calcium metabolism and disorders (hanan)
TRANSCRIPT
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
1/169
Hanan FathyHanan Fathy
Pediatric nephrology unitPediatric nephrology unit
University of AlexandriaUniversity of Alexandria
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
2/169
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
3/169
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
4/169
www.drsarma.in
Diet1000 mg
GUT
800 mgexcreted
absorbs
350 mg
secretes
150 mg
Ca2+
PoolBone
500 mg
500 mg
Kidney 2% filteredload
200 mgexcreted
CALCIUM
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
5/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
6/169
Active and passive transport mechanismsActive: 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 thetight 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 andmagnesium across intestinal and renal tubular cells
which is not affected by calcium status or parathyroid
hormone
Both processes occur throughout the small intestine
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
7/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
8/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
9/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
10/169
Absorption increased by:- Body need
- Vitamin D
- Protein
- Lactose - Acid medium
Absorption decreased by:- Vitamin D deficiency
- Calcium-phosphorus imbalance
- Oxalic acid
- Phosphorous- Dietary fiber
- Excessive fat
- High alkalinity
- Also stresses and lack of exercise
Excretion increased by:- Low parathyroid hormone (PTH)
- High extracellular fluid volume
- High blood pressure
- Low plasma phosphate- Metabolic alkalosis
Excretion decreased by:- High parathyroid hormone
- Low extracellular fluid volume
- Low blood pressure
- High plasma phosphate- Metabolic acidosis
- Vitamin D 3
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
11/169
Daily filtered load
10 gm (diffusible)
99% reabsorbed
Two general mechanisms
Active - transcellular
Passive - paracellular
Proximal tubule and Loopof Henle reabsorption
Most of filtered load
Mostly passive
Inhibited by furosemide
Distal tubule reabsorption
10% of filtered load
Regulated (homeostatic)
stimulated by PTH inhibited by CT
vitamin D has small
stimulatory effect
stimulated by thiazides
Urinary excretion
50 - 250 mg/day
0.5 - 1% filtered load
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
12/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
13/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
14/169
Perspiration
Lactation
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
15/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
16/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
17/169
Normal serum calcium levels are 8.8 - 10.3mg/dL (2.0 to 2.5 mmol/L)
Normal ionized calcium levels are 2.24 - 2.46meq/L (1 to 1.4 mmol per L)
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
18/169
0.8 for each gm of Albumin
0.16mg/dl for each gm of globulin.
(Uca/Pca)
(Ucr/Pcr)
FEca 2% - primary hyperparathyroidism
oq in pH will oqprotein 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
FEca = = Uca/Pca x Pcr/Ucr
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
19/169
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
20/169
20
K Bone Resorption
K Intestinal Absorption
L Renal Excretion
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
21/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
22/169
Physiologic Anatomy of the Parathyroid Gland
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
23/169
Derived embryologically from the third (lower glands)and fourth (upper glands) branchial arches.
Transcription factors are involved in their development :
Hoxa3 (thyroid and thymus)
GATA3 ( mutation : sensorineural deafness, renalanomalies, chromosome 10p13-14)
Several genes, including Tbx1 (thymus, cardiac outowtract and the face, chromosome 22q11) and UDF1L, arelocated on the long arm of chromosome 22.
Mutati ns within the genesresp nsi e forthese fa tors
result in congenital hypoparathyroidism
he SRY-related HMG-box gene 3 (SOX3) ,
located on the X chromosome, isalso thought to be involvedin PT glanddevelopment
andmutationsmay be responsible forX-linkedrecessive FIH .
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
24/169
Structure of PTH
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
25/169
Single-chain 84-amino-acid polypeptide hormone encoded by a
gene on chromosome 11 from prepro PTH, which has an additional31 amino acids.
Synthesis occurs in the ribosomes, where the initial 25 amino acidpre sequence acts as a signal peptide to aid transport through therough endoplasmic reticulum.
The pre sequence is cleaved and pro-PTH then travels to the Golgiapparatus where the 6 amino acid pro sequence is cleaved to yield
the mature hormone, which is stored in secretory vesicles that fusewith the plasma membrane before secretion of the hormone .
Little PTH is stored within the glands and most of the secretedhormone is newly synthesized. Mutations in the PTH gene have
been described.
Normal concentra-
tionsare about 16 pmol/L (1060 pg/mL) but vary depending
on the assay
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
26/169
You are called urgently to examine a term, 2-hour-oldnewborn who has had temperature instability, difficultywith feeding, and a suspected seizure. He has atypicalfacies (wide-set eyes, a prominent nose, and a smallmandible), a cleft palate, and a holosystolic murmur. Statlaboratory tests and chest radiograph reveal markedhypocalcemia, a boot-shaped heart, and no apparent
thymus. Which of the following is the most likelydiagnosis?
A. Ataxiatelangiectasia
B. DiGeorge syndrome
C. Hyper-IgE syndrome
D. SCID
E. Wiskott-Aldrich syndrome
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
27/169
PTH is co-secreted
with chromogranin
A, a protein;
significanceunknown
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
28/169
Stimulators
Decreased serum [Ca2+].
Mild decreases in serum [Mg2+].
An increase in serum phosphate (Since increasedphosphate will complex with serum calcium to
form calcium phosphate, which causes the Ca-sensitive receptors (CaSr) to think that serum Cahas decreased, as CaSR do not sense Calciumphosphate, thereby triggering an increase in PTH)
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
29/169
Intracellular magnesium may serve this secretoryfunction 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.
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
30/169
Most studies fail to demonstrate a direct effect ofserum 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 phosphatemay directly and indirectly regulate PTH expression.
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
31/169
Inhibitors
Increased serum [Ca2+].
Severe decreases in serum [Mg2+]
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
32/169
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 alarge molecule consisting of 1078 amino acid residues of which610 form the extracellular calcium-binding domain, 250comprise the seven-transmembrane domain and another 210 theintracellular cytosolic component.
Ca2+binds to the extracellular domain and inuences PTHsecretion by both phospholipase Cb and G-protein second
messengers.
As a consequence, PTH secretion changes in a sigmoidal fashionin response to acute changes in plasma calcium and there is acontinuous tonic secretion of PTH, which maintains plasma-
ionized calcium at whatever concentration is set by the CaSR .
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
33/169
Calcium Sensing Receptor
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
34/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
35/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
36/169
Result in either inactivation or activation of the receptor, whichresult in hypercalcemia and hypocalcemia, respectively.
Inactivating mutations cause insensitivity to calcium, which shiftsthe curve of PTH secretion in response to plasma calcium to theright . 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 calciumexcretion is thereby reduced. The resulting condition is known asfamilial benign hypercalcemia (FBH) or familial hypocalciuric
hypercalcemia (FHH) .
In contrast, activating mutations of the receptor shift the PTHsecretion curve to the left , causing chronic hypocalcemia andhypercalciuria, a condition known as autosomal dominant
hypocalcemia (ADH)
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
37/169
Parathyroid Hormone Receptors
Type 1 PTH receptor:
PTH and amino-
terminal peptides of
PTHrP.
G protein-coupled
receptor
Type 2 PTH receptor: Binds PTH, but
has very low affinity for PTHrP.Only expressed in a few tissues- its
structure and physiologic
significance are poorly
characterized.
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
38/169
Bone
Increases resorptionIncreases 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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
39/169
Bone fluid calcium in the canaliculi is rapidly mobilized andtransferred to blood by calcium pumps in the membrane.
Mineralized calcium is mobilized more slowly by osteoclast
activity (not shown here).
Fig. 19-21a , Sherwood
12
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
40/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
41/169
PHT decreases OPG production,allowing the protein rank-L, alsomade by osteoblasts, to bind therank-L receptors. This stimulatesosteoclast production andmaturation.
Osteoblasts produce the protein OPG
(osteoprotegerin) which binds
osteoclast rank-L receptors and down
regulates osteoclast production.
2004 Science 305:1420
+PTH
14
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
42/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
43/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
44/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
45/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
46/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
47/169
PTHrP is encoded by a single gene that is highly conservedamong species.
It should probably be described as a polyhormone, because afamily of peptide hormones are generated by alternativesplicing of the primary transcript and through use ofalternative post-translational cleavage sites.
To make matters even more complex, some cells appear to usealternative translational initiation codons to produce forms ofthe protein that are targeted either for secretion or nuclearlocalization.
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
48/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
49/169
It is clear that amino-terminal peptides of PTHrP
share a receptor with PTH, but they also bind to atype of receptor in some tissues that does not bindPTH.
In addition to the secreted forms, there is considerable
evidence that a form of PTHrP is generated in somecells that is not secreted and, via nuclear targetingsequences, is translocated to the nucleus, where itaffects nuclear function.
The consequences of this "intracrine" mode of actionare not yet well characterized, but may modulate suchimportant activities as programmed cell death.
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
50/169
.
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
51/169
Cartilage and Bone Development ,stimulates theproliferation of chondrocytes These effects of PTHrPappear due to interaction of the PTH-like peptide withthe PTH receptor
Placental Transfer of Calcium
Smooth Muscle Functioning
It acts to relax smooth muscle, thereby serving, amongother things, as a vasodilating hormone.
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
52/169
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 widelyexpressed in the CNS, and appear to influence neuronal
survival by several mechanisms. It should be clear fromthe above examples that PTHrP hormones haveprofound effects on a large number of physiologicprocesses.
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
53/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
54/169
An 8-month-old infant presents with the primary complaint ofirritability. He has been exclusively breastfed since birth. Hismother was not interested in providing any supplemental foods
because her milk supply has been adequate. Physicalexamination reveals a fussy infant who has frontal bossing andwhose weight and height are both at the 25th percentile. Theinfant becomes irritable with movement of the left arm. Armradiography reveals a humeral fracture and bowing of both
radii. Chest radiography demonstrates enlargement of thecostochondral 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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
55/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
56/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
57/169
At least four different vitamin D 25 hydroxylases distinguishable
by their different affinities and capacities and intracellularlocalization
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.
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
58/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
59/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
60/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
61/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
62/169
System Tissue
Gastrointestinal hepatocytes Esophagus, stomach, intestine, colonCardiovascular 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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
63/169
Inhibited by Vitamin D
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
64/169
Mutations in the vitamin D receptor occur throughout themolecule but particularly in either the ligand-binding (ligandbinding negative) or the DNA-binding (ligand-bindingpositive) domains.
These mutations cause severe rickets and many individuals,especially those with defects in DNA binding, also havealopecia.
Originally referred to as vitamin D-dependent rickets type II(VDRR-II), it is now more properly called hereditary1,25(OH)2D-resistant rickets (HVDRR) .
In another form of HVDRR, no mutations of the receptor havebeen identified but is thought to be caused by over expressionof a nuclear ribonucleoprotein that binds with the hormone
receptor complex to attenuate its action
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
65/169
Measure 25 OH Vitamin D
Normal- obtained by population measurement,
30-80 ng/mL
Deficient-
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
66/169
Pediatrics 0 12 months
1000 IU / Day
All others
2000 IU / Day
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
67/169
to minimize the health risks associated withUVB radiation exposure while maximizing thepotential benefits of optimum vitamin D status,
{dietary} supplementation and small amountsof sun exposure are the preferred methods ofobtaining vitamin D.
Consensus statement, 2006
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
68/169
Depends on:
Age
Amount of vitamin D obtained from diet
Skin darkness
Sunshine intensity
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
69/169
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
70/169
Cod liver oil 1 TBS
Salmon 3.5 oz.
Mackerel 3.5 oz.
Tuna, canned, in oil, 3 oz.
Sardines 3.5 oz.
Milk (fortified) 8 oz.
Ready to eat cereal (fortified) -1 cup
Egg 1 whole Liver, 3.5 oz.
Cheese, swiss 1 oz.
1,360 IU
360
345
200
250
98
40
20 15
12
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
71/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
72/169
FGF23 is mainly secreted by osteoblasts and osteocytes.
It circulates in plasma and is one of a number of fibroblastgrowth factors that function by fibroblast growth factorreceptors (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 1-hydroxylase so that hyperphosphaturic
conditions caused by raised FGF23 are not accompanied bythe expected increase in 1,25(OH)2D.
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
73/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
74/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
75/169
Normal Tissue
R1 9 S180
PHEX ??
Mesenchymal Tumor
ADHR
Active FGF23
Normal Pi level
Cartilage/bone mineralization
Renal Pi wasting ++
Inactive
S180R1 9
Active FGF23
Rickets/Osteomalacia
TIO
XLH
By H. I. cheong
NPT2a / NPT2c
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
76/169
Normal Tissue
R1 9 S180
Inactive
Normal Pi level
Cartilage/bone mineralization
S180R1 9
Active FGF23
Dentin matrix proteinDentin matrix protein 11 (DMP(DMP11))
AR-hypophosphatemicrickets
Chr. 4q21
Non-collagenous
bone matrix formation
FGF 23
A new member regulating renal Pihandling ?
PHEX ?
DMP1 ?
?
NatGenet. 2006Nov;38(11)
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
77/169
Hypophosphatemic rickets (HR) with decreased renal
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
78/169
SLC34A3sequencing
= At discretion ofreferrer. Othertestsautomatic.
Hypophosphatemic rickets (HR) with decreasedrenalphosphate reabsorption
HR with noFH
HR with FH ofMale-Male
transmission
HR withhypercalciuria
HR with FH
consistent with
AR inheritance
PHEXsequencing
HR with FHconsistent with X-
linkeddominantinheritance
DMP1 sequencing PHEXsequencing
PHEX MLPA
FGF23sequencing
FGF23 sequencing
if consistent withAD inheritance
HR withhepatomegaly and/or
fastinghypoglycaemiawith
a FH consistent withAR inheritance
SLC2A2sequencing
PHEXMLPA
FGF23 sequencing
DMP1 sequencing
ENPP1 sequencing
HR with (orFH of)Generalised Arterial
Calcification ofinfancy
ENPP1sequencing
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
79/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
80/169
Vitamin D Deficiency
Rickets
Vitamin D Dependent
Rickets
Vitamin D Resistant
Rickets
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
81/169
Rickets Rickets Rickets
Cause
Lack exposure to sunlightLack of intake
Anticonvulsant therapy
Intestinal malabsorption
Cause
Deficiency enzyme thatconvert 25-D3 to 1,25-D3
Cause
Phosphate leak at level ofproximal tubules
(not a disease of vitamin D
metabolism)
Lab findings
Low Ca2
Low PO4
High ALP
High PTH
Low 1,25-D3
Lab findings
Low Ca2
Low PO4
High ALP
High PTH
Low 1,25-D3
Lab findings
Normal Ca2
Low PO4
Normal PTH
Treatment
Vitamin D
Treatment
Daily 1,25-D3
Treatment
Phosphate supplements
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
82/169
Three-year-old boy with
vitamin D receptordefect
causing severe ricketswithalopecia
A 1 year old boy presents with generalized seizures His
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
83/169
A 1-year-old boy presents with generalized seizures. Hisgeneral physical examination findings are normal exceptfor a prominently positive Chvostek response. Results of
laboratory studies include total serum calcium of 4.5mg/dL (1.1 mmol/L) and phosphorus of 8.2 mg/dL (2.73mmol/L). Blood urea nitrogen and creatinine values arenormal 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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
84/169
CALCITONIN
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
85/169
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
Promotesrenal excretion of Ca2+
Increased Plasma Calcium Concentration Stimulates CalcitoninSecretion
Calcitonin Has a Weak Effect on Plasma Calcium Concentration in
Adult Human
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
86/169
Product of
parafollicular C cells
of the thyroid
32 aa
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
87/169
Probably not essential for human survival
Potential treatment for hypercalcemia
7 transmembrane segment receptor Stimulates cAMP production in bone and
kidney
A 1 d ld i f t d l t t d l i H
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
88/169
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 womanwhose 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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
89/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
90/169
Denitions
A fall of total calcium below 7.5 mg/dL (1.75 mmol/L), or 2.5mg/dL (0.63 mmol/L) in the ionized calcium concentrationusually denes neonatal hypocalcemia.
In infants up to 3 months of age, hypocalcemia is dened as atotal serum calcium less than 8.8 mg/dL or ionized calciumless than 4.9 mg/dL (1.22-1.4 mM).
The relationship of the total calcium concentration to theionized calcium concentration is atypical in preterm infants,and measurement of the ionized calcium concentration isrequired for accurate assessment of these infants.
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
91/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
92/169
Tetany
Seizure Laryngospasm/stridor
Arrhythmias (Prolonged Q-T interval, conductionabnormalities with bradycardia)
Circumoral numbness
Extremity parasthesiae
Trousseaus sign (carpal spasm by 3 minutes afterinterrupted vascular flow to arm)
Chvosteks sign (facial twitch caused by tapping belowzygoma)
Infants may show lethargy, vomiting, poor feeding
Neurological signs Mental status
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
93/169
and symptoms
Extrapyramidal signs due to
calcification of basal ganglia Calcification of cerebral
cortex or cerebellum
Personality disturbances
Irritability Impaired intellectual ability
Nonspecific EEG changes
Increased intracranial
pressure Parkinsonism
Choreoathetosis
Dystonic spasms
Confusion
Disorientation Psychosis
Psychoneurosis
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 musclei l t
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
94/169
Ectodermal changes
Dry skin
Coarse hair
Brittle nails
Alopecia
Enamel hypoplasia
Shortened premolar roots
Thickened lamina dura
Delayed tooth eruption
Increased dental caries
Atopic eczema
Exfoliative dermatitis
Psoriasis
Impetigo herpetiformis
involvement Dysphagia
Abdominal pain Biliary colic
Dyspnea
Wheezing
Ophthalmologic
manifestations Subcapsular cataracts
Papilledema
Cardiac
Prolonged QT intervalin EKG
Congestive heartfailure
Cardiomyopathy
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
95/169
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 (MUCHMORECOMMON)
Hypomagnesemia
Other
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
96/169
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),
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
97/169
Autoimmune APECED (autoimmune polyendocrinopathy-
candidiasis-ectodermal dystrophy syndrome)
Hypoparathyroidism Primary adrenal insufficiency
Chronic mucocutaneous candidiasis
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
98/169
AcquiredThyroid surgery
Parathyroidectomy
Iron deposition with chronic transfusions
Wilsons disease
Gram negative sepsis, toxic shock, AIDS
? Macrophage-generated cytokines
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
99/169
Target organ insensitivity to PTH
(bone / kidney)
Hypocalcemia
Hyperphosphatemia
Elevated PTH
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
100/169
GNAS1 gene mutations intracellularsignals
Expression in tissues either paternally /
maternally determined Example: renal expression is maternal
Type 1a PHP AD (maternal transmission)
Albrights hereditary osteodystrophy
Albrights
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
101/169
Short stature & limbs
Obesity Round, flat face
Short 4e/5emetacarpals
Archibald sign
Brachydactyly
Potter's thumb
Eye problems
IQ problems
Basal ganglia
calcifications
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
102/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
103/169
Phenotype ofAlbrights
NORMAL serum
calcium
NO PTH resistance
Paternal GNAS1
gene mutation
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
104/169
Type 1b Hypocalcemia, no phenotypic abnormality
AD, maternal transmission
Type 1c
Looks like type 1a
Type 2
No features of Albrights
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
105/169
Newborns (can be unspecific)
Asymptomatic
Lethargy
Poor feeding
Vomiting Abdominal distention
Children
Seizures
Twitching
Cramping
Laryngospasm
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
106/169
Neonatal hypocalcemia:
Early neonatal hypocalcemia (48-72 hours) Prematurity
Poor intake, hypoalbuminemia, reduced responsiveness tovitamin D
Birth asphyxia Delay feeding, increased calcitonin, endogenous phosphate load
high, alkali therapy
Infant to diabetic mother Magnesium depletion functional hypoparathyroidism
hypocalcemia
IUGR
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
107/169
Late neonatal hypocalcemia
Exogenous phosphate load
Phosphate-rich formulas / cows milk
Magnesium deficiency
Transient hypoparathyroidism of newborn
Hypoparathyroidism
Gentamycin (24 hourly dosing schedule)
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
108/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
109/169
Decrease intake or production
Increased catabolism
Decrease 25-hydroxylation by liver
Decrease 1-hydroxylation by kidney
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
110/169
BowingWidening ofwrist
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
111/169
Rickety rossary Frontal bossing
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
112/169
Cupping andsplaying ofmetaphysis
Delayed closure offontanels
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
113/169
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
114/169
A mother brings in her 1-year-old boy for the firsttime because she is concerned about his bowedlegs . The mother is 4 ft 10 in tall and says sheneeded to have surgery to straighten out her bowedlegs when she was an adolescent, as did one of herbrothers. Radiographs of the boys long bones areobtained . Of the following, the MOST likelyserum laboratory findings are
A. low calcium and high phosphorus
B. low calcium and normal phosphorus
C. low calcium and low phosphorusD. normal calcium and high phosphorus
E. normal calcium and low phosphorus
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
115/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
116/169
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
117/169
Pancreatitis
Citrated products
Hungry bone syndrome
Hyperphosphatemia
Fluoride poisoning
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
118/169
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
119/169
Renal Osteodystrophy
Associated with chronic renal failure
Ch. RF Hyperphosphataemiaand Hypocalcaemia
Secondary Hyperparathyroidism
Osteoclastic activity
a) Less excretionand
metabolism of PTH
b) Low orno alpha-1-
hydroxylation
c) Metabolic acidosis Release of calcium hydroxyapetitefrom bone
Osteomalacia Osteitis fibrosa
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
120/169
Total and ionized calcium Magnesium
Phosphate
UKE and s-glucose
PTH
Vitamin D metabolite Urine-CMP and creatinine
S-ALP
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
121/169
CXR
Ankle and wrist XR
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
122/169
ECG
Malabsorption workup
Karyotyping and family screening
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
123/169
You are measuring serum electrolytes at 12 hours of age in a 4,500-g infant deliveredby cesarean section at 36 weeks gestation. The Apgar scores were 6 and 8 at 1 and5 minutes, respectively. The infant is in no acute distress, breathing room air, andgenerally well appearing although he exhibits mild hypotonia The laboratory
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
124/169
generally well-appearing, although he exhibits mild hypotonia. The laboratoryresults 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 (1.7mmol/L).
Of the following, the MOST likely cause of neonatal hypocalcemia for this infant is
A.acute perinatal asphyxiaB. hypoglycemia
C. maternal diabetes mellitus
D. 22q11 deletion syndrome
E. vitamin D deficiency
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
125/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
126/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
127/169
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
128/169
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 nodepbradycardia + arrest
Stop infusion if bradycardia develops
Avoid complete correction of hypocalcaemia
With acidosis and q S-Ca give Ca before correcting acidosis
If q Mg is cause ofq S-Ca treat and correct
hypomagnesaemia
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
129/169
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
130/169
Symptomatic hypocalcaemia
Late neonatal hypocalcaemia Associated with o S-phosphate
Decrease phosphate intake
Give calcium containing phosphate binder
Oral calcium (gluconate) supplementation
100 mg/kg/dose 4 hourly per os
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
131/169
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 gutp q Ca absorption
Advantage in conditions with o 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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
132/169
g p
out aspiration pneumonia reveals rachitic changes
of the ribs. Of the following, the MOST likelyserum 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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
133/169
A 15-year-old boy has been immobilized in a doublehip spica for 6 weeks after having fractured his femur
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
134/169
hip spica for 6 weeks after having fractured his femurin a skiing accident. He has become depressed and
listless during the past few days and has complainedof nausea and constipation. He is found to havemicroscopic hematuria and a blood pressure of150/100 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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
135/169
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 )
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
136/169
136
Critical - > 14 mg %
Moderate - 12 to 14 mg %
Mild 10.4 to 11.9 mg %
Normal 8.5 to 10.3 mg %
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
137/169
Severe hypercalemia is defined as totalserum calcium > 14 mg/dl (> 3.5 mmol/L)
Hypercalcemic crises is present whensevere neurological symptoms orcardiacarrhythmias are present in a patient with
a serum calcium > 14 mg/dl (> 3.5mmol/L) or when the serum calcium is >16 mg/dl (> 4 mmol/L)
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
138/169
Ca++
PTH
VitaminD
Malignancy
Medicines
Endocrine
Genetic
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
139/169
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)
Manifestations of Hypercalcemia
Groans, moans, bones, stones
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
140/169
yp
Acute Chronic
Gastrointestinal Anorexia, nausea,vomiting
Dyspepsia,constipation,pancreatitis
Renal Polyuria, polydipsia Nephrolithiasis,
nephrocalcinosis
Neuro-muscular Depression,confusion, stupor,coma
Weakness
Cardiac Bradycardia, firstdegree atrio-ventricular
Hypertensionblock, digitalissensitivity
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
141/169
Cardiovascular
Hypertension, Increased risk ofCHD
ECG changes of shortened QT interval, PR
prolonged, QRS widened, ST, Bradycardia
Cardiac arrhythmias; Vascular calcification
Others
Itching (Generalized Pruritus)
Keratitis, conjunctivitis
141
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
142/169
Parathyroid gland tumour associated with MEN
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
143/169
MEN type 1 MEN type 2a MEN type 2b
PTH adenoma
Pituitary tumour
Pancreatic tumour
(gastrinoma,
insulinoma)
PTH hyperplasia
Medullary thyroid cancer
Phaeochromocytoma
PTH hyperplasia
Medullary thyroidcancer
Phaeochromocytoma
Mucocutaneousneurofibroma
Dysmorphic features
(marfanoid habitus,
skeletal abN, abN
dental enamel)
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
144/169
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
145/169
Deletion of multiple (20 to30) genes, including theelastin gene on chromosome#7
Elastin (ELN) providesstrength and elasticity tovessel walls
The deletion of the elastingene likely accounts for
many of the physicalfeatures of Williamssyndrome
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
146/169
Small, upturned nose
Long philtrum
Wide mouth
Full lips Small chin
Puffiness around the
eyes
Starburst (white lacy
pattern) on iris
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
147/169
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
148/169
Examination
Assessdegree ofdehydration
Syndromic feature
Presence of ectopic /subcutaneous calcification/rash
Short stature/disproportionate short stature
Generalised lymphadenopathy, organomegaly
Bone pain, fracture
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
149/169
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
150/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
151/169
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)
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
152/169
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
153/169
Commonest cause of hypercalcemia, morecommon in females
80% will be caused by a single parathyroidadenoma
15% hyperplasia
5% multiple adenomas
Rarely caused by parathyroid cancer
Familial hyperparathryoidism is associated withMEN1 and MEN 2A, and usually see hyperplasia
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
154/169
Usually asymptomatic
Symptoms:
Polyuria, polydipsia
Nephrolithiasis, nephrocalcinosis
Fatigue, weakness, myopathy
Depression
Osteopenia, osteoporosis, bone pain,pathologic fractures
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
155/169
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
156/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
157/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
158/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
159/169
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, secretionof PTHrP)
Ovarian dysgerminoma: secrete 1.25(OH)2D
Sx : water-concentrating defect (nephrogenic DI) , neurological
dysfunction d/t rapid elevation in serum Ca
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
160/169
Endocrine cause
Thyrotoxicosis (stimulation osteoclastic bone resorption by T3)
Acute adrenal insufficiency : d/t vol. depletion, change in vit Dmetabolism secondary to glucocorticoid deficiency
Chronic renal failure
P, Ca -> secondary hyperparathyroidism -> tertiaryhyperparathyroidism
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) I hibit b ti (i hibit t l ti
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
161/169
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 aftera while,
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
162/169
Analogs of pyrophosphate that adsorb to bone surface andinterfere with calcium release
Max effect in 2-4 days
Zolendronic acid is more potent and can be given rapidlyi.e. over 15 min. Longer Ca control following use(43days vs 18 days with pamidronate). Can be associatedwith jaw necrosis and renal toxicity in repeated use
Pamidronate, better tolerated. Occasional fevers.
All can have flu like symptoms, uveitis, hypocacemia,AKI
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
163/169
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
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
164/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
165/169
1) Hydration with normal saline (up to 20 mL/kg).
2) Augmentation of calciuresis with furosemide
(2 mg/kg, q4h). require monitoring of intravascular volume
3) Administration of bisphosphonates:
Starting dose of pamidronate in children is 0.5 to 1 mg/kg IVS, over 4 hours.
4) Calcitonin therapy:
A decrease in serum calcium is seen within a few hours of administration
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
166/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
167/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
168/169
-
8/8/2019 Calcium Metabolism and Disorders (Hanan)
169/169