Disorders of Calcium & Phosphorus Metabolism Alfred Tenore, MD Alfonso Vargas, MD Departments of...

Disorders of Calcium & Phosphorus Metabolism Alfred Tenore, MDAlfonso Vargas, MD

Departments of Pediatrics

University of Udine and LSUHSC

Schools of Medicine

I. Introduction

II. Metabolic Action of Hormones

III.Hypercalcemia

Outline

IV. Hypocalcemia

A. PTHB. Vitamin DC. Calcitonin

A. Minerals (Ca, P, Mg)B. Hormones (PTH, Vit D, Calcitonin)

A. Differential diagnosisB. SymptomsC. Treatment

A. GeneralitiesB. SymptomsC. Clinical Entities

V. Rickets

A. Homeostasis of calcium and phosphorus is maintained by a highly integrated and complex endocrine system1. Calcium

normal muscle contraction

Introduction

a. Essential for major cellular functions

membrane functions and permeability

blood coagulation

secretion of peptide hormones

numerous enzymatic reactions

sex

b. Normal serum range is unaffected by:

rate of growth

climatic conditions

2. Phosphorus

a. Fundamental for cell bioenergetics

age

c. Serum concentration is influenced by:

sex

dietary intake

b. Important for activation of most hormone receptors

physical exercise

nyctohemoral variations

Introduction

3. Alkaline Phosphatasea. Synthesized by bone and liver

normal growth or growth spurts

c. Elevated during periods of increased bone forming activity

healing fractures

b. In bone: produced by osteoblasts ( bone forming )

d. Elevated where there is an increase in bone turnover ( since osteoblastic activity is coupled with osteoclastic activity )

Introduction

B. A close relationship exists between Ca and P fluxes

1. Any change in the extracellular concentration of one leads to an inverse change in the concentration of the other

2. The activity of ionic Ca++ in the extracellular fluid regulates the secretion (and biosynthesis) of PTH (and calcitonin) by a negative feedback mechanism

Introduction

PTH, Vitamin D ( 1,25(OH)2D3 ) and CT regulate the flow of calcium and phosphorus in and out of the extracellular fluid compartment through their actions on :

Metabolic Action of Calcium-Regulating Hormones

◊ Bone

◊ Intestine

◊ Kidney

1. Bone (minor effect)

PTH

a. Increases alkaline phosphataseb. Increases the release of calciumc. Increases the release of phosphorus

2. Intestine (indirect effect * )a. Increases absorption of

calciumb. Increases absorption of phosphorus

* The effects are caused by vitamin 1,25(OH)2D3 , whose synthesis is stimulated by PTH

3. Kidney (major effect)

PTH

a. Increases cAMP as intracellular second messenger

magnesium

hydrogen

bicarbonate

b. Stimulates synthesis of 1,25(OH)2-D3

sodium

potassium

b. Increases excretion of phosphorus, as well as:

c. Decreases the excretion of calcium, as well as:

4. Net effect of PTH on the serum concentrations of Ca and P

PTH

Intestine

KidneyBone

Ca P

Net Effect

1. Bone ( indirect effect )

Vitamin D

a. Increases the release of calciumb. Increases the release of phosphorus( This effect requires the presence of PTH )

2. Intestine ( major effect )a. Increases absorption of calciumb. Increases absorption of phosphorus

3. Kidney ( minor effect )a. Improves renal tubular reabsorption of

calciumb. Increases renal tubular reabsorption of phosphorus

4. Net effect of Vitamin D on the serum concentrations of Ca and P

Intestine

KidneyBone

Ca P

Net Effect

Vitamin D

1. Bone ( major effect )

Calcitonin (CT)

a. Inhibits re-absorption of calciumb. Inhibits re-absorption of phosphorus

2. Intestine ( no specific effect )

3. Kidney ( minor effect )a. Decreases renal tubular re-absorption of

calciumb. Decreases renal tubular re-absorption of phosphorus

4. Net effect of Calcitonin on the serum concentrations of Ca and P

Intestine

KidneyBone

Ca — P —

Net Effect

Calcitonin (CT)

Net effects of the three hormones on the serum concentration of Ca and P

PCa

Vitamin D PTH Calcitonin

SUMMARY

A. Rare in children

1. Increased Intestinal Absorption

B. Differential diagnosis :

a. Vitamin D intoxicationb. Idiopathic infantile hypercalcemia

( William S. )c. Sarcoidosis

2. Increased Bone Mobilizationa. Hyperparathyroidismb. Hyperthyroidismc. Immobilizationd. Vitamin A intoxicatione. Metastatic tumors with osteolysisf. Multiple myeloma

3. Uncertain mechanism: Subacute fat necrosis

Hypercalcemia

C. Symptoms

1. Asymptomatic :

2. Non-specific :

a. colicb. polyuria,

polydipsia

3. Renal:

a. general malaise, fatigueb. psychoneurotic complaintsc. weight loss

d. pruritis

4.Gastrointestinal :

a. epigastric painb. constipationc. anorexiad. nausea - vomiting

5. Neuro-Muscular :

a. muscular weaknessb. lethargyc. confusion - stupord. coma

Hypercalcemia

D. Treatment

1. Removal through diuresis :

Hypercalcemia

2. Block absorption :

Inorganic oral phosphate 1 – 3 gm/day in 4 divided doses

3. Increase binding:

a. intravenous hydrationb. furosemide 1 mg/kg iv q

6-8 h

Prednisone 2 mg/kg/day

4. Favor deposition :a. Salmon calcitonin 5-8 MRC U/kg q 6–12 h

IV/IMb. Bisphosphonates5. Mithramycin :

(25 ug/kg as iv bolus)

A. Generalities

1. “True” versus “False” Hypocalcemia

Hypo-calcemia

a. Consider the physiologically active fraction ( ionized calcium ) only

b. Consider the acid-base status of patient

Total Ca: (8.8-10.8 mg/dl) - (2.2-2.7mmol/L)

plasma protein concentration: each decrease of 1 g/dl of albumin results in a decrease of 0.8 mg/dl (0.02 mmol/L) of calcium

Ionized Ca: (4.4-4.9 mg/dl) - (1.1-1.2mmol/L)

Alkalosis increases binding ( ionized Ca )Acidosis decreases binding ( ionized Ca )

A. Generalities

2. Think also of Magnesium

Hypocalcemia

a. As many as 80% of infants with “hypocalcemic” seizures may be hypomagnesemic

b. In some infants the hypocalcemia may be difficult to correct until the hypomagnesemia is corrected

B. Clinical Features

1. paresthesia

Hypocalcemia

2. neuromuscular irritability

3. muscle cramps

4. tetany

5. seizures

C. Clinical Entities

Hypocalcemia

distinctive feature of premature infantsoccurs in first 24 h of life

corrects spontaneously (in most) after 5-10 days of life

phosphate level not necessarily elevatedCauses (single or in combination)

1. Neonatal

a. Early

C. Clinical Entities

1. Neonatal

Hypocalcemia

a. EarlyCauses (single or in combination)sudden interruption of materno-fetal Ca

flux (together with increased fetal need of Ca for growth)anoxia; birth trauma; acidosis; respiratory diffic. (cause cell break-down and increase in inorganic P)inadequate ( immature ) PTH response

end-organ unresponsiveness to PTH

transient neonatal hypercalcitoninemia

inadequate maternal vitamin D

◊

◊

◊

◊

◊

◊

C. Clinical Entities

Hypocalcemia

mostly seen in term infants

occurs from the 3rd day to 2 mos of lifeLevels of phosphorus are consistently elevatedinfants with perinatal hypoxia and/or acidosis are more prone

hypoparathyroidism is the main etiological factor( in most cases it is transient )

1. Neonatal

b. “ Late

”

Algorithm for the diagnosis and treatment of Neonatal Hypocalcemia

Hypocalcemia

“ EARLY ”Neonatal Tetany

HYPOCALCEMIA

< 48 – 72 hrs

of age

> 3 daysof age

“ LATE ”Neonatal Tetany

Treatment :

CalciumDietary management:

Increase Ca and decrease P

C. Clinical Entities

Hypocalcemia

Classification

2. Older Children

a. Hypoparathyroidism

Transient ( neonatal – Immature PTH response)Reversible ( due to Magnesium deficiency)Irreversible ( permanent absence of PTH )

◊

◊

◊

Congenital ( Di George Syndrome )

cardiac defectabsent thymus and/or T-cell defects

Idiopathic ( autoimmune – most frequent )

C. Clinical Entities

Hypocalcemia

Laboratory findings

2. Older Children

a. Hypoparathyroidism

Ca low

P high

PTH low

◊

◊

◊

Alk P’ase low

Mg nl /

low

Diagnostic triad

Algorithm for the diagnosis and treatment of Childhood

Hypocalcemia

Hypocalcemia

Transient(“Neonatal

”)

LOW(hypoparathyroidi

sm)

Treatment : Vit D

(if necessary)

Vit D (1,25)increase Cadecrease P

Ca low P

highPTH

HIGH(Pseudo-

hypo-parathyroidi

sm)Reversible(Mg

defic.)

Permanent(Congenita

l)(idiopathi

c)Mg

C. Clinical Entities

Hypocalcemia

Classification

2. Older Children

b. Pseudo-Hypoparathyroidism (PHP)

◊ Renal unresponsiveness & Bone unresponsiveness

◊ Renal responsiveness & Bone unresponsiveness

◊ Renal unresponsiveness & Bone

responsiveness ◊ Renal responsiveness & Bone

responsiveness

C. Clinical Entities

Hypocalcemia

Totally – PHP Type 1

RenalUN-

responsiveness

BoneUN-

responsiveness

RenalResponsivenes

s

BoneResponsivenes

s

Partially – PHP Type 2 to endog PTH –Pseudo

Idiop HP

Pseudo-Pseudo-Hypo-P

Pseudo Hypo-Hyper-

P

Ps Hyper-

Hypo-P

unresponsiveness

C. Clinical Entities

Hypocalcemia

Laboratory findings

2. Older Children

Ca low

P high

PTH high

◊

◊

◊

Alk P’aselow / high

Mg nl

Diagnostic triad

a. Pseudo-Hypo-parathyroidism (PHP)

Hypocalcemia

Summary table of the various forms of“pseudo”-hypoparathyroidism

b. Pseudo-Hypoparathyroidism (PHP)

Hypo-calcemiaDistinguishing features between Idiopathic and Pseudo-Hypoparathyroidism

(PHP)

% with short metacarpals (stubby fingers) 0 50-75

% with round face, short stat. (obesity) 0 50-75

% with mental retardation 1 63

% with subcut. soft tissue calcifications 2 60

% with papilledema 2 18

% with moniliasis 16 0

Average age of onset (years) 16 8

Female : Male 1 : 1 2 : 1

Hypo-parathyroidismIdiopathic

Pseudo

Rickets

giving rise to

( “ Rickets ”

)

Bone deformities

A.Definition :

Defective mineralization of the osteoid tissue of the skeleton affecting:

1. Epiphyseal growth plates

( “ growing bones ” )where cartilage cells and unmineralized osteoid accumulates

giving rise to

Bone fractures

2. Cortical & Trabecular bone

where resorption(in relation to bone

remodelling)is followed by deposition of osteoid that fails to

mineralize( “ Osteomalacia

” )

Rickets Clinical and Imaging (X-rays)

Rickets

“ Vitamin D Deficiency ”

B. The 3 Basic Etiologies :

1. Failure to form the active metabolite (1,25(OH)2D3) of Vit Da. dietary

deficiencyb. malabsorptionc. liver diseased. renal diseasee. hereditaryf. anticonvulsants “ Vitamin D

Dependency ”

“ Vitamin D Resistance ”

2. Excessive phosphate excretiona. Hypophosphatemic

Ricketsb. Fanconi Syndromec. Lowe Syndrome

3. Accumulation of excess acida. Distal renal tubular

acidosis

Rickets

C. Impaired Vitamin D metabolism is the major cause of rickets

Ca P PTH AP UrineBlood pH Bone

aa acidosis Florid3°

PHASE

1°

aa acidosis rickets2° nl

nl nl nl nl nl nl

Rickets

1. The three stages in the development of Vitamin D Deficiency Rickets

D.

“ Vitamin D Deficiency ”

Rickets

2. Treatment

a. 1000 – 2000 IU/day Vit D2-ErgoCalciferol

b. Treat for several months until healing occurs

c. The Institute of Medicine - IOM of the National Academy of Sciences and the American Academy of Pediatrics Committee on Nutrition advice 400 IU vitamin / day when healing is completed. today some experts recommend 1000 - 2000 IU/day for up to a year for complete bone healing and repletion of reserves

D.

“ Vitamin D Deficiency ”

Rickets

1. Hereditary

a. Vit D Dependency Rickets (VDDR) Type 1

Autosomal recessivedeficiency of 1-hydroxylase enzyme

Treatment

Vitamin D: 50,000-100,000 IU/d (1.25-2.5 mg/d)

◊

25-OHD: 400 – 900 g/day ◊

1,25(OH)2D: 0.5 – 1 g/day ◊

1-OH vitamin D: 0.5 - 2 g/day ◊

b. VDDR Type 2

Autosomal recessive

End-organ resistance to 1,25(OH)2D3

E.

“ Vitamin D Dependency ”

Rickets

2. Anticonvulsant - induced

a. diphenylhydantoin

b. phenobarbital

c. Treatment

Vitamin D: 800 – 2000 IU vitamin / day(in some up to 50,000 IU)

E.

“ Vitamin D Dependency ”

Rickets

1. “ X-linked hypophosphatemic rickets ”

a. Ca normal

b. P low

c. PTH nl / high

a. oral phosphate: 1 – 2 g elemental P

/ day

E.

“ Vitamin D Resistance ”

2. kidney and intestine involved

”3. laboratory studies :

4. Treatment :

c. 1,25(OH)2D: 0.01 – 0.05 g/kg/day (up to 4 g/day)

b. 1-OH vitamin D: 0.01 – 0.02 ng/kg/day

SUMMARY TABLE

Abnormalities of calcium concentrations can be initially assessed by evaluating serum phosphate

and alk. phosphataseDiagnostic considerations with abnormal Ca++ concentrations

decreased

decreased elevated vit D deficiency

decreased

elevated elev / norm Renal failure( BUN & Creat )

decreased

elevated normal Hypoparathyroidism

elevated decreased ~ elev /

normHyperparathyroidism

elevated elevated normal Vit D intoxication

Calcium

Phosphorus

Alk Phosph

Diagnosis

Questions

1) Which of the following metabolic derangements would be the most likely diagnosis for a 36-hour-old infant weighing 1800 g who is irritable, has cardiac arrhythmias, apnea and seizures ? a) hypoglycemia

b) hypocalcemia

c) hyponatremia

e) hyperglycemia

d) hypercalcemia

Questions

1) Which of the following metabolic derangements would be the most likely diagnosis for a 36-hour-old infant weighing 1800 g who is irritable, has cardiac arrhythmias, apnea and seizures ? a) hypoglycemia

b) hypocalcemiac) hyponatremia

e) hyperglycemia

d) hypercalcemia

Questions

2) Which of the following would a full-term child born to a mother with hyperparathyroidism most likely have ?

a) hyperparathyroidism

b) hypoparathyroidism

c) Vitamin D dependency

e) magnesium deficiency

d) Di George syndrome

Questions

2) Which of the following would a full-term child born to a mother with hyperparathyroidism most likely have ?

a) hyperparathyroidism

b) hypoparathyroidismc) Vitamin D dependency

e) magnesium deficiency

d) Di George syndrome

Questions

3) All of the following are characteristic of hypoparathyroidism, except ?a) cataracts

b) paresthesia

c) delayed eruption of teeth

e) hyperphosphaturia

d) pseudotumor cerebri

Questions

3) All of the following are characteristic of hypoparathyroidism, except ?a) cataracts

b) paresthesia

c) delayed eruption of teeth

e) hyperphosphaturia d) pseudotumor cerebri