± 9.8 5.7 ± 19.5 0.1 ± 12.4
69.9 44.1 27.0 51.6 60.9 47.5 42.6 60.1
± ± ± ± ± ± ± ±
22.1 9.1 33.9 43.9 8.7 8.4 22.7 11.3
72.4 43.6 44.6 68.0 61.9 49.1 37.0 56.5
± ± ± ± ± ± ± ±
22.6 10.7 39.2 38.3 6.9 9.2 21.6 10.2
2.5 ± 14.3 0.5 ± 13.2 17.7 ± 40.4 16.3 ± 44.9 1.0 ± 7.9 1.7 ± 7.7 5.7 ± 18.6 3.6 ± 12.3
± ± ± ±
1.6 1.2 2.0 1.3
19.4 ± 5.2
18.0 ± 6.5
1.4 ± 6.5
18.5 ± 5.1
16.6 ± 4.6
1.9 ± 4.9
12.5 ± 2.3 9.6 ± 2.7
12.6 ± 2.2 9.6 ± 2.3
0.1 ± 2.0 0.0 ± 2.4
12.2 ± 2.5 9.0 ± 1.6
13.1 ± 2.1 9.0 ± 1.6
0.9 ± 1.9 0.0 ± 1.9
Higher scores indicate a higher fatigue level. Higher scores indicate better quality of life. Higher scores indicate a higher depression or anxiety level. Mean ± standard deviation (all such values). Significantly different from placebo, P < 0.05.
respondent [27,28]. The questionnaires showed good internal consistency, are sensitive to change [15,17], are available for international [19] use and include well-documented cut-off points [21e23,29]. To our knowledge, this is the first study on the effect of surplus vitamin B 12 treatment in IBS and IBD patients with severe fatigue. A limitation of this study could be the cut-off point that was used for vitamin B12 deficiency. The present study used <150 pmol/L as cut-off point for vitamin B12 deficiency, however there is no consensus on the cut-off point for vitamin B12 deficiency. Finally, serum vitamin B12 is not the most sensitive marker for measuring vitamin B12 status that could indicate that we missed subjects with vitamin B12 deficiency because we were not able to catch them with the biomarker used. However, extra blood was drawn from a sub-sample (n ¼ 35) of the study where the markers holotranscobalamin (holoTC) and methylmalonic acid (MMA) were
measured as indicators of vitamin B12 deficiency. No cases were observed where serum vitamin B12 was normal and holoTC levels were low (21e40 pmol/L) or MMA concentrations were high (>0.45 mmol/L) (data not shown). Additionally, serum vitamin B12 is still mainly used in daily practice to measure vitamin B12 deficiency. IBS and IBD are different diseases. We included both patient groups. This may be acknowledged as a limitation of our study. However, both suffered from severe fatigue even during remission of their disease/complaints. The CRP and haemoglobin blood levels were not different between both groups. In the IBD patients the course of disease and the treatment strategies were not altered during the study observation period. A lot of IBD patients in remission have IBS-like symptoms [6]. With regard to the end point of this study we think that both, IBS patients and IBD patients in remission can be included in this study.
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Based on this randomized, double-blind, placebo-controlled trial, we could not confirm the non-conventional expected effect on fatigue after 8 weeks of surplus treatment with oral vitamin B12 in IBS and IBD patients. Therefore, we conclude that there is no clinical indication for surplus treatment with oral vitamin B12 in this patient group. Conflict of interest All authors declare no conflict of interest. Acknowledgements We thank all participants of the study for their valuable contributions; all participating departments of the Gelderse Vallei hospital and the Wageningen University; Jaques Veeken and Robert de Jonge for their contribution for analysis of the blood samples. References [1] Jones KR, Palsson OS, Levy RL, Feld AD, Longstreth GF, Bradshaw BH, et al. Comorbid disorders and symptoms in irritable bowel syndrome (IBS) compared to other gastroenterology patients. Gastroenterology 2001;120(5, Supplement 1):A66. [2] Hoeymans N, Melse JM, Schoemaker CG. Health and determinants, Public Heath report Future Exploration 2010, 2010 From healthy to better. Bilthoven: RIVM. [3] Romberg-Camps MJ, Bol Y, Dagnelie PC, Hesselink-van de Kruijs MA, Kester AD, Engels LG, et al. Fatigue and health-related quality of life in inflammatory bowel disease: results from a population-based study in The Netherlands: the IBD-South Limburg cohort. Inflamm bowel Dis 2010;16(12): 2137e47. [4] Ghosh S, Mitchell R. Impact of inflammatory bowel disease on quality of life: results of the European Federation of Crohn's and Ulcerative Colitis Associations (EFCCA) patient survey. J Crohn's Colitis 2007;1(1):10e20. [5] Simren M, Svedlund J, Posserud I, Bjornsson ES, Abrahamsson H. Predictors of subjective fatigue in chronic gastrointestinal disease. Alimentary Pharmacol Ther 2008;28(5):638e47. [6] Minderhoud IM, Oldenburg B, van Dam PS, van Berge Henegouwen GP. High prevalence of fatigue in quiescent inflammatory bowel disease is not related to adrenocortical insufficiency. Am J Gastroenterol 2003;98(5):1088e93. [7] Levy RL, Von Korff M, Whitehead WE, Stang P, Saunders K, Jhingran P, et al. Costs of care for irritable bowel syndrome patients in a health maintenance organization. Am J Gastroenterol 2001;96(11):3122e9. [8] Jelsness-Jorgensen LP, Bernklev T, Henriksen M, Torp R, Moum B. Chronic fatigue is associated with increased disease-related worries and concerns in inflammatory bowel disease. World J Gastroenterol 2012;18(5):445e52. [9] Bernklev T, Jahnsen J, Lygren I, Henriksen M, Vatn M, Moum B. Health-related quality of life in patients with inflammatory bowel disease measured with the short form-36: psychometric assessments and a comparison with general population norms. Inflamm Bowel Dis 2005;11(10):909e18.
[10] Thijssen AY, Jonkers DM, Leue C, van der Veek PP, Vidakovic-Vukic M, van Rood YR, et al. Dysfunctional cognitions, anxiety and depression in irritable bowel syndrome. J Clin Gastroenterol 2010;44(10):e236e41. [11] Drossman DA, Whitehead WE, Toner BB, Diamant N, Hu YJ, Bangdiwala SI, et al. What determines severity among patients with painful functional bowel disorders? Am J Gastroenterol 2000;95(4):974e80. [12] Mittermaier C, Dejaco C, Waldhoer T, Oefferlbauer-Ernst A, Miehsler W, Beier M, et al. Impact of depressive mood on relapse in patients with inflammatory bowel disease: a prospective 18-month follow-up study. Psychosom Med 2004;66(1):79e84. [13] Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland PM, Hoefnagels WH, et al. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. Archives Intern Med 2005;165(10):1167e72. [14] Gielissen MF, Verhagen CA, Bleijenberg G. Cognitive behaviour therapy for fatigued cancer survivors: long-term follow-up. Br J Cancer 2007;97(5): 612e8. [15] Vercoulen JH, Swanink CM, Fennis JF, Galama JM, van der Meer JW, Bleijenberg G. Dimensional assessment of chronic fatigue syndrome. J Psychosom Res 1994;38(5):383e92. [16] Beurskens AJ, Bultmann U, Kant I, Vercoulen JH, Bleijenberg G, Swaen GM. Fatigue among working people: validity of a questionnaire measure. Occup Environ Med 2000;57(5):353e7. [17] Fisk JD, Ritvo PG, Ross L, Haase DA, Marrie TJ, Schlech WF. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis Off Publ Infect Dis Soc Am 1994;18(Suppl 1):S79e83. [18] Aitken RC. Measurement of feelings using visual analogue scales. Proc R Soc Med 1969;62(10):989e93. [19] Aaronson NK, Muller M, Cohen PD, Essink-Bot ML, Fekkes M, Sanderman R, et al. Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol 1998;51(11):1055e68. [20] Skevington SM, Lotfy M, O'Connell KA. The World Health Organization's WHOQOL-BREF quality of life assessment: psychometric properties and results of the international field trial. A report from the WHOQOL group. Qual Life Res Int J Qual Life Aspect Treat Care Rehabil 2004;13(2):299e310. [21] Radloff LS. The CES-D scale: a new self-report depression scale for research in the general population. Appl Psychol Meas 1977;1:385e401. [22] Spinhoven P, Ormel J, Sloekers PP, Kempen GI, Speckens AE, Van Hemert AM. A validation study of the Hospital Anxiety and Depression Scale (HADS) in different groups of Dutch subjects. Psychol Med 1997;27(2):363e70. [23] Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J Psychosom Res 2002;52(2):69e77. [24] Ellis FR, Nasser S. A pilot study of vitamin B12 in the treatment of tiredness. Br J Nutr 1973;30(2):277e83. [25] Szigethy E, Craig AE, Iobst EA, Grand RJ, Keljo D, DeMaso D, et al. Profile of depression in adolescents with inflammatory bowel disease: implications for treatment. Inflamm Bowel Dis 2009;15(1):69e74. [26] Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998;92(4): 1191e8. [27] McHorney CA, Kosinski M, Ware Jr JE. Comparisons of the costs and quality of norms for the SF-36 health survey collected by mail versus telephone interview: results from a national survey. Med Care 1994;32(6):551e67. [28] Siemiatycki J. A comparison of mail, telephone, and home interview strategies for household health surveys. Am J Public Health 1979;69(3):238e45. [29] Hanewald GJFP. CES-D: The Dutch Version. An investigation into the reliability and vitality. 1987.
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Randomized Controlled Trial
Surplus vitamin B12 use does not reduce fatigue in patients with Irritable Bowel Syndrome or inflammatory bowel disease: A randomized double-blind placebo-controlled trial Anne-Marie Scholten a, b, 1, Esther Vermeulen a, c, 1, Rosalie A.M. Dhonukshe-Rutten a, Teuni Verhagen a, Angeline Visscher a, Anouk Olivier d, Lilian Timmer d, Ben J.M. Witteman a, e, * a
Department of Human Nutrition, Wageningen University, Wageningen, The Netherlands The Hague University of Applied Sciences, Nutrition and Dietetics, The Hague, The Netherlands c Department of Public Health, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands d The Hogeschool van Amsterdam, University of Applied Sciences, Amsterdam, The Netherlands e Department of Gastroenterology and Hepatology, Gelderse Vallei Hospital, Ede, The Netherlands b
a r t i c l e i n f o
s u m m a r y
Article history: Received 24 November 2016 Accepted 19 October 2017
Objective: In non-conventional care, high doses of vitamin B12 supplementation are used for the treatment of fatigue even in case of normal vitamin B12 blood levels. We performed a randomized placebo controlled trial to investigate the effect of surplus oral vitamin B12 supplementation on fatigue in patients with IBS or IBD. Methods: This randomized double-blind, placebo-controlled trial included 95 out-clinic IBS and IBD patients with deactivating fatigue and normal vitamin B12 blood levels (150 pmol/l) aged 18e65 years. Participants were randomly assigned to receive 1000 mg vitamin B12 daily or a placebo supplement for 8 weeks. The primary outcome measure was fatigue (Checklist Individual Strength (CIS)). In addition, measures of quality of life and depression were examined. Results: No significant difference in scores of the CIS subscale ‘subjective fatigue’ was observed between the intervention group and the control group with changes in scores of 8.1 ± 9.5 and 8.3 ± 10.6 (95% CI 11.65 to 6.71), respectively. The scores on the CIS subscale ‘motivation’ improved with a significant change in scores of 2.2 ± 4.6 (95% CI 4.4 to 0.04). No significantly increased scores were observed for depression or quality of life in the intervention group compared to the control group. Conclusion: This study did not confirm the expected effect of non-conventional surplus vit B12 supplementation on fatigue in IBS or IBD patients. In addition, no positive effect was observed on depression or quality of life. We conclude that surplus treatment with vitamin B12 in IBS and IBD patients suffering from fatigue has no beneficial clinical effect. © 2017 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
Keywords: Vitamin B12 supplementation Fatigue IBS IBD
1. Introduction 1.1. Background Fatigue is a common nonspecific symptom in patients suffering from chronic diseases [1]. Irritable Bowel Syndrome (IBS) is a chronic functional bowel disorder of the gastrointestinal tract. The * Corresponding author. Department of Gastroenterology and Hepatology, Gelderse Vallei Hospital, Postbus 9025, 6710 HN Ede, The Netherlands. E-mail address: [email protected] (B.J.M. Witteman). 1 Shared first co-authorship.
prevalence of IBS is estimated to be 10e20% in the Western population. The percentage of fatigue in IBS patients is up to 60%. One study reports that 14% of the IBS patients is diagnosed with the chronic fatigue syndrome [1]. Inflammatory bowel disease (IBD) involves a chronic inflammatory condition of the digestive tract e.g. Crohn's disease (CD) and ulcerative colitis (UC). The prevalence of IBD in the Netherlands was 57.000 people in 2007 [2]. Seventy percent of patients with IBD suffer from fatigue [3e5]. Two studies report a fatigue prevalence around 40% in IBD patients in remission [3,6]. In IBD patients, fatigue is generally more pronounced in patients with CD than in
https://doi.org/10.1016/j.clnesp.2017.10.004 2405-4577/© 2017 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
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Table 1 Inclusion criteria of the eligible subjects. Eligibility criteria
Definition
IBS
According to the Rome III criteria: Recurrent abdominal pain/discomfort at least 3 days/month in the last 3 months associated with two or more of the following criteria: (1) Improvement with defecation, (2) Onset associated with a change in frequency of stool, (3) Onset associated with a change in form (appearance) of stool. By a histopathologic confirmation 18e65 years old; based on entry date into study * Experience of fatigue for at least 3 months * Elevated or severe fatigue score (27 on the 8item subscale of the CIS) * No use of B12 supplements or B12 injections in last 2 months * No use of iron supplements in last 2 months No subjects who underwent a bowel resection No participation in any kind of therapy that might prevent fatigue No Prednisone therapy Serum vitamin B12 level 150 pmol/l * Male: 8.5e11.0 mmol/l * Female: 7.5e11.0 mmol/l Available
IBD Age Fatigue
Supplement use
Bowel resection Therapy
Vitamin B12 status Haemoglobin levels Signed informed consent
patients with UC. In addition, disease activity and anaemia are positively correlated with fatigue [3]. So, fatigue is an important symptom in IBS and IBD patients and has a negative influence on the clinical outcome. Furthermore, IBS leads to increased health care costs as a result [7]. There are several studies showing that health-related quality of life in IBD and IBS patients is impaired compared to the general population [3,8,9]. Besides fatigue and impaired quality of life, depression and anxiety were present in 22% and 30% of IBS patients, respectively [10]. In IBS patients the presence of anxiety and depression results in more symptoms and a decreased quality of life [11]. Also, in IBD patient's psychological symptoms such as a depressive mood were found in 28% and may affect symptoms in a negative way [12]. Vitamin B12 deficiency is a common cause of fatigue in IBD and is treated with vitamin B12 via oral or parenteral route. In non-conventional care however, high doses (more than 500 ug daily) of vitamin B12 supplementation are used for the treatment of fatigue even in case of normal vitamin B12 blood levels. Yet, to date no scientific evidence for this treatment is available.
who also fulfilled the haemoglobin and serum vitamin B12 criteria were eligible to enter the intervention study. Subjects were recruited over a 1-year period. The study protocol was approved by the Medical Ethics Committee of Wageningen University (approval no: NL31209.081.10). Written consent was obtained from all subjects before the intervention period started. 2.2. Study design The study was conducted as an 8 week, randomized, doubleblind, placebo-controlled trial. Eligible subjects were randomly allocated to receive either tablets containing 1000 mg vitamin B12 (intervention group) or placebo tablets (control group). The intervention period of this study was set on 8 weeks because it was shown earlier that an 8-week period treatment with 1000 mg vitamin B12 was effective in significantly elevating biochemical vitamin B12 levels [13]. The tablets were identical in appearance, smell and taste. Study supplementation was personally delivered to the subjects together with the questionnaires for baseline measurement. Subjects returned the completed questionnaires by mail. Eight weeks after starting the intervention, subjects were asked to complete the same questionnaires. In addition, subjects were asked to maintain their regular diet and physical activity. Randomisation was stratified according to disease (IBS, IBD), gender (male, female), and age (18e29 years, 30e65 years). All study employees and subjects were blinded for the duration of the study to prevent bias. Un-blinding took place after all data was collected. Compliance was checked by tablet registration on a ‘pill calendar’ and by assessing vitamin B12 blood levels before and after the intervention period. 2.3. Sample size To assess the required sample size, a power calculation was performed by using the data from the study from Gielissen et al., 2006 who examined the effect of cognitive behavioural therapy on fatigue [14]. They used the Checklist Individual Strength (CIS) questionnaire and set the clinically relevant difference on 8 points for the CIS subscale ‘Subjective experience of fatigue’. Results of this study showed an even larger decrease of fatigue levels than 8 points. In the present study, we set the clinically relevant difference on 10 points to prove that the effect of vitamin B12 supplementation may be similar to the effect of cognitive behavioural therapy. Therefore, it was calculated that 68 subjects would be a sufficient sample size (power 80%, two-sided, a ¼ 0.05). To account for the probability that 20% of the subjects would not complete the intervention period, the aim was to randomly allocate 80 subjects; 40 subjects per treatment group.
1.2. Objective 2.4. Questionnaires The objective of our study is to determine the effect of surplus high-dose (1000 mg/d) oral vitamin B12 supplementation for 8 weeks on fatigue in IBS and IBD patients with normal serum Haemoglobin (Hb), vitamin B12 levels and C-reactive protein (CRP) blood levels below 10 mg/L.
Questionnaires were sent to the subjects at baseline and at the end of the intervention period to measure fatigue, quality of life and depression (Table 2). 2.5. Fatigue
2. Methods 2.1. Study population In total, 146 out-clinic patients (74% female) diagnosed with IBS or IBD were recruited from a large general hospital (Gelderse Vallei Hospital (GVH), Ede, The Netherlands). Subjects were aged between 18 and 65 years. Patients were recruited during outpatient visits. Subjects that fulfilled the study criteria (Table 1) and signed the informed consent were invited to donate a blood sample. Subjects
To measure fatigue, 3 questionnaires were used; firstly the CIS, which determines subjective fatigue and related behavioural aspects and consists of 20 items with total scores ranging from 20 to 140. Scores between 27 and 35 on the subscale ‘subjective experience of fatigue’ indicate an increased experience of fatigue and scores of 35 or higher indicate severe experience of fatigue [15]. The CIS has been tested in various populations and results have confirmed good internal consistency (Cronbach's a ¼ 0.90), discriminative validity and the sensitivity to change [16]. Secondly,
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Table 2 Overview of questionnaires that patients were asked to complete at baseline and after 8 weeks of intervention. Outcome
Questionnaire
Response format
Score
Fatigue
Checklist Individual Strength (CIS)
7-point Likert scale (20 items) 4 subscales - Subjective fatigue (8 items) - Concentration (5 items) - Motivation (4 items) - Physical activity (3 items) 100 mm horizontal line 5-point Likert scale (40 items) 3 subscales - Cognitive dimension (10 items) - Physical dimension (10 items) - Social dimension (20 items) Likert scale/dichotomous (36 items) 8 subscales - Physical Functioning (10 items) - Social Functioning (10 items) - Role Physical (4 items) - Role emotional (3 items) - Mental Health (5 items) - Energy/Vitality (4 items) - Bodily pain (2 items) - General health (5 items) 5-point Likert scale (26 items) 4 subscales - Physical health (7 items) - Psychological (6 items) - Social relationships (3 items) - Environment (8 items) 4-point Likert scale (20 items) 4-point Likert scale (14 items) 2 subscales - Anxiety (7 items) - Depression (7 items)
Range Range Range Range Range Range Range Range Range Range
20e140 8e56 5e35 4e28 3e21 0e100 0e160 0e40 0e40 0e80
Range Range Range Range Range Range Range Range Range Range Range Range
0e100 (transformed score) 0e100 (transformed score) 0e100 (transformed score) 0e100 (transformed score) 0e100 (transformed score) 0e100 (transformed score) 0e100 (transformed score) 0e100 (transformed score) 4e20 (transformed score) 4e20 (transformed score) 4e20 (transformed score) 4e20 (transformed score)
Visual Analogue Scale (VAS) Fatigue Impact Scale (FIS)
Quality of life
RAND-36 World Health Organisation Quality of Life Assessment-Bref (WHOQOL-BREF)
Depression
Center for Epidemiologic Studies Depression Scale (CES-D) Hospital Anxiety and Depression Scale (HADS)
Range 0e60 (16 ¼ depression) Range 0e21 (8e10 borderline; 11e21 abnormal) Range 0e21 (8e10 borderline; 11e21 abnormal)
the Fatigue Impact Scale (FIS) is a self-report instrument that is developed to understand the impact of fatigue on quality of life and consists of 40 items with total scores ranging from 0 to 160 [17]. The internal consistency has been confirmed (Cronbach's a ¼ 0.93) together with the ability to distinguish between patients groups [17]. Finally, the Visual Analogue Scale (VAS) was used to measure fatigue. This questionnaire is a 100 mm horizontal line with scores ranging from 0 to 100 [18].
Anxiety and Depression Scale (HADS) questionnaire is a self-report questionnaire to indicate depression and anxiety and consists of 14 items with scores ranging from 0 to 21 [22,23]. The internal validity has been confirmed (Cronbach's a ¼ 0.71e0.90) together with the ability to distinguish between the general population, medical outclinic patients and psychiatric patients. Furthermore, using the cutoff point of a score of 8 or higher, the sensitivity and specificity were approximately 80% for both subscales [22].
2.6. Quality of life
2.8. Biochemical analyses
Two questionnaires were used to measure quality of life; The RAND-36 includes one multi-item scale measuring 8 subscales and scores range from 0 to 100. The mean Cronbach's a is 0.84 across different population samples and scores varied significantly between groups with a different disease severity [19]. Secondly, the short form World Health Organisation Quality of Life Assessment (WHOQOL-BREF) is another assessment to measure quality of life which includes 4 domains with scores ranging from 4 to 20 with a mean Cronbach's a of 0.79 [20].
Blood samples were collected from all study subjects at baseline and after the 8-week intervention period and were collected in a 4 ml SST tube to determine serum vitamin B12 levels and haemoglobin. C-reactive protein (CRP) was collected in EDTA tubes. Serum vitamin B12 levels were determined with the Electro Chemi Luminescentie Immuno Assay (ECLIA) on the COBAS 6000 of Roche (Level 340 pmol/l; CV: 2.4%). Serum CRP was measured immunoturbidimetrically on the COBAS 6000 of Roche. Haemoglobin levels were determined with the Sysmex XE-2100 or the XT 2000i (level 7.5 mmol/l; CV: 0.9%).
2.7. Depression 2.9. Statistical analyses To measure depression, two questionnaires were used; the Centre for Epidemiologic Studies Depression (CES-D) questionnaire is a self-report scale designed to measure depressive symptoms in the general population. The scale consists of 20 items divided in 4 domains and total scores range from 0 to 60. A total score of 16 or higher indicates the presence of depressive symptoms [21]. The CES-D has been validated in the general population and the results confirmed good internal consistency (Cronbach's a ¼ 0.79e0.92) with a sensitivity of 100% and a specificity of 88% [21]. The Hospital
Baseline characteristics between the 2 treatment groups were compared with the Student's t test and Chi-square for categorical variables. Levene's test was used to test for equal variances and normal plots were used to assess the normality of the data. Furthermore, compliance between the 2 treatment groups was compared with the Fisher's exact test. Differences in the mean change between the treatment groups were analysed with the independent sample Student's t test. The ManneWhitney U test was
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used when it was not possible to normalise the skewed changes. A P-value <0.05 was considered statistically significant. Due to the sample size and the primary end-points of the study, no distinction was made in the analyses between IBS and IBD patients. All statistical analyses were carried out using SPSS, version 21. 3. Results 3.1. Study population More than 1200 out-clinic patients with IBS or IBD of the GVH patient database were checked and 146 patients were initially selected for our study. In total, 52 potential subjects did not meet the inclusion criteria and were therefore excluded from the study. At baseline, 95 subjects started the intervention period of which 44 subjects were assigned to the intervention group and 51 subjects to the control group. The mean age of the subjects was 41 years and 74% of the total study population was female. No significant differences were observed between the 2 treatment groups in the baseline characteristics (Table 3). Only patients with elevated or severe fatigue were selected for the present study. Fatigue severity was measured with the CIS subscale ‘Subjective experience of fatigue’. The subjects had a mean fatigue severity score of 46.3 ± 7.4 and 94% suffered from severe fatigue at baseline. Compliance was confirmed by a significant increase in vitamin B12 levels of 254 pmol/l (±138 pmol) in the intervention group compared to an increase of 13 pmol/l (±72 pmol) in the placebo group. Changes in haemoglobin levels and CRP levels were not different between the two treatment groups (Table 4). 3.2. Questionnaires Baseline fatigue scores of the three questionnaires (CIS, FIS, VAS) were not significantly different between the two groups (Table 5). No significant difference was observed in the change in total fatigue scores between the two treatment groups after the 8-week intervention period. Both the intervention and the placebo group showed lower scores in all three questionnaires after the intervention period, however not significantly different between the two groups. Except for the CIS subscale ‘motivation’ which showed a significant improvement in the intervention group (2.9 ± 5.6)
Table 3 Baseline characteristics of the subjects by treatment group.
Age (years)a Age category, n (%) 18e29 years 30e65 years Gender, female, n (%) Treatment, n (%) Vitamin B12 BMI (kg/m2)a Serum vitamin B12 (pmol/L) Haemoglobin (mmol/L) CRP (mg/L) Educational level, n (%)b Low Intermediate High Not specified a
IBS (n ¼ 56)
CD (n ¼ 20)
UC (n ¼ 19)
40.3 ± 13.5
42.2 ± 12.5
43.5 ± 13.0
15 (27%) 41 (73%) 48 (86%)
3 (15%) 17 (85%) 14 (70%)
3 (16%) 16 (84%) 8 (42%)
24 (43%) 25.4 ± 4.2 317.5 ± 113.6 8.7 ± 0.69 2.9 ± 4.6
11 (55%) 26.5 ± 5.0 307.2 ± 112.5 8.6 ± 0.54 5.5 ± 8.4
9 (47%) 27.3 ± 3.9 323.0 ± 163.5 8.8 ± 0.60 1.9 ± 2.5
17 (30%) 24 (43%) 15 (27%)
9 (45%) 6 (30%) 5 (25%)
5 5 7 2
(27%) (27%) (37%) (11%)
Mean ± standard deviation (SD). Education; low ¼ elementary and preparatory school, intermediate ¼ secondary school/high school, high ¼ higher education and university, not specified ¼ details of educational level unknown. b
compared to the placebo group (0.6 ± 5.0) after the intervention period with a mean difference of 2.2 (95% CI 4.4 to 0.4), P ¼ 0.046. However, the motivation of the intervention group was higher at baseline compared to the control group, with scores of 18.7 (±5.4) and 15.7 (±5.0), respectively. At baseline, no significant difference was observed in the quality of life score between the intervention and the placebo group. After the intervention period, no significant difference was observed in any of the WHOQOL-BREF domains between the intervention and placebo group. None of the WHOQOL-BREF domains changed with more than 1 point in both groups after the intervention period. In addition, no significant difference was observed in the scores of the RAND-36 questionnaire between the intervention and placebo group after the intervention period. Based on the CESD questionnaire, with a cut-off point of >16, 66% of the subjects experienced depressive symptoms. These cases were not significantly different between both treatment groups. Furthermore, based on the HADS questionnaire, with a cut-off point of 11, 24% of the subjects had ‘abnormal’ depression scores and 78% had ‘abnormal’ anxiety scores. After the intervention period, there were no significantly different changes between the intervention group and the placebo group for any of the depression measures (Table 5). 4. Discussion The present study showed that surplus therapy with 1000 mg vitamin B12 in IBD patients with normal plasma vitamin B12 levels suffering from debilitating fatigue did not significantly improve fatigue scores. Furthermore, no positive effect was observed on depression or quality of life. Only a small improvement was observed on the CIS subscale ‘motivation’ in the intervention group compared to the placebo group. A double-blind cross-over trial performed in patients with fatigue demonstrated a reduction of fatigue after parenteral administration of vitamin B12 injections (5000 mg twice weekly for 2 weeks). The response reached significantly higher scores for general well-being and happiness in the vitamin B12 injection group compared to the placebo group who received a placebo injection twice for two weeks [24]. However, the results of this study are difficult to compare with the present study because fatigue was assessed with other endpoints. Besides, in this study higher vitamin B12 doses were used and the route of administration was different. There was only one study that investigated the effect of cognitive behaviour and evaluated the effect on fatigue. This study showed that cognitive behavioural therapy in adolescents with IBD improved somatic symptoms of depression (including fatigue) irrespective of disease severity or treatment intensification [25]. No observed adverse events were reported in the treatment groups in our study due to the study supplementation. This is consistent with other studies who also did not report adverse effects that were associated with daily oral vitamin B12 intake of 1000 mge2000 mg for a period of 12e16 weeks [13] and 1000 mg for a period of 2e5 years [26]. A major strength of this study is its double blind, randomized, placebo-controlled design. Subjects are considered compliant confirmed by the statistically significant increased serum vitamin B12 levels in the intervention group. Another strength is the validated amount of oral vitamin B12 supplementation that has been demonstrated to be effective in improving serum vitamin B12 blood levels in elderly and is appropriate in daily practise [13]. Furthermore, the wide range of self-report questionnaires used to measure fatigue, quality of life and depression are a strength of this study. An advantage of using self-administered questionnaires is the greater willingness to answer sensitive questions. Furthermore, answers could not be influenced by interactions between interviewer and
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Table 4 Blood parameters at baseline, after 8 weeks, and change after 8 weeks of intervention in the vitamin B12 group and placebo group. Marker
Placebo
Vitamin B12 Baseline n ¼ 44
Serum vitamin B12 (pmol/L) Haemoglobin (mmol/L) CRPc (mg/L) a b c
311.0 ± 113.1 8.8 ± 0.7 3.0 ± 5.7
a
8 weeks n ¼ 44 565.2 ± 205.8 8.8 ± 0.7 3.3 ± 5.2
Change b
254.2 ± 138.0 0.0 ± 0.3 0.3 ± 2.8
Baseline n ¼ 51
8 weeks n ¼ 51
Change
318.5 ± 142.5 8.6 ± 0.6 3.5 ± 5.2
331.1 ± 136.3 8.7 ± 0.7 4.2 ± 6.5
12.6 ± 71.6 0.1 ± 0.5 0.7 ± 7.9
Mean ± standard deviation (all such values). Significantly different from placebo, P < 0.001. CRP ¼ C-reactive protein.
Table 5 Scores at baseline, after 8 weeks, and change in scores after 8 weeks of intervention for the vitamin B12 group and placebo group (n ¼ 92). Questionnaire (range)
Fatigue VASa (0e100) Total CISa (20e140) Subjective fatigue (8e56) Concentration (5e35) Motivation [4e28] Physical activity [3e21] Total FISa (0e160) Cognitive Dimension (0e40) Physical Dimension (0e40) Social Dimension (0e60) Quality of life WHOQOL-BREFb Physical health [4e20] Psychological health [4e20] Social relationships [4e20] Environment [4e20] RAND-36b Physical functioning (0e100) Social functioning (0e100) Role physical (0e100) Role emotional (0e100) Mental health (0e100) Energy/vitality (0e100) Bodily pain (0e100) General health (0e100) Depression/Anxiety Total CES-Dc (0e60) HADSc Anxiety (0e21) Depression (0e21) a b c d e
Vitamin B12 (n ¼ 43)
Placebo (n ¼ 49)
Baseline
8 weeks
Change
Baseline
66.1 ± 17.2d 103.2 ± 19.2 47.3 ± 7.2 21.7 ± 7.5 18.7 ± 5.4 15.6 ± 4.5 70.7 ± 27.9 16.7 ± 7.1 20.4 ± 8.2 33.6 ± 15.2
58.6 88.5 39.2 20.1 15.8 13.3 55.9 13.3 15.8 26.8
± ± ± ± ± ± ± ± ± ±
10.8 13.1 13.2 15.1
± ± ± ±
1.7 1.7 2.8 2.0
11.2 13.4 13.2 15.2
64.1 44.9 24.4 54.5 60.1 47.7 41.1 58.9
± ± ± ± ± ± ± ±
20.7 8.7 30.6 42.6 10.0 9.8 26.9 12.9
72.8 44.6 51.7 57.6 62.1 49.6 35.3 59.0
8 weeks
Change
21.8 24.0 10.2 6.9 5.9 4.7 30.3 7.3 8.4 15.7
7.5 ± 20.2 14.8 ± 21.9 8.1 ± 9.5 1.6 ± 6.8 2.9 ± 5.6e 2.1 ± 4.5 14.8 ± 22.1 3.3 ± 5.9 4.6 ± 6.9 6.9 ± 12.4
61.1 96.2 45.5 21.0 15.7 13.9 66.6 16.2 18.9 31.5
± ± ± ± ± ± ± ± ± ±
23.3 16.6 7.4 7.1 5.0 4.6 28.6 8.7 7.9 15.0
51.1 83.2 37.2 17.7 15.2 13.0 54.4 12.6 16.0 25.9
± ± ± ± ± ± ± ± ± ±
22.2 23.6 11.4 7.8 5.2 4.4 25.6 8.1 7.5 12.7
9.2 ± 22.5 12.4 ± 22.3 8.3 ± 10.6 3.0 ± 7.2 0.6 ± 5.0 0.8 ± 4.4 12.1 ± 18.1 3.6 ± 5.6 3.0 ± 6.1 5.6 ± 9.1
± ± ± ±
1.8 1.8 1.8 2.3
0.3 ± 1.3 0.3 ± 1.7 0.1 ± 2.5 0.1 ± 1.6
10.8 13.5 14.1 15.8
± ± ± ±
1.6 1.8 2.4 2.3
11.4 13.7 14.2 15.9
± ± ± ±
2.0 1.7 2.8 2.0
0.6 0.2 0.1 0.0
± ± ± ± ± ± ± ±
18.5 10.9 39.8 42.1 8.6 10.6 24.2 9.2
8.3 ± 15.3 0.3 ± 14.4 27.3 ± 41.8 3.0 ± 40.6 2.1 ± 9.7 2.1 ± 9.8 5.7 ± 19.5 0.1 ± 12.4
69.9 44.1 27.0 51.6 60.9 47.5 42.6 60.1
± ± ± ± ± ± ± ±
22.1 9.1 33.9 43.9 8.7 8.4 22.7 11.3
72.4 43.6 44.6 68.0 61.9 49.1 37.0 56.5
± ± ± ± ± ± ± ±
22.6 10.7 39.2 38.3 6.9 9.2 21.6 10.2
2.5 ± 14.3 0.5 ± 13.2 17.7 ± 40.4 16.3 ± 44.9 1.0 ± 7.9 1.7 ± 7.7 5.7 ± 18.6 3.6 ± 12.3
± ± ± ±
1.6 1.2 2.0 1.3
19.4 ± 5.2
18.0 ± 6.5
1.4 ± 6.5
18.5 ± 5.1
16.6 ± 4.6
1.9 ± 4.9
12.5 ± 2.3 9.6 ± 2.7
12.6 ± 2.2 9.6 ± 2.3
0.1 ± 2.0 0.0 ± 2.4
12.2 ± 2.5 9.0 ± 1.6
13.1 ± 2.1 9.0 ± 1.6
0.9 ± 1.9 0.0 ± 1.9
Higher scores indicate a higher fatigue level. Higher scores indicate better quality of life. Higher scores indicate a higher depression or anxiety level. Mean ± standard deviation (all such values). Significantly different from placebo, P < 0.05.
respondent [27,28]. The questionnaires showed good internal consistency, are sensitive to change [15,17], are available for international [19] use and include well-documented cut-off points [21e23,29]. To our knowledge, this is the first study on the effect of surplus vitamin B 12 treatment in IBS and IBD patients with severe fatigue. A limitation of this study could be the cut-off point that was used for vitamin B12 deficiency. The present study used <150 pmol/L as cut-off point for vitamin B12 deficiency, however there is no consensus on the cut-off point for vitamin B12 deficiency. Finally, serum vitamin B12 is not the most sensitive marker for measuring vitamin B12 status that could indicate that we missed subjects with vitamin B12 deficiency because we were not able to catch them with the biomarker used. However, extra blood was drawn from a sub-sample (n ¼ 35) of the study where the markers holotranscobalamin (holoTC) and methylmalonic acid (MMA) were
measured as indicators of vitamin B12 deficiency. No cases were observed where serum vitamin B12 was normal and holoTC levels were low (21e40 pmol/L) or MMA concentrations were high (>0.45 mmol/L) (data not shown). Additionally, serum vitamin B12 is still mainly used in daily practice to measure vitamin B12 deficiency. IBS and IBD are different diseases. We included both patient groups. This may be acknowledged as a limitation of our study. However, both suffered from severe fatigue even during remission of their disease/complaints. The CRP and haemoglobin blood levels were not different between both groups. In the IBD patients the course of disease and the treatment strategies were not altered during the study observation period. A lot of IBD patients in remission have IBS-like symptoms [6]. With regard to the end point of this study we think that both, IBS patients and IBD patients in remission can be included in this study.
Please cite this article in press as: Scholten A-M, et al., Surplus vitamin B12 use does not reduce fatigue in patients with Irritable Bowel Syndrome or inflammatory bowel disease: A randomized double-blind placebo-controlled trial, Clinical Nutrition ESPEN (2017), https://doi.org/10.1016/ j.clnesp.2017.10.004
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A.-M. Scholten et al. / Clinical Nutrition ESPEN xxx (2017) e1ee6
Based on this randomized, double-blind, placebo-controlled trial, we could not confirm the non-conventional expected effect on fatigue after 8 weeks of surplus treatment with oral vitamin B12 in IBS and IBD patients. Therefore, we conclude that there is no clinical indication for surplus treatment with oral vitamin B12 in this patient group. Conflict of interest All authors declare no conflict of interest. Acknowledgements We thank all participants of the study for their valuable contributions; all participating departments of the Gelderse Vallei hospital and the Wageningen University; Jaques Veeken and Robert de Jonge for their contribution for analysis of the blood samples. References [1] Jones KR, Palsson OS, Levy RL, Feld AD, Longstreth GF, Bradshaw BH, et al. Comorbid disorders and symptoms in irritable bowel syndrome (IBS) compared to other gastroenterology patients. Gastroenterology 2001;120(5, Supplement 1):A66. [2] Hoeymans N, Melse JM, Schoemaker CG. Health and determinants, Public Heath report Future Exploration 2010, 2010 From healthy to better. Bilthoven: RIVM. [3] Romberg-Camps MJ, Bol Y, Dagnelie PC, Hesselink-van de Kruijs MA, Kester AD, Engels LG, et al. Fatigue and health-related quality of life in inflammatory bowel disease: results from a population-based study in The Netherlands: the IBD-South Limburg cohort. Inflamm bowel Dis 2010;16(12): 2137e47. [4] Ghosh S, Mitchell R. Impact of inflammatory bowel disease on quality of life: results of the European Federation of Crohn's and Ulcerative Colitis Associations (EFCCA) patient survey. J Crohn's Colitis 2007;1(1):10e20. [5] Simren M, Svedlund J, Posserud I, Bjornsson ES, Abrahamsson H. Predictors of subjective fatigue in chronic gastrointestinal disease. Alimentary Pharmacol Ther 2008;28(5):638e47. [6] Minderhoud IM, Oldenburg B, van Dam PS, van Berge Henegouwen GP. High prevalence of fatigue in quiescent inflammatory bowel disease is not related to adrenocortical insufficiency. Am J Gastroenterol 2003;98(5):1088e93. [7] Levy RL, Von Korff M, Whitehead WE, Stang P, Saunders K, Jhingran P, et al. Costs of care for irritable bowel syndrome patients in a health maintenance organization. Am J Gastroenterol 2001;96(11):3122e9. [8] Jelsness-Jorgensen LP, Bernklev T, Henriksen M, Torp R, Moum B. Chronic fatigue is associated with increased disease-related worries and concerns in inflammatory bowel disease. World J Gastroenterol 2012;18(5):445e52. [9] Bernklev T, Jahnsen J, Lygren I, Henriksen M, Vatn M, Moum B. Health-related quality of life in patients with inflammatory bowel disease measured with the short form-36: psychometric assessments and a comparison with general population norms. Inflamm Bowel Dis 2005;11(10):909e18.
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Please cite this article in press as: Scholten A-M, et al., Surplus vitamin B12 use does not reduce fatigue in patients with Irritable Bowel Syndrome or inflammatory bowel disease: A randomized double-blind placebo-controlled trial, Clinical Nutrition ESPEN (2017), https://doi.org/10.1016/ j.clnesp.2017.10.004