DISORDER OF

CALCIUM
 Three organs
 Skeleton

- Parathyroid hormone (PTH)

- Parathyroid hormone–related peptide

(PTHrP)
 Kidney
- Vitamin D

- Calcitonin

 Intestine
 1000 to
1300 g of
calcium

0.1%
99.3% 0.6% ECF
0.03%
plasma
DIETARY CALCIUM BONE
1000 mg of calcium 500 mg is released and deposited

DUODENUM AND SMALL EXTRCELLULAR SPACE

200 mg absorbed
INTESTINE

FECAL CALCIUM KIDNEY

800 mg excreted FILTERED 9000 MG/DAY

200 mg excreted
PTH
Hypocalcemia

 Augmenting calcium mobilization from

bone

 Increasing kidney tubular reabsorption of

calcium

 Enhancing intestinal absorption of

calcium
PTHrP Vitamin D
 Promotes bone resorption  Increase intestinal absorption

 Enhances kidney reabsorption

 Cause bone resorption

 Decreases kidney tubular

reabsorption of phosphate

 Hypercalcemia of malignancy
 Osteocyte-derived glycoprotein that has
calciuric effects and appears to serve as a
counterbalance to PTH and 1α,25(OH)2
in calcium homeostasis
NORMAL: 8.6 to 10.3 mg/dL (2.15–2.57 mmol/L)
FREE CALCIUM: 4.65 to 5.28 mg/dL (1.16–1.32 mmol/L)

Three distinct fractions:

Plasma albumin = 90%
 Protein- bound calcium (40%) Globulins =Active
10% ofcomponent
protein- of extracellular
boundcalcium with regard:
calcium.

- to CaSR signaling
 Free (ionized) calcium (48%) - Cardiac myocyte contractility
- Neuromuscular activity
- Bone mineralization
Comprise the
- fraction of
Other calcium-dependent
 Calcium complexed to various anions plasma calciumprocesses
that can be
(12%)(phosphate, lactate, citrate, and filtered
bicarbonate)
Relationship between calcium ion and the concentration of protein in the
serum
Fall in the serum albumin level:

 Reduces the protein and calcium proteinate levels proportionately, resulting:

 In a fall in the total serum calcium level

 Normal free calcium ion concentration remaining normal
 In conventional units: In SI units:

Adjusted total calcium(mg/dL): Adjusted total calcium (mmol L):

= total calcium(mg dL) + 0.8 (4−albumin[g dL]) = total calcium (mmol L) +0.002(40−albumin[g dL])
ACIDOSIS ALKALOSIS

 Fall in pH of 0.1 unit will cause  Decreases free calcium by enhancing

approximately a 0.1-mEq/L rise in the binding of calcium to albumin
the concentration of ionized calcium
 Hyperparathyroidism Inc movement of CA from
(HPT) or excess PTHrP the skeleton into ECF
through increased Hypercalcemia
production in
malignancy osteoclastic bone resorption
REABSORPTION OF CALCIUM ALONG THE TUBULE

 9000 and 10,000 mg is filtered by the

glomerulus in a 24-hour period
 250 mg/day – amount of calcium
appearing in the urine
 1%–2% of calcium filtered at the
glomerulus appears in the urine
REABSORPTION IN THE PROXIMAL TUBULE
REABSORPTION IN THE LOOP OF HENLE
CA2+ REABSORPTION IN THE DISTAL TUBULE
HYPERCALCEMIA
 Hyperparathyroidism (HPT) or excess PTHrP production in malignancy - caused net calcium

movement from the skeleton into ECF through increased osteoclastic bone resorption

 Increase in the bone resorption rate without an increase in the bone formation rate

 Vitamin D overdose or milk-alkali syndrome – increase intestinal calcium absorption

 PTH enhances calcium transport in the distal tubule of the kidney directly, and indirectly

Increases the activity of the renal 25-hydroxyvitamin D 1α-hydroxylase

Metabolized 25(OH)D3 to biologically active 1α,25(OH)2D3, in mitochondria of proximal and distal tubule

Increases calcium transport in the intestine and kidney

PTH and 1α,25(OH)2D increase bone calcium mobilization and help to maintain serum calcium concentrations
LABORATORY FINDINGS:
ECG:

 Shortened ST segment and reduced QT interval as a result of an increased rate of cardiac

repolarization.

 Widening of the T waves, resulting in an increase in the QT interval in severe hypercalcemia (>16
mg/dL)
SIGNS AND SYMPTOMS :
Level of total serum calcium:

 Mild: [Ca] = 10.4 to 11.9 mg/d Malaise, Weakness and

Minor Joint Pain,

 Moderate: [Ca] = 12.0

- toNausea
13.9 mg/dL
- Vomiting
- Constipation
 Severe (hypercalcemic crisis): [Ca] = 14.0 to 16 mg/dL
- Polyuria
- Mental disturbances, ranging from headache
and lethargy to coma.
 Primary HPT (PHPT) and Malignancy-
associated hypercalcemia

90%

Malignancy - hospitalized patients

PHPT - outpatient clinic

8 to 80 Pg/mL (1–9pmol/L)
8 to 80 Pg/mL (1–9pmol/L)
Familial Primary
Hyperparathyroidism
Syndromes
Familial Hypocalciuric Hypercalcemia
 Total and ionized calcium - elevated
 Rare disease (estimated prevalence,
1/78,000)  PTH level - normal

 Hypercalcemia is typically mild to  Urinary calcium - not elevated

moderate (10.5−12 mg/ dL)
 Do not exhibit the typical complications
associated with elevated serum calcium
concentrations.
 FECA= < 0.01
 Magnesium level is - mildly elevated
 Phosphate - decreased
Neonatal Severe Hyperparathyroidism

 is an extremely rare  total parathyroidectomy, followed by

vitamin D and calcium supplementation.
 disordePatients who inherit two copies of
CaSR alleles bearing inactivating
mutations
Multiple Endocrine Neoplasia

MEN1
 Most common form of familial PHPT
 Parathyroid gland, pituitary gland, and
enteropancreatic tissue.
MEN2
 Medullary thyroid carcinoma,
pheochromocytoma, and PHPT
Vitamin D–Mediated Hypercalcemia
 Combination :
 Increased intestinal calcium absorption
 Excess of the tolerable upper intake of 2000
and bone resorption by vitamin D IU/day is required for this form of hypercalcemia
to develop.
 decreased kidney calcium clearance
Medications:
 Lithium
- Hypercalcemia and HPT is a long-recognized, well-
 Vitamin A described consequence of lithium therapy
 Estrogens and selective estrogen receptor - Prevalence - 4% to 6%
modifiers - Interferes with signal transduction elicited by the
CaSR:
 Thiazide
o Increases the set point for extracellular calcium to
inhibit PTH secretion
o Hyperplasia or adenoma
Medications:
 Lithium
 Vitamin A
 Estrogens and selective estrogen receptor Increased osteoclast-mediated bone resorption
modifiers
 Thiazide
Medications:
 Lithium
 Vitamin A May cause hypercalcemia early during
 Estrogens and selective estrogen receptor treatment, even in the presence of bone
modifiers metastasis.
 Thiazide
Medications:
 Lithium Major reasons for thiazide-induced
 Vitamin A hypercalcemia:
 Estrogens and selective estrogen receptor - Reduction in urinary calcium excretion
modifiers - Volume contraction
 Thiazide - Metabolic alkalosis
Milk-Alkali Syndrome
 Described in patients with duodenal ulcers receiving therapy with sodium bicarbonate and
large amounts of milk.

 Hypercalcemia, hyperphosphatemia, hypocalciuria, and CKD, together with kidney and other
soft tissue calcifications

 Calcium supplements in the form of calcium carbonate - main cause of this syndrome.
 4g of elemental calcium/day, but even 2 g of calcium/day, especially if taken together with
vitamin D
Immobilization

 Suppresses osteoblastic bone formation and increases osteoclastic bone resorption

 10 days to a few weeks for the development of immobilization hypercalcemia

 Bisphosphonates may help decrease hypercalcemia and osteopenia

 Mobilization remains the ultimate cure

Granulomatous Disease
Sarcoidosis – THE MOST COMMON (inappropriate extrarenal production of 1,25(OH)2D by activated
macrophages with increased 1α-hydroxylase activity)(10% and 20%)

 Hypercalcemia is more common in chronic and disseminated granulomatous diseases

 Sun exposure, or even small doses of vitamin D supplementation – precipitate the condition

 glucocorticoids – standard treatment

Primary Hyperparathyroidism

 Caused by excessive and incompletely regulated secretion of PTH, with consequent hypercalcemia and
hypophosphatemia

 50% of hypercalcemic cases in the general population.

 80% to 85% of cases - single enlarged parathyroid gland (adenoma)

 15% to 20% - all four parathyroid glands are hyperplastic

 MEN1 or MEN2
Primary Hyperparathyroidism
 All ages but is most common in older individuals

 Peak incidence is in the sixth decade of life

 After age 50 years, women are about three times more frequently affected than men

 External neck irradiation during childhood - risk factor for PHPT.

 PRAD-1– cyclin D1 oncogene have been observed in about 20% of parathyroid adenomas
Primary Hyperparathyroidism
60% to 80% of cases:
• minimal or no symptoms, and mild hypercalcemia is usually discovered during routine laboratory examination

20% to 25%:
• mild or intermittent hypercalcemia
• recurrent kidney stones, and complications of nephrolithiasis
• parathyroid tumor is small (<1.0 g) and slow-growing

5% to 10%:
• severe and symptomatic hypercalcemia and overt osteitis fibrosa cystica
• parathyroid tumor is usually large (>5.0 g).
Primary Hyperparathyroidism
 Hypercalcemia, inappropriately normal or elevated blood levels of PTH, hypercalciuria,
hypophosphatemia, phosphaturia, and increased urinary excretion of cAMP.

 Surgery is still standard therapy (parathyroidectomy)

• serum calcium levels greater than 1 mg/dL above normal
• reduced bone mass (T-score < −2.5 at lumbar spine, total hip, femoral neck, or distal third of the
radius)
• creatinine clearance less than 60 mL/min
• age younger than 50 years
• Hypercalciuria (>400 mg calcium/24 hours) with increased stone risk
Primary Hyperparathyroidism
 repleted with vitamin D to achieve a 25-hydroxyvitamin D (25[OH]) D level above 20 ng/dL
 maintain calcium intake the same as individuals without PHPT

 Estamibi scanning: most popular and sensitive technique to localize PTH glands, with accuracy rates up to
94%

 Ultrasound
Four classes of medications:

 Calcimimetics  Cinacalce

 Bisphosphonates

 Estrogens

 Selective estrogen receptor modulators

CANCER

 10% to 25%

 Classified into four categories:

• HHM (Humoral Hypercalcemia of Malignancy)
• Local osteolytic hypercalcemia (LOH)
• 1,25 (OH)2 vitamin D−induced hypercalcemia
• ectopic secretion of authentic PTH
Humoral Hypercalcemia of Malignancy

 PTHrP by a malignant tumor accounts for approximately 80% of cases

 PTHrP is a large protein encoded by a gene on chromosome 12

 1,25 (OH)2 vitamin D−induced
hypercalcemia Local osteolytic hypercalcemia (LOH)

 reduction in 1,25(OH)2D levels (in

contrast to PHPT)  20% of patients
 Hypercalcemic  Breast
 hypophosphatemic  Prostate cancers
 Demonstrate increased osteoclastic bone  Hematologic neoplasms
resorption,  Locally produced osteoclast- activating
 Increased urinary cAMP levels, cytokines
 Hypercalciuria.
MANAGEMENT OF
HYPERCALCEMIA

 Mild hypercalcemia (<12 mg/dL)

- do not require immediate
treatment.

 Moderate hypercalcemia (12−14

mg/dL)- requires more aggressive
therapy.

 Severe hypercalcemia (>14

mg/dL)- should be treated
intensively.
Volume Repletion and Loop Diuretics

- Adjusted to obtain a urine output of 150 to 200

mL/h

- Lower CA by 1 to 3 mg/dL by increasing GFR

and decreasing sodium and calcium
reabsorption in the proximal and distal tubules

Decrease S. CA by 2 to 4 mg/dL
Inhibition of Bone Resorption
HYPOCALCEMIA
 Total serum calcium concentration, corrected for protein, of less than 8.4 mg/ dL and
 an ionized calcium level less 1.16 mmol/L
SIGNS AND
SYMPTOMS
DIAGNOSIS
Most common causes of hypocalcemia in the nonacute setting

 Hypoparathyroidism
 Hypomagnesemia
 CKD
 Vitamin D deficiencies
Causes
 They can be broadly classified into one of three:

 PTH-related (hypoparathyroidism and pseudo- hypoparathyroidism)

 Vitamin D–related (low production, vitamin D resistance)
 Miscellaneous causes.
CAUSES
Parathyroid Hormone–Related
Disorders: Hypoparathyroidism and
Pseudohypoparathyroidism
Genetic Causes of Hypoparathyroidism.
Genetic Syndromes With Resistance to
Parathyroid Hormone Action.
Acquired Hypoparathyroidism and
Inadequate Parathyroid Hormone
Production
 Postsurgical Causes.
Vitamin D–Related Disorders
Medications.
MANAGEMENT OF HYPOCALCEMIA