Secondary hyperparathyroidism: Predictors and relationship with vitamin D status, bone turnover markers and bone mineral density.

INTRODUCTION: Secondary hyperparathyroidism (SHPT) has adverse implications for bone health but is relatively understudied. In this study we examine the prevalence and determinants of SHPT and describe the relationship of SHPT with bone turnover markers and bone mineral density (BMD) in older Irish adults. METHOD: Eligible participants (n = 4139) were identified from the Trinity-Ulster-Department of Agriculture (TUDA) study, a cohort of Irish adults aged ≥60 years. Exclusion criteria included an estimated glomerular filtration rate (eGFR) <30 ml/min and serum calcium >2.5 mmol/l to remove hyperparathyroidism due to advanced chronic kidney disease (CKD) and primary hyperparathyroidism respectively. The relationship between SHPT and bone turnover markers and BMD (measured by densitometry) was examined in a subsample (n = 1488). Vitamin D deficiency was defined as 25-hydroxyvitamin D [25 (OH)D] <30 nmol/l. RESULTS: Participants had a mean age of 73.6 ± 7.9 years, 65.1 % were female and 19.4 % were found to be vitamin D deficient. The prevalence of SHPT decreased as vitamin D increased, from 30.6 % in those deficient to 9.8 % in those with 25(OH)D ≥ 50 nmol/l and increased with declining kidney function. In non­calcium supplement users, principal determinants of SHPT were vitamin D deficiency (OR 4.18, CI 3.05-5.73, p < 0.001), eGFR 30-44 ml/min (OR 3.69, CI 2.44-5.57, p < 0.001), loop diuretic use (OR 3.52, CI 2.59-4.79, p < 0.001) and to a lesser extent body mass index (p = 0.001), eGFR 45-59 ml/min (p < 0.001) and 25(OH)D level 30-49 nmol/l (p = 0.002). Similar findings were observed in calcium supplement users, though proton pump inhibitors were also associated with SHPT (OR 1.55, CI 1.08-2.22, p = 0.018) while vitamin D 30-49 nmol/l was not. In participants with SHPT versus those without, bone turnover markers were higher: bone alkaline phosphatase (p = 0.017) and tartrate-resistant acid phosphatase (p = 0.033), whilst there was lower BMD at the neck of femur (0.880 vs. 0.903 g/cm2, p = 0.033) and total hip (0.968 vs. 0.995 g/cm2, P = 0.017). DISCUSSION: The results show that up to one in six older Irish adults had SHPT and this was associated with lower BMD and higher concentrations of bone turnover markers. Both vitamin D deficiency and 25(OH)D level 30-49 nmol/l were important predictors of SHPT. Loop diuretics and PPIs may also increase the risk of SHPT, and their use may need to be carefully considered in this population. Further studies examining the potential impact of these factors on bone health in similar populations to our study sample are warranted.

Falsely elevated parathyroid hormone in a patient with osteoporosis: a case report and review.

BACKGROUND: Parathyroid hormone (PTH) measurements can be falsely elevated due to the hormone binding to other molecules (macro-PTH) or immunoassay interference with heterophile, human anti-animal or other antibodies. This is rare but could lead to incorrect diagnosis, unnecessary investigations or avoidance of teriparatide treatment. We report a case of falsely high PTH levels due to assay interference and review the literature on cases of spuriously elevated PTH. CASE REPORT: An 87-year-old woman attending our bone health clinic with osteoporosis had persistently elevated PTH (383-784 pg/ml) using the Roche Cobas e801 immunoassay despite having normal serum calcium, phosphate, 25 hydroxyvitamin D (> 50 nmol/l) and eGFR (> 60 ml/min). To rule out falsely elevated PTH, a polyethylene glycol precipitation (PEG) test was performed which recovered less than 10% of the hormone resulting in a normal level. PTH was also tested on a different assay (Atellica Siemens) that identified a result of 27 pg/ml. The findings were consistent with immunoassay interference likely due to heterophile antibodies giving rise to a spuriously high PTH. DISCUSSION: The presence of unexpectedly high PTH levels should alert physicians to the possibility of false results due to assay interference or macro-PTH. This highlights the importance of clinically correlating results and of good communication with the testing laboratory. Here, we present the case of an 87-year-old woman with spuriously elevated PTH levels due to immunoassay interference likely mediated by heterophile antibodies. The presence of unexpectedly high PTH levels should prompt consideration of the possibility of false results due to assay interference or macro-PTH.

Vitamin D: determinants of status, indications for testing and knowledge in a convenience sample of Irish adults.

Vitamin D deficiency is common in Irish adults, though there is limited research on its determinants, knowledge of vitamin D or indications for testing. We aimed to explore the determinants of vitamin D status in adults and examine knowledge and reasons for testing. The study population comprised adults who had serum 25-hydroxyvitamin D tested by general practitioners request at a Dublin Hospital in 2020. Questionnaires detailing dietary intake, sun exposure, ethnicity, biophysical factors and vitamin D knowledge were sent to a sample stratified by age, sex and vitamin D status. In total, there were 383 participants, mean age 56·0 (sd 16·6) years. Wintertime deficiency disproportionally affected non-white v. white (60 % v. 24 %, P < 0·001). The greatest predictors of deficiency were low vitamin D intake (< 10 µg/d) (P < 0·001) and non-white ethnicity (P = 0·006), followed by sun avoidance (P = 0·022). It was also more prevalent in those with lower body exposure when outdoors. The majority (86 %) identified vitamin D as important for bone health. However, 40 % were tested for non-clinical indications and half were not aware of the recommended daily allowance (RDA). Low vitamin D intake was the most important determinant of deficiency, but ethnicity and sun exposure habits were also significant predictors. The majority had no clear indication for testing and were not aware of the RDA. Public health policies to improve knowledge and vitamin D intake, especially for those of non-white ethnicity and with reduced sun exposure, should be considered.

Vitamin D status & associations with inflammation in older adults.

Research studies have observed associations of vitamin D with inflammation but data in representative older adult studies is lacking. We aimed to investigate the association of C-reactive protein (CRP) with vitamin D status in a representative sample of the older Irish population. The concentrations of 25-hydroxyvitamin D (25(OH)D) and CRP was measured in 5,381 community dwelling Irish adults aged ≥50 years from the Irish Longitudinal Study on Ageing (TILDA). Demographic, health and lifestyle variables were assessed by questionnaire and categorical proportions of CRP were generated by vitamin D status and age. Multi-nominal logistic regression was used to investigate the association of 25(OH)D and CRP status. The prevalence (mean; 95% confidence interval (95% CI)) of normal CRP status (0-5 mg/dL) was 83.9% (82.6-85.0%), elevated status (5-10 mg/dL) 11.0% (9.9-12.0%) and high status (>10 mg/dL) was 5.1% (4.5-5.8%). Mean (95% CI) CRP concentrations were lower in those with normal vs. deficient 25(OH)D status (2.02 mg/dL (1.95-2.08) vs. 2.60 mg/dL (2.41-2.82); p<0.0001). In a logistic regression analysis, those with insufficient or sufficient 25(OH)D status were less likely to have a high CRP status compared to those with deficient 25(OH)D status (insufficient: coefficient (CE) -0.732, 95% CI -1.12-0.33, p<0.0001; sufficient: CE -0.599, 95% CI -0.95-0.24, p = 0.001). In conclusion older adults with deficient vitamin D status had higher levels of inflammation as measured by CRP. Given that inflammation is an important pathological driver of chronic diseases of ageing, and that emerging evidence suggests that vitamin D therapy can reduce inflammation in some disease settings, optimising vitamin D status could represent an effective low risk/low-cost pathway to modulate inflammation in community dwelling older adults.

Vitamin D intake and status in Ireland: a narrative review.

Vitamin D is crucial for musculoskeletal health, with evidence suggesting non-skeletal benefits. Cutaneous vitamin D synthesis is limited in Ireland due to its northern latitude (52-55°N) and the population is dependent on dietary sources, yet intakes are inadequate. No study to-date has comprehensively examined vitamin D intakes and status in Ireland (Northern Ireland and the Republic). We aimed to review the evidence since 2010 and summarise the results in subgroups of the Irish population. We found that in the largest studies prevalence of deficiency [25-hydroxyvitamin D (25(OH)D) < 30 nm/l] was 15-17% in pregnancy, 15-23% in children and 13% in adults. Approximately half the population had 25(OH)D < 50 nm/l. There were only four small studies in an ethnic population with the largest in Southeast Asians finding that 67% were deficient. All studies found higher rates of deficiency and levels <50 nm/l in winter v. summer. Vitamin D intake was lowest in children (mean 2⋅3-4⋅2 µg/d) and pregnant women (mean 1⋅9-5⋅1 µg/d) and highest in older adults (6⋅9 µg/d), with over 90% of the population not meeting the recommended daily allowance. This review indicates that low vitamin D status and dietary vitamin D intake are widespread with children, adolescents, younger adults, pregnant women and ethnic minorities most at-risk. However, data are sparse in at-risk groups including the Travelling community, non-Europeans and institutionalised adults. Given the significant prevalence of deficiency, public health policies to promote better awareness of recommended vitamin D intakes and explore the options of food fortification are needed to address this issue.

On-campus mental health services for Australian university students: A retrospective analysis of service utilisation.

OBJECTIVE: To investigate on-campus mental health service utilisation by Australian university students. METHOD: Retrospective analysis of clinical data from two on-campus health services (general practice and psychology and counselling service). Descriptive statistics include total consults, demographic factors, diagnoses, presenting concerns and rates of suicidal ideation. RESULTS: Mental health conditions account for the largest proportion of ongoing illness in on-campus health service users, representing 46% of all ongoing health conditions. Depression and anxiety were the most common diagnoses, and stress, anxiety and low mood were the most common presenting concerns. Females utilise mental health services more frequently than males, accounting for 65.3% and 60.1% of patients for the respective services. International students present for specific mental health consults less frequently than domestic students. Rates of suicidal ideation at presentation were high (37%). CONCLUSIONS: This retrospective analysis provides important information regarding the proportion and distribution of mental health conditions and service utilisation amongst Australian university students. There is clear scope for increased access to specialist care, renewed efforts to decrease stigma and increase rates of presentation (particularly amongst international students and males), greater support for general practitioners and more rigorous routine data collection and reporting, both within and across universities nationally.

Low vitamin B12 but not folate is associated with incident depressive symptoms in community-dwelling older adults: a 4-year longitudinal study.

This was a longitudinal study utilising the Irish Longitudinal Study on Ageing (n 3849 aged ≥ 50 years) and investigated the relationship between blood plasma folate and B12 levels at baseline (wave 1) and incident depressive symptoms at 2 and 4 years (waves 2 and 3). A score ≥ 9 on the Center for Epidemiological Studies Depression Scale-8 at wave 2 or 3 was indicative of incident depressive symptoms. B12 status profiles (pmol/l) were defined as < 185, deficient low; 185 to < 258, low normal; > 258-601, normal and > 601 high. Folate status profiles (nmol/l) were defined as ≤ 10·0, deficient low; > 10-23·0, low normal; > 23·0-45·0, normal; >45·0, high. Logistic regression models were used to analyse the longitudinal associations. Both B12 and folate plasma concentrations were lower in the group with incident depressive symptoms v. non-depressed (folate: 21·4 v. 25·1 nmol/l; P = 0·0003; B12:315·7 v. 335·9 pmol/l; P = 0·0148). Regression models demonstrated that participants with deficient-low B12 status at baseline had a significantly higher likelihood of incident depression 4 years later (OR 1·51, 95 % CI 1·01, 2·27, P = 0·043). This finding remained robust after controlling for relevant covariates. No associations of folate status with incident depression were observed. Older adults with deficient-low B12 status had a 51 % increased likelihood of developing depressive symptoms over 4 years. The findings highlight the need to further explore the low-cost benefits of optimising vitamin B12 status for depression in older adults.

Association between vitamin D deficiency and the risk of prevalent type 2 diabetes and incident prediabetes: A prospective cohort study using data from The Irish Longitudinal Study on Ageing (TILDA).

Background: It is hypothesized that vitamin D contributes to the aetiology of type 2 diabetes mellitus (diabetes). This study's objective was to examine the relationships between baseline vitamin D status (as measured by plasma 25-hydroxyvitamin D concentration) and both prevalent diabetes and prospective risk of developing diabetes, including prediabetes, in a population with historically low levels of vitamin D. Methods: In this prospective cohort study, data from The Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort of adults aged ≥50 years residing in Ireland were analysed, including wave 1 (October 2009-June 2011) (n = 5272) and wave 3 (March 2014-October 2015) (n = 3828). Those aged <50 years at baseline or who did not complete the health assessment were excluded. Logistic regression models examined the associations between baseline vitamin D concentration (nmol/L) with prevalent diabetes status and incident diabetes/prediabetes collected at a 4-year follow-up. Models were adjusted for age, sex, education, body mass index, smoking history, physical activity, use of statins, and the season in which the vitamin D concentration was sampled. Findings: Deficient baseline vitamin D concentration was cross-sectionally associated with an increased likelihood of having prevalent diabetes (Relative Risk Ratio [RRR] 1·5, 95% CI: 1·03, 2·18; p = 0·037). In longitudinal analyses evaluating diabetes status 4 years later, there was a 62% increased likelihood (RRR: 1·62, 95% CI: 1·12, 2·35; p = 0·011) of developing prediabetes for those with vitamin D <30 nmol/L compared to those with ≥75 nmol/L. The rate of progression from prediabetes to diabetes between wave 1 and 3 was observed to be 32·5%. Interpretation: Those with lower concentrations of vitamin D, as measured by 25-hydroxyvitamin D, may have different risk profiles with regards to their glycaemic status. Our study had limited power due to the low incidence of diabetes but showed strong associations with incident prediabetes, so further research is required. Optimising vitamin D status at a population level may significantly reduce diabetes. Funding: TILDA is funded by Atlantic Philanthropies, the Irish Department of Health, and Irish Life, while additional funding was provided by the Irish Department of Agriculture, Food and the Marine (13F492) to cover the cost of 25-hydroxyvitamin D analysis.

Low socioeconomic status predicts vitamin D status in a cross-section of Irish children.

Vitamin D is essential for bone and muscle health with adequate status in childhood crucial for normal skeletal development. We aimed to investigate vitamin D status in a convenience sample (n = 1226) of Irish children (aged 1-17 years) who had serum 25-hydroxyvitamin D (25(OH)D) tested by request of their GP at a Dublin Hospital between 2014 and 2020. We examined predictors including age, sex, season and socioeconomic status (SES). Vitamin D deficiency (<30 nmol/l) was prevalent affecting 23 % and was more common in disadvantaged areas (34 %) and in those aged >12 v. ≤12 years (24 % v. 16 %, P = 0⋅033). The greatest predictor was SES (disadvantaged v. affluent, OR 2⋅18, CI 1⋅34, 3⋅53, P = 0⋅002), followed by female sex (OR 1⋅57, CI 1⋅15, 2⋅14, P = 0⋅005) and winter season (October to February, OR 1⋅40, CI 1⋅07, 1⋅84, P = 0⋅015). A quarter of our sample of children were deficient, rising to one-third in those in disadvantaged areas. Females and those aged over 12 years had a higher prevalence of deficiency. Public health strategies to improve vitamin D status in Irish children, including systematic food fortification may need to be considered to address this issue.

Title: Understanding a Low Vitamin D State in the Context of COVID-19.

While a low vitamin D state has been associated with an increased risk of infection by SARS-CoV-2 in addition to an increased severity of COVID-19 disease, a causal role is not yet established. Here, we review the evidence relating to i) vitamin D and its role in SARS-CoV-2 infection and COVID-19 disease ii) the vitamin D status in the Irish adult population iii) the use of supplemental vitamin D to treat a deficient status and iv) the application of the Bradford-Hill causation criteria. We conclude that reverse causality probably makes a minimal contribution to the presence of low vitamin D states in the setting of COVID-19. Applying the Bradford-Hill criteria, however, the collective literature supports a causal association between low vitamin D status, SARS-CoV-2 infection, and severe COVID-19 (respiratory failure, requirement for ventilation and mortality). A biologically plausible rationale exists for these findings, given vitamin D's role in immune regulation. The thresholds which define low, deficient, and replete vitamin D states vary according to the disease studied, underscoring the complexities for determining the goals for supplementation. All are currently unknown in the setting of COVID-19. The design of vitamin D randomised controlled trials is notoriously problematic and these trials commonly fail for a number of behavioural and methodological reasons. In Ireland, as in most other countries, low vitamin D status is common in older adults, adults in institutions, and with obesity, dark skin, low UVB exposure, diabetes and low socio-economic status. Physiological vitamin D levels for optimal immune function are considerably higher than those that can be achieved from food and sunlight exposure alone in Ireland. A window exists in which a significant number of adults could benefit from vitamin D supplementation, not least because of recent data demonstrating an association between vitamin D status and COVID-19. During the COVID pandemic, we believe that supplementation with 20-25ug (800-1000 IU)/day or more may be required for adults with apparently normal immune systems to improve immunity against SARS-CoV-2. We expect that higher monitored doses of 37.5-50 ug (1,500-2,000)/day may be needed for vulnerable groups (e.g., those with obesity, darker skin, diabetes mellitus and older adults). Such doses are within the safe daily intakes cited by international advisory agencies.