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Calcium Homeostasis
and Hypercalcemia
Resident Conference
Robert B. Kamali, M.D.
Nov. 4, 2003
Overview
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Calcium Homeostasis: PTH and Calcitriol
Mechanisms of Hypercalcemia
Causes of Hypercalcemia
Clinical Manifestations of Hypercalcemia
Diagnosis of Hypercalcemia
Treatment of Hypercalcemia (Medical and
Surgical)
Calcium Homeostasis
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Two major hormones modulating calcium and
phosphate homeostasis:
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PTH and Calcitriol
PTH:
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maintainins serum ionized calcium concentrations
within a narrow range
Calcium Homeostasis
PTH
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Raises calcium by:
Accelerating osteoclastic bone resorption
 Increasing renal tubular resorption of calcium
 Increases calcitriol, indirectly raising serum calcium
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Calcium Homeostasis
PTH
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Stimulates the conversion of calcidiol [25-(OH)
D] to calcitriol [1,25-(OH)2 D] in renal tubular
cells
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Its secretion regulated by serum ionized calcium
acting via a sensitive calcium-sensing receptor
on the surface of parathyroid cells
Calcium Homeostasis
PTH
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With small increase in serum ionized calcium
calcium-sensing receptor activatedPTH
secretion is inhibited
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A small decrease in serum ionized calcium 
deactivation of the receptor  stimulating PTH
secretion
Calcium Homeostasis
PTH
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PTH synthesized as a 110-aa polypeptide
cleaved to pro-PTH (90-aa)  PTH (84-aa)
Intact PTH: The major storage, secreted, and
biologically active form of the hormone
Biosynthetic process takes less than one hour
Within seconds after hypocalcemia PTH 1-84
secreted by exocytosis
Calcium regulates release, synthesis and
degradation of PTH
Calcium Homeostasis
PTH
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PTH rapidly cleared from plasma through uptake by
liver and kidney
PTH 1-84 cleaved into amino- and carboxyl-terminal
fragments cleared by the kidney
Intact PTH has a plasma half-life of 2-4 min
Circulating immunoreactive PTH in normal subjects
comprises:
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Intact PTH 5-30%
C-term fragment 70-95%
N-term fragment a small percentage
Calcium Homeostasis
PTH
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Biologic activity of PTH resides in its aminoterminus
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The amino terminus of PTHrP structurally
similar to PTH hypercalcemia in patients with
PTHrP-secreting tumors
Calcium Homeostasis
Vitamin D Synthesis
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Dermal synthesis major source of the vitamin D
Synthesized nonenzymatically in skin from 7dehydrocholesterol during exposure to the UVB rays in
sunlight
Dietary vit D absorbed in the small intestine as a fat
soluble vitamin
Travels to the liver, bound to vitamin D-BP
Hepatic enzyme 25–OHase places an OH group in the
25 position of the vitamin D molecule, resulting in the
formation of 25-hydroxyvitamin D or calcidiol
Calcium Homeostasis
Vitamin D Synthesis
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Calcidiol only about 1% as potent as calcitriol
Calcidiol enters circulation and travels to the
kidney, bound to vit-D-BP
1-alpha-OHase in the tubular cells synthesizes
calcitriol
FUNCTIONS OF CALCITRIOL
[1,25-(OH)2 D3]
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Calcitriol binds to intracellular receptors in
target tissues and regulates gene transcription
Its most important biological action:
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Promoting enterocyte differentiation and intestinal
absorption of calcium
Other effects include:
Stimulation of intestinal phosphate absorption
 Direct suppression of PTH release from the parathyroid
gland
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FUNCTIONS OF CALCITRIOL
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Contributes to the maintenance of normal
plasma concentrations of calcium and
phosphate
Allows mineralization of newly formed bone to
take place
Prevents symptomatic hypocalcemia or
hypophosphatemia
Actions of the Hormones Involved in Calcium Homeostasis
Hormone
PTH ↑Ca
++
, ↓PO4
levels in blood
Vitamin D
↑Ca++ , ↑PO4 levels in
blood
Effect on
kidneys
Effect on bones
Supports
osteoclast
resorption
Effect on GI
Supports Ca++
Indirect effects
via ↑calcitriol resorption and PO4
excretion, activates
from 11-hydroxylation
hydroxylation
No direct effects
↑Ca++ and PO4
absorption
No direct effects
No direct effects
Promotes Ca++
and PO4
excretion
Supports osteoblasts
Calcitonin ↓Ca++ Inhibits osteoclast
, ↓PO4 levels in
resorption
blood when
hypercalcemia
present
Overview
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Calcium Homeostasis: PTH and Calcitriol
 Mechanisms
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of Hypercalcemia
Causes of Hypercalcemia
Clinical Manifestations of Hypercalcemia
Diagnosis of Hypercalcemia
Treatment of Hypercalcemia (Medical and
Surgical)
Mechanisms of Hypercalcemia
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1)Increased GI Absorption
2)Bone Resorption
3)Renal Reabsorption
Vitamin D: Predominant control in GI absorption
 PTH: Principal one at bone surface and in the
kidney
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Underlying Disorders Increasing GI
Absorption
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Major Physiologic
Control: Vitamin D
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Sarcoidosis
Lymphoma
Vitamin D intoxication
Milk Alkali syndrome
Hyperparathyroidism
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1,25-(OH)2D3
1,25-(OH)2D3
Vitamin D
GI Absorption
PTH  increased D
Underlying Disorders Increasing
Bone Resorption
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Hyperparathyroidism
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Adenoma
Hyperplasia
Cancer
Metastatic Cancers
Myeloma
Humoral hypercalcemia
of malignancy
Hyperthyroidism
Paget’s disease
Mediated by
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PTH
PTH
PTH
PTHrP
Cytokines
PTHrP
Thyroxine
?
Underlying Disorders Increasing
Renal Reabsorption
 Hyperparathyroid  PTH
ism
 Thiazides
 FHH
 Adrenal
Insufficiency
 PTH
?
ne resorption (right), or renal reabsorption (bottom) leads to an increased serum calcium level. Several underlying disorders may affect each system and
Overview
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Calcium Homeostasis: PTH and Calcitriol
Mechanisms of Hypercalcemia
 Causes
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of Hypercalcemia
Clinical Manifestations of Hypercalcemia
Diagnosis of Hypercalcemia
Treatment of Hypercalcemia (Medical and
Surgical)
Causes of Hypercalcemia
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Related to PTH
Vitamin D-related
Malignancy
Medications
Other endocrine
Genetic
Other
Causes of Hypercalcemia
PTH
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PTH
 Primary hyperparathyroidism
 Sporadic, familial, associated with MEN I or
II
 Tertiary hyperparathyroidism associated with
CRF or vitamin D deficiency
Tertiary Hyperparathyroidism.
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CRF generally causes hypocalcemia
Untreated hypocalcemia, prolonged high
phosphate and low vitamin D levels can lead to
increased PTH secretion and subsequent
hypercalcemia
Causes of Hypercalcemia
Vitamin D-related
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Vitamin D intoxication: Usually 25hydroxvitamin D in OTC supplements
Granulomatous disease
sarcoidosis
 berylliosis
 Tuberculosis
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Hodgkin’s lymphoma
Causes of Hypercalcemia
Malignancy
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Malignancy
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Humoral hypercalcemia of malignancy (mediated
by PTHrP)
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Solid tumors, especially lung, head, and neck squamous
cancers, renal cell tumors
Local osteolysis (mediated by cytokines)
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multiple myeloma
Causes of Hypercalcemia
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Medications
Thiazide diuretics (usually mild)
 Lithium
 Milk-alkali syndrome (from calcium antacids)
 Vitamin A intoxication (including analogs used to
treat acne)
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Causes of Hypercalcemia
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Other endocrine disorders
Hyperthyroidism
 Adrenal insufficiency
 Acromegaly
 Pheochromocytoma
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Causes of Hypercalcemia
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Genetic disorders
Familial hypocalciuric hypercalcemia: mutated
calcium-sensing receptor
 Nl PTH in 80-85% of patients
 Benign inherited condition
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Causes of Hypercalcemia
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Other
Immobilization, with high bone turnover (e.g.,
Paget’s disease, bedridden child)
 Recovery phase of rhabdomyolysis
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Causes of Hypercalcemia
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Hyperparathyroidism and Malignant neoplasms
account for majority of hypercalcemia
Neoplasms most frequently associated with
hypercalcemia: breast cancer, lung cancer (10% of
squam lung Ca) , and multiple myeloma
Most hypercalcemias in the setting of malignancy
caused by humoral hypercalcemia of malignancy
Single adenomas of the parathyroid gland account for
75% of primary hyperparathyroidism associated with
hypercalcemia
Overview
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Calcium Homeostasis: PTH and Calcitriol
Mechanisms of Hypercalcemia
Causes of Hypercalcemia
 Clinical
Manifestations of
Hypercalcemia
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Diagnosis of Hypercalcemia
Treatment of Hypercalcemia (Medical and
Surgical)
Clinical Manifestations of
Hypercalcemia
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“stones”
“bones”
“abdominal moans”
“psychic groans”
Neuromuscular
Cardiovascular
Other
Clinical Manifestations of
Hypercalcemia
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Renal “stones”
Nephrolithiasis
 Nephrogenic DI: polydipsia and polyuria
 Dehydration
 Nephrocalcinosis
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Clinical Manifestations of
Hypercalcemia
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Skeleton “bones”
Bone pain, arthralgias
 Osteoporosis of cortical bone such as wrist
 In primary hyperparathyroidism: Subperiosteal
resorption, leading to osteitis fibrosa cystica with
bone cysts and brown tumors of the long bones
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Clinical Manifestations of
Hypercalcemia
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Gastrointestinal “abdominal moans”
Nausea, vomiting
 Anorexia
 weight loss
 Constipation
 Abdominal pain
 Pancreatitis
 Peptic ulcer disease
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Clinical Manifestations of
Hypercalcemia
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“psychic groans”
Impaired concentration and memory
 Confusion, stupor, coma
 Lethargy and Fatigue
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Clinical Manifestations of
Hypercalcemia
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Neuromuscular
Reduced neuromuscular excitability and muscle
weakness
 Easy fatigability and muscle weakness more
common in hyperparathyroidism than other
hypercalcemic conditions
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Clinical features of hyperparathyroid myopathy:
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Proximal muscle weakness, wasting and mild
nonspecific myopathic features on electromyogram
and muscle biopsy
Clinical Manifestations of
Hypercalcemia
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Cardiovascular
Shortened QT interval on electrocardiogram
 Cardiac arrhythmias
 Vascular calcification
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Clinical Manifestations of
Hypercalcemia
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Other
Itching
 Keratitis
 Conjunctivitis
 Corneal calcification, band keratopathy
 Carpal tunnel syndrome has occasionally been
associated with hyperparathyroidism
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Clinical Manifestations of
Hypercalcemia
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AMS common in hypercalcemia (particularly when Ca> 14
mg/dL) and generally consist of progressive lethargy, confusion,
and ultimately coma
These reversible symptoms directly related to the degree of
hypercalcemia
HA, elevated CSF protein, and rare convulsions also occur
Hyperparathyroidism been rarely associated with severe CNS
dysfunction, including ataxia, internuclear opthalmoplegia,
corticospinal tract dysfunction, dysarthria, and dysphagia
Hypercalcemia been associated with apnea in children
Overview
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Calcium Homeostasis: PTH and Calcitriol
Mechanisms of Hypercalcemia
Causes of Hypercalcemia
Clinical Manifestations of Hypercalcemia
 Diagnosis
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of Hypercalcemia
Treatment of Hypercalcemia (Medical and
Surgical)
Diagnosis
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Serum Calcium, PO4
Intact PTH (10-60pg/ml)
Serum PTHrP
24 hr urine Ca excretion
Urinary nephrogenous cAMP excretion
99mTc sestamibi scans to predict the location of
abnormal gland
Diagnosis
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Accurate Hx of constitutional symptoms
suggesting malignancy, Accurate FH (MEN,
FHH)
Elevated PTH and concern for FHH:
Take an accurate Hx
 Renal Ca reabsorption:
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Primary hyperparathyroidism: <99%
 FHH: >99% reabsorption
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Overview
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Calcium Homeostasis: PTH and Calcitriol
Mechanisms of Hypercalcemia
Causes of Hypercalcemia
Clinical Manifestations of Hypercalcemia
Diagnosis of Hypercalcemia
 Treatment
of Hypercalcemia
(Medical and Surgical)
Who should be treated?
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If severe hypercalcemia and primary
hyperparathyroidism Surgery mandatory as
soon as Dx can be confirmed by PTH
Most patients with hyperparathyroidism, mild
hypercalcemia  Do not require urgent surgical
or medical Rx
Which patients with asymptomatic hyperparathyroidism
should be treated?
Criteria for Surgery in Primary
Hyperparathyroidism
NIH Consensus Conference on Management of Asymptomatic Hyperparathyroidism in 1991
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Age younger than 50
Serum total calcium level >12 mg/dL (3 mmol per L)
at any time
Hyperparathyroid crisis (Hx of discrete episode of lifethreatening hypercalcemia)
Marked hypercalciuria (urinary calcium excretion >400
mg/d)
Nephrolithiasis (presence of kidney stone on Xray even
if asymptomatic)
Impaired renal function
Osteitis fibrosa cystica
Criteria for Surgery in Primary
Hyperparathyroidism
Reduction of bone mass more than 2 SD
below age-matched controls
 Classic neuromuscular symptoms
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Information from NIH conference: diagnosis and management of asymptomatic primary
hyperparathyroidism: consensus development conference statement. Ann Intern Med 1991;114:593–
7.*—Guidelines from the National Institutes of Health Consensus Development Conference.
Natural History of Primary
Hyperparathyroidism
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Many have benign clinical course without
significant progression
Most asymptomatic patients do not have
progression
Most asymptomatic patients who have
parathyroidectomy have normalization of the
biochemical values as well as increased bone
density studies
How Do You Treat Hypercalcemia?
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Depends on the cause…
1st principle of Rx: Restoration of Nl hydration
In patients with mild hypercalcemia, adequate
hydration should be encouraged and
immobilization discouraged
How Do You Treat Hypercalcemia?
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Mainstay of management in severe
hypercalcemia:
Aggressive IV rehydration. NS: to achieve a UO of
200 mL/hr: If life-threatening circumstances: 6 L of
NS/d plus Lasix 100mg q 2hr might be needed
 Repletion of K and Mg as needed
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Combined use of aboveincrease urinary Ca
excretion to 500mg/d
Treatment of Malignancy-Associated
Hypercalcemia
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IV pamidronate (Aredia), 60 to 90 mg, by 4-hr
infusion
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Often will normalize the serum calcium level, with
peak effects of 24-48 hours after infusion
In severe hypercalcemia refractory to saline
diuresis, calcitonin 2-8U/kg q 6hrs. (Rapid
onset but short duration of effect) Tacyphylaxis
can occur
What Are Some of The Other
Antiresorptive Agents?
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Now used rarely:
Plicamycin (Hepatic necrosis, coagulopathy)
 Gallium nitrate (Nephrotoxic)
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Where Do You Use Glucocorticoids
in Rx of Hypercalcemia?
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In hypercalcemia mediated by vitamin D and in
hematologic malignancies (May be effective in
MM, Leukemia, Hodgkin’s disease and other
lymphomas), Also vitamin D intoxication and
sarcoidosis
glucocorticoids are the first line of therapy after fluids
 Increase urinary Ca excretion
 Decrease intestinal Ca absorption
 Dose: 40-100 mg of prednisone or equivalent divided qid
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How Do You Treat Resistant or
Hypercalcemia Complicated by RF?
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HD with Ca-free dialysate more effective than
PD
Large amounts of PO4 lostcan aggrevated
hypercalcemiaPhosphate supplements
Therapy for the underlying condition
Hypercalcemic crisis from primary
hyperparathyroidism: urgent parathyroidectomy
potentially curative
XII-19
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A person with hypercalcemia caused by sarcoidosis
would have which of the following findings?
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(A)
(B)
(C)
(D)
(E)
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A normal chest x-ray
Increased absorption of calcium from the GIT
Normal urine calcium excretion
Increased serum parathyroid hormone level
Hypogammaglobulinemia
XII-37
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37. A 55-year-old woman presents to her physician with mild
fatigue. Her PMH is unremarkable. She is taking no medication.
No abnormalities are detected on PE. The only abnormality
detected on routine blood testing is an elevated calcium 11.9
mg/dL and a serum inorganic phosphorus of 2 mg/dL. An
immunoreactive PTH level is undetectable. The most likely
etiology for this patient's high serum calcium is
(A) primary hyperparathyroidism
(B) malignancy
(C) hypervitaminosis
(D) hyperthyroidism
(E) familial hypocalciuric hypercalcemia
XII-47
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During a routine checkup, a 67-year-old man is found
to have a level of serum alkaline phosphatase three
times the upper limit of normal. Serum calcium and
phosphorus concentrations and liver LFTs are normal.
He is asymptomatic. The most likely diagnosis is
(A) metastatic bone disease
(B) primary hyperparathyroidism
(C) occult plasmacytoma
(D) Paget's disease of bone
(E) osteomalacia
XII-48
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The most important regulator of serum
1,25(OH)2 vitamin D concentration is
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(A) serum calcium
(B) serum magnesium
(C) serum 25 (OH) vitamin D
(D)parathyroid hormone
(E) prolactin
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XII-55
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The most common presentation of primary
hyperparathyroidism is
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(A)
(B)
(C)
(D)
(E)
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bone fracture
increased serum creatinine
osteitis fibrosa cystica
calcium kidney stones
asymptomatic hypercalcemia
XII-56
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A 34-year-old woman has had three hospital admissions
during the last year because of nephrolithiasis. The rate
of 24-h urinary calcium excretion has been above the
normal range on all three occasions, and serum calcium
concentrations were between 10.2 and 11.5 mg/dL.
The serum phosphorus concentration was 2.4 mg/dL,
and the PTH level was 229 nL eq/mL (normal, less
than 150 nL eq/mL). The most appropriate
management at this time would be:
XII-56
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(A) to begin administration of prednisone, 40 mg
daily, and taper the dose over a period of 4 weeks
(B) to administer thiazide diuretics to decrease calcium
excretion
(C) symptomatic treatment of renal lithiasis only
(D) calcium supplementation to prevent progressive
bone loss
(E) surgical exploration of the neck
XII-60
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A 60-year-old woman has lower-back pain. Radiographic
examination reveals diffuse demineralization and a compression
fracture of the fourth lumbar vertebra. The serum calcium
concentration is 11.5 mg/ dL. CBC and SPEP are normal. This
clinical picture is most compatible with the presence of which of
the following conditions?
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(A)
(B)
(C)
(D)
(E)
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Postmenopausal osteoporosis
Paget's disease
Primary hyperparathyroidism
Multiple myeloma
Osteomalacia
XII-61
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Which of the following conditions is MOST likely to be
associated with a normal serum 25(OH) vitamin D
level?
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(A)
(B)
(C)
(D)
(E)
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Dietary deficiency of vitamin D
Chronic severe cholestatic liver disease
Chronic renal failure
Anticonvulsant Rx with phenobarb or phenytoin
High-dose glucocorticoid therapy
XII-70
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A 41-year-old previously healthy woman presents to an
emergency room complaining of N/V. Her calcium is
found to be 11.7 mg/ dL with an albumin of 4.0 g/dL.
Hyperparathyroidism is diagnosed, and an exploration
of her four parathyroid glands reveals one large
parathyroid tumor, which is removed. One day after the
operation the patient complains of paresthesia in her
hands and around her mouth. Her calcium is 7.3
mg/dL. Her phosphorus is 1.8 mg/dL. Four months
later she still requires aggressive calcium and vitamin D
supplementation. The most likely etiology of her
hypocalcemia is
XII-70
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(A) hypoparathyroidism secondary to
inadvertent surgical removal of all 4 parathyroid
glands
(B) hypoparathyroidism secondary to atrophy
of the 3 remaining parathyroid glands
(C) hungry bone syndrome
(D) parathyroid cancer
(E) magnesium deficiency
XII-109
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Correct statements concerning hypervitaminosis D
include which of the following?
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(A) It may result from prolonged sun exposure.
(B) It usually results from a single excessive dose of
vitamin D2 or D3.
(C) The consequences include hypercalcemia, hypercalciuria, and renal impairment.
(D) Anephric patients cannot develop vitamin D
toxicity
(E) Serum 1,25 (OH) vitamin D levels are elevated.
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