Hanan Fathy

Pediatric nephrology unit

University of Alexandria
 Calcium functions

Calcium is the most abundant mineral in the body

Plays important roles in the body

- As a cofactor for many enzymes (e.g. Lipase) and proteins
• Mineralized tissue (Ca10(PO4)6(OH)2 in
bone, dentin, cementum & enamel)
• Neuromuscular excitability
• Clot formation
• Cell-cell adhesion
• Intracellular second messenger
 Adequate daily intake (AI)
Life Stage  Age  Males (mg/day)  Females (mg/day) 

Infants  0-6 months 210  210 

Infants  7-12 months  270  270 

Children  1-3 years  500  500 

Children 4-8 years  800  800 

Children  9-13 years  1,300  1,300 

Adolescents  14-18 years  1,300  1,300 

Adults  19-50 years  1,000  1,000 

Adults  51 years and older  1,200  1,200 

Pregnancy  18 years and younger -  1,300 

Pregnancy  19 years and older -  1,000 

Breastfeeding  18 years and younger -  1,300 

Breastfeeding  19 years and older -  1,000

 Intake, Uptake and Excretion
Diet
1000 mg
CALCIUM

absorbs
500 mg
GUT 350 mg
Ca2+ Bone
secretes Pool
500 mg
150 mg
Kidney 2% filtered
load

800 mg 200 mg
excreted excreted
www.drsarma.in
Calcium Metabolism:
 Transport mechanism
Active and passive transport mechanisms
• Active: is a saturable, transcellular process which
involves calbindin (calcium-binding protein) – regulated
by the active form of vitamin D
• Passive: The paracellular mechanisms occur by the tight
junctions, which are made up of a combination of
proteins including, amongst others, the claudins: the most
important, claudin 16 , also known as paracellin 1,
facilitates the passive transport of calcium and
magnesium across intestinal and renal tubular cells which
is not affected by calcium status or parathyroid hormone
• Both processes occur throughout the small intestine
Epithelial calcium channels
Gastrointestinal Absorption of Calcium
 Absorption and excretion factors

• Absorption increased by: • Excretion increased by:

- Body need - Low parathyroid hormone (PTH)
- Vitamin D - High extracellular fluid volume
- Protein - High blood pressure
- Lactose - Low plasma phosphate
- Acid medium - Metabolic alkalosis
• Absorption decreased by: • Excretion decreased by:
- Vitamin D deficiency - High parathyroid hormone
- Calcium-phosphorus imbalance - Low extracellular fluid volume
- Oxalic acid - Low blood pressure
- Phosphorous
- High plasma phosphate
- Dietary fiber
- Metabolic acidosis
- Excessive fat
-
- Vitamin D3
High alkalinity
- Also stresses and lack of exercise
  Urinary Calcium

• Daily filtered load • Distal tubule reabsorption

– 10 gm (diffusible)
– 99% reabsorbed
• Two general mechanisms
– Active - transcellular
– Passive - paracellular
• Proximal tubule and Loop
of Henle reabsorption
– Most of filtered load • Urinary excretion
– Mostly passive
– Inhibited by furosemide
– 10% of filtered load
– Regulated (homeostatic)
• stimulated by PTH
• inhibited by CT
• vitamin D has small
stimulatory effect
• stimulated by thiazides
– 50 - 250 mg/day
– 0.5 - 1% filtered load
Calcium absorption from renal
tubules
 Other Routes of Excretion
• Perspiration
• Lactation
 Calcium distribution

• 99% of total body calcium in the bone.

• 1% in ICF ,ECF ,& cell membranes .
• Calcium weight is 400mg/kg in infant &
950mg/kg in adult .
• The 1% can be divided in 3 components :
1) 50% ionized .
2) 40% bound to protein .
3) 10% complex with anions ( citrate, phosphate……….)
• Normal serum calcium levels are 8.8 - 10.3
mg/dL (2.0 to 2.5 mmol/L)

• Normal ionized calcium levels are 2.24 - 2.46

meq/L (1 to 1.4 mmol per L)
 FORMULA
• 0.8 for each gm of Albumin
• 0.16mg/dl for each gm of globulin.
• FEca = (Uca/Pca) = Uca/Pca x Pcr/Ucr
(Ucr/Pcr)

FEca <1% - Familial hypocalciuric hypercalcemia,

FEca >2% - primary hyperparathyroidism
  in pH will  protein bound Ca by 0.12mg/dl
• 80-90% of protein bound Ca is bound to Albumin.
• Increase in serum pH of 0.1 may cause decrease in ionized Ca
of 0.16mg/dl
 Regulation of Calcium
•
Metabolism
Minerals; serum concentration
– Calcium (Ca2+); 2.2-2.6 mM (total)
– Phosphate (HPO42-); 0.7-1.4 mM
– Magnesium (Mg2+); 0.8-1.2 mM
• Organ systems that play an import role in Ca2+ metabolism
– Skeleton
– GI tract
– Kidney
• Calcitropic Hormones
– Parathyroid hormone (PTH)
– Calcitonin (CT)
– Vitamin D (1,25 dihydroxycholecalciferol)
– Parathyroid hormone related protein (PTHrP)
– Fibroblast growth factor 23
20
Physiologic Anatomy of the Parathyroid Gland
 Parathyroid gland
• Derived embryologically from the third (lower glands)
and fourth (upper glands) branchial arches.
Mutations within the genes responsible for these factors
result in congenital hypoparathyroidism
• Transcription factors are involved in their development:
– Hoxa3 (thyroid and thymus)
The SRY-related HMG-box gene 3 (SOX3) ,
–
located on the GATA3 ( mutation
X chromosome, is also :thought
sensorineural deafness,
to be involved renaldevelopment
in PT gland
andanomalies, chromosome
mutations may be responsible10p13-14)
for X-linked recessive FIH .

• Several genes, including Tbx1 (thymus, cardiac outflow

tract and the face, chromosome 22q11) and UDF1L, are
located on the long arm of chromosome 22.
Parathyroid hormone (PTH)
• Structure of PTH
 Parathyroid
• hormone
Single-chain 84-amino-acid polypeptide hormone encoded by a gene
on chromosome 11 from prepro PTH, which has an additional 31
amino acids.

• Synthesis occurs in the ribosomes, where the initial 25 amino acid

pre sequence acts as a signal peptide
Normal to aid transport through the
concentra-
roughtions
endoplasmic reticulum.
are about 1–6 pmol/L (10–60 pg/mL) but vary depending
on the assay

• The pre sequence is cleaved and pro-PTH then travels to the Golgi
apparatus where the 6 amino acid pro sequence is cleaved to yield the
mature hormone, which is stored in secretory vesicles that fuse with
the plasma membrane before secretion of the hormone .

• Little PTH is stored within the glands and most of the secreted
hormone is newly synthesized. Mutations in the PTH gene have been
described.
• You are called urgently to examine a term, 2-hour-old
newborn who has had temperature instability, difficulty
with feeding, and a suspected seizure. He has atypical
facies (wide-set eyes, a prominent nose, and a small
mandible), a cleft palate, and a holosystolic murmur. Stat
laboratory tests and chest radiograph reveal marked
hypocalcemia, a boot-shaped heart, and no apparent
thymus. Which of the following is the most likely
diagnosis?

A. Ataxia–telangiectasia
B. DiGeorge syndrome
C. Hyper-IgE syndrome
D. SCID
E. Wiskott-Aldrich syndrome
 PTH
Biosynthesis
• PTH is co-secreted
with chromogranin
A, a protein;
significance
unknown
 Controls
• Stimulators
• Decreased serum [Ca2+].

• Mild decreases in serum [Mg2+].

• An increase in serum phosphate (Since increased

phosphate will complex with serum calcium to
form calcium phosphate, which causes the Ca-
sensitive receptors (CaSr) to think that serum Ca
has decreased, as CaSR do not sense Calcium
phosphate, thereby triggering an increase in PTH)
Mg2+
• Intracellular magnesium may serve this secretory
function in the parathyroids in that hypermagnesemia
can inhibit PTH secretion and hypomagnesemia can
stimulate PTH secretion.

• However, prolonged depletion of magnesium will

inhibit PTH biosynthesis and secretion, as it will the
function of many cells.

• Hypomagnesemia also attenuates the biological effect

of PTH by interfering with its signal transduction.
 Phosphorus
• Most studies fail to demonstrate a direct effect of
serum phosphate on PTH secretion, but some recent
studies show that high phosphate increases PTH
biosynthesis and vice versa .

• However, serum phosphate has an inverse effect on

calcium concentration and ambient phosphate directly
increases 1,25-D production. Thus, serum phosphate
may directly and indirectly regulate PTH expression.
• Inhibitors
• Increased serum [Ca2+].
• Severe decreases in serum [Mg2+]
 Control of PTH secretion
The calcium-sensing receptor
• Present in many tissues, particularly the parathyroid glands ,
renal tubule, in bone, cartilage and other tissues .

• Its gene is located on chromosome 3q13-21 and the CaSR is a

large molecule consisting of 1078 amino acid residues of which
610 form the extracellular calcium-binding domain, 250
comprise the seven-transmembrane domain and another 210 the
intracellular cytosolic component.

• Ca2+binds to the extracellular domain and influences PTH

secretion by both phospholipase Cb and G-protein second
messengers.

• As a consequence, PTH secretion changes in a sigmoidal fashion

in response to acute changes in plasma calcium and there is a
continuous tonic secretion of PTH, which maintains plasma-
ionized calcium at whatever concentration is set by the CaSR .
Calcium Sensing Receptor
Mechanisms of action of
PTH
 Mutations within the CaSR gene
• Result in either inactivation or activation of the receptor, which
result in hypercalcemia and hypocalcemia, respectively.

• Inactivating mutations cause insensitivity to calcium, which shifts

the curve of PTH secretion in response to plasma calcium to the
right . As a consequence, PTH secretion is switched off at a higher
concentration than normal and hypercalcemia results .

• The receptors are also present in the renal tubule and renal
calcium excretion is thereby reduced. The resulting condition is
known as familial benign hypercalcemia (FBH) or familial
hypocalciuric hypercalcemia (FHH) .

• In contrast, activating mutations of the receptor shift the PTH

secretion curve to the left , causing chronic hypocalcemia and
hypercalciuria, a condition known as autosomal dominant
hypocalcemia (ADH)
 Parathyroid Hormone Receptors
Type 1 PTH receptor: Type 2 PTH receptor: Binds PTH, but
PTH and amino- has very low affinity for PTHrP.
terminal peptides of Only expressed in a few tissues- its
PTHrP. structure and physiologic
G protein-coupled significance are poorly
receptor characterized.
Biologic Effects of Parathyroid Hormone
• Bone
Increases resorption
Increases formation, especially at low and intermittent
concentrations
• Kidney
Decreases calcium excretion (clearance)
Increases phosphorus excretion
• Gastrointestinal Tract
Increases calcium and phosphorus absorption
Indirect effect via 1,25-D production
• Blood
Increases calcium
Decreases phosphorus
 Osteon: schematic detail

Fig. 19-21a , Sherwood

• Bone fluid calcium in the canaliculi is rapidly mobilized and transferred
to blood by calcium pumps in the membrane.
• Mineralized calcium is mobilized more slowly by osteoclast activity
(not shown here).
12
RANK and RANKL
 PTH modulates osteoblast and
and ostoclast activity.
But,
But, osteoclasts
osteoclasts have no PTH receptor.
receptor.

+PTH

2004 Science 305:1420

Osteoblasts produce the protein OPG PHT decreases OPG production,

(osteoprotegerin) which binds
osteoclast rank-L receptors and down
regulates osteoclast production.
14
allowing the protein rank-L, also
made by osteoblasts, to bind the
rank-L receptors. This stimulates
osteoclast production and
maturation.
 Hormone Structures, Receptors and Sources
PTHrP is encoded by a single gene that is highly conserved among
species.

It should probably be described as a polyhormone, because a family of

peptide hormones are generated by alternative splicing of the
primary transcript and through use of alternative post-translational
cleavage sites.

To make matters even more complex, some cells appear to use

alternative translational initiation codons to produce forms of the
protein that are targeted either for secretion or nuclear localization.
PTHrP; Parathyroid Related Protein
• It is clear that amino-terminal peptides of PTHrP
share a receptor with PTH, but they also bind to a type
of receptor in some tissues that does not bind PTH.

• In addition to the secreted forms, there is considerable

evidence that a form of PTHrP is generated in some
cells that is not secreted and, via nuclear targeting
sequences, is translocated to the nucleus, where it
affects nuclear function.

• The consequences of this "intracrine" mode of action

are not yet well characterized, but may modulate such
important activities as programmed cell death.
 .
Parathyroid Hormone-Related Protein
• PTHrP is secreted from a large and diverse set of cells,
and during both fetal and postnatal life.

• Among tissues known to secrete this hormone are

several types of epithelium, mesenchyme, vascular
smooth muscle and central nervous system.

• Although PTHrP is found in serum, a majority of its

activity appears to reflect paracrine signaling
 Physiologic Effects of Parathyroid
Hormone-Related Protein
 Cartilage and Bone Development ,stimulates the
proliferation of chondrocytes These effects of PTHrP
appear due to interaction of the PTH-like peptide with
the PTH receptor

 Placental Transfer of Calcium

 Smooth Muscle Functioning

It acts to relax smooth muscle, thereby serving, among

other things, as a vasodilating hormone.
 Physiologic Effects of Parathyroid Hormone-
Related Protein
• Other Effects: PTHrP is highly expressed in skin.
Overexpretion of PTHrP in skin show alopecia .

• Another interesting defect in PTHrP-null mice is that

teeth develop normally, they fail to erupt.

• Finally, both PTHrP and its receptors are widely

expressed in the CNS, and appear to influence neuronal
survival by several mechanisms. It should be clear from
the above examples that PTHrP hormones have profound
effects on a large number of physiologic processes.
• An 8-month-old infant presents with the primary complaint of
irritability. He has been exclusively breastfed since birth. His
mother was not interested in providing any supplemental foods
because her milk supply has been adequate. Physical
examination reveals a fussy infant who has frontal bossing and
whose weight and height are both at the 25th percentile. The
infant becomes irritable with movement of the left arm. Arm
radiography reveals a humeral fracture and bowing of both
radii. Chest radiography demonstrates enlargement of the
costochondral junctions.

Of the following, the MOST likely diagnosis is

A. congenital syphilis
B. osteogenesis imperfecta
C. vitamin D-deficient rickets
D. vitamin D-resistant rickets
E. vitamin E deficiency
VITAMIN D
 25 hydroxylase enzyme
• At least four different vitamin D 25 hydroxylases distinguishable
by their different affinities and capacities and intracellular
localization

 The first, a low-affinity high-capacity enzyme (CYP27A1) , is located in

mitochondria. There are no reports of rickets resulting from mutations in this
gene but they do cause cerebrotendinous xanthomatosis .

 A second high-affinity low-capacity enzyme (CYP2R1),which

may be of greater physiological significance, is located within
hepatic microsomes. Although they have not yet been fully characterized, cases
of rickets are described associated with mutations

Two other enzymes, CYP3A4 and CYP2J2 , probably also have some effect on
25-hydroxylase but are mainly involved in drug metabolism.
Proposed Mechanism of Action of
1,25-DihydroxyD3 in Intestine
 VITAMIN D RECEPTOR LOCATION
System Tissue
Gastrointestinal hepatocytes Esophagus, stomach, intestine, colon
Cardiovascular cells Cardiomyocytes, Vascular Smooth Muscle,
Endothelial
Renal Proximal and Distal Tubules, collecting duct

Endocrine Parathyroid, pancreatic cells, Thyroid Cells

Reproductive Testis, ovary, placenta, uterus, endometrium

Immune Thymus, bone marrow, B cells, T cells

Respiratory Lung alveolar cells
Skeletal Osteoblasts, osteocytes, chondrocytes
Muscle/Connective Tissue Striated, Fibroblasts, stroma
Skin Epidermis, Breast, hair follicles
CNS Neurons, glia, astrocytes
Inhibited by Vitamin D
 Mutations in vit D receptors
• Mutations in the vitamin D receptor occur throughout the molecule
but particularly in either the ligand-binding (ligand binding
negative) or the DNA-binding (ligand-binding positive) domains.

• These mutations cause severe rickets and many individuals,

especially those with defects in DNA binding, also have alopecia.

• Originally referred to as vitamin D-dependent rickets type II

(VDRR-II), it is now more properly called hereditary 1,25(OH)2D-
resistant rickets (HVDRR) .

• In another form of HVDRR, no mutations of the receptor have

been identified but is thought to be caused by over expression of a
nuclear ribonucleoprotein that binds with the hormone receptor
complex to attenuate its action
 VITAMIN D TESTING
• Measure 25 OH Vitamin D
• “Normal”- obtained by population measurement,
– 30-80 ng/mL
• Deficient- <20 ng/mL
• Insufficient- <35 ng/mL
• Optimal- 80 ng/mL +/- 10 (speakers’ opinion)

• Targets are moving upward!

 National Academy of Science
Tolerable Upper Intake Levels

Pediatrics 0 – 12 months –
1000 IU / Day

All others –
2000 IU / Day
 North American Conference
on Vitamin D
“to minimize the health risks associated with
UVB radiation exposure while maximizing the
potential benefits of optimum vitamin D status,
{dietary} supplementation and small amounts
of sun exposure are the preferred methods of
obtaining vitamin D.”

Consensus statement, 2006

 How much sun?
• Depends on:
– Age
– Amount of vitamin D obtained from diet
– Skin darkness
– Sunshine intensity
 How much sun?
• Significant skin exposure
– Face, neck, arms, hands
– Arms, legs
• Adequate sun strength
• Time
– 25% of the time it would take to cause pinkness of
the skin (Caucasians)
– People with dark skin require significantly more
sun exposure
Holick, 2004
 Food Sources of Vitamin D
• Cod liver oil – 1 TBS • 1,360 IU
• Salmon 3.5 oz. • 360
• Mackerel 3.5 oz. • 345
• Tuna, canned, in oil, 3 oz. • 200
• Sardines 3.5 oz. • 250
• Milk (fortified) 8 oz. • 98
• Ready to eat cereal (fortified) ¾ - • 40
1 cup
• Egg 1 whole • 20
• Liver, 3.5 oz. • 15
• Cheese, swiss 1 oz. • 12
• FGF23 is mainly secreted by osteoblasts and osteocytes.

• It circulates in plasma and is one of a number of fibroblast

growth factors that function by fibroblast growth factor
receptors (FGFRs) in a variety of tissues as a classic hormone.

• FGF23 is the principal “phosphotonin” that acts by FGFR1c

to stimulate phosphate excretion by the Type 2c Na/Pi co-
transporter.

• It also inhibits 1α-hydroxylase so that hyperphosphaturic

conditions caused by raised FGF23 are not accompanied by
the expected increase in 1,25(OH)2D.
Mesenchymal Tumor Normal Tissue

TIO
ADHR R179 S180
Active FGF23

XLH PHEX ??

R179 S180
Active FGF23
Inactive

NPT2a / NPT2c

Normal Pi level
Renal Pi wasting ++

Cartilage/bone mineralization

Rickets/Osteomalacia
By H. I. cheong
 Dentin matrix protein 1 (DMP1)
Normal Tissue
 AR-hypophosphatemic
rickets
R179 S180
 Chr. 4q21 Active FGF23
↓ Non-collagenous DMP1 ?
bone matrix formation ?
PHEX ?
↑ FGF 23 R179 S180
Inactive

A new member regulating renal Pi

handling ? Normal Pi level

Cartilage/bone mineralization
Nat Genet. 2006 Nov;38(11)
 Hypophosphatemic rickets causing bowing of
the legs - bowlegs caused by inherited deficiency of
phosphate
 Hypophosphatemic rickets (HR) with decreased renal
phosphate reabsorption

HR with HR with FH HR with FH of HR with no HR with (or FH of) HR with FH HR with

hepatomegaly and/or consistent with Male-Male FH Generalised Arterial consistent with X- hypercalciuria
fasting AR inheritance transmission Calcification of linked dominant
hypoglycaemia with infancy inheritance
a FH consistent with
AR inheritance

SLC2A2 DMP1 sequencing SLC34A3

FGF23 PHEX ENPP1 PHEX
sequencing sequencing
sequencing sequencing sequencing sequencing

PHEX MLPA PHEX MLPA

FGF23 sequencing FGF23 sequencing

if consistent with
AD inheritance

DMP1 sequencing

ENPP1 sequencing

= At discretion of referrer. Other tests automatic.

Vitamin D Deficiency Vitamin D Dependent Vitamin D Resistant
Rickets Rickets Rickets

Cause Cause Cause

Lack exposure to sunlight Deficiency enzyme that Phosphate leak at level of
Lack of intake convert 25-D3 to 1,25-D3 proximal tubules
Anticonvulsant therapy (not a disease of vitamin D
Intestinal malabsorption metabolism)

Lab findings Lab findings Lab findings

Low Ca2 Low Ca2 Normal Ca2
Low PO4 Low PO4 Low PO4
High ALP High ALP Normal PTH
High PTH High PTH
Low 1,25-D3 Low 1,25-D3

Treatment Treatment Treatment

Vitamin D Daily 1,25-D3 Phosphate supplements
Three-year-old boy with
vitamin D receptor defect
causing severe rickets with
alopecia
• A 1-year-old boy presents with generalized seizures. His
general physical examination findings are normal except
for a prominently positive Chvostek response. Results of
laboratory studies include total serum calcium of 4.5
mg/dL (1.1 mmol/L) and phosphorus of 8.2 mg/dL (2.73
mmol/L). Blood urea nitrogen and creatinine values are
normal for age. Of the following, the MOST likely
diagnosis is

A. dietary calcium deficiency

B. hypoparathyroidism
C. hyperphosphatasia
D. vitamin D deficiency rickets
E. vitamin D-resistant rickets
 CALCITONIN
Peptide hormone secreted by the thyroid gland that
tends to decrease plasma calcium concentration.

Two ways:

1. decrease absorptive activities of the osteoclasts and the

osteocytic effect of the osteocytic membrane – immediate effect

2. decrease formation of new osteoclasts – more prolonged

effect
•Promotes renal excretion of Ca2+
Increased Plasma Calcium Concentration Stimulates Calcitonin
Secretion

Calcitonin Has a Weak Effect on Plasma Calcium Concentration in

Adult Human
 Calcitonin
• Product of
parafollicular C cells
of the thyroid
• 32 aa
 Calcitonin
• Probably not essential for human survival
• Potential treatment for hypercalcemia
• 7 transmembrane segment receptor
• Stimulates cAMP production in bone and
kidney
A 1-day-old infant develops tetany and convulsions. He
was born at 34 weeks’ gestation with Apgar scores of
2 and 4 (at 1 and 5 min, respectively) to a woman
whose pregnancy was complicated by diabetes
mellitus and pregnancy-induced hypertension. Which
of the following serum chemistry values is likely to
be the explanation for his condition?

a. Serum bicarbonate level of 22 meq/dL

b. Serum calcium of 6.2 mg/dL
c. Serum glucose of 45 mg/dL
d. Serum magnesium level of 5.0 mg/dL
e. Intracranial hemorrhage
 Neonatal Hypocalcemia
• Definitions
• A fall of total calcium below 7.5 mg/dL (1.75 mmol/L), or 2.5
mg/dL (0.63 mmol/L) in the ionized calcium concentration
usually defines neonatal hypocalcemia.

• In infants up to 3 months of age, hypocalcemia is defined as a

total serum calcium less than 8.8 mg/dL or ionized calcium
less than 4.9 mg/dL (1.22-1.4 mM).

• The relationship of the total calcium concentration to the

ionized calcium concentration is atypical in preterm infants,
and measurement of the ionized calcium concentration is
required for accurate assessment of these infants.
ACUTE PRESENTATION
• Tetany
• Seizure
• Laryngospasm/stridor
• Arrhythmias (Prolonged Q-T interval, conduction
abnormalities with bradycardia)
• Circumoral numbness
• Extremity parasthesiae
• Trousseau’s sign (carpal spasm by 3 minutes after
interrupted vascular flow to arm)
• Chvostek’s sign (facial twitch caused by tapping below
zygoma)
• Infants may show lethargy, vomiting, poor feeding
• Neurological signs and • Mental status
symptoms
• Confusion
• Extrapyramidal signs due to
calcification of basal ganglia • Disorientation
• Calcification of cerebral • Psychosis
cortex or cerebellum • Psychoneurosis
• Personality disturbances
• Irritability
• Impaired intellectual ability
• Nonspecific EEG changes
• Increased intracranial
pressure
• Parkinsonism
• Choreoathetosis
• Dystonic spasms Adapted from Fitzpatrick, L.A.: The hypocalcemic states
. Disorders of Bone and Mineral Metabolism. M. Favus (ed),
Lippincott Williams & Wilkins, Philadelphia, PA, pp. 568-588, 2002.
• Ectodermal changes • Smooth muscle
involvement
• Dry skin • Dysphagia
• Coarse hair • Abdominal pain
• Brittle nails • Biliary colic
• Alopecia • Dyspnea
• Enamel hypoplasia • Wheezing
• Shortened premolar roots • Ophthalmologic
manifestations
• Thickened lamina dura • Subcapsular cataracts
• Delayed tooth eruption • Papilledema
• Increased dental caries • Cardiac
• Atopic eczema • Prolonged QT interval in
• Exfoliative dermatitis EKG
• Congestive heart failure
• Psoriasis
• Cardiomyopathy
• Impetigo herpetiformis
 Etiology
• Infants and children
– Hypoparathyroidism
• Impaired synthesis / secretion
– Loss/ lack of PTH tissue or defective synthesis
– Primary or acquired conditions
• Defective calcium sensing receptor
• End –organ resistance to PTH
(pseudohypoparathyroidism)
– Hypovitaminosis D (MUCH MORE COMMON)
– Hypomagnesemia
– Other
Synthesis / secretion of PTH
• Genetic
– Autosomal dominant
– Autosomal recessive
– X-Linked
– HDR (hypoparathyroidism associated with
sensorineural deafness and renal dysplasia)
– DiGeorge's syndrome
– Mitochondrial disorders:
• MELAS (mitochondrial encephalopathy, lactic
acidosis and stroke-like episode),
 Synthesis / secretion
• Autoimmune
– APECED (autoimmune polyendocrinopathy-
candidiasis-ectodermal dystrophy syndrome)
• Hypoparathyroidism
• Primary adrenal insufficiency
• Chronic mucocutaneous candidiasis
 Synthesis / secretion
• Acquired
– Thyroid surgery
– Parathyroidectomy
– Iron deposition with chronic transfusions
– Wilson’s disease
– Gram negative sepsis, toxic shock, AIDS
• ? Macrophage-generated cytokines
 Pseudohypoparathyroidism

• Target organ insensitivity to PTH (bone /

kidney)
– Hypocalcemia

– Hyperphosphatemia

– Elevated PTH
 Pseudohypoparathyroidism
(PHP)
• GNAS1 gene mutations – intracellular
signals
– Expression in tissues either paternally /
maternally determined
– Example: renal expression is maternal

• Type 1a PHP
– AD (maternal transmission)
– Albright’s hereditary osteodystrophy
 Albright’s
• Short stature & limbs
• Obesity
• Round, flat face
• Short 4e/5e
metacarpals
• Archibald sign
• Brachydactyly
• Potter's thumb
• Eye problems
• IQ problems
• Basal ganglia
calcifications
Pseudopseudohypoparathyroidism

• Phenotype of
Albright’s

• NORMAL serum
calcium

• NO PTH resistance

• Paternal GNAS1
gene mutation
Pseudohypoparathyroidism
• Type 1b
– Hypocalcemia, no phenotypic abnormality
– AD, maternal transmission

• Type 1c
– Looks like type 1a

• Type 2
– No features of Albright’s
History that suggests hypocalcemia
• Newborns (can be unspecific)
– Asymptomatic
– Lethargy
– Poor feeding
– Vomiting
– Abdominal distention

• Children
– Seizures
– Twitching
– Cramping
– Laryngospasm
• Neonatal hypocalcemia:
– Early neonatal hypocalcemia (48-72 hours)
• Prematurity
– Poor intake, hypoalbuminemia, reduced responsiveness to
vitamin D
• Birth asphyxia
– Delay feeding, increased calcitonin, endogenous phosphate load
high, alkali therapy
• Infant to diabetic mother
– Magnesium depletion → functional hypoparathyroidism →
hypocalcemia
• IUGR
– Late neonatal hypocalcemia
• Exogenous phosphate load
– Phosphate-rich formulas / cow’s milk

• Magnesium deficiency
• Transient hypoparathyroidism of newborn
• Hypoparathyroidism

• Gentamycin (24 hourly dosing schedule)

 Hypovitaminosis D
• Decrease intake or production

• Increased catabolism

• Decrease 25-hydroxylation by liver

• Decrease 1-hydroxylation by kidney

Widening of wrist Bowing
Rickety rossary Frontal bossing
Cupping and splaying of metaphysis
• Delayed closure of
fontanels
• Bossing
• Craniotabes
• Delayed eruption of teeth
• Rickety rosary
• Pectus carinatum
• Harrison sulcii
• Splaying of distal ends of
• long bones bones
• Hypotonia
• Weakness
• Growth retarded
• Recurrent chest infections
• A mother brings in her 1-year-old boy for the first
time because she is concerned about his “bowed
legs” . The mother is 4 ft 10 in tall and says she
needed to have surgery to straighten out her bowed
legs when she was an adolescent, as did one of her
brothers. Radiographs of the boy’s long bones are
obtained . Of the following, the MOST likely
serum laboratory findings are

A. low calcium and high phosphorus

B. low calcium and normal phosphorus
C. low calcium and low phosphorus
D. normal calcium and high phosphorus
E. normal calcium and low phosphorus
 Hypomagnesemia

• Magnesium is required for PTH release

• May also be required for effects on target
organs

• Mechanisms:
– End-organ unresponsiveness to PTH
– Impaired release of PTH
– Impaired formation of 1,25-vitamin D3
 Other
• Pancreatitis

• Citrated products

• Hungry bone syndrome

• Hyperphosphatemia

• Fluoride poisoning
 Other
• Hungry bone syndrome
– After prolonged period of calcium
absorption
– Rebound phase
– Avid uptake of calcium by bone
– Parallel uptake of magnesium by bone

• Following parathyroidectomy
 Renal Osteodystrophy

• Associated with chronic renal failure

Ch. RF Hyperphosphataemia and Hypocalcaemia

Secondary Hyperparathyroidism
a) Less excretion and
metabolism of PTH
Osteoclastic activity
b) Low or no alpha-1-
hydroxylation
c) Metabolic acidosis Release of calcium hydroxyapetite
from bone

Osteomalacia Osteitis fibrosa

 Workup - blood

• Total and ionized calcium

• Magnesium
• Phosphate
• UKE and s-glucose
• PTH
• Vitamin D metabolite
• Urine-CMP and –creatinine
• S-ALP
 Workup - imaging

• CXR
• Ankle and wrist XR
 Workup - other

• ECG
• Malabsorption workup
• Karyotyping and family screening
You are measuring serum electrolytes at 12 hours of age in a 4,500-g infant delivered
by cesarean section at 36 weeks’ gestation. The Apgar scores were 6 and 8 at 1 and
5 minutes, respectively. The infant is in no acute distress, breathing room air, and
generally well-appearing, although he exhibits mild hypotonia. The laboratory
results are:
• Sodium, 135 mEq/L (135 mmol/L)
• Potassium, 4 mEq/L (4 mmol/L)
• Chloride, 105 mEq/L (105 mmol/L)
• Carbon dioxide, 18 mEq/L (18 mmol/L)
• Calcium (total), 6.5 mg/dL (1.63 mmol/L)
• Phosphorus, 5.5 mg/dL (1.8 mmol/L)
• Magnesium 2 mg/dL (0.8 mmol/L) The serum glucose value is 30 mg/dL (1.7
mmol/L).
Of the following, the MOST likely cause of neonatal hypocalcemia for this infant is

A. acute perinatal asphyxia

B. hypoglycemia
C. maternal diabetes mellitus
D. 22q11 deletion syndrome
E. vitamin D deficiency
 Management
1. Dependent on the underlying cause and
severity
2. Administration of calcium alone is only
transiently effective
3. Mild asymptomatic cases: Often adequate
to increase dietary calcium by 1000
mg/day
4. Symptomatic: Treat immediately
 Treatment of hypocalcaemia
Symptomatic hypocalcaemia
– IV Calcium should only be given with close monitoring
– Should be on cardiac monitor
– Mix with NaCl or 5 % D/W (not bicarbonate/lactate containing
solutions)
Risks
– Tissue necrosis/calcification if extravasates
– Calcium can inhibit sinus node  bradycardia + arrest
• Stop infusion if bradycardia develops
– Avoid complete correction of hypocalcaemia
– With acidosis and  S-Ca – give Ca before correcting acidosis
– If  Mg is cause of  S-Ca – treat and correct
hypomagnesaemia
 Treatment of hypocalcaemia
Symptomatic hypocalcaemia

Early neonatal hypocalcaemia

– Neonates: Ca gluconate:10 mg/kg (1 ml/kg of 10%
solution) Slowly IV + monitoring ECG
– Occasionally associated transient hypomagnesaemia
• Treat prior to Ca administration
– Start oral Calcium as soon as possible
– Early neonatal hypocalcaemia normalizes in 2-3 days
– Oral Ca usually necessary for 1 week
Treatment of hypocalcaemia

Symptomatic hypocalcaemia

Late neonatal hypocalcaemia

– Associated with  S-phosphate
– Decrease phosphate intake
– Give calcium containing phosphate binder
– Oral calcium (gluconate) supplementation
– 100 mg/kg/dose 4 hourly per os
 Hypocalcaemia in older
children
• Same dose IV as for neonates
• More often require continuous infusion
• Oral supplementation 50 mg/kg/24 hr elemental Ca
– Ca binds with phosphate in gut   Ca absorption
– Advantage in conditions with  s-phosphate
• Renal failure
• Hypoparathyroidism
• Tumor lysis
• Most need Vit D supplementation
• A 9-month-old exclusively breastfed baby presents
with a seizure. A chest radiograph obtained to rule
out aspiration pneumonia reveals rachitic changes
of the ribs. Of the following, the MOST likely
serum laboratory findings are

A. low calcium and elevated phosphorus

B. low calcium and low phosphorus
C. low calcium and normal phosphorus
D. normal calcium and elevated phosphorus
E. normal calcium and low phosphorus
A 15-year-old boy has been immobilized in a double
hip spica for 6 weeks after having fractured his femur
in a skiing accident. He has become depressed and
listless during the past few days and has complained
of nausea and constipation. He is found to have
microscopic hematuria and a blood pressure of
150/100 mmHg. You should

a. Request a psychiatric evaluation

b. Check blood pressure every 2 h for 2 days
c. Collect urine for measurement of the calcium-
creatinine ratio
d. Order a renal sonogram and intravenous pyelogram
(IVP)
e. Measure 24-h urinary protein
 Definition
• Normal serum calcium levels are 8 to 10 mg/dL
(2.0 to 2.5 mmol/L)

• Normal ionized calcium levels are 4 to 5.6 mg

/dL (1 to 1.4 mmol per L)

• Hypercalcemia is defined as total serum calcium

> 10.5 mg/dl(>2.5 m mol/L ) or ionized serum
calcium > 5.6 mg/dl ( >1.4 m mol/L )
136
 Definition

• Severe hypercalemia is defined as total

serum calcium > 14 mg/dl (> 3.5 mmol/L)

• Hypercalcemic crises is present when

severe neurological symptoms or cardiac
arrhythmias are present in a patient with a
serum calcium > 14 mg/dl (> 3.5 mmol/L)
or when the serum calcium is > 16 mg/dl
(> 4 mmol/L)
Most symptoms are not seen until serum [Ca+2] > 12mg/dL
Rare problem in children than hypocalcemia
When it occurs, it is a serious condition which requires correct
diagnosis before correct treatment can be instituted
Hypercalcemia in adulthood : malignancy
primary hyperparathyroidism
In children : causes are more diverse (particularly in neonate,
infant)
Groans, moans, bones, stones

Manifestations of Hypercalcemia
  Acute  Chronic
Gastrointestinal  Anorexia, nausea, Dyspepsia,
vomiting  constipation,
pancreatitis

Renal  Polyuria, polydipsia  Nephrolithiasis,

nephrocalcinosis

Neuro-muscular  Depression, Weakness

confusion, stupor,
coma 

Cardiac  Bradycardia, first Hypertension

degree atrio- block, digitalis
ventricular  sensitivity
Cardiovascular
• Hypertension, Increased risk of CHD
• ECG changes of shortened QT interval, PR
prolonged, QRS widened, ST , Bradycardia
• Cardiac arrhythmias; Vascular calcification
Others
• Itching (Generalized Pruritus)
• Keratitis, conjunctivitis
141
Parathyroid gland tumour associated with MEN

MEN type 1 MEN type 2a MEN type 2b

PTH adenoma PTH hyperplasia PTH hyperplasia

Pituitary tumour Medullary thyroid cancer Medullary thyroid
Pancreatic tumour Phaeochromocytoma cancer
(gastrinoma, Phaeochromocytoma
insulinoma)

Mucocutaneous
neurofibroma
Dysmorphic features
(marfanoid habitus,
skeletal abN, abN
dental enamel)
 What is Williams Syndrome?

• A rare genetic condition that causes medical

and developmental problems

• 1 in 7,500 births

• Infantile hypercalcemia has been reported for

15% of infants and children with WS
 Etiology
• Deletion of multiple (20 to
30) genes, including the
elastin gene on chromosome
#7
• Elastin (ELN) provides
strength and elasticity to
vessel walls
• The deletion of the elastin
gene likely accounts for
many of the physical
features of Williams
syndrome
Characteristic Facial Appearance

• Small, upturned nose

• Long philtrum
• Wide mouth
• Full lips
• Small chin
• Puffiness around the
eyes
• “Starburst” (white lacy
pattern) on iris
 History
 Symptomes suggestive of hypercalcemia
 Symptomes suggestive of malignancy
 Drug history includig vitamin D therapy, complementary
alternateve medicine, supplements
 Family history of renal stone, hypercalcemia, parathyroidectomy,
multiple endocrine neoplasia
 Examination
 Assess degree of dehydration
 Syndromic feature
 Presence of ectopic /subcutaneous calcification/rash
 Short stature/disproportionate short stature
 Generalised lymphadenopathy, organomegaly
 Bone pain, fracture
 Initial investigation
 Serum Ca, Phospate, ALP, electrolyte, Cr, PTH, 25-(OH)D3
 1,25(OH)2D, PTHrP, DNA for genetic analysis, Urine Ca/Cr
 Subsequent investigation
 Renal US
 Investigation of parents for abnormalities of Ca
homeostasis
 Skeletal survey
 Parathyroid gl. US scan
 Parathyroid gl. SestaMIBI scan
 Normal levels of PTH
 CaSR abnormality (Familial benign hypercalcemia type
I,II,III)
 Suppressed levels of PTH
 Secondary hypercalcemia
 Vitamin D excess (Wiliams syndrome, Idiopathic
hypercalcemia of infancy)
• Hypercalcemia
• Hypercalciuria
• Renal insufficiency
• Soft tissue calcification
• Hypercalcemia may persist for months after vit
D is discontinued due to fat stores
• Can also occur in vit A intoxication
• Commonest cause of hypercalcemia, more
common in females
• 80% will be caused by a single parathyroid
adenoma
• 15% hyperplasia
• 5% multiple adenomas
• Rarely caused by parathyroid cancer
• Familial hyperparathryoidism is associated with
MEN1 and MEN 2A, and usually see hyperplasia
• Usually asymptomatic
• Symptoms:
– Polyuria, polydipsia
– Nephrolithiasis, nephrocalcinosis
– Fatigue, weakness, myopathy
– Depression
– Osteopenia, osteoporosis, bone pain, pathologic
fractures
• Labs:
– Usually mild hypercalcemia
– Normal phosphate
– Increased or inappropriately normal PTH
– Increased urinary calcium excretion
• Imaging
– Loss of cortical bone, see subperiosteal bone resorption (on
radial borders of phalanges)
– “salt and pepper” appearance of skull
– Osteitis fibrosa cystica (fibrous replacement of resorbed bone)
– Brown tumors (collections of osteoclasts in poorly mineralized
bone)
– Renal stones
 Malignancy
 30% of adult pt. with cancer / much less in childhood
cancer
 Poor prognosis in adults / not the case with pediatric pt.
 ALL : local osteolytic hypercalcemia (d/t cytokine, secretion
of PTHrP)
 Ovarian dysgerminoma: secrete 1.25(OH)2D
 Sx : water-concentrating defect (nephrogenic DI) ,
neurological dysfunction d/t rapid elevation in serum Ca
 Endocrine cause
 Thyrotoxicosis (stimulation osteoclastic bone resorption by T3)
 Acute adrenal insufficiency : d/t vol. depletion, change in vit D
metabolism secondary to glucocorticoid deficiency
 Chronic renal failure
 ↑P, ↓Ca -> secondary hyperparathyroidism -> tertiary
hyperparathyroidism
 Immobilisation
 m/c during adolescence in those with spastic quadriplegia or
spinal cord injury
 Results from increased osteoclastic bone resorption and
decreased bone formation
4) Inhibit bone resorption (inhibit osteoclastic
activity )

Bisphosphonates (Pamidronate)
0.5~1.0mg/kg ov 4-6h -> reduction of Ca after 12-
24h,
last for 2-4wks -> sustained period of hypocalcemia
may follow
Intravenous therapy is the preferred route of
administration

Calcitonin (10U/kg, q4h) : rapid effect , wears off after

a while,
• Analogs of pyrophosphate that adsorb to bone surface and
interfere with calcium release

• Max effect in 2-4 days

• Zolendronic acid is more potent and can be given rapidly

i.e. over 15 min. Longer Ca control following use(43 days
vs 18 days with pamidronate). Can be associated with jaw
necrosis and renal toxicity in repeated use

• Pamidronate, better tolerated. Occasional fevers.

• All can have flu like symptoms, uveitis, hypocacemia, AKI

• Effective in PTH and PTH-rP

• Inhibits osteoclast ATP-ase pumps and inhibits

PTH secretion from parathyroid cells

• More effective than the bisphosphonates in one

study

• Potential nephrotoxicity and need for continuous

infusion over 5 days