the return of vitamin d deficiency and rickets

The Return of Vitamin D The Return of Vitamin D Deficiency and RicketsDeficiency and Rickets

ByByPaul Breyer, M.D.Paul Breyer, M.D.

Lecture ContentLecture Content

HistoryHistory Normal Calcium PhysiologyNormal Calcium Physiology EvaluationEvaluation Case StudyCase Study DiscussionDiscussion TreatmentTreatment

HistoryHistory 4000 B.C. No evidence of rickets in Egyptian

mummies 1582 Reusner first described rickets 1650 Francis Glisson published De rachitide

– Severe bone deforming disease– Growth retardation– Enlargement of epiphyses of the long bones– Deformities of the legs– Bending of the spine– Weak and toneless muscles

1822 Sniadecki recognized the importance of sun exposure for the prevention and cure

HistoryHistory 1906 Frederick G. Hopkins developed concept of 1906 Frederick G. Hopkins developed concept of

accessory foodstuffsaccessory foodstuffs 1912 Casimir Funk named them vitamines1912 Casimir Funk named them vitamines 1919 Huldschinski demonstrated the antirachitic effect 1919 Huldschinski demonstrated the antirachitic effect

of ultraviolet lightof ultraviolet light 1922 McCollum and Steenbock discovered the 1922 McCollum and Steenbock discovered the

antirachitic Vitamin Dantirachitic Vitamin D 1924 Hess and Steenbock showed the antirachitic 1924 Hess and Steenbock showed the antirachitic

effect of ultraviolet light was due to activating a effect of ultraviolet light was due to activating a provitamin into Vitamin Dprovitamin into Vitamin D

1927 Windaus indentified the provitamin as ergosterol.1927 Windaus indentified the provitamin as ergosterol. Large scale elimination of Rickets followed the addition Large scale elimination of Rickets followed the addition

of Vitamin D to milkof Vitamin D to milk

Calcium PhysiologyCalcium Physiology CalciumCalcium

– Levels tightly controlled (8.4-10.6 mg/dl) Levels tightly controlled (8.4-10.6 mg/dl) – Critical functions Critical functions

Bone formationBone formation Neuronal conductionNeuronal conduction Cardiac rhythmCardiac rhythm Blood coagulationBlood coagulation Enzyme functionEnzyme function Second messengerSecond messenger Mitotic divisionMitotic division Muscle contractionMuscle contraction

– Active ionized state 40-50%Active ionized state 40-50%– Inactive protein bound 45%Inactive protein bound 45%

0.8 mg/dl reduction in total Ca for every 1.0 g/dl 0.8 mg/dl reduction in total Ca for every 1.0 g/dl decrease in albumindecrease in albumin

Calcium PhysiologyCalcium Physiology Calcium absorptionCalcium absorption

– Primarily in duodenumPrimarily in duodenum– Vitamin D regulated active transportVitamin D regulated active transport– Diffusional transport - concentration Diffusional transport - concentration

Calcium excretion Calcium excretion – Renal tubules reabsorb >97% filtered Renal tubules reabsorb >97% filtered

CaCa– Urine Ca / Cr ratio should be <0.25Urine Ca / Cr ratio should be <0.25– Fecal >> renalFecal >> renal

Calcium Physiology Calcium Physiology Bone accretionBone accretion

– Infants 270 mg / day (RDA 270 mg)Infants 270 mg / day (RDA 270 mg)– Adolescents 400 mg / day (RDA 1300 mg)Adolescents 400 mg / day (RDA 1300 mg)

Calcium regulation Calcium regulation – Parathyroid hormone (PTH)Parathyroid hormone (PTH)– Vitamin DVitamin D– Calcitonin (minor role)Calcitonin (minor role)– Other hormones (estrogen, thyroid, Other hormones (estrogen, thyroid,

cortisol, growth hormone)cortisol, growth hormone)

Parathyroid HormoneParathyroid Hormone PTH ProductionPTH Production

– Pre-prohormone 115 aminoacids Pre-prohormone 115 aminoacids – Cleaved to 84 aa final form (intact PTH)Cleaved to 84 aa final form (intact PTH)– Intact PTH level reflect steady stateIntact PTH level reflect steady state– Binding at PTH receptor splits hormoneBinding at PTH receptor splits hormone

Inactive C-terminal PTHInactive C-terminal PTH Active N-terminal PTHActive N-terminal PTH

– PTH receptor G protein coupled receptorPTH receptor G protein coupled receptor Activates adenylate cyclase (cAMP)Activates adenylate cyclase (cAMP)

Parathyroid HormoneParathyroid Hormone PTH RegulationPTH Regulation

– Calcium levelCalcium level Low Ca level stimulates PTH secretionLow Ca level stimulates PTH secretion High Ca level suppresses PTH secretionHigh Ca level suppresses PTH secretion

– Magnesium levelMagnesium level Low Mg levels impair secretion of PTH and Low Mg levels impair secretion of PTH and

blunts tissue responsiveness to PTHblunts tissue responsiveness to PTH– Phosphorus levelPhosphorus level

Does not directly effect PTH secretionDoes not directly effect PTH secretion Hyperphosphatemia may increase PTH due to Hyperphosphatemia may increase PTH due to

phosphorus-induced suppression of calciumphosphorus-induced suppression of calcium

Parathyroid HormoneParathyroid Hormone PTH actionPTH action

– Kidney (loop of Henle, distal tubule)Kidney (loop of Henle, distal tubule) Moment to moment regulation of serum CaMoment to moment regulation of serum Ca Increases Ca reabsorption, phosphorus wastingIncreases Ca reabsorption, phosphorus wasting Increases synthesis of 1,25-OHIncreases synthesis of 1,25-OH22 Vitamin D via Vitamin D via

direct stimulation of 1direct stimulation of 1-hydroxylase activity-hydroxylase activity– Bone (osteoclasts)Bone (osteoclasts)

For regulation of serum Ca levels in hoursFor regulation of serum Ca levels in hours Leads to bone dissolution (Ca/Phos release)Leads to bone dissolution (Ca/Phos release) Synergistic with 1,25-OHSynergistic with 1,25-OH22 Vitamin D Vitamin D

Vitamin D MetabolismVitamin D Metabolism Skin sourceSkin source

– UV B light (290-315) plus body heat converts UV B light (290-315) plus body heat converts 7-7-dehydrocholesteroldehydrocholesterol to Vitamin D3 (cholecalciferol) to Vitamin D3 (cholecalciferol)

– 10-15 minutes of full body exposure in summer will 10-15 minutes of full body exposure in summer will generates 10,000 - 20,000 IU within 24 hoursgenerates 10,000 - 20,000 IU within 24 hours

– Decreased UV absorption in dark pigmented persons Decreased UV absorption in dark pigmented persons leads to less vitamin D3 production (5-10 times more leads to less vitamin D3 production (5-10 times more exposure needed to generate similar amounts).exposure needed to generate similar amounts).

Dietary sourceDietary source– Mammal Vitamin D3 and plant Vitamin D2 Mammal Vitamin D3 and plant Vitamin D2

(ergocalciferol) absorbed with chylomicrons in (ergocalciferol) absorbed with chylomicrons in duodenumduodenum

StorageStorage– Stored in fat or bound to Vit D binding proteinStored in fat or bound to Vit D binding protein

Vitamin D MetabolismVitamin D Metabolism Liver (Vitamin D transported to liver)Liver (Vitamin D transported to liver)

– Hydroxylated at carbon 25 in hepatic Hydroxylated at carbon 25 in hepatic mitochondria forms 25-OH vitamin D mitochondria forms 25-OH vitamin D (calcidiol)(calcidiol)

– Serum concentration best reflects storesSerum concentration best reflects stores Kidney (25-OH Vit D to kidney on DBP)Kidney (25-OH Vit D to kidney on DBP)

– Enzyme 1Enzyme 1-hydroxylase at proximal tubule-hydroxylase at proximal tubule– Forms 1,25-OHForms 1,25-OH22 Vit D (calcitriol) most active Vit D (calcitriol) most active– Enzyme activity increased by PTH, hypo- Enzyme activity increased by PTH, hypo-

calcemia (PTH) and hypophosphatemia calcemia (PTH) and hypophosphatemia – Activity decreased by calcitriol, phosphorusActivity decreased by calcitriol, phosphorus

Vitamin D MetabolismVitamin D Metabolism Vitamin D actionsVitamin D actions

– Stimulates intestinal absorption of Stimulates intestinal absorption of calcium and phosphoruscalcium and phosphorus

– Enhances bone mineralizationEnhances bone mineralization– With PTH mobilizes Ca and Phos from With PTH mobilizes Ca and Phos from

bonebone– With PTH increases reabsorption of With PTH increases reabsorption of

calcium at distal tubulecalcium at distal tubule

Calcium MetabolismCalcium Metabolism

Vitamin D AbormalitiesVitamin D Abormalities Nutritional deficiencyNutritional deficiency

– Reduced sunlight exposure Reduced sunlight exposure – Dark pigmented skinDark pigmented skin– Breast fed infants (15-50 IU/L)Breast fed infants (15-50 IU/L)– Low birth weight infantsLow birth weight infants– Malabsorption, hepatobiliary dysfunctionMalabsorption, hepatobiliary dysfunction– Anticonvulsant drugs (phenytoin)Anticonvulsant drugs (phenytoin)– Low 25-OH Vitamin D, low calcium, high PTH Low 25-OH Vitamin D, low calcium, high PTH – Leads to both a low Ca and low PhosLeads to both a low Ca and low Phos

Vitamin D AbormalitiesVitamin D Abormalities

Metabolic errorsMetabolic errors– 11 hydroxylase deficiency (AR) hydroxylase deficiency (AR)

– Vitamin D dependent ricketsVitamin D dependent rickets– Normal 25-OH Vitamin D, low 1, 25 OH2 Vitamin DNormal 25-OH Vitamin D, low 1, 25 OH2 Vitamin D

– Abnormal receptor for 1, 25-OH2 Vitamin Abnormal receptor for 1, 25-OH2 Vitamin DD

– Vitamin D resistant rickets - severe Vitamin D resistant rickets - severe – AlopeciaAlopecia– High 1,25-OHHigh 1,25-OH22 vitamin D vitamin D

Chronic renal diseaseChronic renal disease– 11 hydroxlase deficiency hydroxlase deficiency

Signs and Symptoms Signs and Symptoms May be asymptomatic or symptomaticMay be asymptomatic or symptomatic HypocalcemiaHypocalcemia

– Tetany, cramps, paresthesiasTetany, cramps, paresthesias– Stridor from laryngospasmStridor from laryngospasm– Seizures (grand mal, petit mal, focal)Seizures (grand mal, petit mal, focal)

Rachitic deformitiesRachitic deformities– Widening of wrists and anklesWidening of wrists and ankles– Rachitic rosaryRachitic rosary– Bowing of lower extremities (once weight Bowing of lower extremities (once weight

bearing)bearing)– FracturesFractures

Rachitic DeformitiesRachitic Deformities

EvaluationEvaluation History History

– Twitching, carpopedal spasm, laryngospasm, seizure Twitching, carpopedal spasm, laryngospasm, seizure – MedicationsMedications– DietDiet– Sun exposureSun exposure

Physical examinationPhysical examination– Vital signs, height and weight, growth velocityVital signs, height and weight, growth velocity– HyperreflexiaHyperreflexia– TetanyTetany– Rachitic deformitiesRachitic deformities– Chvostek’s sign (twitching after tapping facial nerve)Chvostek’s sign (twitching after tapping facial nerve)– Trousseau sign(carpopedal spasm cuff above SBP x 3min)Trousseau sign(carpopedal spasm cuff above SBP x 3min)

Trousseau signTrousseau sign

EvaluationEvaluation Laboratory studiesLaboratory studies

– Total & ionized calcium levelsTotal & ionized calcium levels– Magnesium, phosphorusMagnesium, phosphorus– Alkaline phosphataseAlkaline phosphatase– Intact PTHIntact PTH– 25-OH and 1,25-OH25-OH and 1,25-OH22 Vitamin D levels Vitamin D levels

Evaluation cont. Radiographic Radiographic

studiesstudies– Rickets surveyRickets survey– Classic Classic

appearanceappearance Electrocardiogram Electrocardiogram

– Prolonged QTc Prolonged QTc intervalinterval

Case StudyCase Study A 4 and ½ month infant boy presented A 4 and ½ month infant boy presented

to our emergency room with a seizure to our emergency room with a seizure The seizure was a generalized clonic The seizure was a generalized clonic

seizure that lasted a minute and seizure that lasted a minute and subsequently left the infant sleepy.subsequently left the infant sleepy.

No history of illness, fever, trauma, No history of illness, fever, trauma, ingestions or previous seizure activity.ingestions or previous seizure activity.

Case Study cont.Case Study cont. Prior to this episode, the child was in Prior to this episode, the child was in

excellent healthexcellent health The child has been exclusively breast fed. The child has been exclusively breast fed. The physical exam was remarkable for an The physical exam was remarkable for an

African American boy with normal weight African American boy with normal weight and length. and length.

His respiratory, cardiac and neurological His respiratory, cardiac and neurological exams were normal.exams were normal.

Case Study cont.Case Study cont. The initial laboratory studies The initial laboratory studies

– Normal glucose of 88 mg/dL (60 – 100)Normal glucose of 88 mg/dL (60 – 100)– Low total calcium of 6.4 mg/dL (9.0 - 11.0)Low total calcium of 6.4 mg/dL (9.0 - 11.0)– Low ionized calcium of 0.88 mmol/L (1.1 - 1.35)Low ionized calcium of 0.88 mmol/L (1.1 - 1.35)– Low phosphorus of 4.0 mg/dL (5.0 - 9.5)Low phosphorus of 4.0 mg/dL (5.0 - 9.5)– Normal magnesium, normal albumin Normal magnesium, normal albumin – Elevated alkaline phosphatase of 1029 U/L Elevated alkaline phosphatase of 1029 U/L

(127 – 438)(127 – 438)

Case Study cont.Case Study cont. Upon further examinationUpon further examination

– widening of his wrists bilaterally widening of his wrists bilaterally – no obvious bowing of his lower extremities.no obvious bowing of his lower extremities.

Additional laboratory studies Additional laboratory studies – Low 25-hydroxyvitamin D level (<4 ng/mL)Low 25-hydroxyvitamin D level (<4 ng/mL)– Elevated intact parathyroid (iPTH) level (Elevated intact parathyroid (iPTH) level (333 pg/mL333 pg/mL))– Normal 1, 25-dihydroxyvitamin D level (39 pg/mL)Normal 1, 25-dihydroxyvitamin D level (39 pg/mL)

Rickets survey abnormal with typical features Rickets survey abnormal with typical features

Rickets SurveyRickets Survey

Vitamin D Deficiency Vitamin D Deficiency RicketsRickets

Stage 1Stage 1– When 25(OH)Vit D concentrations are When 25(OH)Vit D concentrations are

inadequate, intestinal absorption of inadequate, intestinal absorption of calcium is decreased. calcium is decreased.

– In this first brief stage, there is a In this first brief stage, there is a decrease in serum calcium decrease in serum calcium concentration but the serum concentration but the serum phosphorus and alkaline phosphatase phosphorus and alkaline phosphatase levels remain normal.levels remain normal.


Stage 2Stage 2– The low serum calcium stimulates PTH secretion.The low serum calcium stimulates PTH secretion.– Causing increased bone mobilization of both Causing increased bone mobilization of both

calcium and phosphorus, as well as increased calcium and phosphorus, as well as increased tubular reabsorption of calcium and decreased tubular reabsorption of calcium and decreased reabsorption of phosphorus at the kidney.reabsorption of phosphorus at the kidney.

– The PTH also increases 1-hydroxylase activity in The PTH also increases 1-hydroxylase activity in the kidney converting any available 25(OH)D to the kidney converting any available 25(OH)D to the more active form 1,25(OH)2D. the more active form 1,25(OH)2D.

– The serum calcium levels are now normal but The serum calcium levels are now normal but the serum phosphorus levels are now low due to the serum phosphorus levels are now low due to the renal excretion. the renal excretion.


Stage 3Stage 3– The bone stores of calcium fall, the serum alkaline The bone stores of calcium fall, the serum alkaline

phosphatase climbs and the serum calcium levels phosphatase climbs and the serum calcium levels can no longer be maintained.can no longer be maintained.

– Both the serum calcium and serum phosphorus Both the serum calcium and serum phosphorus levels are low and the alkaline phosphatase is high. levels are low and the alkaline phosphatase is high.

– The PTH level is high, the 25(OH)D concentration is The PTH level is high, the 25(OH)D concentration is very low and the 1,25(OH)2D concentration is either very low and the 1,25(OH)2D concentration is either low, normal or high. low, normal or high.

– Most children present to the hospital or clinic in this Most children present to the hospital or clinic in this third stage of rickets.third stage of rickets.

DiscussionDiscussion Vitamin D deficiency rickets is a sunlight Vitamin D deficiency rickets is a sunlight

deficiency diseasedeficiency disease The fortification of milk with vitamin D was The fortification of milk with vitamin D was

thought to have conquered itthought to have conquered it Unfortunately Rickets has made a comebackUnfortunately Rickets has made a comeback The cause in the U.S. is the lack of appreciation The cause in the U.S. is the lack of appreciation

that human milk contains very little Vitamin Dthat human milk contains very little Vitamin D This plus decreased sun exposure due to This plus decreased sun exposure due to

sunblocks or dark pigmented skin have sunblocks or dark pigmented skin have compounded the problem. compounded the problem.


Peak incidence is between 3- 18 Peak incidence is between 3- 18 months of agemonths of age

The usual age range for diagnosis The usual age range for diagnosis was 4-54 months with the majority was 4-54 months with the majority being < 30 months old. being < 30 months old.

Approximately 83 % of children Approximately 83 % of children with rickets are African American with rickets are African American and 96% are breast fed. and 96% are breast fed.


The higher incidence of rickets in breast fed The higher incidence of rickets in breast fed infants is because breast milk is an infants is because breast milk is an inadequate source of vitamin D alone. inadequate source of vitamin D alone.

The vitamin D content of breast milk from a The vitamin D content of breast milk from a mother with adequate vitamin D status is mother with adequate vitamin D status is approximately 22 IU/Lapproximately 22 IU/L

Which is well below the now recommended Which is well below the now recommended 400 IU/d for all infants (AAP) 400 IU/d for all infants (AAP)

Most breast fed infants must obtain the Most breast fed infants must obtain the additional vitamin D from sunlight exposure.additional vitamin D from sunlight exposure.


Infants who spend minimal time outside or Infants who spend minimal time outside or were born in fall will have minimal sun were born in fall will have minimal sun exposure leading to inadequate vitamin D exposure leading to inadequate vitamin D levels. levels.

Infants using topical sunscreens or infants with Infants using topical sunscreens or infants with dark skin pigmentation are at risk for deficiency dark skin pigmentation are at risk for deficiency because of the decrease in UVB absorption. because of the decrease in UVB absorption.

In the skin, melanin is in competition for the UV In the skin, melanin is in competition for the UV B radiation with 7-dehydrocholesterol and can B radiation with 7-dehydrocholesterol and can diminish the production of vitamin D by more diminish the production of vitamin D by more than 90%.than 90%.


To prevent rickets the American Academy of To prevent rickets the American Academy of Pediatrics (AAP) recently recommended a Pediatrics (AAP) recently recommended a minimal intake of 400 IU/d vitamin D (up from minimal intake of 400 IU/d vitamin D (up from 200) for all infants beginning the first few days 200) for all infants beginning the first few days after birth. after birth.

The AAP recommends a vitamin D supplement of The AAP recommends a vitamin D supplement of 400 IU for exclusively or partially breast-fed 400 IU for exclusively or partially breast-fed infants or formula-fed infants who do not infants or formula-fed infants who do not consume at least 32 ounces of a vitamin D-consume at least 32 ounces of a vitamin D-fortified formula (U.S. formulas contain 400 IU/L).fortified formula (U.S. formulas contain 400 IU/L).

Treatment of Vitamin D Treatment of Vitamin D Deficiency RicketsDeficiency Rickets

The treatment of vitamin D deficiency rickets The treatment of vitamin D deficiency rickets requires pharmacologic doses of vitamin D to requires pharmacologic doses of vitamin D to build up the body stores and correct the build up the body stores and correct the deficiency. deficiency.

A total of 200,000 - 600,000 IU of Drisdol A total of 200,000 - 600,000 IU of Drisdol [25(OH)D] with adequate dietary calcium will [25(OH)D] with adequate dietary calcium will effectively treat and cure rickets. effectively treat and cure rickets.

These doses can be given as a one time high-These doses can be given as a one time high-dose bolus (compliance issues) or as a daily dose bolus (compliance issues) or as a daily dose of 2,000 – 10,000 IU/d for 3 to 6 months. I dose of 2,000 – 10,000 IU/d for 3 to 6 months. I start with 8,000 - 10,000 IU (Drisdol 8000 start with 8,000 - 10,000 IU (Drisdol 8000 IU/mL). IU/mL).

Treatment of Vitamin D Treatment of Vitamin D DeficiencyDeficiency

If hypocalcemic, I add calcium carbonate If hypocalcemic, I add calcium carbonate (50 –100 mg elemental Ca/ Kg/ day.(50 –100 mg elemental Ca/ Kg/ day.

Monitor calcium level weekly, once Monitor calcium level weekly, once corrected stop the calcium supplement if corrected stop the calcium supplement if dietary intake is adequate. dietary intake is adequate.

Monitor monthly alkaline phosphatase levels Monitor monthly alkaline phosphatase levels (usually see normalization in 2 to 4 months (usually see normalization in 2 to 4 months depending on the severity of the rickets).depending on the severity of the rickets).

Monitor calcium, phosphorus, urine Monitor calcium, phosphorus, urine calcium/creatinine ratio monthly as well. calcium/creatinine ratio monthly as well.

Treatment of Vitamin D Treatment of Vitamin D DeficiencyDeficiency

Once rickets healed, continue the Once rickets healed, continue the child on 400 IU of vitamin D daily if child on 400 IU of vitamin D daily if still breast feeding to maintain still breast feeding to maintain normal vitamin D levels and normal vitamin D levels and prevent a recurrence in their prevent a recurrence in their rickets.rickets.

Can repeat radiograph in 3 monthsCan repeat radiograph in 3 months Monitor 25 (OH)-D levels yearlyMonitor 25 (OH)-D levels yearly

SummarySummary With the resurgence of vitamin D With the resurgence of vitamin D

deficiency rickets and the risk for deficiency rickets and the risk for serious morbidity, there is an urgent serious morbidity, there is an urgent need for heightened awareness among need for heightened awareness among our health care providers and families.our health care providers and families.

High-risk infants and now older children High-risk infants and now older children who do not receive 400 IU of Vitamin D who do not receive 400 IU of Vitamin D daily should start vitamin D supplement daily should start vitamin D supplement as early as possibleas early as possible.

the return of vitamin d deficiency and rickets

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