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Hypercalcemia: Evaluation and Treatment of the Hypercalcemia in the Hospitalized
Patient
Resident Version
Objectives:
1) Understand the presentation of hypercalcemia
2) Be able to formulate a differential diagnosis for hypercalcemia and
understand the evaluation of causes
3) Be able to effectively treat hypercalcemia
Case History:
A 67 yr. old male rancher from Raton with a history of hypertension presents to the ED
with his wife because of increasing back pain as well as irritability and forgetfulness.
Although unsure of the onset, his wife notes that has back pain has been a problem for
the last six months and has been keeping him awake at night for the last week. She notes
he is particularly irritable with his wife of 43 years, although his irritability now extends
to his family and friends. His executive functions are involved to the point that he is no
longer able to balance their checkbook and his wife has taken over that job. He has
generalized aches in his muscles that seem to worsen through the day.
On initial screen in the ED, the patient’s calcium is 14.5.
What are the most likely causes of this patient’s hypercalcemia?
(see discussion for answers to questions)
A reminder of calcium homeostasis:
Three principle players:
1) PTH
2) Vitamin D (or its active form, Calcitriol)
3) Calcitonin
PTH will:
1)  osteoclast bone resorption
2)  renal resorption of calcium
3)  calcitriol (indirectly  calcium)
4)  phosphate via renal excretion
Byrch Williams, MD Department of Family and Community Medicine
Hypercalcemia: Evaluation and Treatment of the Hypercalcemia in the Hospitalized
Patient
Vitamin D acts in the gut to:
1)  calcium absorption
2)  phosphate absorption
Calcitonin is produced by parafollicular cells and:
1) inhibits osteoclasts
2) opposes effects of PTH at the kidney resulting in Ca loss
The patient’s ROS is notable for:
Confusion and irritability.
Polydipsia and polyuria.
Episode of flank pain and hematuria 2 months ago that resolved before they got to
doctor’s so they returned home.
Feels weak but attributes that to “old age.”
Constipation for at least 4 months.
Otherwise, 10 point ROS was negative
Physical Exam
Exam: BP 148/66, P 64, RR 16 Temp 36.8
Pleasant, appears older than stated age in mild discomfort. His face and neck are very
tan except above line on forehead. Oriented X3. Good affect but quiet.
Neck without masses.
CV: RRR without murmurs
Neuro: 4/5 global strength upper and lower extremities
Lab:
Chem-7 Sodium 143, potassium 4.3, Cl 100, CO2 23, BUN 30, Creat 1.2, calcium 14.5.
Urine dip spec grav 1.005 neg ketones, LE, nitrites.
LFT’s normal. CBC normal.
Thoracic and Lumbar Spine show lytic lesions.
PTH pending.
Which of these symptoms may due to the patient’s hypercalcemia and what other
symptoms might you expect?
Byrch Williams, MD Department of Family and Community Medicine
Hypercalcemia: Evaluation and Treatment of the Hypercalcemia in the Hospitalized
Patient
What labs and studies would you want to elucidate the patient’s hypercalcemia?
Based on his symptoms and calcium of 14.8, what further action and management is
warranted?
Discussion:
Differential Diagnosis
Ninety percent of hypercalcemia develop from two conditions: hyperparathyroidism and
malignancy. Generally, hyperparathyroidism will lead to a gradual increase in calcium,
however, malignancy and primary hyperparathyroidism may both lead to hypercalcemic
crisis (Ca> 14).
Other causes:
1) Drugs (thiazides, diurectics, lithium, theophyline)
2) Increased bone turn over (hyperthyroidism, Paget’s)
3) Granulomatous diseases (sarcoid, Tb, Cocci, histoplasmosis)
4) ID: hepatitis, AIDS
5) Milk-alkali syndrome: Rare form of renal failure resulting from increasing
calcium carbonate use particularly among osteoporotic women
Milk-alkali syndrome reported to be third most common cause of hypercalcemia in
hospitalized patients without end-stage renal disease,
Picolos MK, Lavis VR, Orlander PR. Milk-alkali syndrome is a major cause of hypercalcemia among non-end-stage renal disease
inpatients. Clin Endocrinol (Oxf.) 2005 Nov;63(5):566-76
Byrch Williams, MD Department of Family and Community Medicine
Hypercalcemia: Evaluation and Treatment of the Hypercalcemia in the Hospitalized
Patient
Clinical Signs and Symptoms
The symptoms of hypercalcemia are described by “Stones, bones, abdominal moans and
psychic groans.”





Renal Stones: Nephrolithiasis and nephrocalcinosis
Skeletal Bones: Bone pain, arthritis, osteoporosis
GI Moans: Nausea, vomiting, anorexia, weight loss, constipation, abdominal pain,
PUD, pancreatitis
Neuromuscular psychic groans: Impaired concentration and memory, confusion,
lethargy, muscle weakness
Don’t forget the cardiac manifestations! Hypertension, arrhythmias, AV block
Hypercalcemia Workup
Before any workup, confirm the diagnosis and evaluate for life threatening arrhythmias:
 Confirm the patient’s calcium level by doing an ionized calcium or checking the
patient’s albumin and correcting:
Corrected Calcium= (4-[plasma albumin]) X 0.8 + [serum calcium]
 Check an EKG for shortened QT which occurs with hypercalcemia.
Recommended work up starts with history and physical and drawing of a PTH. In the
face of hypercalcemia, a normal or high PTH confirms hyperparathyroidism, either
primary or tertiary.
If PTH is suppressed, look for malignancy, particularly lung, breast cancers and multiple
myeloma. PTHrP (PTH related peptide) is the primary mediator of malignancy related
hypercalcemia in solid tumors and can be tested. Most cases of hypercalcemia related to
malignancy are associated with advanced disease and poor prognosis. If your patient with
hypercalcemia has a low PTH and no obvious malignancy, think of another cause of the
elevated calcium.
You may consider testing for other causes as well:
 24 hour urine calcium and creatinine (familial hypocalciuric hypercalcemia)
 Calcitriol (1,25(OH2) Vitamin D)
 Electrophoresis if multiple myeloma is suspected
 Thyroid function tests
The following flow chart indicates the sequence of testing:
Byrch Williams, MD Department of Family and Community Medicine
Hypercalcemia: Evaluation and Treatment of the Hypercalcemia in the Hospitalized
Patient
Evaluation of Hypercalcemia*
Hypercalcemia
Total Ca++ >10.5 mg/dL (2.63 mmol/L)
or ionized Ca++ >5.6 mg/dL (1.4
mmol/L)
• Clinical features of hypercalcemia
• Possible causative diseases
• Possible causative medications
(diuretics, vit D, calcium carbonate)
Measure
intact PTH
(iPTH)
Suppressed iPTH
Normal or Elevated iPTH
Consider malignancy workup
Check 24hr urine
calcium
Solid tumors
• PTHrP:
o Adeno
o Squamous
• Alk phos: bone lysis (breast)
Hematologic malignancies
• Positive myeloma screen
• Calcitriol:
o
o
Low
Normal or Elevated
Familial hypocalciuric
hypercalcemia
Primary or Tertiary
Hyperparathyroidism
Lymphoma
Granulomatous diseases
If negative consider:
Hyperthyroidism
Adrenal insufficiency
Consult surgery to discuss
possible parathyroidectomy
*Adapted from Carroll, M, Schade, D. A practical approach to Hypercalcemia, AFP2003; 67: 1959-1968.
Treatment
Treatment is dictated by the severity of symptoms and is based on three principles:
 mobilization
 hydration
 calciuresis - hydration plus loop diuretic
Byrch Williams, MD Department of Family and Community Medicine
Hypercalcemia: Evaluation and Treatment of the Hypercalcemia in the Hospitalized
Patient
Mild- serum calcium 10.5-12 mg/dL (2.63-3 mmol/L)
 No specific treatment necessary
 Monitor blood pressure, serum calcium, renal function
Moderate - serum calcium 12-13.5 mg/dL (3-3.38 mmol/L)
 Decision to treat may be based on symptoms
 Hydration and salt replacement with IV saline
 Loop diuretic may be required, especially in cases of congestive heart failure or
renal insufficiency
 May consider bisphosphonate
Severe- serum calcium > 13.5 mg/dL (3.38 mmol/L)
 Aggressively treat!
 Hydration and salt replacement with IV normal saline with loop diuretic
 Monitoring of hemodynamic and electrolyte status
 Bisphosphonates- Zoledronic acid (Zometa) and pamidronate (Aredia) are
bisphosphonates that offer single-dose therapies (for malignancy-related causes)
 Calcitonin and glucocorticosteroids (granulomatous disease) may have adjunctive
role in selected cases
 Consider dialysis in severe cases
 Treatment of underlying disease (usually secondary to malignancy)
 If elevated PTH, urgent parathyroidectomy should be performed
Results of a systematic review favor use of high-dose potent bisphosphonates in the
treatment of hypercalcemia of malignancy, irrespective of baseline calcium. High-dose
potent bisphosphonates increase the number of patients achieving normocalcemia and
delayed time to relapse.
Saunders Y, Ross JR, et al. Systematic review of bisphosphonates for hypercalcaemia of malignancy.Palliat Med. 2004 Jul;18(5):41831.
A related systematic review showed that bisphosphonates significantly reduce skeletal –
related events (SREs) and delay the time to first SRE in patients with bony metastatic
disease but do not affect survival.
Ross JR, Saunders Y, et al. A systematic review of the role of bisphosphonates in metastatic disease.Health Technol Assess.
2004;8(4):1-176.
Limited evidence suggests zoledronic acid may be more effective in response rate and
duration of response than pamidronate.
Major P, Lortholary A, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled
analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001 Jan 15;19(2):558-67
Byrch Williams, MD Department of Family and Community Medicine
Hypercalcemia: Evaluation and Treatment of the Hypercalcemia in the Hospitalized
Patient
Review Questions:
1) Which of the following are typical symptoms of hypercalcemia?
A. muscle weakness
B. depression
C. memory impairment
D. personality changes and psychoses
E. pruritus
F. anorexia
G. constipation
H. polyuria
I. cardiac arrhythmias
J. loss of thirst
2) A 65 yo male with hypertension on HCTZ presents to a clinic appointment to discuss
lab results drawn at his last visit. Lab results are significant for a calcium of 12.6 and
normal albumin. He has no other significant past medical history and his ROS is
negative. What is the most likely cause of this patient’s hypercalcemia?
A.
B.
C.
D.
E.
Diuretic use
Primary hyperparathyroidism
Malignancy
Tuberculosis
Milk-Alkali Syndrome
Which of the following statements are true concerning malignant hypercalcemia?
A. The hypercalcemia is usually seen early in course of the disease
B. Treating the hypercalcemia usually improves survival
C. The hypercalcemia can frequently be controlled with bisphosphonates
D. Tumors that commonly produce hypercalcemia are: breast, lung, head/neck, kidney,
bladder, ovary, cervix, vulva, skin
E. The most common occult cause of malignant hypercalcemia is Multiple Myeloma
F. The following should be added to the usual workup for hypercalcemia if malignancy is
suspected: alk phos, CBC, PTHrP, serum protein electrophoresis, 1,25 diOH VitD,
appropriate x-rays, bone scan, and TNFa
Answers
1) Answer: All except J
2) Answer: B There are over 25 causes of hypercalcemia but 80-90 percent of cases are
caused by either hyperparathyroidism or malignancy. It is uncommon for hypercalcemia
of malignancy to appear without a previous diagnosis of cancer or obvious signs of
cancer. In this asymptomatic man, malignancy is an unlikely cause. While diuretic use
Byrch Williams, MD Department of Family and Community Medicine
Hypercalcemia: Evaluation and Treatment of the Hypercalcemia in the Hospitalized
Patient
increases the risk of hypercalcemia and should be withheld, it is less likely to be causing
this man’s elevated calcium than primary hyperparathyroidism (the etiology of 50% of
hypercalcemia). Other causes include: milk-alkali syndrome (perhaps responsible for up
to 12% of hypercalcemia), granulomatous disease such as sarcoidosis and tuberculosis,
hyperthyroidism, genetic disorders, Paget’s disease and others, but these are all less likely
causes.
3) Answer: C, D, E. F is false because a TNFa is not useful even if it could be ordered (it
is not clinicallyavailable). The cytokines are locally produced and, therefore, the serum
levels are probably not elevated. The other tests are indicated.
References:
 Agus, Z. Etiology of Hypercalcemia In: UpToDate online15.1, 11/1/06. Online:
 www.utdol.com/utd/content/topic.do?topicKey=minmetab/4264&type=A&selecte
dTitle=3~112
 Carroll, M, Schade, D. A practical approach to Hypercalcemia, AFP2003; 67:
1959-1968.
 Fukagawa, M, Kurokawa, K, Papadakis, M. Hypercalcemia In: Gonzales, R,
Zeiger, R, ed. Current Medical Diagnosis and Treatment. On line:
www.accessmedicine.com/resourceTOC.aspx?resourceID=1.
 Lew JI, Solozarno CC, Irvin GL. Long-term results of parathyroidectomy for
hypercalcemic crisis. Arch Surg. 2006 Jul;141(7):696-9
 Major P, Lortholary A, et al. Zoledronic acid is superior to pamidronate in the
treatment of hypercalcemia of malignancy: a pooled analysis of two randomized,
controlled clinical trials. J Clin Oncol. 2001 Jan 15;19(2):558-67
 Picolos MK, Lavis VR, Orlander PR. Milk-alkali syndrome is a major cause of
hypercalcemia among non-end-stage renal disease inpatients. Clin Endocrinol
(Oxf.) 2005 Nov;63(5):566-76
 Ross JR, Saunders Y, et al. A systematic review of the role of bisphosphonates in
metastatic disease.Health Technol Assess. 2004;8(4):1-176.
 Saunders Y, Ross JR, et al. Systematic review of bisphosphonates for
hypercalcaemia of malignancy.Palliat Med. 2004 Jul;18(5):418-31.
Byrch Williams, MD Department of Family and Community Medicine