Disorders of Calcium Metabolism:
Hypercalcemia
Steven Chessler, MD, Ph.D.
March, 2015
Internal Medicine noon conference
(F5)
History and Physical
A 45 year-old female consults you because of a low bone mineral
density (BMD). She relates that she availed herself of a free
screening test of her BMD. The results indicated that she had
osteopenia, so she called your office for an appointment. The
checklist that she filled out indicates that she is in good health and
on no medications. She looks well and the physical is unrevealing.
Laboratory
Her routine laboratory evaluation is essentially normal, including
normal renal function, except for a serum calcium of 10.6, where
10.5 is the upper limit of normal. A DEXA reveals normal bone
mineral density.
What labs would you order to
follow-up on the Ca++?
History and Physical
A 45 year-old female consults you because of a low bone mineral
density (BMD). She relates that she availed herself of a free
screening test of her bone mineral density (BMD). The results
indicated that she had osteopenia, so she called your office for an
appointment. The checklist that she filled out indicates that she is
in good health and on no medications. She looks well and the
physical is unrevealing.
Laboratory
Her routine laboratory evaluation is essentially normal, including
normal renal function, but includes a serum calcium of 10.6,
where 10.5 is the upper limit of normal. A DEXA reveals normal
bone mineral density
What labs would you order to
follow-up on the Ca++?
Results
Repeat Ca++: 10.8
Albumin: 4 mg/dl
Phos: 3 mg/dl (2.5-4.0)
PTH (at same time): 42 pg/ml (nl: 11-54)
After verifying the lab results thus far,
which would be the best test to help
confirm the most likely diagnosis and avoid
possible unnecessary treatment?
A. 1,25-dihyroxyvitamin D
B. 25-hydroxyvitamin D
C. Spot urine Ca++
D. 24 hour urine Ca++
E. PTHrP
Answer is D:
•
Twenty-four-hour urine for calcium will help in the differential
diagnosis of FHH. If marked hypercalciuriais present (ie, > 400
mg/d), a more complete urinary biochemical stone profile should
be considered. In the presence of abnormal findings indicating
increased calcium-containing stone risk and marked
hypercalciuria, a guideline for surgery is met.
24 hour urine is 114 mg/24 hours. (normal 100-300)
Best single next step to help establish diagnosis?
A. Family history
B. Sestamibi imaging of parathyroid glands
C. Surgical exploration of parathyroid glands
D. TSH and free T4
Same case, but now result is:
24 hour urine is 450 mg/24 hours (normal 100-300). Also,
there is no history of renal stones, fracture, mental status
changes or other symptoms.
Most appropriate therapy (per current guidelines)?
A. Cinacalcet
B. Parathyroid surgery
C. Alendronate
D. Either parathyroid surgery or monitoring over time
E. Monitoring over time
Primary Hyperparathyroidism: Management Guidelines (2013)
surgery recommended if:
Measurement
Result
Serum calcium (>upper limit of nl.)
1.0 mg/dL (0.25 mmol/L)
Skeletal
A. BMD by DXA: T-score <-2.5 at
lumbar spine, total hip, femoral
neck, or distal 1/3 radius
B. Vertebral fracture
Renal
A. Creatinine clearance <60 cc/min
B. 24-h urine for calcium >400 mg/d
and increased stone risk by
biochemical stone risk analysis
C. Presence of nephrolithiasis or
nephrocalcinosis by x-ray,
ultrasound, or CT
Age, y
<50
Hypercalcemia/hyperparathyroidism:
clinical signs
• GI:
– Nausea, vomiting, abdominal pain
– Constipation
• Renal:
– Polyuria, dehydration
– Renal failure
– Nephrolithiasis
Hypercalcemia/hyperparathyroidism:
clinical signs
• Neurological
–
–
–
–
Fatigue
Confusion
Depression
Stupor, coma
• Skeletal
– Bone pain and tenderness
– Spontaneous fracture (compression fx’s)
Hyperparathyroidism/Hypercalcemia
– signs/symptoms
• Neuromuscular
– Muscle weakness, hypotonia
• Cardiovascular
– Hypertension
– Short QT interval
Hypercalcemia: major causes
• Primary hyperparathyroidism (PHPT)
• Malignancy
• Others
Hyperparathyroidism: causes
• Primary
– Adenoma (90%)
– Multiple gland enlargement (10%)
• MEN 1
• MEN 2A
• Familial hyperparathyroidism
– Carcinoma (<1%)
– Familial benign hypercalcemia (FBH)
• Secondary (normo- or hypocalcemic)
– Renal failure
– Vitamin D deficiency
Primary hyperparathyroidism
• Affects approximately 100,000 patients a year.
• Prevalence: 0.1 to 0.3% of the general population.
• More common in women (1:500) than in men (1:2000).
• Patients with single adenoma (~90%): minimally invasive
surgery
 Sestamibi imaging ~90% sensitive, ~98% specific
 Minimally invasive = incision length < 2.5 cm
 Intraoperative PTH testing confirms biochemical cure
Malignant hypercalcemia: major
causes
• PTHrP - mediated
– Breast carcinoma
– Squamous carcinoma (lung, head & neck,
esophagus)
– Renal carcinoma
• Cytokine/osteoclast activating factor - mediated
– Myeloma (lymphoma, leukemia)
• Tumor production of calcitriol
– Lymphoma
Hypercalcemia: other causes
• Drugs:
–
–
–
–
–
Vitamin D
Calcium carbonate (milk alkali syndrome)
Lithium
Thiazide diuretics
Vitamin A
• Sarcoidosis, other granulomatous disorders
• Hyperthyroidism
REVIEW, Ca++ metabolism:
PTH, Vitamin D and Calcium homeostasis
1. Calcium and phosphorus
2.
3.
4.
5.
Bone
Vitamin D
Parathyroid Hormone
Calcitonin
Extracellular Calcium
• Three definable fractions of
calcium in serum:
– Ionized calcium 50%
– Protein-bound calcium 41%
• 90% bound to albumin
– Calcium complexed to serum
constituents 9%
• Citrate and phosphate
Calcium turnover
Renal Excretion
• The kidneys account for the bulk of
regulated calcium excretion
• Three distinct locations along the renal
tubule are involved
• The regulation of calcium excretion at each
of the three renal sites is different
Renal Excretion
• Proximal
convoluted tubule
– Accounts for 70% of
calcium reabsorption
– Mainly paracellular
pathway
Renal Excretion
• Proximal convoluted
tubule
• Thick ascending limb of
loop of Henle
 20 % of calcium reabsorption
Calcium sensing receptor
(CaSR)
FHH, FBH (familial benign/hypocalciuric hypercalcemia)
Caskey F J , Pickett T M Nephrol. Dial. Transplant. 2005;20:1752-1755
Renal Excretion
• Proximal convoluted tubule
• Thick ascending limb
• Distal convoluted
tubule
– PTH regulation
– 8% of calcium
reabsorption
20-24
PTH, Vitamin D and Calcium homeostasis
1. Calcium and phosphorus
2. Bone
3. Vitamin D
4. Parathyroid Hormone
5. Calcitonin
20-25
Calcium Regulation: Bone Exchange
• Bone is dynamic and is constantly
remodeled
• Calcium is exchanged between blood and
bone daily (roughly 400 mg/day); 10% of
skeleton per year
• Ongoing remodeling allows bone to store
and release calcium as needed to help
maintain homeostasis
Normal bone remodeling cycle
Case: Man With Lethargy, Fatigue
and Weakness
• 60 yr old male presents with complaints of fatigue
and weakness over 1 month.
• PMHx: Negative; no history CHF or kidney disease
• PE: significant for memory and cognitive
defects
• Lab: Ca 15.0 mg/dL
PO4 2.3 mg/dL
60 yr old male presents with complaints of fatigue and weakness
over 1 month. Renal function is normal.
PMHx: Negative; no history CHF or kidney disease
PE: significant for memory and cognitive defects
Lab: Ca 15.0 mg/dL, PO4 2.3 mg/dL
Most likely cause of hypercalcemia?
A) Vitamin D intoxication
B) Granulomatous disease
C) Malignancy
D) Acute hyperparathyroidism
E) Chronic hyperparathyroidism
After admission, the patient becomes
increasingly obtunded. How do you treat?
Severe hypercalcemia:
• Principles of therapy
– Expand ECF volume
– Increase urinary calcium excretion
– Decrease bone resorption
• Indications for therapy
– Symptoms of hypercalcemia
– Plasma [Ca] >15 mg/dl
Hypercalcemia - Treatment
– NS bolus to restore volume; then 100 – 200 ml/hr
– Bisphosphonates (onset 24-48 hrs)
– Calcitonin 4 – 8 IU q6-8 hrs (onset immediate,
resistance develops in 24-48 hrs)
– [Mg and K prn]
Despite having administered zoledronic acid (4
mg IV), hypercalcemia is not brought under
adequate control.
The best option for prolonged control is now to
add:
A) A drug targeting the calcium-sensing receptor (CaSR).
B) Pamidronate
C) A loop diuretic
D) A drug targeting the calcitonin receptor
E) A drug targeting RANK ligand (RANKL)
Rank Ligand (RANKL) and osteoprotegerin
(OPG) balance bone loss and formation
• RANKL is a key inducer of osteoclast formation
• By binding with RANKL, OPG (or denosumab) prevents RANKL
Ligand from binding with RANK on the surface of osteoclasts and
their precursors.
PTH, Vitamin D and Calcium homeostasis
Lecture outline
1. Calcium and phosphorus
2. Bone
Hormonal control of Ca2+
3. Vitamin D
4. Parathyroid Hormone
5. Calcitonin
Synthesis of Vitamin D
• Parathyroid hormone (PTH) stimulates 1,25(OH)2-Vitamin D synthesis.
• The first hydroxylation reaction takes place in the
liver yielding 25-hydroxyl D
• Second hydroxylation reaction takes place in the
kidney yielding 1,25(OH)2-D3 (calcitriol; 1,25-dihydroxyvitamin D).
• Sarcoidosis, other granulomatous disorders,
certain malignancies (lymphoma) can also
produce 1,25(OH)2-D3
20-35
REGULATION OF RENAL 1α-HYDROXYLASE PRODUCTION
Stimulates
Inhibits
PTH
Low calcium
Low phosphate
Calcitonin
1,25(OH)2D3
High calcium
High phosphate
Case: A 36 yo African-American male with a 5
month history of cough and dyspnea is found to
have a calcium level of 10.9 mg/dl (normal <
10.6). His only medication is an albuterol MDI.
He smokes 1-2 packs per day. He is thin and illappearing. Physical exam is only notable for lungs
having scattered crackles bilaterally and cervical
lymphadenopathy.
Laboratory results:
Albumin— 4 mg/dL (normal)
Creatinine: 1.0 mg/dL
Repeat Ca++: 10.8 mg/dL
Phosphate: 4.5 mg/dL
PTH: 9 pg/ml
25-hydroxyvitamin-D: 25 ng/ml
(8.5-10.5 mg/dL)
(2.5-4.4 mg/dL)
(11-54 pg/ml)
(30-74 ng/ml)
The cause of the hypercalcemia will most likely be
revealed by:
A. Measurement of 24 hour urine calcium
B. Measurement of serum PTHrP
C. Measurement of serum 1,25-dihydroxyvitamin-D
D. Sequencing of the gene encoding the CaSR
Answer: C (has sarcoid or TB so measure 1,25-dihydroxyvit.-D)
From: UpToDate, Diagnostic approach to hypercalcemia:
“Measurement of the serum phosphate concentration and urinary
calcium excretion also may be helpful in selected cases.
Hyperparathyroidism and humoral hypercalcemia of malignancy (due
to PTH-related protein) may be associated with frank
hypophosphatemia or low-normal serum phosphate levels resulting
from inhibition of renal proximal tubular phosphate reabsorption. In
comparison, the serum phosphate concentration is normal or elevated
in granulomatous diseases, vitamin D intoxication, immobilization,
thyrotoxicosis, milk-alkali syndrome, and metastatic bone disease.“
Summary: vitamin D action
• Main action of 1,25-(OH)2-D is to stimulate
absorption of Ca2+ (and phosphate) from
the intestine.
also:
• acts on osteoblasts to increase RANKL and thus
activate osteoclasts to increase Ca++ resorbtion.
• is necessary for proper bone formation.
PTH, Vitamin D and Calcium homeostasis
1. Calcium and phosphorus
2. Bone
3. Vitamin D
4. Parathyroid Hormone
5. Calcitonin
20-41
Parathyroid Hormone
Calcium
regulates
PTH
secretion
via a CaSR
PTH and calcium+phosphate homeostasis
PTH, Vitamin D and Calcium homeostasis
Lecture outline
1.
2.
3.
4.
Calcium and phosphorus
Bone
Vitamin D
Parathyroid Hormone
5. Calcitonin
Calcitonin
• Decreases plasma Ca2+ and phosphate
concentrations, mainly by decreasing bone
resorption.
• Synthesized and secreted by the parafollicular
cells (aka C cells) of the thyroid gland.
• Release stimulated by hypercalcemia and inhibited
by hypocalcemia
Slide credit: Dale Buchanan Hales Ph.D.
Calcitonin effects
• Calcitonin rapidly inhibits osteoclast activity
o causes inhibition of osteoclast motility, alterations in
cell morphology and osteoclast inactivation.
• Kidneys
o inhibits calcium reabsorption (increases excretion)
o also increases phosphorus excretion
• Role in calcium homeostasis unclear
Hormone
Effect on bones
Effect on gut
Effect on kidneys
Parathyroid
hormone
increase Ca++,
decrease PO4
levels in blood
Promotes
resorption
Indirect effects
via increase in
calcitriol from 1hydroxylation
Promotes Ca++
reabsorption and
PO4 excretion,
activates 1hydroxylation
Calcitriol
(RANKL→bone
(vitamin D)
Ca++, PO4 levels resportion)
increase in
blood
Increases Ca++
and PO4
absorption
No direct effects
Calcitonin
No direct effects
Promotes Ca++
and PO4
excretion
Inhibits
resorption
Hypocalcemia:
clinical signs
•
•
•
•
•
Paresthesias
Tetany (carpopedal spasm)
Trousseau’s, Chvostek’s signs
Seizures
Chronic: cataracts, basal ganglia Ca
Trousseau’s sign
Hypocalcemia: causes
• Hypoparathyroidism
– Surgical (thyroid, parathyroid surgery)
– Autoimmune
– Magnesium deficiency
• PTH resistance (pseudohypoparathyroism)
• Vitamin D deficiency
• Vitamin D resistance
• Other: renal failure, pancreatitis, tumor lysis
END