CALCIUM METABOLISM PTH VITAMIN D HYPERCALCEMIA HYPOCALCEMIA MILK ALKALI SYNDROME FAMILIAL HYPERCALCEMIC HYPOCACALCIURIA

1. CALCIUM
Guide Dr DR M D MOTLAG

2. Normal calcium metabolism

3. 1-2 kg
The human body contains approximately 1100
g of calcium

5. Ion mg/dL Ionised Protein bound Complexed
Ca2 + 8.5–10.5
mg/dL
45 percent
exists as the
physiologically
active ionized
(or free)
calcium
40 percent is
bound to
albumin
15 percent is
complexed
with citrate,
sulfate, or
phosphate

6. ALBUMIN CALCIUM CORRECTION
• corrected calcium concentration is calculated by adding 0.8 mg/dL to
the total calcium level for every decrement in serum albumin of 1.0
g/dL
• below the reference value of 4.1 g/dL for albumin, and, conversely, for
elevations in serum albumin

7. Compartment % Function
Extracellular matrix 99% Calcifed matrix of bone
Extracellular fluid 0.1% • Cement for tight junctions;
• role in myocardial and smooth
muscle contraction;
• neurotransmitter release at
synapses;
• Role in excitability of neurons;
• cofactor in coagulation cascade
Intracellular 0.9% • Signal in second messenger
pathways;
• Role in muscle contraction

9. • Normal calcium level in the body
• Normal serum Ca = 8.5–10.5 mg/dL
• Ionized Ca = 50%,
• Ca bound to protein = 40%,
• Ca bound to anions - 10%
The complexed and ionized Ca2+ fractions (approximately 60% of plasma Ca2+ ) can cross the plasma membrane

11. • Acidosis increases “free” or
ionized Ca2+ in the plasma.
• Alkalosis decreases ionized
Ca2+ in the plasma.

12. • Hyperventilation  respiratory alkalosis decreased ionised ca2+
results in neuromuscular hyperexcitability manifested by numbness
and carpal spasm caused by reduced neuronal threshold for the
action potential firing.

13. Carpopedal spasm

14. Rebreathing in to paperbag is not
recommende as patient can go in to hypoxia

15. GIT
Diet
1000 mg of calcium per day
ECF
ABSORPTION 400 to 500 mg
300 mg lost in
digestive secretion
900mg in lost in stools
Glomerular
Filtrate 10000 mg
100mg lost in urine
9900mg
reabsorbed
Stable
1088000 mg
bone
remodelling
Exchangeable
4000 mg
(<1%)
Rapid exchange
20000 mg
Accretion 300mg
Reabsorption
300mg

16. GIT
Diet
1000 mg of calcium per day
ECF
ABSORPTION 400 to 500 mg
300 mg lost in
digestive secretion
900mg in lost in stools
 constant
Glomerular
Filtrate 10000 mg
100mg lost in urine
9900mg
reabsorbed
Stable
1088000 mg
bone
remodelling
Exchangeable
4000 mg
(<1%)
Rapid exchange
20000 mg
Accretion 300mg
Reabsorption
300mg
the net absorption is only 100 to 200 mg

18. Calcium handling in GIT
Active pathway Paracellular
Saturable active Nonsaturable passive
At low calcium supply At high calcium supply
transcellular pathway
via the transient
receptor potential
vanilloid 6 (TRPV6)
channel
apical membrane of the
duodenum and proximal
jejunum
throughout the length of
the intestine

19. transcellular pathway of calcium reabsorption
Ca 2+ is taken up into the
body across the brush border
of intestinal epithelial cells via
channels known as transient
receptor potential vanilloid
type 6 (TRPV6)
binds to an
intracellular protein known as
calbindin-D 9k
The absorbed Ca2+ is thereby
delivered to the basolateral membrane
of the epithelial cell, from where it can
be transported into the bloodstream by
either a Na + /Ca 2+ exchanger (NCX1)
or the Ca 2+ -Mg 2+ ATPase, PMCA 1b

20. The active transcellular pathway is vitamin D–
dependent and plays a major role in absorption
when the Ca 2+ supply is limited

21. Renal handling of calcium
Percentage
of ca2+
part Mechanism
70 % Proximal tubule in conjunction with sodium
reabsorption
20 % TALH through a passive,
paracellular mechanism
mediated by the tight junction
protein, claudin-16
10 to 15 Distal nephron Transcellular mechanism 
PTH dependent active
Only ionized (free, non-protein-bound) calcium is filtered by the
glomerulus

22. Calcium and magnesium transport in the thick
ascending limb
Ca and Mg are reabsorbed passively across the
paracellular pathway, driven by the lumen-positive
electrical potential
Loop diuretics by inhibits NKCC2 
disrupt lumen positive electrical
potential  hypocalcemia &
hypomagnesemia

23. Calcium reabsorption in distal nephron
Calcium enters the cell via the transient receptor
potential vanilloid 5 (TRPV5) channel on the apical
membrane, is transported to the basolateral membrane
by calbindin-D28k, and is extruded from the cell by the
basolateral NCX1 (a 3Na/Ca exchanger) and PMCA1b (a
Ca-ATPase) channels.

24. • ROLE OF vitamin D IN Ca2+
ABSORPTION IN DISTAL NEPHRON
• the increase in the Ca 2+ -binding
protein calbindin-D 28K and in the
expression of Ca 2+ transporters in
the basolateral membrane

25. • ROLE OF PTH IN DITSAL NEPHRON
• PTH  activate adenylyl cyclase ↑
cAMPlevels stimulate protein
kinase  phosphorylates  activates
TRPV5increases calcium
reabsorption in the distal nephron
• increases the expression of the
calcium transport proteins, TRPV5,
calbindin-D28k, NCX1, and PMCA1b,
in the distal nephron, which also
enhances renal calcium reabsorption

26. Hormones involved in calcium metabolism
• Parathyroid hormone (PTH)
• calcitriol (1,25-dihydroxyvitamin D)
• fibroblast growth factor 23 (FGF23)

27. Action of PTH
Small Intestine Kidney Bone Parathyroid
gland
No direct action Distal
tubules
• Stimulates Ca
reabsorption by
the thick
ascending limb of
Henle’s loop and
the distal tubule
• Inhibits P i
reabsorption by
proximal
nephrons
(represses NPT2a
expression
• Promotes osteoblastic
growth and survival
• Regulates M-CSF, RANKL,
and OPG production by
osteoblasts
• Chronic high levels promote
net Ca and P i release from
bone
No direct
action
indirectly on the intestine
through its effects on
synthesis of 1,25(OH)2
D to increase serum
calcium concentrations
proximal
renal
tubules
Stimulates 1α-
hydroxylase activity

29. Calcitriol
• Parathyroid cells contain vitamin
D receptors, and the PTH gene
contains a vitamin D-response
element.
• Calcitriol, by binding to the vitamin
D receptor, inhibits PTH gene
expression and, therefore, PTH
synthesis .
• Calcitriol also inhibits
parathyroid cell proliferation.

30. FGF23
• phosphaturic action,
• inhibiting PTH synthesis and secretion
• FGF-23 also regulates vitamin D
metabolism by inhibiting expression of
CYP27B1 (the gene encoding 1-alpha-
hydroxylase) and promoting expression
of CYP24A1 (the gene encoding 24-
alpha-hydroxylase), resulting in
decreased calcitriol and increased
24,25-dihydroxyvitamin D (inactive
form)

33. HYPERCALCEMIA
S Ca2+ > 10.5 mg/dL

34. Causes of hypercalcemia

35. Parathyroid mediated Non-parathyroid mediated Medications Miscellaneous
Primary
hyperparath
yroidism
Sporadic Hypercalc
emia of
malignanc
y
• PTHrP
• Increased
calcitriol
• Osteolytic bone
metastases and
local cytokines
• Thiazide diuretics
• Lithium
• Teriparatide
• Abaloparatide
• Excessive vitamin
A
• Theophylline
toxicity
• Hyperthyroidism
• Pheochromocytoma
• Adrenal insufficiency
• Immobilization
• Parenteral nutrition
• Milk-alkali syndrome
Inherited
• MEN
• Familial
isolated
• Hyperpara
thyroidism
-jaw tumor
syndrome
• Familial hypocalciuric
hypercalcemia
• Tertiary
hyperparathyroidism
(renal failure)
Vitamin D
intoxicati
on
Chronic
granulom
atous
disorders

36. • Among all causes of hypercalcemia, primary hyperparathyroidism and
malignancy are the most common,
• > 90 percent of cases
• PRIMARY HYPERPARATHYROIDISM  MC CAUSE
• asymptomatic individual has had hypercalcemia or some manifestation of
hypercalcemia such as kidney stones for >1 or 2 years, it is unlikely that malignancy
is the cause
• MALIGNANCY2ND MOST COMMON CAUSE
• if an In patients with malignancy , the interval between detection of hypercalcemia
and death, especially without vigorous treatment, is often <6 months.

38. CF
• Mild
• Asymptomatic
• vague neuropsychiatric symptoms
• Trouble concentrating, personality changes, or depression
• peptic ulcer disease
• Nephrolithiasis
• nausea, anorexia, constipation, or pancreatitis
• NEPHROGENIC DI
• POLYURIA POLYDYPSIA
• electrocardiographic changes
• bradycardia, AV block, and short QT interval

39. History
• Features a/w primary hyperparathyroidism
• Mostly asymptomatic with s Ca2+ lower or at 11 mg/dl
• HTN
• Hypercalcemia > 6 months
• Features a/w malignancy
• Symptoms of malignancy with s ca2+ > 14mg/dl
• Hypercalcemia with renal stones  hypercalcemia of c/c duration  malignancy
unlikely
• Use of drugs
• Antacids
• Calcium
• Lithium therapy

40. Investigation
CXR To rule out granulomatous ds
Electrolytes
BUN
S cr
Phosphate
Serum protein electrophoresis
• High serum chloride
• Low serum HCO3
Ratio of chloride to bicarbonate
> 33:1 primary
hyperparathyroidism
• Raised PTH Hyperparathyroidism
Low serum chloride
High HCO3 elvated BUN
• Milk alkali syndrome
High total protein
Reversed AG ratio
• MM

41. ECG changes in hypercalcemia
• The main ECG abnormality seen with hypercalcaemia is shortening of
the QT interval
• In severe hypercalcaemia, Osborn waves (J waves) may be seen
• The Osborn wave (J wave) is a positive deflection at the J point (negative in
aVR and V1). It is usually most prominent in the precordial leads
• Ventricular irritability and VF arrest has been reported with extreme
hypercalcaemia

42. Very short QT interval
J waves = notching of the terminal QRS, best seen in lead V1

43. serum creatinine should be
measured to assess renal function;
hypercalcemia may impair renal
function, and renal clearance of PTH
may be altered depending on
the fragments detected by the assay.
elevated calcium and low
phosphorus
ECTOPIC
PTH
SECRETION

44. DIAGNOSIS OF FHH
• calcium/creatinine clearance ratio =
𝑢𝑟𝑖𝑛𝑒 𝑐𝑎𝑙𝑐𝑖𝑢𝑚/𝑠𝑒𝑟𝑢𝑚 𝑐𝑎𝑙𝑐𝑖𝑢𝑚
urine creatinine/serum creatinine
• <0.01 is suggestive of FHH,
• particularly when there is a family history of mild, asymptomatic hypercalcemia.
• sequence analysis of the CASR gene GNA11 or AP2S1 genes definitive
diagnosis of FHH, although as noted above, in rare families FHH may

45. Measures to increase urinary
excretion
Measures to inhibit bone
resorption
Measures to decrease intestinal
absorption
Volume restoration
expansion & saline
diuresis
4-6 L of 0.9 %
NS in 24 hrs
 correct
dehydration
volume
expansion &
natriuresis
• Pamidronate 90 mg IV over 4
hours
• Zoledronic acid 4 mg
intravenously over ~30 min
• ibandronate (2 mg intravenously
over 2 h)
Glucocorticoids
Ketoconazole
Hydroxyl chloroqione
Frusemide • For forced
diuresis
• 20-160mg
IV 8 hrly
Plicamycin (mithramycin) used
rarely due to its high toxicity
Oral phosphate
Hemodialysis In severe
cases / or
absent renal
function
Calcitonin 4 IU/kg sc 12 hrly
Inhibit bone resorption & increase
urinary calcium excretion (RAPID
ACTION)
Galliumm nitrate 100-200mg/m2
for 5 days  not used d/t 5 days

46. Loop diuretcis (frusemide)
• reduce paracellular
reabsorption of calcium in
the loop of Henle and
thus may slightly enhance
calcium excretion
• Used after volume
restoration

47. IV bisphosphonates
• used for the treatment of hypercalcemia of malignancy in adults.
• IV bisphosphonates can be used to decrease the liberation of calcium from bone
in persistent hypercalcemia.
• Pamidronate 60 mg is infused over 2 to 4 hours;
• For severe hypercalcemia (>13.5 mg/dL), 90 mg can be given over the same duration.
• A hypocalcemic response is typically seen within 2 days and may persist for 2
weeks or longer. Treatment can be repeated after 7 days if hypercalcemia recurs.
• Zoledronate is a more potent bisphosphonate that is given as a 4-mg dose infused
over at least 15 minutes.
• Hydration should precede bisphosphonate use.
• Renal insufficiency is a relative contraindication

48. calcitonin
• Calcitonin inhibits bone resorption and
increases renal calcium excretion.
• Rapid action
• Salmon calcitonin, 4 to 8 IU/kg
intramuscularly (IM) or SC q6–12h,
lowers serum calcium 1 to 2 mg/dL
within several hours in 60% to 70% of
patients.
• Although it is less potent than other
inhibitors of bone resorption, it has no
serious toxicity, is safe in renal failure,
and may have an analgesic effect in
patients with skeletal metastases

49. • Glucocorticoids
• effective in hypercalcemia due to hematologic malignancies and
granulomatous production of calcitriol.
• Intravenous hydrocortisone (100–300 mg daily) or oral prednisone (40–60 mg
daily) for 3–7 days is used most often.
• After serum calcium stabilizes, the dose should be gradually reduced to the
minimum needed to control symptoms of hypercalcemia
• Other drugs, such as ketoconazole, chloroquine, and hydroxychloroquine,
may also decrease 1,25(OH)2D production and are used occasionally.

50. • Gallium nitrate
• inhibits bone resorption as effectively as the IV bisphosphonates
• similar delayed onset of 2 days. It is given as a 100- to 200-mg/m2/d
continuous infusion for up to 5 days, unless normocalcemia is achieved
sooner.
• significant risk of nephrotoxicity and it is contraindicated if the serum
creatinine is >2.5 mg/dL

51. Plicamycin
• Acts by inhibiting bone resorption
• 100-200mg/m2 dor 5 days
• C/I in patients wih severe hepatic renal and marrow disorders
• Action begins in 12 hrs peak at 48 hrs
• The dose can be repeated at 3 to 7 days

52. • denosumab
• 120 mg sc on days 1, 8, 15, and 29, and then every 4 weeks
• effective in treating hypercalcemia refractory to bisphosphonates

53. HD in hypercalcemia
• very severe hypercalcemia (>16 mg/dL)
• CHF
• renal insufficiency

54. Mx of A/C hypercalcemia
Mild hypercalcemia • Adequate hydration
Severe hypercalcemia (13-15mg/dl) • IV 0.9% saline 2–4 L/day
• use of loop diuretics to enhance sodium and
calcium excretion
• Zoledronic acid 4 mg IV or pamidronate 60–90 mg
IV
• IM/SC calcitonin 100 U 3 times daily for frst 24–48
hours in life-threatening hypercalcaemia

55. Management of c/c hypercalcemia
• Bisphosphonates
• Glucocorticoids :
• Effective in particular situations such as Vitamin D intoxication, Sarcoidosis,
Malignancy
• Calcitonin
• Phosphat
• Dialysis - Quick and effective and is likely to be needed in severe cases
with renal failure
• Plicamycin*
• Gallium Nitrate*

57. Cinacalcet
• Cinacalcet
• calcimimetic which enhances
the sensitivity of the calcium-
sensing receptor, so reducing
PTH levels, and is licensed for
tertiary hyperparathyroidism
and as a treatment for patients
with primary
hyperparathyroidism who are
unwilling to have surgery or are
medically unft

58. Lithium causing hypercalcemia
• Lithium may cause hyperparathyroidism by reducing the sensitivity of
the calcium-sensing receptor (CaSR)

59. Lithium causing hypercalcemia
• causes hypercalcemia in ~10% of treated patients.
• complete reversal of hypercalcemia when lithium is stopped.
• long-standing stimulation of parathyroid cell replication by lithium
may predispose to development of adenomas
• Parathyroid surgery should not be recommended unless hypercalcemia
and elevated PTH levels persist after lithium is discontinued
• Rx
• Discontinue lithium
• alternative medications for the underlying psychiatric illness

60. MALIGNANCY CAUSING HYPERCALCEMIA

61. humoral hypercalcemia of malignancy (HHM)
• Due to secretion of parathyroid hormone (PTH)-related protein
(PTHrP)
• accounts for up to 80 percent of patients with hypercalcemia of
malignancy
• The most common cause of hypercalcemia in patients with
nonmetastatic solid tumors and in some patients with non-Hodgkin
lymphoma
• Patients with HHM most often have squamous cell carcinomas (lung, head,
and neck) or renal, bladder, breast, or ovarian carcinomas

62. homology with PTH, particularly at the
amino-terminal end, at which the first
13 amino acids
Structural divergence after the first 13
amino acids of the molecule
PTHrP to simulate some of the actions of
PTH
immunologic distinctiveness from PTH
• increases in bone resorption and distal
tubular calcium reabsorption
• inhibition of proximal tubular
phosphate transport
• less likely than PTH to stimulate 1,25-
dihydroxyvitamin D production 
does not increase intestinal calcium
absorption
hypercalcemia in HHM is due to the combined
effects of PTHrP on kidney and bone

63. • Typical laboratory findings in patients with HHM include the following
• Elevated serum PTHrP
• Very low or suppressed serum intact PTH (secretion of endogenous PTH is
suppressed by PTHrP-mediated hypercalcemia)
• Normal to low serum 1,25-dihydroxyvitamin D

64. Role of PTHrP in malignancy
• useful tumor marker for assessing the response to treatment of the
tumor
• predict the response to bisphosphonates.
• > 12 pmol/L
• with both a smaller reduction in hypercalcemia and with recurrence of hypercalcemia
within 14 days of therapy

65. Osteolytic metastases
• Characteristics
• Low or suppressed serum intact PTH
• Low or low-normal serum 1,25-dihydroxyvitamin D
• Low or low-normal serum PTHrP (although tumor metastases in bone may
secrete PTHrP locally, it is not usually measurable in a serum assay)
• Extensive skeletal metastases or marrow infiltration

66. Rx of Malignancy-Related Hypercalcemia
• control of tumor; reduction of tumor mass usually corrects
hypercalcemia

67. Denosumab

68. • Denosumab,
• human monoclonal antibody to RANKL
• highly effective for preventing bone complications in patients with bone
metastases from prostate cancer, breast cancer, and other solid tumors, and
in multiple myeloma.
• It also prevents treatment-related bone loss in men treated with androgen
deprivation therapy for prostate cancer and in women with breast cancer who
are treated with aromatase inhibitors

69. Familial hypocalciuric hypercalcaemia
autosomal dominant disorder
inactivating mutation in one of the
alleles of the CaSR gene, which reduces
the ability of the parathyroid gland to
‘sense’ ionised calcium concentrations
Defective CaSR in parathyroid 
increased PTH  hypercalcemia
Defective CaSR in kidney 
hypocalciuria

70. Familial hypocalciuric hypercalcemia (FHH)
FHH type 1 MOST
COMMON
involving inactivating
mutations in the calcium
sensor receptor (CaSR)
FHH type 2 with rare families having
mutations in the Gα
11 protein (GNA11)
FHH type 3 adaptor-related protein
complex 2, σ-2
subunit (AP2S1)

71. DIFFERENTIATING FEATURES FROM PRIMARY
HYPERPARATHYROIDISM
FHH primary HPT
>99% reabsorption <99% renal calcium reabsorption
Affected in first decade of life, rarely occurs in patients
with primary HPT or the MEN syndromes
who are aged <10 years
Autosomal dominant • AD in MEN
• Sporadic
Parathyroidectomy  cure • Parathyroidectomy  permanent
hypoparathyroidism and hypocalciuria
persisted

72. DIAGNOSIS OF FHH
• calcium/creatinine clearance ratio =
𝑢𝑟𝑖𝑛𝑒 𝑐𝑎𝑙𝑐𝑖𝑢𝑚/𝑠𝑒𝑟𝑢𝑚 𝑐𝑎𝑙𝑐𝑖𝑢𝑚
urine creatinine/serum creatinine
• <0.01 is suggestive of FHH,
• particularly when there is a family history of mild, asymptomatic hypercalcemia.
• sequence analysis of the CASR gene GNA11 or AP2S1 genes definitive
diagnosis of FHH, although as noted above, in rare families FHH may

73. Rx of FHH
• Total parathyroidectomy in neonatal severe hypercalcemia in
homozygous severe impairment of CaSR function

74. GRANULAR DISEASES A/W HYPERCALCEMIA
• sarcoidosis and tuberculosis are probably most
common
• activated mononuclear cells (particularly
macrophages) in the lung and lymph nodes
produce calcitriol from calcidiol independent of
PTH
• Increased intestinal calcium absorption induced by high
serum calcitriol concentrations is the primary
abnormality, although a calcitriol-induced increase in
bone resorption may also contribute
• Diagnosis
• low-normal or low parathyroid hormone (PTH) level
(non-PTH mediated hypercalcemia)
• serum 1,25-dihydroxyvitamin D level may be elevated

75. TREATMENT OF GRANULAR DISEASES A/W
HYPERCALCEMIA
• STEROIDS
• Inhibition of calcitriol synthesis by the activated mononuclear cells
• Ketoconazole
• general inhibitor of P450 enzymesdecrease calcitriol production
• chloroquine, or hydroxychloroquine
• act by decreasing the inflammatory activity of the disease.

76. Vitamin D Intoxication
• Chronic ingestion of 40–100 times the normal physiologic requirement
of vitamin D (amounts >40,000–100,000 U/d)  significant
hypercalcemia
• Diagnosis
• elevated levels of 25(OH)D >100 ng/mL
• Rx
• restriction of dietary calcium intake
• appropriate attention to hydration.
• discontinuation of vitamin D, usually lead to resolution of hypercalcemia.
• vitamin D stores in fat may be substantial, and vitamin D intoxication may persist
for weeks after vitamin D ingestion is terminated.
• Such patients are responsive to glucocorticoids, which in doses of 100 mg/d of
hydrocortisone or its equivalent usually return serum calcium levels to normal over several
days; severe intoxication may require intensive therapy.

77. Idiopathic Hypercalcemia of Infancy
• Williams’ syndrome
• autosomal dominant disorder
• genetic mutations involving microdeletions at the elastin locus and perhaps other
genes on chromosome 7
• characterized by multiple congenital development defects
• supravalvular aortic stenosis,
• mental retardation,
• elfin facies,
• hypercalcemia due to abnormal sensitivity to vitamin D
• 24-hydroxylase deficiency that impairs metabolism of 1,25(OH)2D,
• mutations involving the sodium-dependent phosphate transporters
(NPT2a or NPT2c).

78. HYPERCALCEMIA ASSOCIATED
WITH HIGH BONE
TURNOVER

79. Increasd bone turn over
• Hyperthyroidism
• due to increased bone turnover, with bone resorption exceeding bone formation.
• managed by treatment of the hyperthyroidism
• Immobilization
• after spinal cord injury and paraplegia or quadriplegia.
• With resumption of ambulation, the hypercalcemia in children usually returns to normal.
• decreased bone formation and increased bone resorption  hypercalcemia
• Thiazides
• Hypocalciuric
• Augmentation of action of PTH
• enhancement of proximal tubular resorption of sodium and calcium in response to sodium depletion
• Vitamin A Intoxication
• increase bone resorption
• dietary faddism
use of thiazides as an
adjunct to therapy in hypoparathyroid patients

80. HYPERCALCEMIA ASSOCIATED
WITH RENAL
FAILURE

81. Severe Secondary HPT

82. Secondary hyperparathyroidism

83. Causes of secondary hyperparathyroidism
• chronic renal failure  MC cause
• Low vitamin D intake,
• Rickets,
• osteomalacia,
• malabsorption

84. • The bone disease seen in patients with secondary HPT and CKD is
termed renal osteodystrophy
• affects primarily bone turnover.

85. Secondary hyperparathyroidism in CKD
• Elevated PTH
• FGF23 production by osteocytes (and possibly osteoblasts) in bone
• FGF23 is a potent inhibitor of the renal 1-alpha hydroxylase and the FGF23-
dependent reduction in 1,25(OH)2

86. CKD
Decrease in GFR
Increased phosphate
load in blood
Defective conversion of 25hydroxyvitamin D
to its active metabolite,1,25-
dihydroxyvitamin D,
• due in part to renal tubular cell damage
• elevated FGF23 levels
hypocalcaemia
increased PTH production by the parathyroid glands
Elevated FGF23
The FGF23 promotes
phosphate excretion,
thereby compensating in
part for the reduced
glomerular fltration of
phosphate.

89. • Rugger Jersey spine is
seen in CRF
• d/t 2*
hyperparathyroidism

90. Rx
• reduction of excessive blood phosphate
• restriction of dietary phosphate
• use of nonabsorbable phosphate binders
• sevelamer
• selective addition of calcitriol (0.25–2 μg/d) or related analogues
• Intravenous calcitriol (or related analogues) several pulses each week

91. Secondary hyperparathyroidism
• In CRF
• Ca2+↓
• PTH↑
• ↑PO4
• In malnutrition, ricket osteomalacia
• Ca↓
• PTH ↑
• ↓ PO4

92. TERTIARY HYPERPARATHYROIDISM
• Occurs after prolonged secondary hyperparathyroidism, causing
glands to act autonomously having undergone hyperplastic or
adenomatous change.
• This causes Ca2+ from secretion of PTH unlimited by feedback
control. Seen in chronic renal failure.
• no longer responsive to medical therapy, a state of severe HPT in
patients with CKD that requires surgery
• Parathyroid surgery is necessary to control this condition

93. TERTIARY HYPERPARATHYROIDISM
• Ca2+↑,
• PTH↑
• ↓PO4

94. Cinacalcet
• Cinacalcet
• calcimimetic which enhances
the sensitivity of the calcium-
sensing receptor, so reducing
PTH levels, and is licensed for
tertiary hyperparathyroidism
and as a treatment for patients
with primary
hyperparathyroidism who are
unwilling to have surgery or are
medically unft

95. Other skeletal disorders have been frequently
associated in the past with CKD patients treated
by long-term dialysis
• Aluminum deposition in bone an osteomalacia-like picture
• d/t aluminum-containing antacids or aluminum excess in the dialysis regimen
• Aluminum is present at the site of osteoid mineralization, osteoblastic activity is
minimal, and calcium incorporation into the skeleton is impaired.
• acute dementia
• unresponsive and severe osteomalacia.
• Bone pain, multiple nonhealing fractures, particularly of the ribs and pelvis, and a proximal
myopathy occur.
• Hypercalcemia develops when these patients are treated with vitamin D or calcitriol
because of impaired skeletal responsiveness.
• Calcium carbonate preferred over aluminum-containing antacids
• “aplastic” or “adynamic” bone disease
• low- turnover bone disease
• excessive PTH suppression
• PTH levels are lower than typically observed in CKD patients with secondary HPT

96. Milk alkali syndrome
• Rare now a days
• excessive ingestion of calcium and absorbable antacids such as milk
or calcium carbonate
• Triad
• hypercalcemia,
• alkalosis,
• renal failure

98. • mild hypercalcemia → bicarbonate retention → alkalosis → renal
calcium retention → severe hypercalcemia

99. Hypercalcemia Kidney Vasoconstriction decreases the glomerular filtration
rate (GFR)
Activation of the calcium-sensing
receptor in the medullary thick
ascending limb, which inhibits the
Na-K-2Cl cotransporter.
Natriuresis depletion of water
Blockade of antidiuretic hormone
(ADH)-dependent water
reabsorption in the collecting duct
Depletion of H2O
PTH Decreased PTH (Parathyroid
hormone (PTH) diminishes
proximal HCO3- reabsorption by
reducing the activity of Na+-H+
exchanger in the luminal
membrane and the Na+-3HCO3-
cotransporter in the basolateral
membrane )
Alkalosis

100. Hypocalcemia

101. Hypocalcemia
• A serum calcium <8.4 mg/dL with a normal serum albumin or an
ionized calcium <4.2 mg/dL

102. CAUSES OF HYPOCALCEMIA

103. • CITRATED BLOOD ON RAPID TRANSFUSION  HYPOCALCEMIA
• SO FOR EVER 4 UNITS OF BLOOD  GIVE 10 ML OF 10 % CALCIUM
GLUCONATE

104. Transient hypocalcemia
• not associated with tetany and resolve with improvement in the
overall medical condition.
• severe sepsis,
• burns,
• acute kidney injury,
• extensive transfusions with citrated blood
• Alkalosis
• acute pancreatitis
• Medications such as protamine, heparin, and glucagon

105. Chronic hypocalcemia
• usually symptomatic and requires treatment
• chronic renal failure,
• hereditary and acquired hypoparathyroidism,
• vitamin D deficiency,
• PHP, and
• hypomagnesemia.
• associated with both deficient PTH release and impaired responsiveness to the
hormone
• reversible gland dysfunction

106. Causes of hypocalcemia
Hypoalbuminemia Hypoparathyroidism Defect in vitamin D
metabolism
Miscellaneous Severe hyperacute
phosphatemia
Pseudohypocalcemia • Post surgical 
HUNGRY BONE
SYNDROME
• Hypomagnesemia
• Idiopathic
• Nutritional
• Malabsorption
• Anticonvulsants
• Renal failure
• Respiratory
alkalosis
• Sepsis
• Toxic shock
syndrome
• Massive
transfusion
of citrated
blood
• Tumor lysis syndrome
• Rhabdomyolysis

107. MOST COMMON ETIOLOGIES OF
HYPOCALCEMIA
• impaired PTH production
• impaired vitamin D production

108. MANIFESTATION
MILD ASYMPTOMATIC
MODERATE • paresthesias, usually of the fingers, toes, and
circumoral regions, and is caused by increased
neuromuscular irritability.
SEVERE • seizures,
• carpopedal spasm,
• bronchospasm,
• laryngospasm, and
• prolongation of the QT interval

109. ECG
• Sinus bradycardia
• prolonged QT interval

110. investigations
• Albumin
• Serum PTH
• Serum phosphorus
• Vitamin D
• Magnesium

111. • serum calcium
• albumin, phosphorus, and
magnesium levels.
PTH level
absent or reduced PTH
hypoparathyroidism
elevated PTH level
vitamin D axis
25-hydroxyvitamin D NUTRITIONAL renal insufficiency or
suspected
vitamin D resistance, serum
1,25(OH)2D

112. ETIOLOGY SERUM CALCIUM SERUM PHOSPHATE SERUM PTH
TOTAL IONISED
HYPOALBUMINEMIA LOW NORMAL N N
ALKALOSIS N LOW N N – HIGH
VITAMIN D
DEFICIENCY
LOW LOW LOW HIGH
CRF LOW LOW HIGH HIGH
HYPOPARATHYROIDIS
M
LOW LOW HIGH LOW

113. • Pseudohypocalcemia
• describes the situation in which the total calcium is reduced due to
hypoalbuminemia, but the corrected [Ca2+] and ionized calcium remain
within the normal ranges.

114. Signs of neuromuscular irritability in
hypocalcemia
Na + channel voltage-
gating is dependent on the
extracellular Ca 2+ concentration.
Decreased plasma Ca 2+
concentrations reduce the
voltage threshold for the action
potential firing neuromuscular
hyperexcitability
Test Procedure
Chvostek ipsilateral contraction of facial
muscles elicited by tapping the skin
over the facial nerve
Trousseau carpal spasm induced by infl ation
of the blood pressure cuff to 20
mm Hg above the patient’s systolic
blood pressure for 3–5 minutes

115. Trousseau’s sign Chvostek sign

116. RX
Acute, symptomatic
hypocalcemia
• calcium gluconate, 10 mL 10% wt/vol (90 mg or
2.2 mmol) intravenously, diluted in 50 mL of 5%
dextrose or 0.9% sodium chloride, given
intravenously over 5 min
• IF SEVERE 60ML OF CALCIUM GLUCONATE IN
500ML OF 5 % DEXTROSE
Chronic hypocalcemia
due to
hypoparathyroidism
• calcium supplements (1000–1500 mg/d elemental
calcium in divided doses) and either vitamin D2 or
D3(25,000–100,000 U daily) or calcitriol [1,25(OH)2
D, 0.25–2 μg/d]
IF NOT RELIEVED
WITH Ca2+
INFUSION 
CHECK S Mg2+

117. Rx of Hypocalcemia
• 10 ml of calcium gluconate (10% ) given slowly over 10 minutes
• Severe symptomatic
• 60 ml of calcium gluconate in 500ml of 5% dextrose

118. Chronic management
• Oral calcium supplements.
• Calcium carbonate (40% elemental calcium) or calcium acetate (25%
elemental calcium) can be given with the goal administration of 1 to 2 g of
elemental calcium PO tid
• Vitamin D.
• Simple dietary deficiency can be corrected by the use of ergocalciferol 400 to
1,000 IU/d. However, in conjunction with other hypocalcemic disorders, larger
doses may be required. A 6- to 8-week regimen of 50,000 IU should be dosed
weekly in those with underlying impairments in vitamin D metabolism (i.e.,
renal insufficiency) and daily in patients with severe malnutrition or
malabsorption

119. calcitriol
• rapid onset of action.
• SHORTEST DURATION OF ACTION
• The initial dosage is 0.25 mcg daily, and most patients are maintained
on 0.5 to 2.0 mcg daily.
• The dose can be increased at 2- to 4-week intervals.

120. • nutritional vitamin D deficiency
• low doses of vitamin D (50,000 U, 2–3 times per week for several months)
• vitamin D deficiency due to malabsorption
• Higher doses 100,000 U/d or more

121. Application of calcium based
knowledge

122. Coronary artery calcium score
• marker of the extent of coronary atherosclerosis than the severity of
stenosis
• The determination of the CAC score by computed tomography is
based on axial slices, with a thickness of 3 mm, without overlapping
or gaps, limited to the cardiac region

124. Coronary artery calcium scoring agatston
units