Hepatobiliary circulation and dominant urinary excretion of homogentisic acid in a mouse model of alkaptonuria.

Altered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway. Increased biofluid concentration and tissue accumulation of the phe-tyr pathway metabolite homogentisic acid (HGA) is central to pathophysiology in the inherited disorder alkaptonuria (AKU). Accumulation of metabolites upstream of HGA, including tyrosine, occurs in patients on nitisinone, a licenced drug for AKU and hereditary tyrosinaemia type 1, which inhibits the enzyme responsible for HGA production. The aim of this study was to investigate the phe-tyr metabolite content of key biofluids and tissues in AKU mice on and off nitisinone to gain new insights into the biodistribution of metabolites in these altered metabolic states. The data show for the first time that HGA is present in bile in AKU (mean [±SD] = 1003[±410] µmol/L; nitisinone-treated AKU mean [±SD] = 45[±23] µmol/L). Biliary tyrosine, 3(4-hydroxyphenyl)pyruvic acid (HPPA) and 3(4-hydroxyphenyl)lactic acid (HPLA) are also increased on nitisinone. Urine was confirmed as the dominant elimination route of HGA in untreated AKU, but with indication of biliary excretion. These data provide new insights into pathways of phe-tyr metabolite biodistribution and metabolism, showing for the first time that hepatobiliary excretion contributes to the total pool of metabolites in this pathway. Our data suggest that biliary elimination of organic acids and other metabolites may play an underappreciated role in disorders of metabolism. We propose that our finding of approximately 3.8 times greater urinary HGA excretion in AKU mice compared with patients is one reason for the lack of extensive tissue ochronosis in the AKU mouse model.

Caries clusters at lesion-severity thresholds: A Sierra Leone case study.

OBJECTIVES: Despite being almost entirely preventable, globally, dental caries is extremely prevalent. Moreover, dental caries will continue to present an even larger challenge for lower income countries, particularly those in the African context, as they transition to a more Western diet. Hence, epidemiological data providing insight into disease patterns and trends is critical to inform public health action. The purpose of this study was to examine dental caries clusters by caries detection threshold among 15-year-old adolescents in Sierra Leone, using data from the latest national survey, and to explore associated sociodemographic factors. METHODS: This paper presents a secondary analysis of oral health data on 490 15-year-olds from the Sierra Leone national oral health survey of schoolchildren. Hierarchical cluster analysis of dental caries experience was conducted across all surfaces at four decay detection thresholds using the International Caries Detection and Assessment System (ICDAS) (clinical: ICDAS 2-6, cavitated: ICDAS 3-6, obvious: ICDAS 4-6 and extensive obvious: ICDAS 5-6 decay) across the four regions of Sierra Leone. Ordered logistic regression was used to estimate the association of sociodemographic factors with generated clusters relating to clinical and obvious decay experience. These are of both clinical and epidemiological relevance. RESULTS: A 3-cluster decay pattern representing a 'low' to 'high' decay experience distribution was observed under each decay detection threshold across surfaces. For clinical decay (including visual enamel caries), 28.8% had low, 55.1% medium and 15.9% high caries status. In the adjusted model, the only significant risk factor across obvious and clinical decay thresholds was region, with adolescents outside the Western region more likely to experience decay. CONCLUSION: This study suggests that adolescents in Sierra Leone fall into three distinct caries clusters: low, medium to high decay experience distribution, regardless of decay threshold. It reinforces the importance of recognizing dental caries detection thresholds and the use of contemporary epidemiological methodology. This suggests that adolescents outside the Western region are likely to have higher caries experience. The data also provides insight to the nature of adolescents in each cluster and should help to inform policy and planning of the integration of oral health into primary care and school systems.

Modelling a Consultant Workforce for the United Kingdom: needs-based planning for Dental Public Health.

OBJECTIVE: To develop a needs-based workforce planning model to explore specialist workforce capacity and capability for the effective, efficient, and safe provision of services in the United Kingdom (UK); and test the model using Dental Public Health (DPH). BASIC RESEARCH DESIGN: Data from a national workforce survey, national audit, and specialty workshops in 2020 and 2021 set the parameters for a safe effective DPH workforce. A working group drawing on external expertise, developed a conceptual workforce model which informed the mathematical modelling, taking a Markovian approach. The latter enabled the consideration of possible scenarios relating to workforce development. It involved exploration of capacity within each career stage in DPH across a time horizon of 15 years. Workforce capacity requirements were calculated, informed by past principles. RESULTS: Currently an estimated 100 whole time equivalent (WTE) specialists are required to provide a realistic basic capacity nationally for DPH across the UK given the range of organisations, population growth, complexity and diversity of specialty roles. In February 2022 the specialty had 53.55 WTE academic/service consultants, thus a significant gap. The modelling evidence suggests a reduction in DPH specialist capacity towards a steady state in line with the current rate of training, recruitment and retention. The scenario involving increasing training numbers and drawing on other sources of public health trained dentists whilst retaining expertise within DPH has the potential to build workforce capacity. CONCLUSIONS: Current capacity is below basic requirements and approaching 'steady state'. Retention and innovative capacity building are required to secure and safeguard the provision of specialist DPH services to meet the needs of the UK health and care systems.

Vitamin D: 100 years of discoveries, yet controversy continues.

Over the past 100 years, many major breakthroughs and discoveries have occurred in relation to vitamin D research. These developments include the cure of rickets in 1919, the discovery of vitamin D compounds, advances in vitamin D molecular biology, and improvements in our understanding of endocrine control of vitamin D metabolism. Furthermore, recommended daily allowances for vitamin D have been established and large clinical trials of vitamin D, aimed at clarifying the effect of Vitamin D in the prevention of multiple diseases, have been completed. However, disappointingly, these clinical trials have not fulfilled the expectations many had 10 years ago. In almost every trial, various doses and routes of administration did not show efficacy of vitamin D in preventing fractures, falls, cancer, cardiovascular diseases, type 2 diabetes, asthma, and respiratory infections. Although concerns about side-effects of long-term high-dose treatments, such as hypercalcaemia and nephrocalcinosis, have been around for four decades, some trials from the past 5 years have had new and unexpected adverse events. These adverse events include increased fractures, falls, and hospitalisations in older people (aged >65 years). Several of these clinical trials were powered appropriately for a primary outcome but did not include dose response studies and were underpowered for secondary analyses. Furthermore, more attention should be paid to the safety of high doses of vitamin D supplementation, particularly in older people. In addition, despite universal recommendations by osteoporosis societies for combining calcium supplements with vitamin D there remains insufficient data about their efficacy and effect on fracture risk in the highest risk groups. More trials are needed for people with severe vitamin D deficiency (ie, serum 25-hydroxyvitamin D <25nmol/L [10ng/mL]). In this Personal View, we summarise and discuss some of the major discoveries and controversies in the field of vitamin D.

Determinants of tyrosinaemia during nitisinone therapy in alkaptonuria.

Nitisinone (NIT) produces inevitable but varying degree of tyrosinaemia. However, the understanding of the dynamic adaptive relationships within the tyrosine catabolic pathway has not been investigated fully. The objective of the study was to assess the contribution of protein intake, serum NIT (sNIT) and tyrosine pathway metabolites to nitisinone-induced tyrosinaemia in alkaptonuria (AKU). Samples of serum and 24-h urine collected during SONIA 2 (Suitability Of Nitisinone In Alkaptonuria 2) at months 3 (V2), 12 (V3), 24 (V4), 36 (V5) and 48 (V6) were included in these analyses. Homogentisic acid (HGA), tyrosine (TYR), phenylalanine (PHE), hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and sNIT were analysed at all time-points in serum and urine. Total body water (TBW) metabolites were derived using 60% body weight. 24-h urine and TBW metabolites were summed to obtain combined values. All statistical analyses were post-hoc. 307 serum and 24-h urine sampling points were analysed. Serum TYR from V2 to V6, ranging from 478 to 1983 µmol/L were stratified (number of sampling points in brackets) into groups < 701 (47), 701-900 (105), 901-1100 (96) and > 1100 (59) µmol/L. The majority of sampling points had values greater than 900 µmol/L. sPHE increased with increasing sTYR (p < 0.001). Tyrosine, HPPA and HPLA in serum and TBW all increased with rising sTYR (p < 0.001), while HPLA/TYR ratio decreased (p < 0.0001). During NIT therapy, adaptive response to minimise TYR formation was demonstrated. Decreased conversion of HPPA to HPLA, relative to TYR, seems to be most influential in determining the degree of tyrosinaemia.

Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults.

BACKGROUND: Vitamin D supplements are widely recommended for bone health in the general population, but data on whether they prevent fractures have been inconsistent. METHODS: In an ancillary study of the Vitamin D and Omega-3 Trial (VITAL), we tested whether supplemental vitamin D3 would result in a lower risk of fractures than placebo. VITAL was a two-by-two factorial, randomized, controlled trial that investigated whether supplemental vitamin D3 (2000 IU per day), n-3 fatty acids (1 g per day), or both would prevent cancer and cardiovascular disease in men 50 years of age or older and women 55 years of age or older in the United States. Participants were not recruited on the basis of vitamin D deficiency, low bone mass, or osteoporosis. Incident fractures were reported by participants on annual questionnaires and adjudicated by centralized medical-record review. The primary end points were incident total, nonvertebral, and hip fractures. Proportional-hazards models were used to estimate the treatment effect in intention-to-treat analyses. RESULTS: Among 25,871 participants (50.6% women [13,085 of 25,871] and 20.2% Black [5106 of 25,304]), we confirmed 1991 incident fractures in 1551 participants over a median follow-up of 5.3 years. Supplemental vitamin D3, as compared with placebo, did not have a significant effect on total fractures (which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group; hazard ratio, 0.98; 95% confidence interval [CI], 0.89 to 1.08; P = 0.70), nonvertebral fractures (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P = 0.50), or hip fractures (hazard ratio, 1.01; 95% CI, 0.70 to 1.47; P = 0.96). There was no modification of the treatment effect according to baseline characteristics, including age, sex, race or ethnic group, body-mass index, or serum 25-hydroxyvitamin D levels. There were no substantial between-group differences in adverse events as assessed in the parent trial. CONCLUSIONS: Vitamin D3 supplementation did not result in a significantly lower risk of fractures than placebo among generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass, or osteoporosis. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; VITAL ClinicalTrials.gov number, NCT01704859.).

Unmet need in Sierra Leone: a national oral health survey of schoolchildren.

OBJECTIVE: Sierra Leone (SL), in West Africa, with a population of over 7.5 million people has suffered the effects of a civil war previously, and more recently Ebola & Covid-19. Dental care is very limited, mostly in the capital Freetown and the private sector. No dental education is available in the country. The objective of this research was to investigate the oral health needs of schoolchildren at key ages, to inform future action. MATERIALS AND METHODS: This first national oral health survey of schoolchildren at 6-, 12- and 15-years was conducted in urban and rural settings across all four regions using a multi-stage cluster sampling in line with the WHO guidelines, adapted according to contemporary survey methods to include 'International Caries Detection and Assessment System (ICDAS)'. Whilst parents were invited to complete a questionnaire for 6-year-old children, 12- and 15-year-olds self-completed a questionnaire. Data were weighted according to age and regional population and analysed using STATA v.15 and SPSS v.22. RESULTS: A total of 1174 children participated across 22 schools from all four regions. Dental caries was prevalent (over 80% of all age-groups having clinical decay; ICDAS score ≥ 2) and largely untreated. No children had fillings and only 4% had missing teeth. Amongst 6, 12 and 15-year-olds, average decay levels at ICDAS > 3 threshold was 3.47 (primary teeth), 2.94 and 4.30 respectively. Almost, 10% (n = 119) of all children reported experiencing pain in their teeth with 7% (n = 86) children having PUFA lesions present. At least one in five children required one or more dental extractions. 'Age' was a significant predictor of dental caries experience and the odds of having dental caries experience was higher in rural areas at D3-6MFT (p < 0.05). CONCLUSION: The findings demonstrate a vast unmet oral health need in the children of SL. Using ICDAS as an epidemiological tool in a low-income country provides valuable insight to the pattern of oral disease to inform health service planning. Urgent action is required to address this silent epidemic.

Temporal adaptations in the phenylalanine/tyrosine pathway and related factors during nitisinone-induced tyrosinaemia in alkaptonuria.

BACKGROUND: Adaptations within the phenylalanine (PHE)/tyrosine (TYR) pathway during nitisinone (NIT) are not fully understood. OBJECTIVE: To characterise the temporal changes in metabolic features in NIT-treated patients with alkaptonuria. PATIENTS AND METHODS: Serum (s) and 24-urine (u) homogentisic acid (sHGA, uHGA24), TYR (sTYR, uTYR24), PHE (sPHE, uPHE24), hydroxyphenylpyruvate (sHPPA, uHPPA24), hydroxyphenyllactate (sHPLA, uHPLA24) and sNIT were measured at baseline (V1) and until month 48 (V6) in 69 NIT-treated patients, recommended to reduce protein intake. The 24-h urine urea (uUREA24), creatinine (uCREAT24) and body weight were also measured. Amounts of tyrosine metabolites in total body water (TBW) were derived by multiplying the serum concentrations by 60% body weight, and sum of TBW and urine metabolites resulted in combined values (c). RESULTS: uUREA24 and uCREAT24 decreased between V1 and V6 during NIT, whereas body weight and sNIT increased. Linear regression coefficient between uUREA24 and uCREAT24 was extremely strong (R = 0.84). sPHE, TBWPHE and cPHE24 increased gradually from V1 to V6. A decrease in cTYR24/cPHE24, sTYR/sPHE and TBWTYR/TBWPHE was seen from V2 to V6. Serum, 24-urine and combined TYR, HPPA and HPLA either remained stable or decreased from V2 to V6. DISCUSSION: The gradual increase in PHE suggests adaptation to increasing TYR during NIT therapy. The decrease in protein intake resulted in decreased muscle mass and increased weight gain. CONCLUSION: Progressive adaptation by decreasing PHE conversion to TYR occurs over time during NIT therapy. A low protein diet results in loss of muscle mass but also weight gain suggesting an increase in fat mass.

Management of temporomandibular disorders: a rapid review of systematic reviews and guidelines.

Temporomandibular disorders (TMD) impact a significant proportion of the population. Given the range of management strategies, contemporary care should be evidence-informed for different TMD types. A knowledge-to-action rapid review of systematic reviews published in the past 5 years and guidelines published in the past 10 years concerning the management of TMD was conducted. The Cochrane, Embase, MEDLINE, PEDro, and PubMed databases were searched. A qualitative data analysis was undertaken, with quality assessment completed using the AMSTAR 2 checklist. In total, 62 systematic reviews and nine guidelines considering a range of treatment modalities were included. In concordance with current guidelines, moderate evidence supports a multi-modal conservative approach towards initial management. Contrary to existing guidelines, occlusal splint therapy is not recommended due to a lack of supporting evidence. The evidence surrounding oral and topical pharmacotherapeutics for chronic TMD is low, whilst the evidence supporting injected pharmacotherapeutics is low to moderate. In concordance with current guidelines, moderate quality evidence supports the use of arthrocentesis or arthroscopy for arthrogenous TMD insufficiently managed by conservative measures, and open joint surgery for severe arthrogenous disease. Based on this, a management pathway showing escalation of treatment from conservative to invasive is proposed.

Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuria.

BACKGROUND: Although changes in the tyrosine pathway during nitisinone therapy are known, a complete characterization of the induced tyrosinaemia is lacking to improve disease management. PATIENTS AND METHODS: Our research aims were addressed by 24-h blood sampling. 40 patients with alkaptonuria (AKU), treated with 0, 1, 2, 4 and 8 mg nitisinone daily (n = 8), were studied over four weeks. Serum homogentisic acid (sHGA), tyrosine (sTYR), phenylalanine (sPHE), hydroxyphenylpyruvate (sHPPA), hydroxyphenyllactate (sHPLA) and nitisinone (sNIT) were measured at baseline and after four weeks. RESULTS: sNIT showed a clear dose-proportional response. sTYR increased markedly but with less clear-cut dose responses after nitisinone. Fasting and average 24-h (Cav) sTYR responses were similar. Individual patient sTYR 24-h profiles showed significant fluctuations during nitisinone therapy. At week 4, sTYR, sHPPA and sHPPL all showed dose-related increases compared to V0, with the greatest difference between 1 and 8 mg nitisinone seen for HPLA, while there was no change from V0 in sPHE. sHGA decreased to values around the lower limit of quantitation. DISCUSSION: There was sustained tyrosinaemia after four weeks of nitisinone therapy with significant fluctuations over the day in individual patients. Diet and degree of conversion of HPPA to HPLA may determine extent of nitisinone-induced tyrosinaemia. CONCLUSION: A fasting blood sample is recommended to monitor sTYR during nitisinone therapy Adaptations in HPPA metabolites as well as the inhibition of tyrosine aminotransferase could be contributing factors generating tyrosinaemia during nitisinone therapy.

Spatiotemporal representativeness of air pollution monitoring in Dublin, Ireland.

The importance of selecting appropriate air pollution monitoring sites in a city is vital for accurately reporting air quality, enhancing the quality of high-resolution modelling and informing policy to implement measures to deliver cleaner air in the urban environment. COVID-19 restrictions impacted air quality in urban centres worldwide as reduced mobility led to changes in traffic-related air pollution (TRAP). As such, it offered a unique dataset to examine the spatial and temporal variations in air quality between monitoring stations in Dublin, Ireland. Firstly, an analysis of mobility data showed reductions across almost all sectors after COVID-19 restrictions came into place, which was expected to lower TRAP. In addition, similar changes in air quality were evident to other cities around the world: reductions in fine particulate matter (PM2.5) and nitrogen dioxide (NO2) concentrations and an increase in ozone (O3) concentrations. Average daily and diurnal concentrations for these three pollutants presented more statistically significant spatial and temporal changes during COVID-19 restrictions at monitoring sites with urban or traffic classifications than suburban background sites. Furthermore, substantial reductions in the range of average hourly pollutant concentrations were observed, 79% for PM2.5 and 75% for NO2, with a modest 24% reduction for O3. Correlation analysis of air pollution between monitoring sites and years demonstrated an improvement in the R2 for NO2 concentrations only, suggesting that spatiotemporal homogeneity was most notable for this TRAP due to mobility restrictions during COVID-19. The spatiotemporal representativeness of monitoring stations across the city will change with greener transport, and air quality during COVID-19 can provide a benchmark to support the introduction of new policies for cleaner air.

Individual participant data (IPD)-level meta-analysis of randomised controlled trials to estimate the vitamin D dietary requirements in dark-skinned individuals resident at high latitude.

CONTEXT AND PURPOSE: There is an urgent need to develop vitamin D dietary recommendations for dark-skinned populations resident at high latitude. Using data from randomised controlled trials (RCTs) with vitamin D3-supplements/fortified foods, we undertook an individual participant data-level meta-regression (IPD) analysis of the response of wintertime serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among dark-skinned children and adults residing at ≥ 40° N and derived dietary requirement values for vitamin D. METHODS: IPD analysis using data from 677 dark-skinned participants (of Black or South Asian descent; ages 5-86 years) in 10 RCTs with vitamin D supplements/fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D intake estimates across a range of 25(OH)D thresholds. RESULTS: To maintain serum 25(OH)D concentrations ≥ 25 and 30 nmol/L in 97.5% of individuals, 23.9 and 27.3 µg/day of vitamin D, respectively, were required among South Asian and 24.1 and 33.2 µg/day, respectively, among Black participants. Overall, our age-stratified intake estimates did not exceed age-specific Tolerable Upper Intake Levels for vitamin D. The vitamin D intake required by dark-skinned individuals to maintain 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L was 66.8 µg/day. This intake predicted that the upper 2.5% of individuals could potentially achieve serum 25(OH)D concentrations ≥ 158 nmol/L, which has been linked to potential adverse effects in older adults in supplementation studies. CONCLUSIONS: Our IPD-derived vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25, 30 and 50 nmol/L are substantially higher than the equivalent estimates for White individuals. These requirement estimates are also higher than those currently recommended internationally by several agencies, which are based predominantly on data from Whites and derived from standard meta-regression based on aggregate data. Much more work is needed in dark-skinned populations both in the dose-response relationship and risk characterisation for health outcomes. TRAIL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews (Registration Number: CRD42018097260).

Treatment of osteoporotic fractures in alkaptonuria by teriparatide stimulates bone formation and decreases fracture rate - A report of two cases.

Two cases of advanced alkaptonuria (AKU) with co-existing osteoporosis are described. Case 1 developed multiple non-vertebral fragility fractures, while Case 2 developed vertebral fragility fractures, both refractory to bisphosphonates. Difficulties in diagnosing osteoporosis in AKU complicated by extensive calcifying and ossifying spondylosis are discussed. Both patients continued to fracture despite nitisinone therapy for metabolic control of AKU, as well as bisphosphonate antiresorptive therapy for osteoporosis. Subsequently the patients were treated with teriparatide 20 µg subcutaneous injections daily for two years, leading to reduction in fractures soon after commencing therapy in both cases. Markers of bone remodelling P1NP and CTX were stimulated. No complications due hypercalcaemia or calcification were encountered in either case. We conclude that teriparatide is an effective adjunct in the treatment of AKU when bisphosphonates prove ineffective.

Editorial - Delivering Better Oral Health 2021 - What's new and where next?

Delivering Better Oral Health (DBOH) was fi rst published in 2007 (Department of Health et al., 2007) at the request of the Department of Health to the British Association of Community Dentistry (BASCD). It was led by Dr Sue Gregory, who was at that time President of BASCD; and, thereafter, appointed Deputy Chief Dental Officer for England. The purpose of the document was to support dental teams in a more preventive approach to dental care based on the best available evidence. Practitioners have access to an enormous amount of information, and it was intended that DBOH would provide a simple guide to the evidence, explaining what the research meant in practical terms for the preventive advice and treatment of their patients. The approach promoted preventive care for all patients and additional support for those most at risk of poor oral health. DBOH was to be a living document, regularly updated. It was revised in 2009 and 2014, when after the Health and Social Care Act (2012), Public Health England took on the leadership of its development. In 2017 revisions responsed to changes in guidance; the publication by the Scientific Advisory Committee on Nutrition of the Carbohydrates and Health Report (SACN, 2015) which led to a revised healthier eating section and the Chief Medical Officers' (2016) new guidelines on alcohol were also incorporated.

Perspectives of community-dwelling older adults with dementia and their carers regarding their oral health practices and care: rapid review.

AIM: To review evidence on oral health practices, beliefs/views and experiences of community-dwelling older adults living with dementia, including their carers. MATERIALS AND METHODS: A search of key terms across six databases including Pubmed, Web of Science and OVID (Embase, MEDLINE [R] and PsycINFO) and Google Scholar was conducted, supplemented by reference screening. The Mixed Methods Appraisal Tool (MMAT) 2018 was used to assess the methodological quality. RESULTS: Eighteen studies reported across 19 papers were included in the review. Papers largely focused on normative needs (n = 13), whilst also reporting oral health-related experiences (n = 2), practices (n = 7), and beliefs/views (n = 9), of community dwellers with dementia. Generally, people living with dementia presented with poor oral and dental health, the exception being one study where dental care was integrated with memory clinic services. Maintenance of oral health focused only on toothbrushing. Overall, people living with dementia have reduced capacity for self-performed oral hygiene and high reliance on caregivers. There was a paucity of evidence on their perceptions of oral health and quality of life, the findings of which were equivocal, with weak evidence suggesting possible difficulty in identifying and communicating their needs. Experiences of accessing dental care, when explored, appear to be system dependent. CONCLUSION: There was limited research evidence on oral health-related practices, beliefs/views and experiences of people with dementia. Recommendations for future research are presented.

Steroidogenesis in patients with adrenal incidentalomas: Extended steroid profile measured by liquid chromatography-mass spectrometry after ACTH stimulation and dexamethasone suppression.

OBJECTIVE: Describe the secretion and profile of adrenal steroids in patients with adrenal incidentalomas compared to control subjects. DESIGN, SETTING AND PARTICIPANTS: A prospective study, 73 patients with adrenal incidentalomas, 21 bilateral and 52 unilateral and 34 matched controls in University Hospital. METHODS: Collect fasting blood sample before and 60 min after ACTH test (250 µg IV). One week later, perform overnight 1 mg dexamethasone test. The following steroids were measured by liquid chromatography-mass spectrometry (LC-MS): pregnenolone, 17-OH pregnenolone, 17-OH progesterone, 11-deoxycorticosterone, 11-deoxyortisol, 21-deoxycortisol, corticosterone, cortisol, androstenedione and aldosterone. RESULTS: Mean baseline serum cortisol was higher in incidentalomas, bilateral 361 ± 124, (range 143-665) nmol/L,(p < .0001), unilateral 268 ± 89 3.2 (range 98-507) nmol/L (p < .019) compared to controls 207 ± 100 (range 72-502) nmol/L. ACTH stimulation showed significantly higher levels in bilateral and unilateral cases compared to controls. After dexamethasone, mean serum cortisol levels suppressed in bilaterals 89 ± 69 (range 30-3) nmol/L (p < .0001), 58 ± 52 (range 16-323) nmol/L in unilateral (p < .01) compared to 26 ± 9 (range 7-46) nmol/L in controls. Mean baseline serum corticosterone was higher in bilateral 9.3 ± 4.8 (range 2.4-18.4) nmol/L (p < .005) and unilateral 7.3 ± 5.7 (range 0.1-30.3) nmol/L (p < .01) compared to controls 4.2 ± 2.4 (range 1.1-10.2) nmol/L, after ACTH stimulation significantly increased to higher levels in bilateral (p < .0002) and unilateral cases (p < .044) compared to controls. After dexamethasone, mean levels were 2.5 ± 2.6 (range 0.5-12.5) nmol/L in bilateral (p < .0006), 1.5 ± 1.6 (range 0.3-9.3) nmol/L in unilateral (p < .09) and 0.75 ± 0.46 (range 0.1-2.1) nmol/L in controls. Mean baseline serum 11-deoxycorticosterone (DOC) was higher in bilaterals 0.32 ± 0.23 (range 0.08-1.1) nmol/L (p < .03) compared to controls 0.15 ± 0.21 (range 0.08-1.1) nmol/L. ACTH stimulation increased levels to 3.27 ± 1.72 (range 0.5-7.4) nmol/L in bilateral cases compared to controls 1.369 ± 1.53 (range 0.1-7.1) nmol/L (p < .0001). Dexamethasone decreased levels to baseline (p ns). There were significant differences in serum 21-deoxycortisol (p < .0002) and serum pregnenolone (p < .004) only after ACTH stimulation. CONCLUSIONS: There is increased activity in several steroid biosynthesis pathways and higher steroid levels in bilateral compared to unilateral cases and evidence of hypercortisolism in 30% unilateral and 62% of bilateral incidentalomas.