Vitamin D deficiency in Inflammatory Bowel Disease - prevalence, predictors and associations with fatigue and pain
The Vitality Study
Svein Oskar Frigstad, M.D
Institute of clinical medicine University of Oslo
Faculty of Medicine 2022
© Svein Oskar Frigstad, 2022
Series of dissertations submitted to the Faculty of Medicine, University of Oslo ISBN 978-82-8377-980-6
All rights reserved. No part of this publication may be
reproduced or transmitted, in any form or by any means, without permission.
Cover: Hanne Baadsgaard Utigard.
Print production: Reprosentralen, University of Oslo.
Table of contents
Acknowledgements ... 5
Norsk sammendrag – Norwegian summary ... 7
Thesis summary ... 8
Papers in the thesis ... 9
Abbreviations ... 10
1.0 Introduction ... 11
1.1 Inflammatory bowel disease ... 11
1.2 Vitamin D ... 12
1.3 Vitamin D deficiency and IBD ... 20
1.4 Patient Reported Outcomes (PRO) ... 24
1.5 Fatigue ... 26
1.6 Pain ... 31
1.7 The rationale behind the Vitality Study ... 33
2.0 Thesis aims ... 34
3.0 Materials and methods ... 35
3.1 Study design and recruitment ... 35
3.2 Data collection ... 35
3.3 Study design and statistical analyses ... 39
3.4 Ethical considerations ... 39
4.0 Results ... 40
4.1 Patient population ... 40
4.2 Study outcomes ... 42
4.3 Summary of papers ... 44
5.0 Discussion ... 47
5.1 Methodological discussion ... 47
5.2 Discussion of main findings ... 52
6.0. Conclusions ... 57
7.0. Future perspectives ... 58
8.0 References ... 59
Acknowledgements
The present work was performed at the Department of Research and Development at Østfold Hospital Trust and Vestre Viken Bærum Hospital. Financial support was provided through a research fellowship from Østfold Hospital Trust and unrestricted research grants from Tillotts Pharma, Norway and Pharmacosmos, Denmark for editorial support.
Professor Lars-Petter Jelsness-Jørgensen has been my supervisor. He has always broadened my perspectives and has impressive knowledge and skills in methodology and research techniques as well as a profound understanding of the clinical relevance of science from the patients’ perspective. Even with my frustration over time management, he has kept a positive attitude and inspired me to keep up my efforts, supporting me in every way. My co-
supervisors have been associate professor Marte Lie Høivik, professor Tomm Bernklev, and professor Bjørn Moum. As a team they have contributed with their perspectives, knowledge and criticism, teaching me the secrets of an academic understanding to the big questions in clinical research and practice. Their support, encouragement and when needed a push outside the comfort zone, have been invaluable in my learning and development.
The thesis builds upon the work of many others. Firstly, I would like to thank all members of the Vitality study group, and thanks are especially owed to the study nurses for helping to collect data and questionnaires in all the hospitals co-operating in the study. Gunnhild Seim at Oslo University Hospital deserves special appreciation for handling all the stool tests before forwarding them for analyses in the laboratories in Lovisenberg Diaconal Hospital by Vendel Kristensen, MD and Vestre Viken Hospital Trust by Trine Lauritzen, MD. The vitamin D analyses were handled by Sara Rinne Dahl, MD at the Hormone Laboratory at Oslo
University Hospital, Aker. Her insights in the methodology of vitamin D analyses have been invaluable.
Professor and biostatistician Milada Cvankarova has been guiding me through all statistical analyses and interpretation of results throughout the work. Developing my understanding for practical statistics in medical research have been among the most intriguing and fun aspects of the whole period as a PhD student. Her intelligence and charm are both blinding, and I have always enjoyed our meetings, short or long.
Also, my thanks are extended to all the co-authors that have participated in both patient recruitment, data-collection, scientific discussions and critical revision of the manuscripts. In particular, Øystein Hovde, Tore Grimstad, Jørgen Jahnsen, and Gert Huppertz-Hauss have provided insights in their fields of expertise that significantly have improved the presentation and interpretation of the results.
I would like to thank the University of Oslo for giving me the opportunity to be a PhD student and providing useful education and support throughout the work. Especially, I would like to honor the availability and service given by the IT department at Forskningsparken.
Support from my affiliated institutions has been highly appreciated. I am grateful to my boss, Niels Kristian Thybo, Head of Department of medicine at Vestre Viken Bærum Hospital, for his encouragement and understanding in the need to find time for scientific work in the everyday struggle of clinical work and management. I am grateful to the leadership of the Research Departments at both Østfold Hospital Trust and Vestre Viken Bærum Hospital for making the co-operation between the two institutions possible. Especially, I would like to extend my thanks to Kirstin Flebu Jørundland, the now retired librarian at Vestre Viken Bærum Hospital for the best service possible, whenever I have needed to find literature or set up a search for relevant information in my research work.
Clinical research is not feasible without patients who are willing to participate and broaden our perspectives. My sincere thanks to all the patients who participated in the Vitality study.
Last, but not least, working life is shallow without love and support from friends and family.
Almost every day my mother has asked if I have been able to find the time to work on my research projects, and not only what others expect me to do. My father, who unfortunately passed away three years ago, would have been so proud of me for finally reaching my goal.
Thanks to all my fantastic friends who are always there for me when the going gets tough.
My thesis is dedicated to Akash, who lights a spark in my heart every morning. Thank you for making every day meaningful and always showing me what is important in life.
Norsk sammendrag – Norwegian summary
Flere studier har vist at vitamin D mangel er vanlig hos pasienter med inflammatorisk tarmsykdom (IBD). Rapportert prevalens varierer mellom ulike populasjoner og grad av sykdomsaktivitet. Før Vitality-studien var kunnskap om vitamin D status hos pasienter med IBD i Norge begrenset. Dessuten hadde ingen studier utforsket vitamin D og mulige
assosiasjoner med fatigue og smerter ved IBD.
Målet med denne avhandlingen var å kartlegge forekomst og mulige kliniske prediktorer for vitamin D mangel ved IBD, samt å undersøke om vitamin D mangel har sammenheng med pasientrapporterte utfallsmål som fatigue og smerter i denne pasientgruppen. Avhandlingen er basert på tre vitenskapelige artikler utgående fra Vitality-studien utført av ‘The Vitality Study Group’, og resultatene er utelukkende basert på tverrsnittsdata fra studien.
Studiedeltakere ble rekruttert fra ni sykehus i Sør-Norge. Alle vitamin D analyser ble utført på det samme akkrediterte laboratoriet på Oslo universitetssykehus (Hormonlaboratoriet).
Spørreskjema som er validert for pasienter med IBD, ble brukt til å kartlegge fatigue (The Fatigue Questionnaire) og smerte (Brief Pain Inventory).
Vår studie viste at vitamin D mangel er vanlig hos pasienter med IBD i Norge, særlig ved Crohns sykdom, og dessuten hyppigere forekommende enn i normalbefolkningen. Om lag halvparten av pasientene hadde vitamin D mangel. Vitamin D mangel var assosiert med økt pasientrapportert sykdomsaktivitet, hyppigere tilbakefall og høyere inflammatorisk aktivitet.
Ingen statistisk signifikant assosiasjon ble funnet mellom vitamin D mangel og fatigue, og heller ikke mellom vitamin D mangel og smerteintensitet.
Thesis summary
Several studies have shown that vitamin D deficiency is common in patients with
inflammatory bowel disease (IBD). The reported prevalence rates vary according to study population and disease activity. Prior to the Vitality study, the knowledge of vitamin D status in patients with IBD in Norway was limited. Furthermore, there were no studies investigating vitamin D and its potential effect on health outcomes such as fatigue and pain in patients with IBD.
The goal of this thesis was to investigate the prevalence and possible clinical predictors of Vitamin D deficiency in IBD, and whether a deficiency might be associated with patient reported outcomes such as increased fatigue and pain severity. The thesis is based on three scientific articles from the Vitality study performed by the Vitality Study group, and the results presented are based solely on cross-sectional data.
Study participants were recruited from nine hospitals in the southeastern and western regions of Norway. All analyses of vitamin D were performed in the same accredited laboratory at Oslo University Hospital. Questionnaires validated in patients with IBD were used to measure patient reported outcomes such as fatigue (the Fatigue Questionnaire) and pain (Brief Pain Inventory).
We found that vitamin D deficiency was common in a Norwegian outpatient population with IBD, especially in Crohn’s disease, and more prevalent than in the general population.
Around half of the patients had vitamin D deficiency. Vitamin D deficiency was associated with increased patient-reported disease activity, a relapsing disease course and higher
inflammatory activity. No statistically significant associations between vitamin D deficiency and fatigue, nor between vitamin D deficiency and pain severity were revealed.
Papers in the thesis
I Frigstad SO, Høivik M, Jahnsen J, Dahl SR, Cvancarova M, Grimstad T, Berset IP, Huppertz-Hauss G, Hovde Ø, Torp R, Bernklev T, Moum B, Jelsness-Jørgensen LP. Vitamin D deficiency in inflammatory bowel disease: prevalence and predictors in a Norwegian outpatient population. Scand J Gastroenterol 2017;52(1):100-6.
II Frigstad SO, Høivik ML, Jahnsen J, Cvancarova M, Grimstad T, Berset IP, Huppertz-Hauss G, Hovde Ø, Bernklev T, Moum B, Jelsness-Jørgensen LP. Fatigue is not associated with vitamin D deficiency in inflammatory bowel disease patients. World J. Gastroenterol 2018, 24, 3293–3301.
III Frigstad, SO, Høivik, ML, Jahnsen J, Cvancarova M, Grimstad T, Berset IP, Huppertz- Hauss G, Hovde Ø, Bernklev T, Moum B, Jelsness-Jørgensen LP. Pain Severity and Vitamin D deficiency in IBD Patients. Nutrients 2020, 12(1), 26.
Abbreviations
IBD Inflammatory bowel disease CD Crohn’s disease
UC Ulcerative colitis
HBI Harvey Bradshaw Index
CDAI Crohn’s Disease Activity Index
SCCAI Simple Clinical Colitis Activity Index UCAI Ulcerative Colitis Activity Index HRQoL Health Related Quality of Life PRO Patient Reported Outcome
PROM Patient Reported Outcome Measures FQ The Fatigue Questionnaire
BPI Brief Pain Inventory
HADS Hospital Anxiety and Depression Scale BNSQ Basic Nordic Sleep Questionnaire SF-36 Short-Form 36
MFI-20 Multidimensional Fatigue Inventory 25-OH-D 25-hydroxyvitamin D
1,25-OH-D 1,25-dihydroxyvitamin D VDP Vitamin D binding protein VDR Vitamin D receptor
LC-MS/MS Liquid Chromatography combined with tandem mass spectrometry Anti-TNF Anti-Tumor necrosis factor
5-ASA 5-Aminosalicylic acid CRP C-reactive protein
SPSS Statistical Package for Social Sciences
1.0 Introduction
1.1 Inflammatory bowel disease
Inflammatory bowel disease (IBD) consists mainly of Crohn’s disease (CD) and ulcerative colitis (UC), which are chronic inflammatory disorders of the gastrointestinal tract (1-3). In UC, the inflammation is located in the colon, while CD may affect any part of the
gastrointestinal tract (1, 4). Patients with IBD report a variety of symptoms such as diarrhea with or without blood, abdominal pain, weight loss and fatigue (1, 5, 6). The symptoms vary from mild symptoms to severe life-threatening disease. Disease onset is usually in early adulthood and the course of disease is typically characterized by periods of symptom flares and periods with quiescent disease (2). Extraintestinal manifestations are reported in at least 25 % of patients with IBD, most commonly related to joints, skin, eyes, liver- and biliary system (4). These may cause considerable symptoms and also contribute to reduced health- related quality of life and work productivity (7).
Medical treatment consists of different medications reducing inflammation, traditionally mesalamine (5-ASA), immunosuppressives (azathioprine, methotrexate) and steroids (prednisone, prednisolone, budesonide). In recent years biological treatments (infliximab, adalimumab, vedolizumab, ustekinumab) designed to inhibit the inflammatory processes have emerged and improved the treatment options for patients with IBD. Even with more efficient drugs, surgery is still needed for many patients. In CD the probability of intra-abdominal surgery is up to 50 % during the first 10 years of disease (5, 8). In UC the colectomy rates have decreased over time (9). Nevertheless, around 10-15 % of patients will have a total - or partial colectomy performed during the first 10 years of disease (10, 11). Several studies have reported an increased risk with disease duration longer than 20 years, but in Norway these rates seem to be around 13 % in patients with UC, 20 years after diagnosis (12, 13).
The incidence and prevalence of IBD seems to be increasing with time also in other regions around the world, indicating its emergence as a global disease (14, 15). The highest incidence rates of IBD have been reported in northern Europe, the UK and North America (2, 14).
In Norway the last measured incidence was 6.5/100.000 per year for CD and 13/100.000 per year for UC in the period 1990 to 1993 (16, 17). In a recent registry-based study, the
incidence rates have been estimated to be higher in recent years, 14.1-16.0/100.000 per year
for CD and 24.7-28.4/100.000 for UC in the period 2010 to 2017 (18). The prevalence rate of IBD in Norway has been estimated at 0.27 % for CD and 0.50 % for UC (18).
The aetiology of IBD is not fully known, but there is a common understanding that the development of disease is a result of a combination of genetic susceptibility and
environmental factors (3, 4). Smoking represents one of the most consistently reported risk factors for CD as well as it seems to protect against UC (3, 4, 19). In addition, changes in the microbiota are reported in IBD, and are likely to be a consequence of changes in environment including hygiene and diet (3, 19).
It has been shown that the incidence of both UC and CD increases with higher latitude, first reported in Europe, but also supported by studies from Asia, Australia and North America (3, 20-22). Furthermore, it is known that both UC and CD are more often diagnosed during winter and that CD runs a clinical course with more exacerbations in the darker months of the year when exposure to sunlight is scarce (23, 24).
This has led to the assumption that increased exposure to sunlight provides protection from IBD via the vitamin D pathway (21, 22). The interpretation of a possible association between vitamin D status and the incidence of IBD is, however, confounded by several factors, and a causal relationship has not been established (25, 26).
1.2 Vitamin D
1.2.1 Vitamin D - from vitamin to hormone
Vitamin D is not strictly a vitamin and is widely recognized as a hormone. Vitamins are defined as organic compounds that need to be ingested and are necessary for normal functioning. Hormones are synthesized in the body from simple precursors and often have their effects in other organs than where they are produced. We now know that vitamin D primarily is produced in the skin following exposure to ultra-violet B (UV-B) radiation, and secondarily ingested in the diet and absorbed by the small intestine. The discovery of effects in multiple physiological processes at different sites in the body has added to the
understanding of vitamin D as a hormone (27).
Long before the mechanisms were established, epidemiologists already in the 19th century described that rickets was found more often in urban areas, was more common during winter, and was not found in countries rich in sunshine (28). Around 1920 different groups of
scientists demonstrated that exposure to sunlight or artificial ultraviolet light had healing effects in children suffering from rickets (29, 30). Only several years later it was
demonstrated that the known effect of sunlight is mediated through the synthesis of an antirachitic substance in the skin (31, 32). The discovery that cod liver oil also comprised a cure for rickets led to the discovery of vitamin D as a nutritional substance (33, 34). But the synthesis of pre-vitamin D in the skin and activation of vitamin D was not accurately described before 1978 (35, 36).
1.2.2 Vitamin D - sources and synthesis
Vitamin D is now known to be a group of prohormones where vitamin D2 (ergocalciferol) and D3 (cholecalciferol) are the main components. Vitamin D2 is made from yeast and is the most common form in fortification of food products and occurs naturally in mushrooms.
Vitamin D3 is produced in the skin following exposure to sunlight and is found in animal products, mainly in oily fish (wild salmon, herring, tuna, sardines, trout and mackerel), liver from fish or beef, red meat (pork) and the yolks of eggs. Most supplements contain vitamin D3, but supplements containing vitamin D2 are probably equally efficient (37, 38).
In Norway, butter, margarine and certain types of milk has traditionally been fortified with vitamin D. In the later years, some types of bread, cereals, cooking oils and fruit juices have been fortified with vitamin D. Nevertheless, most Norwegians do not get enough vitamin D through the diet and need exposure to sunlight during summer or supplements (routinely recommended during winter). The vitamin D production is, however, dependent on several factors such as latitude, time of day and use of sun protection. In Southern Norway vitamin D can be produced in the skin only from April to September, and further north in the country for even shorter periods (39-41). Sun exposure on arms and legs 10-30 minutes three times per week during daytime in the summer may be sufficient as vitamin D is stored in fatty tissues and can be mobilized during winter (42). In people with darker skin however, the exposure needs to be 2-10 times longer to produce the same amount of vitamin D (43). Also, with increasing age the ability to synthesize vitamin D decreases (44, 45).
1.2.3 Vitamin D - physiology and metabolism
In the skin 7-dehydrocholesterol is transformed into pre-vitamin D following UVB radiation from sunlight. There is a mechanism in place to avoid intoxication as prolonged sun exposure results in conversion to inactive metabolites (42). Pre-vitamin D is spontaneously converted into Vitamin D and transported to the liver where it is metabolized into 25-hydroxyvitamin D (25-OH-D) or calcidiol by the enzyme 25-hydroxylase (CYP2R1). Vitamin D ingested in the diet and from supplements is also transported to the liver and metabolized into 25-OH-D via the same enzymatic pathway. In the kidney and other organs 25-OH-D are transformed into the active form 1,25-dihydroxyvitamin D (1,25-OH-D) or calcitriol by the enzyme 25-OH-D-
1 hydroxylase (CYP27B1) (27). Both 25-OH-D and 1,25-OH-D are catabolized in the kidneys to calcitronic acid and excreted in the bile (43).
In the circulation all forms of vitamin D are bound to vitamin D binding protein (DBP). The longer half-life of 25-OH-D (2-3 weeks) compared to 1,25-OH-D (4-6 hours) makes it a good reservoir of vitamin D. The activated 1,25-OH-D binds to the intracellular vitamin D receptor (VDR) regulating gene expression in a wide array of physiological functions (27).
Vitamin D promotes absorption of calcium in the small intestine, enabling normal
mineralization of bone. The renal production of 1,25-OH-D is tightly regulated by parathyroid hormone (PTH), calcium and phosphate levels in the blood, and fibroblast growth factor 23 (FGF-23). Low calcium levels increase PTH, which in turn stimulates the activation of 1,25- OH-D in the kidneys, but also increased resorption of bone (27). High levels of calcium and phosphate leads to decreased activation of 1,25-OH-D in the kidneys and increased urinary excretion of phosphate. The physiology and metabolism of vitamin D is shown in Figure 1.
The discovery that many tissues and cells in the body have vitamin D receptors and that some also have the enzymatic machinery (CYP27B1) to convert 25-OH-D into 1,25-OH-D was a breakthrough in the understanding of the effects of vitamin D (27). Many tissues expressing VDR respond to the activated form of 1,25-OH-D, and activation also takes place at cellular level (27). VDR classically was described in the intestine, bones and kidney regulating the calcium homeostasis (27). In later years VDR has been found throughout the body including the brain, prostate, lung, colon, skeletal muscle and immune cells (46, 47). The regulatory mechanisms of these non-skeletal actions of vitamin D are so far incompletely understood.
Skin
7-deoxycholesterol Sunlight
UVB-radiation
Previtamin D3
Diet and supplements
Vitamin D
25-hydroxyvitamin D (calcidiol) Major circulating
metabolite Liver (Vitamin D 25-hydroxylase)
1-25-dihydroxyvitamin D (calcitriol)
Biologically active substance Inactivation
(tachysterol, lumisterol)
Storage Fatty tissue
Excretion in bile (calcitronic acid) Parathyroid
Hormone (PTH)
Calcium Phosphate
FGF-23
Bone
Extrarenal 1-alpha hydroxylase
Vitamin D2 (ergocalciferol)
Vitamin D3
(cholecaciferol) CH3
H O
CH2
H O
CH2
÷
÷ +
Intestine
Kidney
(25- hydroxyvitamin D
1-alpha hydroxylase)
Immune system adaptive and innate immunity Cellular proliferation
and differentiation Calcium homeostasis
Calsium absorption and uptake
Figur 1. Physiology and metabolism of vitamin D
1.2.4 Vitamin D - measurement and methods
The biomarker used to determine vitamin D status is 25-OH-D rather than the biologically active hormone 1,25-OH-D for several reasons. Firstly, the serum concentration of 25-OH-D has a longer half-life and reflects the vitamin D provided from sun exposure, dietary intake, supplements as well as storage (27). Additionally, the level of 25-OH-D better reflects the vitamin D status as the active 1,25-OH-D has a low physiological concentration and may be normal or even increased also when there is an insufficiency of vitamin D (48). In active inflammation 1,25-OH-D may be increased, and it has been speculated that this may be part of a regulatory mechanism with increased extra-renal conversion into the active metabolite with potential anti-inflammatory effects (48, 49).
Different methods for analysis of vitamin D and its metabolites are available and may differ between laboratories and in clinical studies. Studies investigating the effects of vitamin D may rely heavily on the accurate assessment and method used. Several methods have been used including competitive protein binding assays (CBP), radioimmune assays (RIA), chemiluminescence assays (CLIA), liquid chromatography (LC) or liquid chromatography combined with tandem mass spectrometry (LC-MS/MS). Automated immunoassays available in many clinical laboratories have been reported to have an increased risk of producing lower readings than the actual value (50). Therefore, the vitamin D standardizing program (VDSP) was initiated to standardize the measurement of vitamin D metabolites and reduce the
inconsistencies in vitamin D quantification developing a reference system and protocols (51).
Methods using LC-MS/MS are currently recommended as a gold standard in both clinical practice and research (52).
1.2.5 Vitamin D deficiency – levels and definitions
There is no consensus on optimal levels of 25-hydroxyvitamin D as measured in serum, and the recommendations are based on different outcomes. Historically, vitamin D deficiency was determined by a concentration of 25-OH-D < 25 nmol/L or the level necessary to avoid rickets or osteomalacia (53, 54). Vitamin D deficiency has later been defined as a 25- hydroxyvitamin D level of less than 50 nmol/L (20 ng/mL) (27, 55-58). The National
Academy of Medicine (formerly called Institute of Medicine) proposed this definition in 2010 based on the assumption that this level was sufficient to ensure skeletal health (58).
Currently, the recommendations are based on levels that are sufficient to suppress PTH (50-75 nmol/L) and maximally increase the intestinal calcium absorption (>75 nmol/L) (56). A level
> 75 nmol/L has also been associated with increased muscle strength, an optimal level for bone mass density, as well as decreased number of falls in the elderly (27, 59). Recent guidelines and studies suggest that levels of 25-OH-D below 50 nmol/L constitute vitamin D deficiency, and that levels above 75 nmol/L represent sufficient levels (60). Accordingly, serum concentrations in the range 50-75 nmol/l are defined as vitamin D insufficiency (27, 54). These recommendations continue to be based merely on the classical skeletal effects of vitamin D, and there are no current recommendations regarding the non-skeletal actions of vitamin D. The levels of serum 25-OH-D necessary for immunological effects are at best uncertain, since levels of 1,25-OH-D in tissues not necessarily correlate with the serum 25- OH-D concentration (49).
1.2.6 Vitamin D deficiency – prevalence
Estimates of vitamin D deficiency defined as 25-OH-D below 50 nmol/L have been reported as 24% (US), 37% (Canada) and 40% (Europe) (61-63). In Norway the Oslo Health study (HUBRO) found that only 14 % of ethnic Norwegians living in the Oslo area had 25-OH-D concentration below 50 nmol/L (58). In another Norwegian general population-based study (The HUNT study) the overall prevalence of vitamin D deficiency was 40 % (64). The HUNT study may, to a certain extent, overestimate prevalence of vitamin D deficiency in the general population, because participants were living at higher latitudes with only a minority taking dietary supplements of vitamin D. Worldwide prevalence of severe vitamin D deficiency (25- OH-D < 25 nmol/L) has been reported in > 20 % of the population also in countries at latitudes closer to the equator, such as Tunisia, Pakistan, India and Afghanistan (54, 63).
1.2.7 Risk factors for vitamin D deficiency
Vitamin D deficiency is a global health problem. The main risk factors are low sun exposure related to geographical latitude, use of clothes covering the body and lifestyle. The older population is especially at risk both due to spending less time outside, lower production of vitamin D in the skin and reduced hydroxylation into 1,25-OH-D in the kidneys. Children and young adults are also potentially at risk, especially among big city dwellers and the non-white population (27, 54). Specific categories of patients with different chronic diseases and failure
in organs involved in the vitamin D metabolism and people using certain medications are also at increased risk as shown in Table 1.
Table 1 – Risk groups for vitamin D deficiency
Epidemiology Higher geographical latitude, older age, increased skin pigmentation, air pollution, sun avoidance or little time spent outdoors, use of sunscreen Chronic diseases Kidney failure, heart disease, chronic liver disease, autoimmune
disorders, organ transplant recipients, obesity, malabsorption, cancer Surgery Small bowel resection, gastrostomy, bariatric surgery
Medications Glucocorticoids, antiepileptic drugs, cholestyramine, antiretroviral, antifungal, rifampicin
1.2.8 Vitamin D and health outcomes
It is well known that Vitamin D deficiency in adults can precipitate or exacerbate osteopenia and osteoporosis, cause osteomalacia and muscle weakness, and increase the risk of fracture (27). Additionally, research suggests that vitamin D play an important role in decreasing the risk of many chronic illnesses, including several autoimmune diseases, infectious diseases, and cardiovascular disease (27). Similarly, critically ill patients have a high prevalence of vitamin D deficiency associated with poorer outcomes (65). Several studies have even demonstrated a role of vitamin D reducing the risk of acute viral respiratory infections and pneumonia, but so far, a protective role of vitamin D against severe covid-19 infection has not been established (66). In epidemiological studies vitamin D deficiency has also been
associated with increased risk of all-cause mortality (54).
Vitamin D deficiency and a possible association with risk of different malignancies have also been suggested. Most data are from observational studies, and no causal relationship has been firmly established (54). In 2014 two meta-analyses showed no significant decrease in the incidence of cancer but revealed a lower all-cause mortality and a lower cancer-related mortality in patients who received vitamin D supplementation (67-69). Vitamin D deficiency has, however, been associated with increased risk of colorectal cancer in patients with IBD (70).
1.2.9 Vitamin D and autoimmunity
The immune system functions as the body’s defense against anything not recognized as belonging to ourselves, including pathogenic microorganisms, but sometimes a response is also generated against our own cells. This failure of self-recognition by the immune system, resulting in an attack on our own body, is called autoimmunity. In the last decades, vitamin D has been recognized as an important factor in the regulation of both innate and adaptive immunity, and thus may have a modulatory role in autoimmune diseases such as IBD (71). In animal models it has been shown that vitamin D may affect the inflammatory response through effects on the intestinal barrier, antigen-presenting cells and adaptive T-cells (25, 27, 72, 73).
Vitamin D has been shown to play a role in the defense against bacteria by inducing the production of cathelicidin, an antimicrobial peptide, in macrophages, but also in the intestinal epithelium. It has been suggested that this may affect the interplay between the microbiota and the epithelium in IBD, as well as the previously established effect against mycobacterial infection (27, 74, 75).
Adaptive immune responses may be modulated by vitamin D via several mechanisms, and this may attenuate an over-activation of the inflammatory response seen in autoimmunity.
Dendritic cells present antigens to T cells and thus links the innate and adaptive immune system (3). Following stimulation by vitamin D, dendritic cells have a reduced response to bacterial antigens, and thus the activation of T-cells is inhibited (76). Additionally, the inflammatory response is inhibited by 1,25-OH-D binding the VDR on dendritic cells, shifting the cytokine production to an anti-inflammatory state favoring Th2 lymphocyte development over the Th1 lymphocyte pathway (71). It has been shown that in addition to T- cell regulation, anti-inflammatory cytokines are increased by vitamin D in IBD patients (77).
Finally, it has been demonstrated in patients with UC that high levels of vitamin D are associated with a favorable anti-inflammatory to pro-inflammatory cytokine ratio, and that this translates into increased presence of mucosal healing and even a decreased risk of clinical relapse (78).
As the current recommendations on vitamin D thresholds are based on bone health, they
may not properly address the risks for patients with inflammatory diseases such as IBD.
Circulating 25-OH-D may serve as a substrate for both renal and non-renal conversion to 1,25-OH-D, and the serum concentration of 25-OH-D may not always reflect the optimal level for physiological processes at tissue level (71). It has been suggested, however, that higher levels than 75 nmol/L are necessary for immune-mediated effects. At this level the maximal suppression of PTH is reached resulting in suppression of the renal hydroxylation of 25-OH-D into the active 1,25-OH-D, and extra-renal conversion may be stimulated
potentiating effects at tissue level (79). This remains a controversial issue, and no consensus exists, underlining the limitation of using cut-off points established from bone health to determine the optimal level for patients with IBD.
1.3 Vitamin D deficiency and IBD
The knowledge that vitamin D may attenuate inflammation and have distinct immunological functions, has initiated a tremendous interest in the role of vitamin D in the epidemiology and clinical course of IBD. It is well known that the incidence of IBD increases with higher latitude, and that both UC and CD are diagnosed more frequently during the winter months (20, 23, 24). In a French study, low exposure to sunlight has been shown to be a risk factor for developing IBD (21). A causal relationship cannot readily be assumed, as the association between vitamin D level and sun exposure on one hand and the incidence of IBD on the other is likely to be confounded by several factors.
Vitamin D deficiency is common in IBD, occurring more frequently than in the general population (80-83). Prevalence rates of vitamin D deficiency in IBD range from 16% to 95 % and is more common in CD than in UC (80-85). In Norway, severe vitamin D deficiency (25- OH-D < 30 nmol/L) has been shown to be prevalent in patients with CD (86). In patients with IBD, the factors that are likely to contribute to vitamin D deficiency include malabsorption secondary to mucosal disease and prior surgical resection (25, 85, 86). Furthermore, factors such as reduced sunlight exposure, insufficient physical activity, smoking, medications and reduced vitamin D intake in the diet may contribute to this condition in IBD patients (21, 25, 48, 85, 87).
It is known from earlier research that patients with IBD have an increased risk of osteopenia and osteoporosis mainly due to steroid use (86, 88). Immune activity may also directly enhance bone turnover and reduce bone mass density (86, 89). In this context vitamin D provides an important and maybe underutilized pathway to preserving bone health in IBD (86).
Vitamin D deficiency has been shown to increase the risk for colitis in animal models (48, 85). More recent studies support that vitamin D may affect mucosal immunity by modulating the interaction between microbiota and the intestinal epithelium (74, 75). In several clinical observational and cross-sectional studies, vitamin D deficiency has been associated with increased IBD disease activity (71, 85).
In IBD, vitamin D deficiency has been associated with disease activity in several studies, as shown in Table 2. In CD, several studies suggest that low 25-OH-D is associated with active disease (70, 73, 80, 90-94), whereas others do not support this hypothesis (95, 96). In UC, the results are more conflicting. Some studies have shown an inverse association with vitamin D level and disease activity (94, 97, 98), but in other studies such an association has not been shown (80, 96).
In only a few studies, the relationship between vitamin D deficiency and objective markers of inflammation have been studied. In CD an association between vitamin D deficiency and increased C-reactive protein (CRP), a systemic marker of inflammation, has been shown (73, 93). An association between fecal calprotectin, an intestinal marker of inflammation, has been shown in both UC and CD (92). In a large American study, however, neither increased CRP nor increased fecal calprotectin were associated with vitamin D deficiency (94).
Regarding clinical outcomes such as increased need for surgery, radiological examinations and hospitalization has been shown in IBD patients with inadequate vitamin D concentrations (85, 99). Furthermore, studies have shown that both UC- and CD patients treated with anti- TNF medication have increased rates of remission and longer drug survival time if vitamin D levels are normal (100, 101). Vitamin D deficiency has also been associated with impaired health-related quality of life in patients with IBD (25, 80, 102).
Table 2. Association between vitamin D deficiency and disease activity in IBD First author Year Cohort Disease activity Other outcomes
Joseph 2009 CD 34 Disease activity
(HBI)
Jørgensen 2010 CD 94 Trend towards lower
relapse rate
Ulitsky 2011 UC 101
CD 403
Disease activity in CD (HBI)
No association in UC (SCCAI)
Kelly 2011 CD 75 No association to
disease activity
Hassan 2013 UC 34
CD 26
No association with disease activity Ananthakrishnan 2013 1454 UC
1763 CD
Associated to risk of surgery and
hospitalization Jørgensen 2013 CD 182 Disease activity
(HBI) and CRP
Garg 2013 UC 31
CD 40
Fecal calprotectin in UC and CD
No association to CRP in either UC or CD Blanck 2013 UC 34 Disease activity
(6-point Mayo)
Raftery 2015 CD 119 Associated with
increased CRP No association with increased CDAI
Dolatshahi 2016 UC 50 Disease activity (Truelove & Witts)
Kabbani 2016 UC 368
CD 597
Disease activity (HBI, UCAI)
Associated to surgery, hospitalization and medication use Gubatan 2017 UC 70 Reduced relapse rate
Abbreviations: IBD; inflammatory bowel disease, UC; ulcerative colitis, CD; Crohn’s disease, HBI; Harvey Bradshaw index, SCCAI; Simple clinical colitis activity index, CDAI; Crohn’s disease activity index, UCAI; Ulcerative colitis activity index, CRP; C-reactive protein.
1.3.1 Effects of Vitamin D supplementation in IBD
No established recommendation on vitamin D supplementation exists specifically for IBD patients as neither recommended thresholds, nor potential beneficial effects have been firmly established. The Norwegian Directorate of Health (2018) recommends a daily intake of at least 10 micrograms (400 IU) of vitamin D for adults and 20 micrograms (800 IU) for the older population above 75 years. The recommendation is based on the estimated need for keeping the concentration of 25-OH-D above 50 nmol/L and thus ensuring good bone health.
A majority will not meet the requirements without taking supplements, and in Norway there is a general recommendation of taking supplements or liver cod oil in the winter months. In the summer, exposure to sunlight 3-6 min (arms. legs, face) equals a dose of 400 IU (42). In chronic diseases as well as in older age, higher doses may be needed, but so far general recommendations do not support high-dose supplementation (above 800 IU per day).
Only a few studies have investigated vitamin D as a therapeutic agent in IBD. Several of these studies suggest that vitamin D supplementation may reduce inflammatory markers in IBD. A Danish randomized controlled study of 94 patients demonstrated a reduction in CRP among patients with CD receiving 1200 IE of vitamin D daily (91). With use of a high dose of vitamin D3, 300.000 IU given once as an injection in another study, the level of serum CRP was significantly reduced also in UC patients in clinical remission on otherwise stable
maintenance treatments (103). On clinical outcomes beyond disease activity scores, one study has shown longer lasting response of biologicals with adjuvant vitamin D supplementation (100). In the Danish interventional study mentioned above, a trend towards lower relapse rates with supplementation of vitamin D was seen, but the finding was not statistically significant (91).
Several interventional studies add to the debate of which 25-OH-D concentration should be recommended for IBD patients to achieve health outcomes beyond bone health. Interestingly, an Irish pilot study concluded that patients treated with high-dose supplementation (2000 IU daily) who also achieved a 25-OH-D concentration > 75 nmol/l, had significantly lower CRP than those with concentrations below this threshold. A more targeted approach was attempted in a small study of 10 IBD patients receiving high doses (in most patients up to 10000 IU per day over 4 weeks) aiming to reach 25-OH-D concentrations 100-126 nmol/L with a
significant improvement of clinical disease activity scores (104). Supplementation of vitamin
D in low doses probably has no pronounced anti-inflammatory effects in IBD patients. This is supported by findings in a Slovakian cross-sectional study of 220 IBD patients (102).
In the mentioned studies, however, the patients were not uniformly vitamin D deficient at baseline. The effects in vitamin D deficient patients may be more pronounced, and further studies are needed to evaluate this. Potential negative effects of vitamin D also need to be addressed, as supplemental intake of doses above 4000 IU per day over time may increase risk of poorer health outcomes in some populations (71). Vitamin D toxicity, however, is very rare, but can be caused by ingestion of excessively high doses. Doses of more than 50.000 IU per day is needed to raise the 25-OH-D concentration to 374 nmol/L associated with
hypercalcemia and hyperphosphatemia, but in general concentrations above 125 nmol/L are not recommended (58, 105).
Further studies are needed before the general recommendations may be revised, although several key opinion leaders tend to recommend higher target thresholds and high-dose supplementation in IBD patients who have insufficient levels of vitamin D.
1.4 Patient Reported Outcomes (PRO)
Patient reported outcomes (PROs) are any health status report coming directly from the patient, without interpretation by a clinician or others (US, FDA 2009). A series of outcomes may originate directly from the patients, such as symptoms, daily function, health-related quality of life, fatigue, pain, disease-related worries and adherence to treatments. The outcome can be measured as severity of a symptom, state of the disease or change from a previous assessment.
The relevance of the different outcomes depends on the situation in which they are collected and for what purpose. The use of PROs may draw attention to aspects of the disease or treatment previously not recognized (106). In clinical studies, use of PROs may also demonstrate effects beyond the most commonly used endpoints and markers (107).
The goal of PRO measurement is to quantify qualitative information. PRO instruments or Patient reported outcome measures (PROMs) have traditionally been paper-based self- administered questionnaires, but currently digital or internet-based solutions are increasingly
used. The development of a questionnaire is commonly based on qualitative methods such as explorative interviews and focus groups. A questionnaire can consist of a single question or item, but PROMs are very often multi-dimensional questionnaires developed to measure complex concepts that often include both physical, psychological, social and emotional aspects of life in relation to a disease (106).
Questionnaires can be generic or disease specific. Generic instruments focus on broad aspects of health status and may be used in general populations and across a wide range of diseases.
Disease specific questionnaires are developed to detect aspects important for a certain disease, and contain items reflecting issues considered important by patients in that particular disease (107).
PROMs need to comply with certain criteria to be useful in clinical research, namely validity, reliability, sensitivity and responsiveness. Validity means that the questionnaire measures what it is intended to measure, avoiding bias. A reliable test is consistent, repeatable and reproducible over time. This means that if the patient’s condition is stable over time, a PROM should maintain very similar scores on each measured occasion. Sensitivity means the ability of a test to correctly identify cases, for example to discriminate between high and low burden of a certain outcome. Responsiveness describes the ability of the test to detect a relevant change that has occurred in the follow-up of a patient (106).
In clinical research, a PRO should be obtained from a validated questionnaire (106). The reliability and validity in the target patient group needs to be considered when choosing a questionnaire for a particular study, and prior use in a similar patient demographic is highly relevant. The optimal choice is a questionnaire that has already been validated in the disease under study (107).
In order to be used in different languages, setting and cultures, questionnaires need to be translated, linguistically and psychometrically validated before being used in either clinical studies- or practice. The translation process should follow a set of rules to ensure that the translated questionnaire is in all ways equivalent to the original (106). In short, translation should involve a two-stage process with translation, for example from English into
Norwegian, by at least two native speakers, followed by a back-translation into the original language. A native speaker of the original language who is unfamiliar with the original
questionnaire should perform the back-translation. This process may have to be repeated until there are no discrepancies in content and meaning between the original and translated version.
Following the translation process, a validation study in patients should be performed (108).
Measuring PROs may be confounded by various sources of bias, as summarized in Table 3.
With self-report bias we understand the deviation between the self-reported and true values of the same measure. Bias represent a measurement error that may be random or systematic, and may be constant or varying (109). In observational studies, it is in general not possible to quantify the overall bias, and the various causes of bias may be difficult to separate (106).
Table 3 – Biased reporting and response shift
Recall bias Ability to validly recall the information requested
Selective reporting bias Not reporting problems considered to be unrelated to the illness Response acquiescence Tendency to give positive and pleasing responses
Social desirability Tendency to give the considered socially desirable answer Response shift Subjective change in perception over time
In clinical studies, biased reporting and response shift may result in measurement bias. Indeed, in clinical practice positive response shift may even be encouraged, as an effort is often made to help patients with coping mechanisms and adapting to their illness. In an observational study in patients with chronic disease, this should be taken into consideration when interpreting results. In a randomized trial, biased reporting may be argued to occur equally across the randomized groups, and an assessment bias may be of less importance (106).
In IBD, several PROMs have been developed seeking to cover domains and concepts resulting from consequenses of a chronic disease and their impact on the patients’ health- related quality of life, including fatigue and pain.
1.5 Fatigue
Fatigue in chronic diseases may be described as a persistent and pervasive sense of tiredness, weakness or exhaustion resulting in a reduced capacity for physical or mental work that is typically not relieved by adequate rest or sleep (110-112). In a sense fatigue may be a normal state existing as a protective mechanism intervening where optimal performance is no longer
feasible, for example following hard work or acute systemic illness such as infections. In patients with chronic diseases, however, fatigue more often presents itself as a pathological condition.
Understanding fatigue as a multidimensional construct is meaningful, and there are different aspects of fatigue that are potentially separable components and parts of a syndrome (113).
Consequently, fatigue may be divided into physical fatigue and cognitive or mental fatigue (114). Physical fatigue may be defined subjectively by patients as the difficulty of completing or initiating a manual task, and objectively as a measurable decrease in performance. Mental fatigue may be described subjectively as clouding of thought or difficulty concentrating, and objectively measured as decreased cognitive performance. Chronic fatigue has been defined as substantial fatigue persisting for six months or more (115).
Patients with fatigue describe an overwhelming feeling of tiredness, reduced energy levels, reduced muscle strength and cognitive impairment. This supports a multidimensional approach to understanding fatigue, and this is reflected in the questionnaires developed for fatigue (114, 116-118). Fatigue has a physical, as well as a cognitive and affective dimension.
Patients may exhibit one or a combination of these different aspects, and questionnaires measuring the physical as well as the cognitive and affective dimensions of fatigue may be more relevant when assessment of fatigue is performed (114). When deciding which
measurement tool to use for investigating fatigue in chronic disease, consensus is lacking, but it may be preferable to choose a multidimensional scale that has been validated in various diseases and has been shown to be responsive to change after therapeutic intervention (6, 114).
In IBD, the inflammatory bowel disease fatigue (IBD-F) patient self-assessment scale was developed by Czuber-Dochan et.al in 2014, specifically for patients with IBD (119). Most questionnaires, however, are generic as fatigue may largely be explained by transdiagnostic factors (120). The Functional assessment of chronic illness therapy fatigue scale (FACIT-F) has been validated, also in patients with IBD (121). The Fatigue questionnaire (FQ) has been translated into Norwegian and psychometrically tested in IBD patients (122, 123). The Fatigue impact score (FIS) and VAS-F are also both validated, but not in populations with IBD (124, 125). Moreover, the SF-36 have been validated in Norwegian in patients with IBD, and the vitality sub score may be used to measure fatigue in IBD patients (126). This is,
however, a multi-symptom scale not specifically designed to measure fatigue. The most frequently used measurement tools in IBD and their properties are summarized in Table 4.
Table 4. Most frequently used measurement tools in fatigue in IBD Multi-symptom scales
SF-36 Multi-symptom scale for measurement of HRQoL, the vitality sub score may be used to measure fatigue, translated version validated in IBD patients (Bernklev, 2005)
Fatigue specific scales
FACIT-F Developed in cancer patients, validated in IBD and healthy populations (Tinsley, 2011)
FSS Translated and validated in Norwegian
VAS-F Developed to measure fatigue severity, validated (Lee, 1991), and translated into Norwegian
FQ Validated in Norwegian also in IBD, reference data from a Norwegian background population (Loge, 1998)
MFI-20 Validated (Smets, 1995), translated into Norwegian, not validated in IBD, applied in cancer and chronic liver disease FIS Developed in chronic fatigue syndrome, later validated also in
gastrointestinal diseases (Lundgren-Nilsson, 2019) IBD-F Developed in IBD and validated (Czuber-Dochan, 2014) Abbreviations: SF-36; Short Form 36, HRQoL; Health-related quality of life, FACIT-F;
Functional assessement of chronic illness therapy fatigue scale FSS; Fatigue severity scale, VAS-F; Visual analogue scale - Fatigue, MFI-20; Multidimensional fatigue inventory, FIS;
Fatigue impact scale, IBD-F; Inflammatory bowel disease fatigue, FQ; The fatigue Questionnaire, IBD; Inflammatory bowel disease
1.5.1 Fatigue in IBD
Fatigue is common in IBD, with a prevalence of 44-86% in active disease and 22-41% in remission (114, 116, 127). Furthermore, there is increasing evidence that fatigue is reported more frequently in IBD than in the background population, as well as negatively associated with health-related quality of life (HRQoL) (6, 114, 116, 128, 129). Patients with IBD often report fatigue as one of their most troublesome symptoms (130).
In patients with IBD, some studies have shown that fatigue is more commonly reported in female IBD patients (116, 127, 129, 131), while in other studies gender has not been shown to have an impact on fatigue (6, 132). In a study of fatigue in newly diagnosed and untreated patients with IBD, fatigue was more prevalent in younger patients (133). Furthermore, fatigue has been shown to be associated with daily smoking in patients with CD (6).
Fatigue is more commonly reported in active disease in IBD, as well as in other inflammatory disorders (114, 134-137). Severity of symptoms, however, may not always reflect active inflammation, and only in a few studies the association between fatigue and objective markers of inflammation has been evaluated (130, 133, 138). Nevertheless, fatigue often persists after the patient has achieved clinical remission without objective signs of active inflammation.
Also it is often resistant to treatment escalation. These observations indicate that fatigue is not only a symptom related to inflammation, and that the total burden of clinical disease activity may contribute to the experience of fatigue (114). Indeed, a Swedish study on fatigue in gastrointestinal disorders have interestingly reported that patients with functional
gastrointestinal disorders have more severe fatigue than patients with organic gastrointestinal diseases (139). The same study group has shown that fatigue severity is associated with a higher symptom burden in patients with irritable bowel syndrome (IBS) (140). Also in patients with IBD in clinical remission, fatigue seems to be more common in patients with coexisting IBS-like symptoms (141).
Duration of disease may influence the reporting of fatigue, but in a Norwegian cohort of IBD patients, the prevalence of fatigue was significantly higher in patients with active disease than in those with quiescent disease 20 years after being diagnosed. Patients in clinical remission, however, did not report more fatigue than in the background population (127). This may represent a resolution of fatigue over time, but disease duration may also result in under- reporting, as patients may get used to living with fatigue symptoms over time (response shift).
Other factors that have consistently been associated with fatigue are depressive symptoms, also in patients with IBD (127, 129, 131, 133). This may be partly explained by an overlap of symptoms between these conditions. Furthermore, perceived psychological stress seems to be associated with the presence of fatigue (142). Fatigue, however, is often seen in patients with no psychological comorbidity (143). It has therefore been argued that fatigue and depression
represents separate conditions, even if fatigue has been shown to predict the onset of depression (144).
Sleep disturbance has been shown to be of importance in the perception of fatigue in IBD (127, 145), and it has recently been shown that nocturnal diarrhoea is asscociated with fatigue levels in IBD (129). Furthermore, sleep disturbance is common in IBD as well as in other inflammatory conditions (146, 147). There is also some evidence that sleep deprivation may increase inflammatory activity, but this has not been studied in patients with IBD (148). Poor sleep has, however, been linked to increased burden of symptoms in IBD (147).
Lack of evidence to support management of fatigue in IBD contributes to the fact that these symptoms are largely being overlooked by healthcare professionals. Moreover, a gap in health care providers knowledge and understanding of the complexity of fatigue in IBD and the impact the condition has on people’s lives has been demonstrated (134). Investigating unexplored pathways of such troublesome symptoms is therefore still needed, both from a clinical and scientific point of view. A recent Cochrane review from 2020 concludes that the effects of interventions for the management of fatigue in IBD are uncertain. The evidence suggests that electroacupuncture may result in a reduction of fatigue, but the data to support this treatment is sparse. Furthermore, the effects of cognitive behavioral therapy and solution- focused therapy are unclear as the quality of the evidence is low. Biologicals may reduce fatigue, but this effect has been shown only in patients already known to respond to the treatment with reduction in disease activity (149).
In a recent study, however, a beneficial effect of high-dose oral thiamine on chronic fatigue in IBD was shown (150). In IBD, anemia has been associated with fatigue, but an association between iron deficiency and fatigue has not been established in patients without anemia (116, 128, 151, 152). Intravenous iron replacement has, however, been shown to improve fatigue scores in IBD patients with iron deficiency with or without anemia at baseline (153). It is of interest to note that recent data indicate that vitamin D improves iron absorption through a downregulation of hepcidin, possibly rendering higher levels of iron available for the synthesis of hemoglobin (154, 155). Furthermore, vitamin B12, selenium, zinc and
magnesium have all been associated with fatigue in several other conditions (114). Such data supports correction of micronutrient deficiencies also in IBD patients reporting fatigue.
1.5.2 Vitamin D and fatigue
Vitamin D deficiency has been associated with muscle weakness which is known to be one of the main symptoms of fatigue (27). We know that skeletal muscles express the VDR and may require Vitamin D for optimal function (27). For this reason, there has been an interest in the potential effect of vitamin D in reduction of the physical dimension of fatigue. It has been shown that low levels of vitamin D have been associated with fatigue in patients with cancer (156). Furthermore, vitamin D supplementation has shown improvement of fatigue scores in patients with cancer and other chronic inflammatory diseases (157-159). In a 2018 Cohrane review it was concluded, however, that the effects of vitamin D on fatigue and HRQoL in patients with multiple sclerosis are unclear, as only small studies have been conducted (160).
1.6 Pain
According to the International association for the study of pain (IASP), pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue
damage or described in terms of such damage. In normal circumstances acute pain alerts us to avoid or minimize injury and triggers protective responses. Chronic pain, on the other hand, may affect physical and psychological health and have detrimental effects on our well-being (161).
Pain is a subjective experience with combined sensory, emotional and cognitive components.
Nociception is the term used to describe the neurological events involved in the processing of stimuli ultimately leading to a conscious awareness of pain. When nociceptors on afferent sensory neurons are exposed to potential damaging stimuli, the signals are led from the peripheral nerves to the spinal cord and the brain (162). Nociceptors characteristically have a high threshold for activation but may be sensitized for example by inflammation (163, 164).
No single area of the brain is responsible for the experience of pain, and several areas are known to be involved in the perception, attention, learning, emotional and autonomic responses that produces the experience of pain (161). Furthermore, descending neurological pathways modulates the nociceptive transmission in a complex interplay of mechanisms (165).
This complexity of the transmission and interpretation of pain makes it difficult to measure and quantify. Additionally, pathological pain may be present in chronic disease. Pathological pain has no biological benefit, and may arise even from stimuli that normally do not provoke pain (166). This may be caused by damage to the nervous system, inflammation or even without any evident explanation. Such pain is dysfunctional and may be a cause of disability and considerable distress for patients. Because of this highly subjective nature of pain, self- reporting of pain provides the most valid instrument to measure the experience of pain.
1.6.1 Pain in IBD
In IBD, abdominal pain is frequently reported, and may be caused by gut distension, obstruction and inflammation (164). Inflammatory sensory pathways become sensitized during active inflammation, and this may lead to a persistent change in the experience of pain (164). However, abdominal pain certainly may be evident even without active inflammation.
In this regard, the high prevalence of symptoms of irritable bowel disease in patients with IBD may be of importance, since pain is a hallmark among these symptoms (164, 167, 168).
In UC, such symptoms have been shown to be as common in remission as in active
inflammation (169). Furthermore, an American study on abdominal pain in patients with UC also concluded that many patients report abdominal pain in the absence of active
inflammation (170).
Many patients with IBD are also troubled by extra intestinal manifestations that may be associated with pain, such as arthralgia, skin lesions, oral aphthous lesions and bone disease (171, 172). Lower back pain and other musculoskeletal pain is also commonly reported, and do not always correspond to disease activity (173). Abdominal pain, joint pain and lower back pain have all been associated with reduced health-related quality of life in IBD (7).
Modulating factors, including different psychological factors, may significantly contribute to the clinical manifestation and severity of pain (174-176). Moreover, emotional problems and inadequate coping mechanisms have been associated with development of chronic pain syndromes (164).
1.6.2 Vitamin D and pain
Vitamin D deficiency is known to cause musculoskeletal pain in other conditions, e.g., osteomalacia (27). Furthermore, a Norwegian study from a multi-ethnic general practice population, found that vitamin D deficiency was associated with more severe pain in patients with a primary complaint of either headache or musculoskeletal pain (177). Moreover, vitamin D has been reported to inhibit mediators of pain in other inflammatory diseases (178, 179). These findings may suggest a role of vitamin D deficiency in the experience of pain.
1.7 The rationale behind the Vitality Study
Prior to the Vitality study, several studies had shown that vitamin D deficiency was common in patients with IBD. The reported prevalence rates varied extensively according to study population and disease activity. Prior to the Vitality study, the knowledge of vitamin D status in patients with IBD in Norway was limited. There were no previous studies investigating vitamin D and its potential effect on health outcomes such as fatigue and pain in IBD patients.
Vitamin D deficiency had, however, been shown to be associated with fatigue in other conditions. Vitamin D deficiency has been linked with muscle weakness, one of the main symptoms of fatigue. Thus, vitamin D may be an important factor to consider in physical fatigue. Other mechanisms are also possible, through loss of local effects in the brain, which may play a role in cognitive functioning and thus result in cognitive fatigue. Fatigue may be confounded by depression as there is an overlap of symptoms between the two conditions.
Thus, there was a need for studies that could adjust for depressive symptoms in analyses of the potential relationship between fatigue and vitamin D.
Vitamin D deficiency had been shown to be associated with muscle - and skeletal pain. Pain is common in IBD, and a role of vitamin D in chronic pain had been suggested. In other
inflammatory diseases, Vitamin D was reported to inhibit mediators of pain. Thus, a
heightened sensitivity to pain with insufficient levels of vitamin D could not be ruled out, and this potential link had not been studied in IBD patients.
The Vitality study was not designed to investigate a specific hypothesis, but rather as an explorative, hypothesis generating study. In this thesis, based on data from the Vitality study, however, we hypothesized that vitamin D deficiency is prevalent in IBD, associated with disease activity, fatigue and severity of pain in patients with IBD.
2.0 Thesis aims
To determine the prevalence of vitamin D deficiency in IBD
To investigate possible clinical predictors for vitamin D deficiency in UC and CD
To investigate associations between vitamin D deficiency fatigue and pain in IBD patients
3.0 Materials and methods
3.1 Study design and recruitment
Patients were recruited from nine hospitals in the southeastern and western part of Norway as part of an observational, multicenter study (the Vitality study). The design of the study was mainly cross-sectional, but a longitudinal component was specifically used for validation and testing of some of the included PROMs. This thesis, as well as the three separate scientific articles, however, are based solely on cross-sectional data.
Inclusion criteria were: age ≥ 18 years, a verified diagnosis of IBD based on endoscopic, biochemical and histological findings according to the Lennard-Jones criteria (180), ability to read and understand Norwegian language and to give written informed consent. The inclusion period lasted from March 2013 to April 2014. At each of the included centers, a senior
gastroenterologist was responsible for the study. Random sampling was implemented.
Patients were included consecutively at the outpatient clinics, regardless of treatment given.
3.2 Data collection
Data were collected by interviews, from medical records, laboratory tests and questionnaires.
3.2.1 Clinical and sociodemographic variables
The clinical and sociodemographic variables obtained in the Vitality study are summarized in Table 5. In this thesis, only the data used in the study of vitamin D are further explored.
Table 5. Sociodemographic and clinical variables
Sociodemographic variables Clinical data
Age Diagnosis
Gender Disease duration
Height Relapses last year
Weight UC extenta
Relationship status CD localizationa
Education CD behaviora
Employment status Perianal diseasea
Work disability Prior intra-abdominal surgery
Smoking status Current use of medication
Dietary assessment Vitamin D supplementation
Physical activity Comorbidities
Abbreviations: UC; ulcerative colitis, CD; Crohns’s disease, aMontreal classification
3.2.2 Laboratory tests
Serum 25-OH-D from all patients was analyzed by one central accredited laboratory with liquid chromatography tandem mass spectrometry (LC-MS/MS). Vitamin D deficiency was defined as 25-OH-D concentration < 50 nmol/L, and vitamin D insufficiency was defined as a 25-OH-D concentration of 50-75 nmol/L (27). This is consistent with the reference range reported by most Norwegian clinical biochemical laboratories, and at the time the study was performed the most relevant cut-off. All vitamin D analyses were performed at the Hormone laboratory (Department of Medical Biochemistry, Oslo University Hospital, Norway).
Other biochemical analyses were performed at the local laboratories at the participating centers. C-reactive protein (CRP) levels of 5 mg/L or higher were chosen to indicate active inflammation (181, 182).
The stool samples for the measurement of fecal calprotectin were sent by mail and analyzed centrally with Calpro Easy Extract (Calpro AS, Norway). Fecal calprotectin < 100 mg/kg was set as the cut-off for disease in remission, while higher levels were defined as active
inflammation, consistent with the method used for the analyses (183).
