维生素D缺乏评估防治指南-美国内分泌协会2011

Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline Michael F. Holick, Neil C. Binkley, Heike A. Bischoff-Ferrari, Catherine M. Gordon, David A. Hanley, Robert P. Heaney, M. Hassan Murad, and Connie M. Weaver Boston University School of Medicine (M.F.H.), Boston, Massachusetts 02118; University of Wisconsin (N.C.B.), Madison, Wisconsin 53706; University Hospital Zurich (H.A.B.-F.), CH-8091 Zurich, Switzerland; Children’s Hospital Boston (C.M.G.), Boston, Massachusetts 02115; University of Calgary Faculty of Medicine (D.A.H.), Calgary, Alberta, Canada T2N 1N4; Creighton University (R.P.H.), Omaha, Nebraska 68178; Mayo Clinic (M.H.M.), Rochester, Minnesota 55905; and Purdue University (C.M.W.), West Lafayette, Indiana 47907 Objective: The objective was to provide guidelines to clinicians for the evaluation, treatment, and pre- vention of vitamin D deficiencywith an emphasis on the care of patients who are at risk for deficiency. Participants: The Task Forcewas composed of a Chair, six additional experts, and amethodologist. The Task Force received no corporate funding or remuneration. ConsensusProcess:Consensuswasguidedby systematic reviewsofevidenceanddiscussionsduring several conference calls and e-mail communications. The draft prepared by the Task Force was reviewed successively by The Endocrine Society’s Clinical Guidelines Subcommittee, Clinical Affairs Core Committee, and cosponsoring associations, and it was posted on The Endocrine Society web site for member review. At each stage of review, the Task Force received written comments and incorporated needed changes. Conclusions:ConsideringthatvitaminDdeficiencyisverycommoninallagegroupsandthatfewfoods contain vitamin D, the Task Force recommended supplementation at suggested daily intake and tol- erable upper limit levels, depending on age and clinical circumstances. The Task Force also suggested the measurement of serum 25-hydroxyvitamin D level by a reliable assay as the initial diagnostic test inpatients at risk fordeficiency. Treatmentwitheither vitaminD2or vitaminD3was recommended for deficient patients. At the present time, there is not sufficient evidence to recommend screening indi- vidualswhoarenotat risk fordeficiencyor toprescribevitaminDtoattain thenoncalcemicbenefit for cardiovascular protection. (J Clin Endocrinol Metab 96: 0000–0000, 2011) Summary of Recommendations 1.0 Diagnostic procedure 1.1 We recommend screening for vitamin D deficiency in individuals at risk for deficiency. We do not recommend population screening for vitamin D deficiency in individ- uals who are not at risk (1|QQQQ). 1.2 We recommend using the serum circulating 25-hy- droxyvitamin D [25(OH)D] level, measured by a reliable assay, to evaluate vitamin D status in patients who are at risk for vitamin D deficiency. Vitamin D deficiency is de- fined as a 25(OH)D below 20 ng/ml (50 nmol/liter). We recommend against using the serum 1,25-dihydroxyvita- min D [1,25(OH)2D] assay for this purpose and are in favor of using it only in monitoring certain conditions, such as acquired and inherited disorders of vitamin D and phosphate metabolism (1|QQQQ). ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2011 by The Endocrine Society doi: 10.1210/jc.2011-0385 Received February 14, 2011. Accepted May 18, 2011. Abbreviations: BMD, Bone mineral density; BMI, body mass index; CI, confidence interval; I2, inconsistency; IOM, Institute of Medicine; MI, myocardial infarction; OHase, hydroxy- lase; 1,25(OH)2D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; OR, odds ratio; RCT, randomized controlled trials; RDA, recommended dietary allowance; RR, relative risk. S P E C I A L F E A T U R E C l i n i c a l P r a c t i c e G u i d e l i n e J Clin Endocrinol Metab, July 2011, 96(7):0000–0000 jcem.endojournals.org 1 2.0 Recommended dietary intakes of vitamin D for patients at risk for vitamin D deficiency 2.1 We suggest that infants and children aged 0–1 yr re- quireat least400IU/d (IU�25ng)ofvitaminDandchildren 1 yr and older require at least 600 IU/d to maximize bone health. Whether 400 and 600 IU/d for children aged 0–1 yr and 1–18 yr, respectively, are enough to provide all the po- tential nonskeletal health benefits associatedwith vitaminD to maximize bone health and muscle function is not known at this time. However, to raise the blood level of 25(OH)D consistently above 30 ng/ml (75 nmol/liter) may require at least 1000 IU/d of vitamin D (2|QQQQ). 2.2 We suggest that adults aged 19–50 yr require at least 600 IU/d of vitamin D to maximize bone health and muscle function. It is unknown whether 600 IU/d is enough to provide all the potential nonskeletal health ben- efits associated with vitamin D. However, to raise the blood level of 25(OH)D consistently above 30 ng/ml may require at least 1500–2000 IU/d of vitamin D (2|QQQQ). 2.3 We suggest that all adults aged 50–70 and 70� yr require at least 600 and 800 IU/d, respectively, of vitaminD. Whether 600 and 800 IU/d of vitamin D are enough to pro- videallof thepotentialnonskeletalhealthbenefits associated with vitamin D is not known at this time. However, to raise the blood level of 25(OH)D above 30 ng/ml may require at least1500–2000IU/dofsupplementalvitaminD(2|QQQQ). 2.4 We suggest that pregnant and lactating women re- quireat least600IU/dofvitaminDandrecognize thatat least 1500–2000 IU/d of vitamin Dmay be needed to maintain a blood level of 25(OH)D above 30 ng/ml (2|QQQE). 2.5We suggest that obese children and adults and chil- dren and adults on anticonvulsant medications, glucocor- ticoids, antifungals suchasketoconazole, andmedications for AIDS be given at least two to three times more vitamin D for their age group to satisfy their body’s vitamin D requirement (2|QQQQ). 2.6We suggest that themaintenance tolerable upper lim- its (UL) of vitamin D, which is not to be exceeded without medical supervision, should be 1000 IU/d for infants up to 6 months, 1500 IU/d for infants from 6 months to 1 yr, at least 2500IU/dforchildrenaged1–3yr,3000IU/dforchildrenaged 4–8yr,and4000IU/d foreveryoneover8yr.However,higher levels of 2000 IU/d for children 0–1 yr, 4000 IU/d for children 1–18yr,and10,000IU/dforchildrenandadults19yrandolder may be needed to correct vitamin D deficiency (2|QQQQ). 3.0 Treatment and prevention strategies 3.1 We suggest using either vitamin D2 or vitamin D3 for the treatment and prevention of vitamin D deficiency (2|QQQQ). 3.2 For infants and toddlers aged 0–1 yr who are vi- taminD deficient, we suggest treatment with 2000 IU/d of vitaminD2or vitaminD3, orwith 50,000 IUof vitaminD2 orvitaminD3onceweekly for6wk toachieve ablood level of 25(OH)D above 30 ng/ml, followed by maintenance therapy of 400-1000 IU/d (2|QQQQ). 3.3 For children aged 1–18 yr who are vitamin D de- ficient,we suggest treatmentwith 2000 IU/d of vitaminD2 or vitamin D3 for at least 6 wk or with 50,000 IU of vi- tamin D2 once a week for at least 6 wk to achieve a blood level of 25(OH)D above 30 ng/ml, followed by mainte- nance therapy of 600-1000 IU/d (2|QQQQ). 3.4 We suggest that all adults who are vitamin D defi- cient be treated with 50,000 IU of vitamin D2 or vitamin D3 once a week for 8 wk or its equivalent of 6000 IU of vitamin D2 or vitamin D3 daily to achieve a blood level of 25(OH)D above 30 ng/ml, followed bymaintenance ther- apy of 1500–2000 IU/d (2|QQQQ). 3.5 In obese patients, patients with malabsorption syn- dromes,andpatientsonmedicationsaffectingvitaminDme- tabolism,wesuggestahigherdose (twoto three timeshigher; at least 6000–10,000 IU/d) of vitamin D to treat vitamin D deficiency tomaintain a 25(OH)D level above 30 ng/ml, fol- lowedbymaintenance therapyof3000–6000IU/d(2|QQQQ). 3.6 In patients with extrarenal production of 1,25(OH)2D, we suggest serial monitoring of 25(OH)D levels and serum calcium levels during treatment with vi- tamin D to prevent hypercalcemia (2|QQQQ). 3.7 For patients with primary hyperparathyroidism and vitamin D deficiency, we suggest treatment with vi- tamin D as needed. Serum calcium levels should be mon- itored (2|QQQQ). 4.0 Noncalcemic benefits of vitamin D 4.1 We recommend prescribing vitamin D supplemen- tation for fall prevention.We do not recommend prescrib- ing vitamin D supplementation beyond recommended daily needs for the purpose of preventing cardiovascular disease or death or improving quality of life (2|QQQQ). Method of Development of Evidence- Based Clinical Practice Guidelines TheTaskForcecommissioned theconductof twosystematic reviews of the literature to inform its key recommendations. The Task Force used consistent language and geographical descriptionsofboth the strengthof recommendationand the quality of evidence using the recommendations of the Grad- ing of Recommendations, Assessment, Development, and Evaluation (GRADE) system. The Clinical Guidelines Subcommittee of The Endo- crine Society deemed vitamin D deficiency a priority area in need of practice guidelines and appointed a Task Force 2 Holick et al. Guidelines on Vitamin D Deficiency J Clin Endocrinol Metab, July 2011, 96(7):0000–0000 to formulate evidence-based recommendations. The Task Force followed the approach recommended by the GRADE group, an international group with expertise in development and implementation of evidence-based guidelines (1). A detailed description of the grading scheme has been published elsewhere (2). The Task Force used the best available research evidence to develop some of the recommendations. The Task Force commissioned the conduct of two systemic reviews of the literature to inform its key recommendations. The Task Force also used consistent language and graphical descriptions of both the strength of a recom- mendation and the quality of evidence. In terms of the strength of the recommendation, strong recommenda- tions use the phrase “we recommend” and the number 1, and weak recommendations use the phrase “we suggest” and the number 2. Cross-filled circles indicate the quality of the evidence, such thatQEEE denotes very low quality evidence; QQEE, low quality; QQQE, moderate quality; and QQQQ, high quality. The Task Force has confidence that persons who receive care according to the strong rec- ommendations will derive, on average, more good than harm. Weak recommendations require more careful con- sideration of the person’s circumstances, values, and pref- erences to determine the best course of action. Linked to each recommendation is a description of the evidence and the values that panelists considered in making the recom- mendation; in some instances, there are remarks, a section in which panelists offer technical suggestions for testing conditions, dosing, andmonitoring. These technical com- ments reflect the best available evidence applied to a typ- ical person being treated. Often this evidence comes from the unsystematic observations of the panelists and their values and preferences; therefore, these remarks should be considered suggestions. Vitamin D Photobiology, Metabolism, Physiology, and Biological Functions Vitamin D is unique among hormones because it can be made in the skin from exposure to sunlight (3–7). Vitamin Dcomes in two forms.VitaminD2 isobtained fromtheUV irradiation of the yeast sterol ergosterol and is found nat- urally in sun-exposed mushrooms. Vitamin D3 is synthe- sized in the skin and is present in oil-rich fish such as salmon,mackerel, and herring; commercially available vi- tamin D3 is synthesized from the cholesterol precursor 7-dehydrocholesterol naturally present in the skin or ob- tained from lanolin (3). Both vitamin D2 and vitamin D3 are used for food fortification and in vitamin D supple- ments. Vitamin D (D represents D2, or D3, or both) that is ingested is incorporated into chylomicrons, which are ab- sorbed into the lymphatic system and enter the venous blood. Vitamin D that comes from the skin or diet is bi- ologically inert and requires its first hydroxylation in the liver by the vitamin D-25-hydroxylase (25-OHase) to 25(OH)D (3, 8). However, 25(OH)D requires a further hydroxylation in the kidneys by the 25(OH)D-1�-OHase (CYP27B1) to form the biologically active formof vitamin D 1,25(OH)2D (3, 8). 1,25(OH)2D interacts with its vi- tamin D nuclear receptor, which is present in the small intestine, kidneys, and other tissues (3, 8). 1,25(OH)2D stimulates intestinal calcium absorption (9). Without vi- tamin D, only 10 to 15% of dietary calcium and about 60% of phosphorus are absorbed. Vitamin D sufficiency enhances calcium and phosphorus absorption by 30– 40%and80%, respectively (3, 10). 1,25(OH)2D interacts with its vitamin D receptor in the osteoblast to stimulate the expression of receptor activator of nuclear factor �B ligand; this, in turn, interacts with receptor activator of nuclear factor �B to induce immature monocytes to be- come mature osteoclasts, which dissolve the matrix and mobilize calcium and other minerals from the skeleton. In the kidney, 1,25(OH)2D stimulates calcium reabsorption from the glomerular filtrate (3, 11). The vitamin D receptor is present in most tissues and cells in the body (3, 12). 1,25(OH)2D has a wide range of biological actions, including inhibiting cellular prolifera- tion and inducing terminal differentiation, inhibiting an- giogenesis, stimulating insulin production, inhibiting renin production, and stimulating macrophage cathelici- din production (3, 12–14). In addition, 1,25(OH)2D stim- ulates its own destruction by enhancing the expression of the25-hydroxyvitaminD-24-OHase (CYP24R) tometab- olize 25(OH)D and 1,25(OH)2D into water-soluble inac- tive forms. There are several tissues and cells that possess 1-OHase activity (3, 7, 12, 13). The local production of 1,25(OH)2D may be responsible for regulating up to 200 genes (15) that may facilitate many of the pleiotropic health benefits that have been reported for vitamin D (3–7, 12). Prevalence of Vitamin D Deficiency Vitamin D deficiency has been historically defined and recently recommended by the Institute ofMedicine (IOM) as a 25(OH)D of less than 20 ng/ml. Vitamin D insuffi- ciency has been defined as a 25(OH)D of 21–29 ng/ml (3, 10, 16–20). In accordance with these definitions, it has been estimated that 20–100%of U.S., Canadian, and Eu- ropean elderly men and women still living in the commu- nity are vitamin D deficient (3, 21–25). Children and young and middle-aged adults are at equally high risk for J Clin Endocrinol Metab, July 2011, 96(7):0000–0000 jcem.endojournals.org 3 vitamin D deficiency and insufficiency worldwide. Vita- minDdeficiency is common inAustralia, theMiddle East, India, Africa, and SouthAmerica (3, 26, 27). In theUnited States,more than 50%ofHispanic andAfrican-American adolescents in Boston (28) and 48% of white preadoles- cent girls inMaine had 25(OH)D below 20 ng/ml (29). In addition, 42%ofAfrican-American girls andwomenaged 15–49 yr throughout the United States had a blood level of 25(OH)D below 15 ng/ml at the end of the winter (30), and 32% of healthy students and physicians at a Boston hospital had 25(OH)Dbelow20 ng/ml (31). Pregnant and lactating women who take a prenatal vitamin and a cal- cium supplement with vitamin D remain at high risk for vitamin D deficiency (32–34). Causes of Vitamin D Deficiency The major source of vitamin D for children and adults is exposure to natural sunlight (3, 7, 35–37). Very few foods naturally containor are fortifiedwith vitaminD.Thus, the major cause of vitamin D deficiency is inadequate expo- sure to sunlight (5–7, 38).Wearing a sunscreen with a sun protection factor of 30 reduces vitamin D synthesis in the skin bymore than 95% (39). People with a naturally dark skin tone have natural sun protection and require at least three to five times longer exposure to make the same amount of vitamin D as a person with a white skin tone (40, 41). There is an inverse association of serum 25(OH)D and body mass index (BMI) greater than 30 kg/m2, and thus, obesity is associated with vitamin D de- ficiency (42). There are several other causes for vitamin D deficiency (3, 38). Patients with one of the fat malabsorp- tion syndromes and bariatric patients are often unable to absorb the fat-soluble vitamin D, and patients with ne- phrotic syndrome lose 25(OH)D bound to the vitamin D-binding protein in the urine (3). Patients on a wide va- riety of medications, including anticonvulsants and med- ications to treat AIDS/HIV, are at risk because these drugs enhance the catabolism of 25(OH)D and 1,25(OH)2D (43). Patients with chronic granuloma-forming disorders, some lymphomas, andprimary hyperparathyroidismwho have increased metabolism of 25(OH)D to 1,25(OH)2D are also at high risk for vitamin D deficiency (44, 45). Consequences of Vitamin D Deficiency Vitamin D deficiency results in abnormalities in calcium, phosphorus, and bone metabolism. Specifically, vitamin Ddeficiency causes adecrease in the efficiencyof intestinal calcium and phosphorus absorption of dietary calcium and phosphorus, resulting in an increase in PTH levels (3, 10, 22, 23). Secondary hyperparathyroidism maintains serum calcium in the normal range at the expense of mo- bilizing calcium from the skeleton and increasing phos- phorus wasting in the kidneys. The PTH-mediated in- crease in osteoclastic activity creates local foci of bone weakness and causes a generalized decrease in bone min- eral density (BMD), resulting in osteopenia and osteopo- rosis. Phosphaturia caused by secondary hyperparathy- roidism results in a low normal or low serum phosphorus level. This results in an inadequate calcium-phosphorus product, causing amineralizationdefect in the skeleton (3, 46). In young children who have little mineral in their skeleton, this defect results in a variety of skeletal defor- mities classically known as rickets (24, 47). In adults, the epiphyseal plates are closed, and there is enough mineral in the skeleton to prevent skeletal deformities so that this mineralization defect, known as an osteomalacia, often goesundetected.However,osteomalaciacausesadecrease in BMDandisassociatedwith isolatedorgeneralizedachesand pains in bones and muscles (48, 49). Vitamin D deficiency also causes muscle weakness; affected children have diffi- culty standingandwalking (47,50),whereas theelderlyhave increasing sway and more frequent falls (51, 52), thereby increasing their risk of fracture. Sources of Vitamin D Amajor source of vitaminD formost humans comes from exposure of the skin to sunlight typically between 1000 h and 1500 h in the spring, summer, and fall (3–5, 7). Vi- taminDproduced in the skinmay last at least twice as long in the blood compared with ingested vitamin D (53). When an adult wearing a bathing suit is exposed to one minimal erythemal dose ofUV radiation (a slight pinkness to the skin 24 h after exposure), the amount of vitamin D produced is equivalent to ingesting between 10,000 and 25,000 IU (5). A variety of factors reduce the skin’s produc- tion of vitamin D3, including increased skin pigmentation, aging, and the topical application of a sunscreen (3, 39, 40). Analterationinthezenithangleof thesuncausedbyachange in latitude, season of the year, or time of day dramatically influences the skin’s production of vitamin D3 (3, 5). Above and below latitudes of approximately 33°, vitamin D3 syn- thesis in the skin is very low or absent during most of the winter. Few foods naturally contain vitamin D2 or vitamin D3 (Table 1). In the United States and Canada, milk is fortified with vitamin D, as are some bread products, orange juices, ce- reals, yogurts, and cheeses (3). In Europe, most countries do not fortify milk with vitamin D because in the 1950s, 4 Holick et al. Guidelines on Vitamin D Deficiency J Clin Endocrinol Metab, July 2011, 96(7):0000–0000 there was an outbreak of vitamin D intoxication in young c