VITAMIN D DEFICIENCY PATHWAY SUMMARY Assessment Cnsider vitamin D in children with the fllwing risk factrs: Dark skin Limited sun expsure Lw dietary intake Chrnic use f medicatins Malabsrptin prblems Obesity Premature birth Chrnic renal disease r histry f renal transplant Infants that are breastfed withut vitamin D supplementatin and grwth is faltering Infants f breastfeeding mthers with dark skin r cvered (minimal skin expsure) withut vitamin D supplementatin r lw intake f fds cntaining vitamin D Labratry Study Request fr 1,25 dihydrxyvitamin D will be intercepted by the team and the prvider frm letter will be sent t the rdering prvider Therapeutics The Children s Hspital Clrad Vitamin D Cmmittee recmmends that all individuals, wh are supplemented, take nce-daily vitamin D3 r its weekly equivalent t maintain serum 25(OH)D levels f at least 30 ng/ml. Recmmendatins fr fllw up: Vitamin D levels shuld be rechecked after 6 t12 weeks Vitamin D can be evaluated sner if medically indicated. Patients with chrnic illness shuld have their vitamin D levels checked annually Cnsider Endcrinlgy referral if deficiency is resistant t treatment r patient has dcumented rickets that is nt assciated with vitamin D deficiency (hypphsphatemic rickets). Preventin Infrmatin regarding apprpriate sun expsure, the use f vitamin D supplements, and eating a diet rich in calcium and vitamin D shuld be made available t each patient. Table 1. Dsing Recmmendatins Frequently Asked Questins Page 1 f 11
TABLE OF CONTENTS Pathway Summary Target Ppulatin Backgrund Definitins Initial Evaluatin see Recmmendatin fr Screening Labratry Studies Imaging Therapeutics Preventin Frequently Asked Questins Parent Prvider Educatin Material Appendix A. Sample Labratry Request Letter References Clinical Imprvement Team TARGET POPULATION Inclusin Criteria Patients with risk factrs fr lw vitamin D levels Exclusin Criteria Pediatric patients with chrnic medical cnditins which may require large dses and mre frequent fllw up. Patients with dcumented Rickets, that is nt assciated with vitamin D deficiency (hypphsphatemic) BACKGROUND DEFINITIONS Vitamin D is a fat-sluble vitamin that acts as a sterid hrmne. The bdy makes vitamin D frm chlesterl thrugh the actin f the sun s UVB rays n the skin. Factrs such as skin clr, age, amunt and time f sun expsure, and gegraphic lcatin affect hw much vitamin D the bdy makes. The primary functin f vitamin D is t maintain nrmal bld cncentratins f calcium and phsphrus, in additin t supprting bne, cardivascular, pancreas, muscle, and brain health1. Nrmal bne mineralizatin depends n adequate calcium and phsphate and this is maintained by vitamin D. Lw vitamin D results in decreased calcium and phsphate, which leads t secndary hyperparathyridism causing inadequate mineralizatin and lss f skeletal mass. When grwth plates have clsed, this can lead t stemalacia; if the grwth plates have nt clsed, rickets may develp. RECOMMENDATION FOR SCREENING Nte: Screening fr vitamin D levels shuld be reserved fr patients with risk factrs fr deficiency. Universal screening f all patients is nt recmmended 2,3. Cnsider assessing vitamin D status in children with the fllwing risk factrs: Dark skin 1 Limited sun expsure, including frequent sunscreen use and cultural cnventin assciated with cvering bdy 3 Lw dietary intake, including vegan/macrbitic diets r allergy/intlerance 3 Chrnic use f medicatins (e.g. anticnvulsants, sterids [including inhaled]) 2 Page 2 f 11
Malabsrptin prblems (including celiac disease, cystic fibrsis, etc.) 2 Obesity 1 Premature birth 3 Chrnic renal disease r histry f renal transplant Infants that are breastfed withut vitamin D supplementatin and grwth is faltering Infants f breastfeeding mthers with dark skin r cvered (minimal skin expsure) withut vitamin D supplementatin r lw intake f fds cntaining vitamin D 3 LABORATORY STUDIES Vitamin D levels are measured by ttal serum 25-hydrxyvitamin D [als referred t as 25(OH)D] 2. Since the develpment f 1,25-dihydrxyvitamin D testing, prper utilizatin based n clinical need has been prblematic. Testing 25-hydrxyvitamin D is mst useful in nutritin assessment, primarily due t its lnger half-life. The circulating half-life f 1,25- dihydrxyvitamin D is relatively shrt, which limits utility fr verall vitamin D assessment. Testing can be useful in the diagnsis f renal dysfunctin in cnjunctin with parathyrid hrmne. 1,25-dihydrxyvitamin D is elevated in sarcidsis and primary hyperparathyridism, and decreased in renal failure and hyperparathyridism. Labratry Apprval Prcess Test requests fr 1,25 dihydrxyvitamin D will be flagged fr review by the lab and sent t the rdering prvider fr review. Labratry team respnsibility: Request fr 1,25 dihydrxyvitamin D will be intercepted by the team and the prvider frm letter will be sent t the rdering prvider. After the rdering prvider respnds with their decisin, the lab team will either: OR Send the specimen fr prcessing Cancel the request and redirect, if apprpriate, t 25(OH)D testing The lab team will dcument the case and decisin in their database Prvider respnsibility: In the event the rdering prvider des nt respnd within tw days, the request will be sent t the n-call prvider fr the grup. The n-call prvider can decide t apprve the testing r redirect testing if clinically indicated Evaluatin f Labratry Results Vitamin D status as measured by 25(OH)D Deficiency = Less than 10 ng/ml At risk fr rickets, pathlgic fractures, and nn-skeletal disease Insufficiency = 10 t 20 ng/ml At risk fr bne disease including stepenia/steprsis, musculskeletal pain, and nn-skeletal disease including peridntal disease At risk fr insufficiency = 20 t 30 ng/ml (interpretatin shuld take int accunt time f year, skin clr, and presence f besity r medical cnditin) At risk fr nn-skeletal disease (cardiac, nclgic) Page 3 f 11
Sufficiency = 30 t 96 ng/ml Txicity = Greater than 96 ng/ml Hypercalcemia Hypercalciuria Kidney stnes Hyperphsphatemia THERAPEUTICS Gastrintestinal distress, bne pain Recmmendatins fr supplementatin: These recmmendatins d nt differentiate between the use f chlecalciferl (D3) r ergcalciferl (D2), as there is insufficient data t shw any significant difference in absrptin, particularly at therapeutic levels 5. Fr patients wh require large weekly dses (i.e., 50,000 Internatinal Units [IUs]) ergcalciferl (D2) is preferred: hwever, it shuld be nted that patient insurance may require prescriptin and prir authrizatin (PAR). The American Academy f Pediatrics recmmends daily dsing; hwever, the dsing schedule (daily versus weekly) shuld be individualized t minimize financial issues and treatment burden, particularly in patients with chrnic illness 6. Other cnsideratins include the ptential fr vitamin D txicity if a weekly high-dse regimen is inadvertently cntinued r pssible lss f efficacy if the weekly dse is missed. The Children s Hspital Clrad Vitamin D Cmmittee recmmends that all individuals, wh are supplemented, take nce-daily vitamin D3 r its weekly equivalent t maintain serum 25(OH)D levels f at least 30 ng/ml. Table 1. Dsing Recmmendatins 25(OH)D Level Daily dsing fr children 0 t less than 10 years f age Daily dsing fr patients 10 t 18 years f age Deficiency: Less than 10 ng/ml Insufficiency: 10 t 20 ng/ml At-risk-fr-insufficiency: 20 t 30 ng/ml 2000 Internatinal Units (nrmal weight) 4000 Internatinal Units (bese, BMI greater than 95%) 1000 Internatinal Units (nrmal weight) 2000 Internatinal Units (bese BMI greater than 95%) 400 t 800 Internatinal Units (nrmal weight) 1000 Internatinal Units (bese, BMI greater than 95%) 4000 Internatinal Units (nrmal weight) 8000 Internatinal Units (bese, BMI greater than 95%) 2000 Internatinal Units (nrmal weight) 4000 Internatinal Units (bese, BMI greater than 95%) 800 Internatinal Units (nrmal weight) 1000 Internatinal Units (bese, BMI greater than 95%) Cnsider increased supplementatin in patients with at-risk medical cnditins (i.e., premature birth status, renal impairment, CF, malabsrptin), if dark skin, r limited dietary intake. *** Dsing amunt shuld be inclusive f all supplements (ie. Vitamin D, multivitamin, Omega-3, etc) Page 4 f 11
Recmmendatins fr fllw up: Vitamin D levels shuld be rechecked after 6 t12 weeks when supplementatin is initiated, r with any dse change. Vitamin D can be evaluated sner if medically indicated. A dse respnse t therapy shuld be evident n labratry evaluatin within 4 t 6 weeks f supplementatin. Patients with chrnic illness (CF, renal disease, etc.) shuld have their vitamin D levels checked annually as part f rutine health maintenance, and regardless f supplementatin status. Cnsider Endcrinlgy referral if deficiency is resistant t treatment r patient has dcumented rickets that is nt assciated with vitamin D deficiency (hypphsphatemic rickets). Children s Hspital Clrad Endcrinlgy department is available fr phne cnsultatin at any time with questins r cncerns (720-777- 6128). PREVENTION Infrmatin regarding apprpriate sun expsure, the use f vitamin D supplements, and eating a diet rich in calcium and vitamin D shuld be made available t each patient. Preventin and maintenance measures t avid deficiency thrugh vitamin D supplementatin are suggested as fllws: Breast feeding infants up t 12 mnths ld: 400 Internatinal Units/day Inadequate sun expsure r limited dietary intake: 1 t 18 years ld: 400 t 800 Internatinal Units/day Adults: 800 Internatinal Units/day Pregnant and lactating wmen: 6400 Internatinal Units/day, if baby is nt being supplemented t supprt 400 Internatinal Units recmmendatin in breast milk Obese patients: 1000 Internatinal Units/day Patients with at-risk medical cnditins (i.e. premature birth status, renal impairment, CF, malabsrptin, etc), may require higher maintenance dses and mre frequent fllw up. FREQUENTLY ASKED QUESTIONS What are the frms f vitamin D? Chlecalciferal (vitamin D3) A naturally ccurring frm f vitamin D made by the skin upn sun expsure (UVB rays) Fund in fds and mst supplements, including cd liver il and sheep lanlin Calcidil (25-hydrxyvitamin D) A prehrmne made directly frm chlecalciferl in the liver Lw bi-activity, but a majr circulating frm in the bld stream Used t measure vitamin D deficiency Calcitril (1,25 dihydrxyvitamin D3) An activated frm f vitamin D made frm calcidil in the kidneys and bdy tissue Mst ptent sterid hrmne in the bdy Page 5 f 11
Ergcalciferl (vitamin D2) Nt naturally ccurring in the bdy, made in the labratry and used in prescriptin vitamin D Is there a difference between the frms f Vitamin D in supplements? There are tw main frms f vitamin D in supplements: chlecalciferl and ergcalciferl There is n evidence f significant difference in absrptin between the different frms, especially at therapeutic levels What is the cntrversy regarding vitamin D sufficiency? The Institute f Medicine (IOM) and Endcrine Sciety recmmendatins disagree n the level f sufficiency in assessments f bne health fr determining deficiency threshlds. There ften isn t a specific level abve which ne is prtected, nr is there a level at which disease is inevitable. Treating t a 25(OH)D level greater than 30 ng/ml may nt prduce additinal benefits abve treating t a level f greater than 20 ng/ml; hwever, the health risks f ding s appear t be minimal but therapy may be expensive fr patients Are there drug interactins that make a patient mre at risk? Crticsterids Reduce calcium absrptin resulting in impaired vitamin D metablism Bile acid sequestrants (eg. chlestyramine) Orlistat May impair absrptin f vitamin D Shuld be taken several hurs apart May impair absrptin f vitamin D Shuld be taken at least 2 hurs apart Phenbarbital and phenytin: increase the hepatic metablism f vitamin D t inactive cmpunds and decrease calcium absrptin, which als impairs vitamin D metablism. Is there a specific time my patients shuld take their supplement? We advise taking vitamin D supplements with the largest meal f the day t imprve absrptin. Shuld I advise my patients t get mre sun? Mnitred sun expsure Clrad is abve the 31 degree latitude cut ff, increasing risk f vitamin D deficiency Unprtected sun expsure (UVB rays): Light skin tnes: 10 t 5 minutes daily n arms/legs prvides 2000 t 3000 Internatinal Units Darker skin: requires 5 t 6 times lnger Shuld I screen fr metablic r underlying malabsrptin if my patient is deficient? Mst patients d nt have any ther disease prcesses, and thus lead t unnecessary evaluatin. Cnsider additinal screening, nly fr patients with signs r symptms suggesting underlying disease prcesses (e.g. diarrhea, frequent upper respiratry infectins, r skin changes such as dry skin r hair lss). If my patient has vitamin D deficiency, shuld I screen fr steprsis? Additinal screening is nly indicated if clinical histry (bne pain, fractures, etc.) is suggestive f steprsis. Bne density testing is expensive and very lw yield. Page 6 f 11
When shuld I repeat labratry evaluatin after starting supplementatin? Labs shuld be repeated in 6 t 12 weeks. Des insurance typically cver supplementatin? Insurance usually des nt cver vitamin D supplementatin. Very high dses (i.e. 50,000 Internatinal Units per week) may be available thrugh prir authrizatin (PAR), but are nt typically recmmend except in cases f severe deficiency. PARENT AND PROVIDER EDUCATION MATERIALS Handuts: Vitamin D supplements Dsing chart Table f dietary vitamin D Page 7 f 11
APPENDIX A. SAMPLE LABORATORY TEST LETTER Dear Prvider, Our lab received a request fr 1,25 dihydrxy vitamin D fr yur patient,. This request requires review befre it will be sent fr prcessing. Recent studies fund that mre than 50% f rders were placed in errr, where 25-hydrxy vitamin D was the intended test t assess nutritinal status. 25-hydrxy vitamin D is mst useful in nutritin assessment, primarily due t its lnger half-life. It is elevated with vitamin D intxicatin, and decreased with malabsrptin, nutritinal deficiency, and in liver disease. This test is perfrmed daily in Children's Hspital Clrad Labratry. The circulating half-life f 1,25 dihydrxy vitamin D is relatively shrt, which limits utility fr verall vitamin D assessment. Testing can be useful in the diagnsis f renal dysfunctin in cnjunctin with parathyrid hrmne. 1,25- dihydrxy is elevated in sarcidsis and primary hyperthyridism, and decreased in renal failure and hypparathyridism. There are tw ptins fr hw t prceed with this test: We can cancel the rder fr 1,25 dihydrxy vitamin D and yu can write an add-n cmmunicatin fr 25 hydrxyl vitamin D- we d nt need a new rder r specimen. Prceed with the test as yu have rdered it. Please let us knw if we can be helpful and hw yu want t prceed. We aplgize fr any incnvenience if this was the test yu intended. Sincerely, The Labratry Team and Vitamin D Cmmittee at Children's Hspital Clrad Page 8 f 11
REFERENCES 1. Alia JF. Clinical Review: The 2011 reprt n dietary reference intake fr vitamin D: where d we g frm here? J Clin Endcrinl Metab 2011;96:2987-96. 2. Hlick MF, Binkley NC, Bischff-Ferrari HA, et al. Evaluatin, treatment, and preventin f vitamin D deficiency: an Endcrine Sciety clinical practice guideline. J Clin Endcrinl Metab 2011;96:1911-30. 3. Dietary Reference Intakes fr Calcium and Vitamin D: The Natinal Academies Press; 2011. 4. Pramythin P, Hlick MF. Vitamin D supplementatin: guidelines and evidence fr subclinical deficiency. Curr Opin Gastrenterl 2012;28:139-50. 5. Biancuzz RM, Clarke N, Reitz RE, Travisn TG, Hlick MF. Serum cncentratins f 1,25-dihydrxyvitamin D2 and 1,25-dihydrxyvitamin D3 in respnse t vitamin D2 and vitamin D3 supplementatin. J Clin Endcrinl Metab 2013;98:973-9. 6. Grdn CM, Williams AL, Feldman HA, et al. Treatment f hypvitaminsis D in infants and tddlers. J Clin Endcrinl Metab 2008;93:2716-21. 7. Classifying recmmendatins fr clinical practice guidelines. Pediatrics 2004;114:874-7. Page 9 f 11
CLINICAL IMPROVEMENT TEAM MEMBERS Kimberly Gracey, PA-C Clinical Nutritin Helen Seagle, MS, RD, CPS Clinical Nutritin Phil Zeitler, MD Endcrinlgy Denise Pickard, MSN, RN Clinical Care Guideline Crdinatr Vitamin D Cmmittee Members Nutritin: Nancy Krebs, MD (Sectin Head), Kimberly Gracey, PA-C, Helen Seagle, MS RD CSP, Whitney Abramic, RD CNSC, Sherry Archuleta, MS RD CNSC (Directr Clinical Nutritin) Endcrinlgy: Phil Zeitler, MD Pulmnlgy: Cathy Lingard, MS RD CNSC Kidney Center: Rse Wlschuk, RD NICU: Kim Vllrath, MS RD, Susan Marshall, MS RD CNSC CSP EDU: Cinda Nab, RD Hematlgy/Onclgy: Debra Stiller, RD CNSC Labratry: Linda Gabel APPROVED BY Pharmacy and Therapeutics Cmmittee - Octber 2014 Clinical Care Guideline and Measures Review Cmmittee - Octber 2014 MANUAL/DEPARTMENT ORIGINATION DATE Clinical Care Guidelines/Quality Nvember 3, 2014 LAST DATE OF REVIEW OR REVISION Nvember 3, 2014 APPROVED BY Daniel Hyman, MD, MMM, Chief Quality Officer, Children s Hspital Clrad REVIEW/REVISION SCHEDULE Scheduled fr full review n Octber 1, 2018 Clinical pathways are intended fr infrmatinal purpses nly. They are current at the date f publicatin and are reviewed n a regular basis t align with the best available evidence. Sme infrmatin and links may nt be available t external viewers. External viewers are encuraged t cnsult ther available surces if needed t cnfirm and supplement the cntent presented in the clinical pathways. Clinical pathways are nt intended t take the place f a physician s r ther health care prvider s advice, and is nt intended t diagnse, treat, cure r prevent any disease r ther medical cnditin. The infrmatin shuld nt be used in place f a visit, call, cnsultatin r advice f a physician r ther health care prvider. Furthermre, the infrmatin is prvided fr use slely at yur wn risk. CHCO accepts n liability fr the cntent, r fr the cnsequences f any actins taken n the basis f the infrmatin prvided. The infrmatin prvided t yu and the actins taken theref are prvided n an as is basis withut any warranty f any kind, express r implied, frm CHCO. CHCO declares n affiliatin, spnsrship, nr any partnerships with any listed rganizatin, r its respective directrs, fficers, emplyees, agents, cntractrs, affiliates, and representatives. Page 10 f 11
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