Say g $ 3 8 2 Chapter 22.12 Vitamin D, Nutritional Rickets and Hypervitaminosis D S Balasubramanian Vitamin D refers to the precursors of the active secosteroid hormone 1,25-dihydroxyritamin D, (1,25-OH, D,), named as calcitriol, Recognition of tickets as a childhood bone disease led to the discovery of vitamin D, a fat-soluble prohotmone. In the beginning of 20th century, the antrachitie effect of cod liver oil ‘was fist described. Evidence forthe fact that there are benefits, extending beyond bones has resulted in renewed interes in this direction. An increasing variety of noncaleemic actions is reported In the recent times, partcalarly those related to decreasing risk of common cancers, autolmriune diseases, infectious diseases, heart dicease, neurocognitive cisonders, peychiatie illnesses, allergy, hme, diabetes mellitus, pain and even mortality EPIDEMIOLOGY OF VITAMIN D DEFICIENCY ‘Vitamin D deficiency is considered as the most under-diagnosed, sul unler-tretea satin ecient in the world ais widely prevalent in al parts of the world irrespective of age, gender, race and geography. The prevalence in India is reported to be as high as 70-100% in the genetel population. The reasons for this are factors, such as non-fortifeation of dairy products, socioreligious and cultural practices not facilitating adequate sun exposure. As consequence, subclinical vitamin D deficiency is prevalent in epldemie proportions in both urban and rural setings, and across all socioeconomic and geographic stata inthe society. The other reasons for the high prevalence include vegetarianism, low calelurn Intake, high phytate dlet, lactose intolerance and genctc factors, ETIOLOGY OF VITAMIN D DEFICIENCY Vitamin D deficiency s eammon in infants who are dark-skinned and exclusively breastfed 5eyond 3-6 months of age, particularly in the background of matersal vitamin D deficiency during pregnancy or prematurity Vitamin D deficiency is also common among children who are on vegetarian and unusual diets, use anticonvulsant or antirerovital medications, or those with malabsorption. Additional isk factors include residence at higher latitudes, winter season, and other causes of low sun exposure (Hox 1), Genetic pleosrorphism predisposing individuals to vitamin D deficiency ickes has been recently VITAMIN D METABOLISM ‘Vitamin D, (ergocaleifero) Is obtained only from diet, whereas vitamin Ds (cholecaliferal is found in cod liver oll and oly fish, ands the form synthesize in skin, Sunlight, specially ultraviolet B rays in the 290-315 nm range, converts 7-dehydrocholesterol (present in skin) to previtamin D,. At normal skin temperature, Previtamin D, thermally Bomerizes during a period of hours to vitamin D;, ltbinds(o vitamin D-bindingproteinand is transported to the liver for 25-ydrosylation and then to the kidney. The vitamin D binding proteir-250HD complex is excreted and then, reabsorbed in the proximal tubule through the endocytic receptors megalin and cubilin, where it undergoes 1-hydroxylation by CYP27B1 resulting in the ztive metabolite 1,25-diydroxyvitamin D [ealetriol,1,25(01,D|- 1,25(0H),D binds to the vitamin D receptor, which heterodimerizes with the retinoic acid receptor, {o form a ligand-receptor complex that targets specific response elements on the genome (Fig. 1). Pees Disorder of vitamin synthesis. Increase skin pigmentation “Topical application of sunscreen agents Greicothnng preventing sutight enpooie ighsisebullaings and urbanization Geographical location Latitude (> 400 north or south) Winter season ‘Arpolluton cloud cover igh attode ‘oldance of sunlight for cosmetic reascns and feat of skin cancet Decreased intake of vitamin D—vegetariansm [Decreased maternal vitamin O stores andexclusve breastfeeding Malabsorption Celiac disease Pancreatic insufficiency Chronic cholestasis Decreased synthesis or increased degradation of 25(0H)D Chronic lve disease ‘rua fami sonaze, antifungals anticonvulsants) Genetic actors, Sun sei 8 Ge) omar L + 240190 —+ 1280810 ver weray ‘nese \" sbsoaton Parathyroid glands UpTit secretion Diet: fortication/supplementation Vitamin 0,= ergocaliterat Figure 1 vitamin D metabolism MECHANISM OF ACTION Maintaining an adequate level of serum calcium and phosphorus Js the most important biochemical function of vitamin D ‘without which only 10-19% of dietary caleium and about 60% of phosphorus willbe absorbed, Vitamin D receptorsexstina variety Of cells esponsible fr the biological eet on more than mineral ‘metabolism. The primary action of 125(OH),D is to timate intestinal calcium absorption. Vitamin D sulcieney increases calciumand phosphors absorption. the interaetion of 1,25(08),) with its receptor in the osteoblast stimulates the expression of receptor aetvatr of a nuclear factor ligand, which interacts with receptor activator of & nuclear factor resulting in induction of ‘immature monoeytes to become mature osteoclasts, which in turn results in dissolution of the matex and mobilization of calcium nd other minerals rom the skeleton, In aio, 1,25(0H),D also Stimulates caleium reabsorption fom the glomerular trate Most tssues and cells in the body contain reeeptors for 1,25(OH),D which has a wide range of tologeal actions, neluding inhibiingcllular proliferation andinducingterminaldiflerenation, inhibiting angiogenesis, stimulating inal production, inhibiting renin production, and stimulating macrophage cathelicidin production, In aditon,1.25{01), stimulates its own destuctonby enhancing the expression of the 25-hydroxyvitamin D-24- Olase(CYP24R) to metabalize25{OH)D and 1,25(0H),D intowater- soluble inaetve forms, Several tsues and cells possess 1-OHase activity. Locally produced 1,25(0H),D In various tissues may be Involved in the regulation of up to 200 genes, thereby facilitating many ofthe pleiottopic health benefits due vitamin D. Though the conversion to the active 1,25(0H). form is tghtiy regulated by parathyroid hormone (PTH) and low levels of calium and phosphorus, the conversion of D to 25(011)D is not well regulated. PTH srelease from the parathyroid gland in response to decreased calctam and/or elevated shosphoras levels PIHt sumulates the Kidneys to increase calcium resorption and activate CYP27B1 t0 synthesize more 1,25(0H),D and aetvates osteoblasts that facilitate the conversion of preosteoslasts to osteoclasts. Osteoclasts dissolve bone to fee up caleium to correct the effects of deficiency that orginally activated the parcthyroid gland seerewe PTH. Production of excess of active vitamin Dis inhibited by a negative feedbackloop. 1,25(0H),D inhibits PTH, simulates the release of ibrolast growth factor 23 (FGP2) from oxeoblasts, and also induces the enzyme CYP2AAL, FGF2S reduces dreulating phosphorus by altering kidney production ofa sodhunephosphorus evraispovter an ible Ue ‘itamin-D-activating enzyme CYP27B1. CYP24A1 enzyme places & hydroxy group on €-24 of 1,25(0H,D,feitating its metabolism into calitriol and subsequent excretion inthe bile. DAILY REQUIREMENTS AND SOURCES For most humans, vitamin D comes from exposure of the skin {o sunlight, When compared with ingested vitamin D, what Is produced inthe skin maylast atleast twice as longin the blood. The Fecommended dietary allowance of vitamin D for children 1-18 ‘yeats, pregnant and lactating women is 600 1U (15 meg) cay. This, intake can be provided in the dit or as a vitamin D supplement, ‘The estimated adequate ntake for Infants up to 12 months Is, 400 TU (10 meg) daily. Routine supplementation of vitamin D to exclusively breastfed infants is yet not recommended in India, The present recommendations for dietary vitamin D intake are primarily based upon the beneficial effects of ealcium and vitamin Don skeletal health. The evidence supporting a benefit of vitamin D om estraskeletal outcomes has so far been weak, inconsistent, Inconclusiveas to causality and insufficient and, thetefore, has not been used aca hasis fr dletary reerenee intake development RICKETS ‘The pathological definiticn of rickets, the failure to mineralize newly formed bone, mears that preformed osteoid is unmine zed (osteomalacia) and endochondral calcification at the growth plate is absent or reduced with associated growth-plate deformity. Rickets and osteomalacia. are both disorders of deficient mineralization of organic matrix, but with fndamental diferences. Rickets is a disease of the physes (growth plates) iatactercea sot oly by deficient ier aiaion of et tiage and osteoid but also by retaxded endochondral ossification, which causes excessive accumulation of physeal cartilage, growth fllure and skeletal deformities. The abnormalities of mineralization and ossification are caused by insufficient circulating levels of caleiurn tnd phosphate ions. As rid.ts is a disorder of open growth plates, itis seen only in children and manifests mostly daring infancy (usually less than 18 morths of age) and the adolescent growth spurt. In osteomalacia, an insufficient Ca xP product causes failure ‘of normal mineralization of osteoid, Inid down either at sites of bone turnover or by the periosteum in the process of membranous bone formation. These processes occur in both adultsand children, Hence, osteomalacia can 3¢ present at any age, Abnormalities of ineral ion homeostasis kad to skeletal deformity by disrupting endochondral ossification rather than just causing deficient ation ofeantlage and ortoid, Staging of Rickets Stage! Following vitamin D deficiency, intestnal absorption of calcium declines causing hypocalcemia, which can be clinically silent or lead to Seizures or other manifestations. In response, secondary hhyperparathyroidism (HPTH) develops, mobilizing calcium and phosphate from bone, increasing renal calcium reabsorption and phosphate excretion, and upregulating renal 25-hydroxyvitamin, D-loshydroxylase (J-OHase) 0 Increase calcitriol and, hence, {testinal calelum absorption. Stageil ‘There is normalization of circulating caleium. PTH and alkaline phosphatase (ALP) are elevated and there is hypophosphatemia, Caleitriol levels can be elevated. at this time, hence, their ‘measurement is generally not useful inthe diagnosis of vitamin D Aeficency. At this stage, physeal manifestation of rickets become apparent clinically and radiographically, Stage im ‘With worsening vitamin D deficiency, substrate 25-hydroxyvitamin, D (25D) levels fall low enough that calitiol can no longer be ‘maintained despite PTH stimulation of 1-OHase. This leads 10 decreased intestinal calcium absorption, return of hypocalcemia, \worseningof secondary HPTH, and lord clinical and radiographic features of rickets, al Features Flori skeletal features are most prevalent benween 3 months and 18 ‘months of age due o development of deformities of weight-bearing limbs. In infants, deformities occur in the forearms, whereas, in toddlers, bow legs (gent varum) (Fig. 2) or knock knees (gent valgum) are offen seen, Cranfotabes, poor growth in height and, \welght, frontal bossing ofthe skull, swelling of wrists, knees and, ankles and increased sweatingare frequently present. Rachiterosary (Fig. 2) due to expansion of the costochondral junctions and an Inward diaphragmatic pull ofthe soft ribcage gives rise to Harrison's sulcus (groove). Denttion may be delayed, and development of {ooth enamel may be impaired. lritabilty, secondary to bone pan, {sa common feature in ichitc infants Muscle weakness leads (0 hypotonia and delayed motor development, such as late walking. Adolescents with rickets usually present with vague symptoms, such as aches and pains in lower limbs, often with exercise. Muscle ‘weakness and the proximal myopathy may cause difficulty in cdimbing stairs. Hypocaleemic tetany may occur in adolescents. Flori signs of rickets are rare in adolescents. Pelvic deformities, that develop during female adolescence can later lead to obstructed labor due to cephalopetvic disproportion. Diagnosis Biochemical Changes Hlevated ALP is a reliable marker of disease activity because it partcipatesin the mineralization of bone an growth plate cartilage ATP levels are normal pte S00 H/T in neamates and 1,000 TH in cildren up © 9 years of age and decease ater puberty. Serum phosphorus concentrations usually are lw in both ealeipenie and Dhosphopenie rickets, Serum calcium levels ave usually low in Caleipene rickets, but may be norman some stages ofthe disease due o secondary HPTH. The serum concentration of PTH iselevated Incaleipenicrickets butis normalin phosphopenicrickets able ). Radiographic Findings ‘he following findings may be seen: (a) widening of the ‘epiphyseal plate (b) cupping and splaying ofthe epiphyseal end 924 Winn ‘SI9P0SIq |EUORLANN pue Ut8 AY g $ 3 8 & of metaphysis with stippling and formation of cortical spurs (6) delay in appearance of the epiphyseal bone centers which are small and osteopenic;(d) asteopenic shafs of the long bones and thin cortices () fuzzy trabecular pattern which is coarse, with a sround-glass appearance; and (F) deformed shafts of the long bones (Figs 4 and 5) Extreme deficiency may lead to pathological cures and looser zones (Milkman’s fractures). Looser zones are pseudofractures, narrow radiolucent ines, 2-5 mm wide, with selerotie borders, and are typical findings in osteomalacia and are bilateral and symmetic and le perpendicular to the cortical ‘margins of bones. Milknan syndrome is the combination of ‘multiple, bilateral and syrrmetric pseucdofractures. Figure 2 Gowiegs anddouble mallolin a child with rickets Bone Mineral Density Is those with osteomalacia related to vitamin D deficiency, markedly reduced spine, hip and forearm bone density [as ‘measured by dusk-energy Xray absomtiometry (DXA)} may be served though bone mineral density (BMD) is not necessary required forthe diognosis of osteomalacia, and reduced BMD does not distinguish osteapoross from osteomslaca Vitamin D Levels ‘Measurement of25{OH)D levels isthe eal tool toassess vitamin D status. 25{OH)D Is the main circulating orm of vitamin D andhasa half-life of2-8 weeks in contrast to 1,25(0H),D which has a shorter Figure Rachitcrosary Figure 4 Skiagram ofthe chest shouting widening ofthe anterior ‘ends ofthe ribs and decreased bone density ta! Figure 5 Skiagram ofthe wilst showing cupping, fraying and ‘decreased bone mineral censty 1 Stages of viaminD deficiency in elation to biochemical markers and rediographic features Stages ___Plasmacakcim __Plasmaphosphorus__ ALP. PTH 25(081 __1.25(0H),03 Radiography aly Nib t 7 T Y N Osteopenia Moderate NIL 1 1 m™ 4 1 Rachiti changes 1+ Severe uw th ci ria NA Rachitic changes 2+half-life of about 4 hours. Measurement of 1,25(0H),D is neither reliable nor recommended for assessment of vitamin D stores. For children with caleipenc rickets, measurement of serum 25(0H)D helps co distinguish rickets caused by vitamin D deficieney from other causes of caleipenicrickets. Serum concentration of 25(0H] accurately reflects the amount of vitamin D stored in the body, and, hence is low in. nutitional rickets, whereas Ic Is normal or slightly increased in the her forms of rickets. 1,25(0H),D can be low, normal or increased in caleipentc rickets. 1,25{0H),D levels paradoxically may intially increase in response to rsing levels subsequently decrease because its substrate, 25(OH)D, is limited but Is always increased in VDDR type Tl and hhypophosphatemic rickets Majority of children with vitamin D deficiency rickets have serum 25{0H)D concentrations less than 25 nmol (10 ng/mL), and often less than 12.5 nmol/L (5 ng/mL), though serum 25(OH) D concentrations may notbe markedly reduced in overtly rachitic children who have lov dietary calcium intake. The most widely accepted standards for defining vitamin D status in children and adolescents are: vitamin D sufficiency. 25(0H)D more than or equal to 20 ng/mL; vitamin D insufficiency. 15-20 ng/ml; and vitamin D deficiency: © 15 ng/ml. A level less than 5 ng/ml. has been considered as an indicator of severe deficiency (Table 2) ‘Values of more than 100 ng/ml. are considered as vitamin D excess and above 150 ng/ml. as irtaxication. Treatment ‘The ideal eatment for vitamin D deficiency consists of administration of vitamin D; (cholecaleiferol) since ergocalciferol (D,} is noc widely available, The dose recommended for treatment of vitamin D deficient rickets is 1,000 IU daly for newborns less than 1 month, 1,000-5,000 IU daily for infants 1-12 months ol, and 5,000-10,000 10 daily or children 1 year and older. Treatment shouldbe continued unti there s biochemical evidence of recovery and radiographic evidente of healing which ueually aocure by 12 weeks. Thereafter, the dose of vitamin D can be reduced to 4400 10/600 TU dally. Calum intake should be maintained at 50-75 mg/kg of elemental calcium per day in three divided doses to avoid Inumgry bone syndrome. Skeletal deformities. regress completely if appropriate medieal therapy s given ‘Sloss therapy consist of administration o (a) high dose of oral vitamin D (600,000 1U) given on a single day, then maintained at 400-1,000 IU of vitamin D per day; or (b) 50,000 1U of vitamin D, ‘weekly for & weeks orally (teenagers) followed by 400 TU/day. This, regime however, has a potential for hypercalcemia. Lesser doses ‘of 150,000 or 200,000 1 hve been reported to be equally effective ‘with lesser side effects. Since normalization of vitamin D status, ‘may not be achieved ater L2 weeks even in those given single high ‘Table3 Treatment regimensfor vitamin Ddefciency Table2 Vitamin status based on 25(0H levels Vitamin 0 status USIOM clsscation ae 12 nmol or$ ng/mb Deficiency 37 nmolLor 1S ng/ml. Insufficiency 375-50 nmol. or 15-20ng/mt Sufficiency 50-2€0 nmol or 20-100 ng/ml. mest 2 2500 oF 100 ayn. Intencation > 375 mol. or> 150 ng/mL SEndocrine Society lassiction Deficiency << 20ng/m (50 nmol) Insufficiency 21-2Eng/mk (525-725) pmol. Sufiency > 30am. Toxty 3150%g/mL 1 meg = 4010; 0025 meg is 10 dose sto therapy, it s necessary to recheck the vitamin D status 12weeks alter initiating therapy (Table3), Prevention Sun exposure allows for cutaneous vitamin D synthesis. During ‘most seasons, 10-15 min of sun expostce near midday is sufiient for adequate vitamin D synthesis in light skinned individuals. However, darker skin pigmentation, winter season, ot northern, latitudes can markedly reduce skin synthesis of vitamin D and Increase the need for dietary sources Studies are necessary (0 assess the Impact of these recommendations in darkeskinned children, and it is possible that relaxation of these measures in, dark-skinned children will allow for suficient cutaneous vitamin synthesis inthe summer months, particularly at lower latitudes. ‘American Academy of Pediars recommends that all exclusively. breastfed Infants should receive 400 TU/day of vitamin D supplements, based on the fct that breastmilk has very low vitamin D content, and that cutaneous vitamin D synthesis from sun exposure is inconsistent and unpredictable. At present, there are no ach recommendations for Indian infants, Gtanderds for defining vitamin D sufficieney in healthy children are not well, established. In children, radiological changes of rickets and low bbone density have been reported at 25(OH)D levels of less than 16-18 ng/ml (40-45 nmol/L), and ALF levels have been noted to rise at25(OH)D levelsless than 20 ng/mL (50 nmol/L). Atthistime,, there is litle evidence from studies in children to indicate that vitamin D levels above the threshold of20 ng/ml. (50 nmol/L) are necessary to optimize calcium absorption or bone density Agesroup Daily regimen Weeklycegimen ——_Stosstherapy Maintenance (@-12 weeks) (8-12 nes) dosage <1 month 1.00010 50.0001)" ‘Not Recommended "400-100 Uday 1-12month ‘1000-5000 so,0c01) ‘akh-Glaths units over 1-Sdays 400-1000 Uiday cal preferably 3 aks)" 118 years 500010 S000) 3-6lakhs units over 15 daysoral* 600-1000 Uiday ‘Any age with obesity malabsorption 6000-10000 U/day 3900-600 Uiday syndrome o those on medkations affecting vitamin Dstatus “Toconvert Utomeg of calcio vie by 40. + Parenteral vamucsulr theap)~best voided unes theres sevee malabsorbion a concer for compliance to oral regimens 923 Winn ‘S19P0SIq |EUORLANN pue UtSay g $ 3 8 2 VITAMIN D TOXICITY Despite robust skin production, vitamin D toxicity cannot occur fiom skin production. This is due to the fact that once maximum cutaneous production occurs, addtional sun exposure willnotresult in adaltional net input to te system. The same vltreviolet B (UVD) that produces vitamin Dinthe skin also degrades i, causing a steady state that limits cutaneous production toa maximum of~ 20,000 10 day. There have been no reports of vitamin D toxicity from either sun exposure of from exposuretoarificlal UVB light. The intake at which the dnp of vitamin T hernmes tote ie nat clea. The suggested tolerable upper iniake lee (UL) for vitamin D is 100 micrograms (4,000 10) daily for healthy adults and children 9-18 years. Vitamin D intoxication generally occurs after inappropriate use of vitamin D preparations. Symptoms of acute intoxication are ddue to hypercalcemia andinclude confusion, polyuria, polydipsia, anorexia, vomiting, and muscle weakness. Long-term intoxication fan cause bone demineralization and pain. in children, the hypercalcemia can cause brain injury. Chronic intoxication may cause nephrocaldnosis and bone demineralization (Box 2). Diagnosis of vitamin D toxicltyis confirmed by igh serra caleium, high serum vitamin D 25(OH) and normal PTH, Treatment ‘The main goal of treatment is conection of bypercaleemia Emergency intervention it necessary when the calcium exceeds 1M mg/d. Elects of toxicity may last for months because of storage in fatty tissues. Treatment’ measures include: discontinuation of intake; dit low in caleium and phosphorus. Acute taxiity will require intravenous hydration with saline; and loop diuretics, furosemide. Corticosteroids calcitonin and bisphosphonateshave also been used, Hypercalcemia Hypercaleiuia Hyperphosphatemia Pours Poldpsia Ectopecalefiation off ssues kidney and lung) Nausea/voriting Anorexia Constiation Headache: Hypertension IN A NUTSHELL 1. There has been increasing inteestin the recent times on the role of vitamin D, the sunshine hoimone net only in skeletal disorders but also in relation to its benefits on extraskeletal health 2. There isa high prevalence of vitamin D deficiency in India cutting across age, sex and geographical location. 3. The options available for prevention of vitamin D deficiency include sensible sunlight exposure, changes in dietary habits, routine supplementation and food orifiation. 4. Nutritional rickets manifests mostly in infants and toddlers ‘with bony deformities. Vitarnin D deficiency in infancy may also present with hypocalcemic seizures. 5. Measurement of 25(0HID levels is the ideal method to determine and define the vitamin D status. Measurement of alkaline phosphatase levels in plasma isa useful screening ‘est for vitamin D deficiency. 6. Treatment of deficiency with vitamin D, with a varlety of regimens have been recommended which are equally effective, 7. Hypervitaminosis D_marifesting with features of hyper- ‘akcemia needs to be recognized early and appropriately "eated to prevent serious consequences. Men moa Balasubramanian 5, Dhanaalshmi K, Amperaari S. tain D detency in ‘hhidhood—arevew ofcurent quidelneson dagnossandmanagemen, Indian Peat. 201330669-75. ier C),Bshop NL Fikes Lance. 2014383156576 Holick ME, Binkley NC, BichofFerari HA eal. Evasion treatment and prevetion of vitamin D defen: an Endocrine Society clical practice (uidelne Clin Endocrine Meta 20119519130 oss AC, Manson JE, Abrams SA, et al The 2011 report on dietary reference Intaes for calc and vitamin D fom the Insitute of Madcne what linc need to krow? J Cla Endocrinol Meta, 201196538 Sahay M, Sahay R.Rcketitamin D deficiency and dependency, Indian J Endcinol Metab, 20121816176 ‘hai 1 ughal Yamin Land eicheath par 1 elt aspects) Arch (is Chi 2013683637, kets: Part edi fadiol. 201343 ‘howe RM Chesney RW. Rckets Part Pele Racol. 201 ‘howe BM, Chesney RW.