Consensus - reference ranges of vitamin D [25(OH)D] from the Brazilian medical societies. Brazilian Society of Clinical Pathology/Laboratory Medicine (SBPC/ML) and Brazilian Society of Endocrinology and Metabolism (SBEM)
Jornal Brasileiro de Patologia e Medicina Laboratorial, vol.53 no.6 Rio de Janeiro Nov./Dec. 2017, http://dx.doi.org/10.5935/1676-2444.20170060
Consensus of Medical groups in Brazil
Many people need 30-60 ng
No test until medical problems are noticed(wrong)
- Consensus category listing has
28 items along with related searches
- MS and vitamin D consensus from Brazil - 40-100 ng, not monotherapy – Feb 2014
- 30 to 50 ng of vitamin D is optimal – Central Europe consensus Sept 2013
- Seniors need at least 4,000 IU vitamin D, no test needed – Consensus Jan 2014
- High Risk category listing has
35 items along with related searches
The consensus fails to consider as high risk: obese, dark skin, little access to sun, spinal cord injury, Sickle Cell,
- Overview Toxicity of vitamin D - many groups consider toxicity to be >150 ng, not >100 ng
- Vitamin D (40-70 ng) in Children’s Health – review Sept 2014
- Is 50 ng of vitamin D too high, just right, or not enough
- Vitamin D has already cleared 100 percent of lesions from over 1,000 MS patients in Brazil
After achieving 150 ng of vitamin D, but not with monotherapy
- Dr. who got patients to vitamin D level of 80 ng
2,500 patients became extremely healthy: visits dropped from 4/year down to 1/year
- 25 experts recommend vitamin D level of min 30 ng – Nov 2009
Carlos Eduardo S. Ferreira1 2
Sergio S. Maeda2
Marcelo C. Batista1
Leonardo S. Vasconcellos3
Miguel Madeira4 5
Lilian M. Soares6
Victória Z. C. Borba7
Carolina A. Moreira7
1Hospital Israelita Albert Einstein, São Paulo, Brazil.
2Escola Paulista de Medicina/Universidade Federal de São Paulo (EPM/UNIFESP), São Paulo, Brazil.
3Universidade Federal de Minas Gerais (UFMG), Minas Gerais, Brazil.
4Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.
5Hospital Federal de Bonsucesso, Rio de Janeiro, Brazil.
6Laboratório Hermes Pardini, Minas Gerais, Brazil.
7Universidade Federal do Paraná (UFPR), Paraná, Brazil.
CORRESPONDING AUTHOR Carlos Eduardo dos Santos Ferreira, Avenida Albert Einstein; Hospital Albert Einstein, 627, 4º andar; Morumbi; CEP: 05652-901; São Paulo-SP, Brasil; e-mail: carlosesf at einstein.br.
Vitamin D is considered a pre-hormone and plays a crucial role in calcium homeostasis and, consequently, in bone health. The best source of vitamin D is the skin in response to sunlight. Only small amounts of this vitamin are found in some foods (especially fatty fish), which makes availability of vitamin D in the diet limited. Brazilian population studies show that the prevalence of hypovitaminosis D in our country is high.
Objective: To define the reference intervals for vitamin D [25(OH)D].
Consensus of specialists - literature review.
Conclusion: The standardization of reference intervals is fundamental for the correct diagnosis and treatment of hypovitaminosis D.
Vitamin D is considered a pre-hormone and plays a crucial role in calcium homeostasis and, consequently, in bone health. The best source of vitamin D is the skin in response to sunlight. Only small amounts of this vitamin are found in some foods (especially fatty fish), which makes the availability of vitamin D in the diet limited. Brazilian population studies show that the prevalence of hypovitaminosis D in our country is high.
The vitamin D synthesized in the skin or absorbed through dietary intake is transported in blood circulation by a specific protein - vitamin D binding protein (VDBP) - and is metabolized first in the liver and then in the kidney, where it undergoes the first and second hydroxylation, respectively. This physiology is close regulated with the presence of compensatory mechanisms in order to avoid high levels predisposing to toxicity.
Vitamin D deficiency has important clinical effects in bone and muscle, raising the risk for diseases such as osteoporosis and osteomalacia, as well as increasing the risk of falls and fractures.
Data from studies on vitamin D levels in different regions of the world confirm the high prevalence of hypovitaminosis D, mainly associated with age over 60 years, high-latitude, winter, hyperpigmentation of the skin, less sunlight exposure, presence of chronic diseases, dietary habits, pregnancy, breastfeeding and absence of foods fortified with vitamin D.
In Brazil, hypovitaminosis D has been documented in several regions of the country, which justifies a critical analysis of its diagnostic criteria. For this purpose, both a correct recommendation for the examination order and the appropriate processing of the sample associated with a critical interpretation/ evaluation of the results are essential to prescribe an effective treatment based on the current scientific evidence.
The laboratory determination of the metabolite 25-hydroxyvitamin D [25(OH)D] should be used in the evaluation of an individual's vitamin D status. Assuming that hypovitaminosis D is very prevalent in our country and it has significant clinical importance, this paper aims to discuss and suggest good practice for ordering and interpreting the results, as well as the definition of reference values for 25(OH)D, according to the age group and the presence or absence of chronic diseases. This document is represented by a committee composed of specialists from the Department of Bone Metabolism of the Brazilian Society of Endocrinology and Metabolism [Sociedade Brasileira de Endocrinologia e Metabologia (SBEM)] and the Brazilian Society of Clinical Pathology/Laboratory Medicine [Sociedade Brasileira de Patologia Clínica/Medicina Laboratorial (SBPC/ML)] for the development of recommendations based on scientific evidence available from current literature on vitamin D.
The main groups at risk for hypovitaminosis D are listed below:
- elderly - over 60 years of age;
- individuals who are not exposed to the sunlight or who have a contraindication to sunlight exposure;
- individuals with recurrent fractures or falls;
- pregnant and breastfeeding women;
- osteoporosis (primary and secondary);
- metabolic bone diseases, such as rickets, osteomalacia and hyperparathyroidism;
- chronic kidney disease;
- malabsorption syndromes, such as after bariatric surgery and inflammatory bowel disease;
- individuals taking medications that may interfere with the formation and degradation of vitamin D, such as antiretroviral, glucocorticoids and anticonvulsants therapy.
RECOMMENDATIONS FOR ORDERING 25(OH)D
The main clinical recommendations for ordering the 25(OH)D serum level are the diseases or clinical conditions listed above, based on data from clinical history, physical examination, and complementary exams.
There is no evidence to order the 25(OH)D serum level for the adult population without reported comorbidities. Therefore, indiscriminate population screening is not recommended.
The most well-known and studied actions of vitamin D are related to bone metabolism, in which its role is crucial. It participates in the intestinal calcium absorption, in the modulation of parathyroid hormone (PTH) secretion, in bone cell and muscle function.
Hypovitaminosis D leads to a deficiency in calcium absorption and thus, causes secondary hyperparathyroidism, which, in turn, may lead to loss of bone mass due to increased resorption and, consequently, to fractures. In situations in which the vitamin D level is extremely low [25(OH)D < 10 ng/ml], a defect in mineralization of bone tissue may occur, characterizing diseases, rickets in children and osteomalacia in adults. Bone pain, muscle weakness, bone deformities and fractures are clinical features of severe vitamin D deficiency. The presence of extraskeletal effects of vitamin D is still under investigation. Meta-analysis with intervention studies suggest that correcting the deficiency reduces general mortality and supplementation would probably has a protective role against cancer, especially in the large intestine. Randomized and placebo-controlled intervention studies are scarce and still unable to demonstrate evidence of many other effects which have been described in other systems. Therefore, supplementation aiming at these other effects is not yet justified.
The main methods for 25(OH)D measurement are:
- competitive assays using vitamin D binding proteins (VDBP) or anti-25(OH)D antibodies, including radioimmunoassay and enzyme immunoassay, chemiluminescence or electrochemiluminescence assays. These assays are widely available in clinical laboratories and do not require advanced technology. However, they present several limitations, such as the different reactivity of 25(OH)D2 and 25(OH)D3 ligands and the incomplete dissociation of 25(OH)D from their binding proteins;
- chromatographic methods such as high-performance liquid chromatography with ultraviolet detection or coupled with tandem mass spectrometry (LC-MS/MS). LC-MS/MS is considered the gold standard for the 25(OH)D measurement because it presents less analytical interference and measures vitamin D directly. However, there are some limitations to its wide use in the clinical laboratory, among them, high cost of equipment, maintenance, specific validations, sample preparation increasing test run time and highly skilled professionals. In addition, it may be subjected to C3-epimer interference, leading to falsely elevated values, especially in children under one year of age.
There is also considerable variation between the 25(OH)D levels obtained in the different methods, hindering the clinical interpretation of the results. The major challenge of the diagnostic market is to ensure a better harmonization between the different tests available, allowing a better comparison of the results between different laboratories. Efforts such as the Vitamin D Standardization Program (EUA) and the Vitamin D External Quality Assessment Scheme (RU) directly target this standardization.
The clinical laboratory is responsible for reporting these reference ranges in published reports and should be based on up-to-date literature data, medical society's guidelines and clinical team opinions. There are different ways of defining reference ranges. For 25(OH)D, the evaluation of clinical studies in the literature is currently the best way to define reference intervals, as these studies attempt to investigate the benefits of maintaining certain values in specific populations. However, most of these studies have used, in the past, the Diasorin® radioimmunoassay to measure 25(OH)D, whereas nowadays, most clinical laboratories employ automated, non-isotopic assays for this analysis. Since the correlation between these methods is not so direct, values obtained with the radioimmunoassay may not be transposable to the assays most commonly used today. To suggest reference ranges applicable to all laboratories, the methods would need to be more comparable, however, as described above for vitamin D measurement, there is still considerable variation among the different methods available, generating an additional complicating factor for the definition and the interpretation of these intervals. Although this variation has been reduced in recent years by the standardization programs previously mentioned, the problem of the matrix effect still exists, that is, the interference caused by non-specific endogenous components that vary from sample to sample and can interact with specific immunoassay reagents. This effect may cause unpredictable changes in the results, which can hardly be corrected by the simple standardization of the calibrators of the tests. For this reason, some experts such as Binkley and Carter (2017) suggest that laboratories should apply specific reference intervals, depending on the immunoassay used, in line with what was done with other hormones, or using chromatographic methods by reducing the matrix effect.
Based on literature data, our consensus in relation to the ideal 25(OH)D values for the population should be stratified according to age and individual clinical characteristics:
- above 20 ng/ml - desirable value for healthy population (up to 60 years of age);
- between 30 and 60 ng/ml - recommended value for at-risk groups such as elderly, pregnant, breastfeeding women, patients with rickets/osteomalacia, osteoporosis, patients with a history of falls and fractures, secondary causes of osteoporosis (diseases and medications), hyperparathyroidism, inflammatory diseases, autoimmune diseases, chronic kidney disease and malabsorption syndromes (clinical or post-surgical);
- above 100 ng/ml - risk of toxicity and hypercalemia.
This consensus will allow an improved standardization and dissemination to laboratories and physicians regarding the 25(OH)D reference intervals suggested by the medical societies SBPC/ML and SBEM directly involved with the flow of orders, processing, release and interpretation of results of this analyte.
The rate of scientific publications is very dynamic and, should new evidence arise, the societies will make the appropriate updates.
- Hermann M, Christopher-John LF, Pusceddu I, Fabregat-Cabello N, Cavalier E. Assessment of vitamin D status - a changing landscape. Clin Chem Lab Med. 2017; 55(1): 3-26.
- Binkley N, Carter G. Toward clarity in clinical vitamin D status assessment: 25(OH)D assay standardization. Endocrinol Metab Clin N Am. 2017; 46: 885-99.
- Manson JE, Brannon PM, Rosen CJ, Taylor CL. Vitamin D deficiency - is there really a pandemic? N Engl J Med. 2016.
- de Boer IH, Levin G, Robinson-Cohen C, et al. Serum 25-hydroxyvitamin D concentration and risk for major clinical disease events in a communitybased population of older adults. Ann Intern Med. 2012.
- Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011.
- Heaney RP, Holick MF. Why the IOM recommendations for vitamin D are deficient. J Bone Miner Res. 2011.
- Bouillon R, van Schoor NM, Gielen E, et al. Optimal vitamin D status: a critical analysis on the basis of evidence-based medicine. J Clin Endocrinol Metab. 2013.
- Cauley JA, Greendale GA, Ruppert K, et al. Serum 25 hydroxyvitamin D,bone mineral density and fracture risk across the menopause. J Clin Endocrinol Metab. 2015.
- Soares LM, Pedrosa W, Elói-Santos SM, Vasconcellos LS. 25-Hydroxyvitamin D threshold values should be age-specific. Clin Chem Lab Med. 2017; 55(7): e140-2.
- Holick MF. Vitamin D deficiency. N Engl J Med. 2007; 357(3): 266-81.
- Maeda SS, Borba VZ, Camargo MB, et al. Recommendations of the Brazilian Society of Endocrinology and Metabology (SBEM) for the diagnosis and treatment of hypovitaminosis D. Arq Bras Endocrinol Metab. 2014; 58(5): 411-33.
- Holick MF, Chen TC, Lu Z, Sauter E. Vitamin D and skin physiology: a D-lightful story. J Bone Miner Res. 2007; 22 Suppl 2: V28-33.
- Granic A, Hill TR, Davies K, et al. Vitamin D status, muscle strength and physical performance decline in very old adults: a prospective study. Nutrients. 2017; 9(4).
- Holick MF. Deficiency of sunlight and vitamin D. BMJ. 2008; 336(7657): 1318-9.
- Maeda SS, Saraiva GL, Kunii IS, et al. Factors affecting vitamin D status in different populations in the city of Sao Paulo, Brazil: the Sao PAulo vitamin D Evaluation Study (SPADES). BMC Endocr Disord. 2013; 13: 14.
- Maeda SS, Saraiva GL, Hayashi LF. Seasonal variation in the serum 25-hydroxyvitamin D levels of young and elderly active and inactive adults in Sao Paulo, Brazil: the Sao PAulo vitamin D Evaluation Study (SPADES). Dermatoendocrinol. 2013; 5(1): 211-7.
- Borba VZ, Vieira JG, Kasamatsu T, Radominski SC, Sato EI, Lazaretti- Castro M. Vitamin D deficiency in patients with active systemic lupus erythematosus. Osteoporos Int. 2009; 20(3): 427-33.
- Franco CB, Paz-Filho G, Gomes PE, et al. Chronic obstructive pulmonary disease is associated with osteoporosis and low levels of vitamin D. Osteoporos Int. 2009; 20(11): 1881-7.
- Kulak CA, Borba VZ, Bilezikian JP, Silvado CE, Paola L, Boguszewski CL. Bone mineral density and serum levels of 25 OH vitamin D in chronic users of antiepileptic drugs. Arq Neurpsiquiatr. 2004; 62(4): 940-8.
- Campos DJ, Biagini GL, Funke VA, Bonfim CM, Boguszewski CL, Borba VZ. Vitamin D deficiency in children and adolescents submitted to hematopoietic stem cell transplantation. Rev Bras Hematol Hemoter. 2014; 36(2): 126-31.
- van der Meer IM, Karamali NS, Boeke AJ, et al. High prevalence of vitamin D deficiency in pregnant non-Western women in The Hague, Netherlands. Am J Clin Nutr. 2006; 84(2): 350-3; quiz 468-9.
- van Schoor N, Lips P. Global overview of vitamin D status. Endocrinol Metab Clin North Am. 2017; 46(4): 845-70.
In VitaminDWiki Vitamin D levels are lower than 20 ng in half of the world – Dec 2017
- Arantes HP, Kulak CA, Fernandes CE, et al. Correlation between 25-hydroxyvitamin D levels and latitude in Brazilian postmenopausal women: from the Arzoxifene Generations Trial. Osteoporos Int. 2013; 24(10): 2707-12.
- Saraiva GL, Cendoroglo MS, Ramos LR, et al. [Prevalence of vitamin D deficiency, insufficiency and secondary hyperparathyroidism in the elderly inpatients and living in the community of the city of Sao Paulo, Brazil]. Arq Bras Endocrinol Metab. 2007; 51(3): 437-42.
- Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev. 2001; 22(4): 477-501.
- Vieth R, Ladak Y, Walfish PG. Age-related changes in the25-hydroxyvitamin D versus parahtyroid hormone relationship suggest a different reason why older adults require more vitamin D. J Clin Endocrinol Metab. 2003; 88(1): 185-91.
- Aloia JF, Chen DG, Yeh JK, Chen H. Serum vitamin D metabolites and intestinal calcium absorption efficiency in women. Am J Clin Nutr. 2010; 92: 835-40.
- Heaney RP, Dowell S, Hale CA, Bendich A. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr. 2003; 22: 142-6.
- Need AG, O'Loughlin PD, Morris HA, Coates PS, Horowitz M, Nordin BEC. Vitamin D metabolites and calcium absorption in severe vitamin D deficiency. J Bone Miner Metab. 2008; 23: 1859-63.
- Gallagher JC, Jindal PS, Smith LM. Vitamin D does not increase calcium absorption in young women: a randomized clinical trial. J Bone Miner Res. 2014; 29(5): 1081-7.
- Artaza-Artabe I, Sáez-López P, Sánchez-Hernández N, Fernández-Gutierrez N, Malafarina V. The relationship between nutrition and frailty: effects of protein intake, nutritional supplementation, vitamin D and exercise on muscle metabolism in the elderly. A systematic review. Maturitas. 2016; 93: 89-99.
- Rizzoli R, Stevenson JC, Bauer JM, et al. The role of dietary protein and vitamin D in maintaining musculoskeletal health in postmenopausal women: a consensus statement from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Maturitas. 2014; 79(1): 122-32.
- Beaudart C, Buckinx F, Rabenda V, et al. The effects of vitamin D on skeletal muscle strength, muscle mass, and muscle power: a systematic review and meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2014; 99(11): 4336-45.
- Priemel M, von Domarus C, Klatte TO, et al. Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res. 2010; 25(2): 305-12.
- Heaney RP, Holick MF. Why the IOM recommendations for vitamin D are deficient. J Bone Miner Res. 2011; 26(3): 455-7.
- Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited. J Clin Endocrinol Metab. 2012; 97(4): 1153-8.
- Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011; 96(1): 53-8.
- Rosen CJ, Abrams SA, Aloia JF, et al. IOM committee members respond to Endocrine Society Vitamin D guideline. J Clin Endocrinol Metab. 2012; 97(4): 1146-52.
- Rosen CJ, Adams JS, Bikle DD, et al. The nonskeletal effects of vitamin D: an Endocrine Society scientific statement. Endocr Rev. 2012; 33(3): 456-92.
- Cianferotti L, Bertoldo F, Bischoff-Ferrari HA, et al. Vitamin D supplementation in the prevention and management of major chronic diseases not related to mineral homeostasis in adults: research for evidence and a scientific statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO). Endocrine. 2017; 56(2): 245-61.
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