Robyn M. Lucas

Sun exposure and vitamin D are independent risk factors for CNS demyelination

Objectives: To examine whether past and recent sun exposure and vitamin D status (serum 25-hydroxyvitamin D [25(OH)D] levels) are associated with risk of first demyelinating events (FDEs) and to evaluate the contribution of these factors to the latitudinal gradient in FDE incidence in Australia. Methods: This was a multicenter incident case-control study. Cases (n = 216) were aged 18–59 years with a FDE and resident within one of 4 Australian centers (from latitudes 27°S to 43°S), from November 1, 2003, to December 31, 2006. Controls (n = 395) were matched to cases on age, sex, and study region, without CNS demyelination. Exposures measured included self-reported sun exposure by life stage, objective measures of skin phenotype and actinic damage, and vitamin D status. Results: Higher levels of past, recent, and accumulated leisure-time sun exposure were each associated with reduced risk of FDE, e.g., accumulated leisure-time sun exposure (age 6 years to current), adjusted odds ratio (AOR) = 0.70 (95% confidence interval [CI] 0.53–0.94) for each ultraviolet (UV) dose increment of 1,000 kJ/m2 (range 508–6,397 kJ/m2). Higher actinic skin damage (AOR = 0.39 [95% CI 0.17–0.92], highest grade vs the lowest) and higher serum vitamin D status (AOR = 0.93 [95% CI 0.86–1.00] per 10 nmol/L increase in 25(OH)D) were independently associated with decreased FDE risk. Differences in leisure-time sun exposure, serum 25(OH)D level, and skin type additively accounted for a 32.4% increase in FDE incidence from the low to high latitude regions. Conclusions: Sun exposure and vitamin D status may have independent roles in the risk of CNS demyelination. Both will need to be evaluated in clinical trials for multiple sclerosis prevention.

The High Prevalence of Vitamin D Insufficiency across Australian Populations Is Only Partly Explained by Season and Latitude

Background Inadequate sun exposure and dietary vitamin D intake can result in vitamin D insufficiency. However, limited data are available on actual vitamin D status and predictors in healthy individuals in different regions and by season. Methods We compared vitamin D status [25-hydroxyvitamin D; 25(OH)D] in people < 60 years of age using data from cross-sectional studies of three regions across Australia: southeast Queensland (27°S; 167 females and 211 males), Geelong region (38°S; 561 females), and Tasmania (43°S; 432 females and 298 males). Results The prevalence of vitamin D insufficiency (≤ 50 nmol/L) in women in winter/spring was 40.5% in southeast Queensland, 37.4% in the Geelong region, and 67.3% in Tasmania. Season, simulated maximum daily duration of vitamin D synthesis, and vitamin D effective daily dose each explained around 14% of the variation in 25(OH)D. Although latitude explained only 3.9% of the variation, a decrease in average 25(OH)D of 1.0 (95% confidence interval, 0.7–1.3) nmol/L for every degree increase in latitude may be clinically relevant. In some months, we found a high insufficiency or even deficiency when sun exposure protection would be recommended on the basis of the simulated ultraviolet index. Conclusion Vitamin D insufficiency is common over a wide latitude range in Australia. Season appears to be more important than latitude, but both accounted for less than one-fifth of the variation in serum 25(OH)D levels, highlighting the importance of behavioral factors. Current sun exposure guidelines do not seem to fully prevent vitamin D insufficiency, and consideration should be given to their modification or to pursuing other means to achieve vitamin D adequacy.

UVR, Vitamin D and Three Autoimmune Diseases - Multiple Sclerosis, Type 1 Diabetes, Rheumatoid Arthritis

Abstract We review the evidence indicating a possible beneficial role for UVR on three Th1-mediated autoimmune diseases: multiple sclerosis, type 1 diabetes and rheumatoid arthritis in relation to recent developments in photoimmunology. Recent work suggests that UVR exposure may be one factor that can attenuate the autoimmune activity leading to these three diseases through several pathways involving UVB and UVA irradiation, UVR-derived vitamin D synthesis and other routes such as α-melanocyte-stimulating hormone, calcitonin gene related peptide and melatonin. Ecological features, particularly a gradient of increasing prevalence of multiple sclerosis and type 1 diabetes with higher latitude, provide some support for a beneficial role of UVR. Analytical studies provide additional support, particularly as low vitamin D has been prospectively associated with disease onset for all three diseases, but are not definitive. Randomized controlled trial data are required. Further, we discuss how associated genetic studies may assist the accumulation of evidence with regard to the possible causal role of low UVR exposure and/or low vitamin D status in the development of these diseases.

Estimating the global disease burden due to ultraviolet radiation exposure.

BACKGROUND WHOs global burden of disease studies, undertaken since 1996, apportion the total global disease burden, measured in disability-adjusted life years (DALYs), to specific diseases and injuries. Recent assessments of the relative burden due to specific environmental risk factors, plus an understanding of the nature of the risk factor, may guide resource allocation in risk factor management. We report here the global disease burden due to ultraviolet radiation (UVR) exposure. METHODS A systematic literature review identified nine diseases with sufficient evidence of a causal relationship with UVR exposure and for which the population attributable fraction (PAF) for UVR could be estimated. For cutaneous malignant melanoma and cataract, the PAF was directly applied to disease burdens already calculated by WHO. For seven other diseases, we developed population-level exposure-disease relationships and used these to calculate disease incidence and mortality, and thence disease burden. We also estimated the disease burden from rickets, osteomalacia and osteoporosis that might result if global UVR exposure was reduced to very low levels. RESULTS UVR exposure is a minor contributor to the worlds disease burden, causing an estimated annual loss of 1.6 million DALYs; i.e. 0.1% of the total global disease burden. A markedly larger annual disease burden, 3.3 billion DALYs, might result from reduction in global UVR exposure to very low levels. CONCLUSIONS Sun protection messages are important to prevent diseases of UVR exposure. However, without high dietary (or supplemental) intake of vitamin D, some sun exposure is essential to avoid diseases of vitamin D insufficiency.

Prevalence and concurrence of anxiety, depression and fatigue over time in multiple sclerosis

Background: Anxiety, depression and fatigue are commonly reported by persons with multiple sclerosis (PwMS). Objectives: We estimated the prevalence of each factor in a representative sample of PwMS, and in subgroups defined by age, sex and disease duration, at cohort entry and over time. We further examined whether and how these factors clustered together. Methods: A population-based longitudinal cohort of 198 PwMS was followed 6-monthly for 2.5 years. The Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety (cut-point >7) and depression (>7) and the Fatigue Severity Scale (FSS) to measure fatigue (≥5). Results: At cohort entry, prevalence of anxiety was 44.5% (95%CI 37–51%), depression 18.5% (95%CI 12.6–23.4%), and fatigue 53.7% (95%CI 47–61%). Fatigue was more common in males than females (RR 1.29, p=0.01), with attenuation of the effect after adjustment for Expanded Disability Status Scale (adjusted RR 1.18, p=0.13). Prevalence of anxiety (but not depression or fatigue) decreased by 8.1% per year of cohort observation (RR 0.92, 95%CI 0.86–0.98, p=0.009), with the effect more pronounced in women (14.6%, RR 0.85, 95%CI 0.79–0.93, –<0.001) than men (2.6%, RR 1.03, 95%CI 0.90–1.17, p=0.77). There was no apparent seasonal variation in the prevalence of any of the three factors (p>0.05). All three factors occurred contemporaneously at cohort entry in a higher proportion of the cohort than expected by chance (p<0.001). Conclusions: Anxiety, depression and fatigue are common in PwMS and tend to cluster together. The findings are important for clinical management of PwMS and to the exploration of possible shared causal biological pathways.

Variability in vitamin D assays impairs clinical assessment of vitamin D status

Background:  Measuring serum 25(OH)D concentration is common in clinical practice despite the questionable reliability of assays.

Association or causation: evaluating links between "environment and disease".

Epidemiological studies typically examine associations between an exposure variable and a health outcome. In assessing the causal nature of an observed association the “Bradford Hill criteria” have long provided a background framework — in the words of one of Bradford Hill’s closest colleagues an “aid to thought”. First published exactly 40 years ago these criteria also provided biomedical relevance to epidemiological research and quickly became a mainstay of epidemiological textbooks and data interpretation. Their checklist nature suited the study of simple direct causation by disciplines characterized by classic scientific and mathematical training. Most diseases have a multifactorial pathogenesis but the conceptualization of their causation varies by discipline. While it is scientifically satisfying to elucidate the many component causes of an illness in public health research the more important emphasis is on the discovery of necessary or sufficient causes that are amenable to intervention. Even so over the four decades since Bradford Hill’s paper appeared the range of multivariate multistage and multi-level research questions tackled by epidemiologists has evolved as have their statistical methods and their engagement in wider-ranging interdisciplinary research. Within that context it is often not appropriate to seek the discrete cause or causes of a disease but rather to identify a complex of interrelated and often interacting factors that influence the risk of disease. This complicates the assessment of causality. (excerpt)

Offspring number, pregnancy, and risk of a first clinical demyelinating event The AusImmune Study

Objective: To examine the association between past pregnancy, offspring number, and first clinical demyelination risk. Methods: Cases (n = 282) were aged 18–59 years with a first clinical diagnosis of CNS demyelination (first clinical demyelinating event [FCD]) and resident within 1 of 4 Australian centers (from latitudes 27° south to 43° south) from 2003 to 2006. Controls (n = 542) were matched to cases on age, sex, and study region, without first clinical diagnosis of CNS demyelination. Results: Higher offspring number was associated with FCD risk among women (p < 0.001) but not men (p = 0.71); difference in effect; p = 0.001. Among women, higher parity was associated with reduced risk of FCD (adjusted odds ratio 0.51 [95% confidence interval 0.36, 0.72] per birth) with a similar magnitude of effect observed among classic first demyelinating events (adjusted odds ratio 0.47 [95% confidence interval 0.29, 0.74]). The apparent beneficial effect of higher parity was also evident among parous women only (p < 0.001). Among cases, a clear female excess was evident for those with low but not high (4 or more) offspring number. Factors such as human leukocyte antigen DR15 genotype did not appear to modify the association between higher parity and a reduced FCD risk among women. Conclusions: These findings are consistent with a cumulative beneficial effect of pregnancy. Temporal changes toward an older maternal age of parturition and reduced offspring number may partly underlie the increasing female excess among MS cases over time.

Future health implications of prenatal and early-life vitamin D status

Current or recent low vitamin D status (or proxy measures such as dietary intake or ambient ultraviolet radiation) is linked to several chronic diseases, including osteoporosis, cancers, and cardiovascular and autoimmune diseases. Low prenatal vitamin D status may also increase susceptibility to such diseases in later life via specific target organ effects and/or through changes to the developing immune system. Maternal vitamin D supplementation during pregnancy could be an important public health measure to decrease risk of a range of chronic diseases, but further research is required to clarify beneficial and adverse effects of high prenatal vitamin D.

Vitamin D deficiency and pregnancy: from preconception to birth.

Vitamin D is important for bone health, as well as an increasing number of other health outcomes. Here we discuss the evidence relating to vitamin D in pregnancy, from preconception to the perinatal period. During pregnancy extra calcium required for fetal skeletal growth is attained by both maternal bone resorption and increased absorption from dietary sources, necessitating increased maternal vitamin D. Many women have low vitamin D status during pregnancy and may require supplementation, although optimal serum levels and intake required to achieve those levels is not yet well defined. Evidence from animal studies, with some supportive human evidence, suggests that fertility may be impaired in mothers with low vitamin D. During pregnancy, maintaining vitamin D and calcium levels may decrease the risks of pre-eclampsia, while gestational diabetes mellitus appears to be more common in those with low vitamin D status, although there is insufficient evidence of causality. The evidence in relation to increased risks of bacterial vaginosis and caesarean section similarly requires confirmation in carefully designed observational and experimental studies. This review outlines the emerging evidence that maternal vitamin D status during pregnancy is important for the health of the mother and offspring across a range of possible health outcomes.