disorders of calcium & phosphorus metabolism alfred tenore, md alfonso vargas, md departments of...
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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