2. Introduction
Commonly encountered in clinical practice.
Hypercalcemia affects 0.5% to 1% of the general population.
Diagnosis is often made incidentally.
Hyperparathyroidism and hypercalcemia due to malignancy
cause 90% of all hypercalcemia.
Hypercalcemic crisis is a medical emergency.
3. Definition
Hypercalcemia is a corrected total serum calcium value
above the upper limit of the normal range or an elevated
ionized calcium value.
The skeleton contains 99% of total body calcium. The
remaining 1% circulates through out the body.
Among circulating calcium, 50% is free (ionized), 40%
protein-bound, and 10% complexed to phosphate, citrate,
bicarbonate, sulfate, and lactate. Only elevations in the
free calcium are associated with symptoms and signs.
4. Distribution of circulating calcium
Reference: Greenspan's Basic and Clinical Endocrinology – 9th
Edition
Conversion factor: 0.2495
5. Classification of Hypercalcemia:
According to level of corrected total serum calcium value
hypercalcemia can be classified into:
o Mild Hypercalcemia (Corrected Ca level >10.5 mg/dL
to less than 12 mg/dL)
o Moderate Hypercalcemia (Corrected Ca Level 12 to 14
mg/dL)
o Severe Hypercalcemia (A level greater than 14 mg/dL)
Corrected Calcium = (4.0 mg/dL – [Serum Albumin]) x 0.8 +
[Observed Calcium]
6. Clinical Features of Hypercalcemia
Can be completely asymptomatic.
Central nervous system effects:
Lethargy, depression, psychosis, ataxia, stupor, and coma
Neuromuscular effects:
Weakness, proximal myopathy, and hypertonia
Cardiovascular effects:
Hypertension, bradycardia (and eventually asystole), a shortened QT interval
(ECG)
Renal effects:
Stones, decreased GFR, polyuria, nephrocalcinosis;
Gastrointestinal effects:
Nausea, vomiting, constipation and anorexia
Eye findings such as band keratopathy
Systemic metastatic calcification.
9. Mechanism of
hypercalcemia
Variables affecting
Calcium metabolism
Target organs for
Calcium Metabolism
Increased bone
resorption
Increased renal
reabsorption or
decreased
excretion
Increased gut
absorption
Parathyroid
hormone (PTH)
1,25(OH)2D
Calcitonin
Calcium
Phosphate
Fibroblast growth
factor-23 (FGF-23)
Bones
Gut
Kidneys
10. Common causes of Hypercalcemia
PRIMARY HYPERPARATHYROIDISM: Primary
hyperparathyroidism results from the excessive secretion
of PTH and typically produces frank hypercalcemia.
Primary hyperparathyroidism is approximately 2 to 3 times
more common in women than in men.
The diagnosis of primary hyperparathyroidism in a
hypercalcemic patient can be made by determining intact
PTH level.
The definitive treatment of primary hyperparathyroidism
is parathyroidectomy.
11. Common causes of Hypercalcemia (cont.)
MALIGNANCY-ASSOCIATED HYPERCALCEMIA: Malignancy-
associated hypercalcemia is the second most common
form of hypercalcemia.
It can be presented as a part of paraneoplastic syndrome
(eg: parathyroid hormone (PTH)-related protein (PTHrP))
or due to direct bony metastasis.
It is most common in squamous cell carcinoma of the lung,
head, and neck, renal cell carcinoma, breast cancer,
multiple myeloma, and lymphoma.
13. Common causes of Hypercalcemia (cont.)
Calcium & Vitamin D (Hypervitaminosis –D) over
Supplimentation
Sarcoidosis and Other granulomatous disorders
ENDOCRINOPATHIES: Thyrotoxicosis, Adrenal Insufficiency.
ENDOCRINE TUMORS: pheochromocytoma (may be associated
with MEN-2), VIPomas.
Thiazide Diuretics & Indapamide
Hypervitaminosis A
Milk Alkali Syndrome (Rare nowadays)
Immobilization
Acute Renal Failure due to rhabdomyolyses
14. Investigations for management of
hypercalcemia
General Investigations:
S. Calcium Level
S. PO4 Level
S. Alkaline phosphates
S. Parathyroid level
S. Vitamin-D level
S. Total protein, S. Albumin
ECG
Specific Investigations: Varies according to cause.
15. Indication of treatment of
Hypercalcemia
Patients with asymptomatic or mildly symptomatic (eg,
constipation) hypercalcemia (calcium <12 mg/dL [3 mmol/L])
do not require immediate treatment.
Similarly, a serum calcium of 12 to 14 mg/dL (3 to 3.5 mmol/L)
may be well tolerated chronically and may not require
immediate treatment.
However, an acute rise to these concentrations may cause
marked changes in sensorium, which requires more aggressive
measures.
In addition, patients with a serum calcium concentration >14
mg/dL (3.5 mmol/L) require treatment, regardless of
symptoms.
16. Treatment approach for mild hypercalcemia
Patients with asymptomatic or mildly symptomatic
hypercalcemia (calcium <12 mg/dL) do not require
immediate treatment.
However, they should be advised to avoid factors that can
aggravate hypercalcemia, including thiazide diuretics,
volume depletion, prolonged bed rest or inactivity, and a
high calcium diet (>1000 mg/day).
Adequate hydration (at least six to eight glasses of water
per day) is recommended to minimize the risk of
nephrolithiasis.
Additional therapy depends mostly upon the cause of the
hypercalcemia.
17. Treatment approach for moderate
hypercalcemia
Asymptomatic or mildly symptomatic individuals with
chronic moderate hypercalcemia (calcium between 12 and
14 mg/dL) may not require immediate therapy.
It is important to note that an acute rise to these
concentrations may cause marked changes in sensorium,
which requires more aggressive therapy.
In these patients, treatment with saline hydration and
bisphosphonates, as described for severe hypercalcemia
on next page.
18. Treatment approach for severe hypercalcemia
Patients with calcium >14 mg/dL (3.5 mmol/L) require more
aggressive therapy.
Volume expansion with isotonic saline at an initial rate of 200 to
300 mL/hour that is then adjusted to maintain the urine output at
100 to 150 mL/hour.
In the absence of renal failure or heart failure, loop diuretic
therapy to directly increase calcium excretion is not
recommended, because of potential complications.
Administration of salmon calcitonin (4 IU/kg) and repeat
measurement of serum calcium in several hours. It can be
repeated every 6 to 12 hours (4 to 8 IU/kg).
The concurrent administration of zoledronic acid (ZA; 4 mg
intravenously [IV] over 15 minutes) or pamidronate (60 to 90 mg
over two hours), preferably ZA because it is superior to
pamidronate in reversing hypercalcemia related to malignancy.
19. Treatment approach for severe hypercalcemia
(Cont.)
The administration of calcitonin plus saline should result
in substantial reduction in serum calcium concentrations
within 12 to 48 hours. The bisphosphonate will be
effective by the second to fourth day, thereby maintaining
control of the hypercalcemia.
Additional, more aggressive measures are necessary in the
rare patient with very severe, symptomatic
hypercalcemia.
Hemodialysis should be considered, in addition to the
above treatments, in patients who have serum calcium
concentrations in the range of 18 to 20 mg/dL and
neurologic symptoms but a stable circulation or in those
with severe hypercalcemia complicated by renal failure.
20. Preventing recurrence of hypercalcemia
Follow-up therapy is aimed at preventing recurrence of
hypercalcemia. In patients with hypercalcemia of
malignancy, progressive hypercalcemia will inevitably
accompany tumor progression, and therefore, the
underlying disease causing the hypercalcemia should be
treated, if at all possible.
Many patients with malignancy may also have metastatic
bone disease and will have to receive IV ZA or
pamidronate every three to four weeks as part of their
treatment to prevent skeletal complications.
21. THERAPY DOSE ROUTE MONITOR/COMMENT
Normal Saline 200-300 mL/h IV Cardiopulmonary function with
examination, central venous pressure and
chest radiograph
Furosemide 20-80 mg every
2-4 h or
40 mg/h CI
IV Serum and urine electrolytes. Replace K,
Mg, and PO4 based on serum levels and
urinary losses.
Salmon
calcitonin
4-8 IU/kg every
6-12 h
IM, SC Allergic reaction. Give a skin test of 1 IU
intradermally before treatment. Effective
only during first 48-72 h.
Zoledronic
acid
4 mg IV over
15 min every
2-4 weeks PRN
IV Drug of choice for malignancy-associated
hypercalcemia. Caution with chronic kidney
disease and myeloma.
Cinacalcet 30-90 mg b.i.d.-
q.i.d.
PO Take with meals. Monitor parathyroid
hormone, Ca, and PO4 at least 12 h
after dose.
Gallium
nitrate
200 mg/m2/day CI
over 4 h PRN for
5 days
IV Avoid in renal failure. Monitor creatinine,
PO4, and complete blood count.
Dialysis Low or no calcium
dialysate
Hemodialysis/
peritoneal
dialysis
Hypercalcemic crisis or refractory
hypercalcemia. Useful in renal failure.
22. Therapy Advantages Limitations
CALCITONIN Safe and relatively nontoxic, Although a
relatively weak agent, it works rapidly,
lowering the serum calcium concentration
by a maximum of 1 to 2 mg/dL (0.3 to 0.5
mmol/L) beginning within four to six hours.
It’s most useful with hydration.
The efficacy of calcitonin is
limited to the first 48 hours,
even with repeated doses,
indicating the development of
tachyphylaxis, perhaps due to
receptor downregulation.
BISPHOSPHONATES They are effective in treating
hypercalcemia resulting from excessive
bone resorption of any cause. They are
more potent than calcitonin and saline for
patients with moderate or severe
hypercalcemia.
Their maximum effect occurs in
two to four days, so that they
are usually given in conjunction
with saline and/or calcitonin,
which reduce calcium
concentration more rapidly.
Bisphosphonates have potential
nephrotoxicity.
23. Zolendronic Acid in Renal impairment
The U.S. Food and Drug Administration (FDA) and Novartis
Pharmaceuticals have advised healthcare professionals
about dose reductions for zoledronic acid injection
(Zometa) when treating advanced cancer in patients with
mild to moderate renal impairment.
Dose Modification:
CrCl >60 mL/min: 4 mg
CrCl 50-60 mL/min: 3.5 mg
CrCl 40-49 mL/min: 3.3 mg
CrCl 30-39 mL/min: 3 mg
CrCl <30 mL/min: Not recommended
24. In clinical trials of zoledronic acid for the treatment of
hypercalcemia of malignancy, patients with serum
creatinine concentrations as high as 4.5 mg/dL were
eligible for participation.
However, physician must be cautious when using IV
bisphosphonates to treat hypercalcemia in patients with
impaired renal function (creatinine >4.5 mg/dL).
Adequate hydration with saline and treatment with a
reduced dose and/or slower infusion rate may minimize
risk.
25. Alternative treatment in hypercalcemia with
severe renal impairment
Denosumab: Denosumab is an option for patients with hypercalcemia
that is refractory to zoledronic acid (ZA) or in whom bisphosphonates
are contraindicated due to severe renal impairment.
Denosumab, unlike bisphosphonates, is not cleared by the kidney,
and as a consequence, there is no restriction of its use in patients
with chronic kidney disease, for whom bisphosphonates are used
with caution or contraindicated.
Severe renal impairment (serum creatinine 2.5 to 5.7 mg/dL),
denosumab improved serum calcium within two to four days.
However, the optimal dose of denosumab in the setting of renal
impairment is uncertain.
Dialysis — Hemodialysis with little or no calcium in the dialysis fluid
and peritoneal dialysis (though it is slower) are both effective therapies
for hypercalcemia and are considered treatments of last resort.
26. Outcome of few cases of
Hypercalcemia in Endocrinology
dept. of BIRDEM
27. Brief case summary (1):
Mrs. Nur Jahan Begum, 76 years old female patient with h/o
HTN for 40 years and CKD for 8 months presented with
complaints of:
Altered mental status and drowsiness for 5 days
Right leg swelling, pain and redness for 8 days.
Patient got admitted in Endocrinology dept. as a referred
case of hypercalcemia (suffering for 8 months, no h/o
calcium or vit-D supplementation with high iPTH level).
On clinical examination, Patient was severely dehydrated.
Pulse: 68b/m, BP: 100/60mmHg. Temp: 100 degree F. R/R: 18
breaths/min. GCS: 13/15. There was no focal neurological
symptoms.
28. Investigations:
S. Total Calcium 13.5mg/dL. Corrected calcium: 14.188 mg/dL
S. Total Protein: 56.7 gm/L. S. Albumin: 31.4 g/L.
S. PO4 : 1.6 mg/dL.
ALP: 256 U/L
iPTH: 982 pg/ml
S. Creatinine: 1.92 mg/dL
24 hour urinary calcium: 273 mg/day
ECG: Short QT interval.
USG of W/A: Suggestive of Early renal parenchymal disease.
USG of Neck: Multiple Nodules in both lobes of thyroid gland.
X-ray Both Hand: Osteopenia
X-ray Skull: Osteopenia, No Lytic Lesion.
BMD: T Score: Osteoporosis. (T Score: -3.6 in AP Spine)
Vitamin-D level: Report Pending
Sestamibi scan: Pending
Other routine investigations were also done.
29. Diagnosis & management
Diagnosis: HTN, CKD, Hypercalcemia due to (?) Primary
Hyperparathyroidism, Osteoporosis, Cellulitis of right leg.
Management: For management of severe hypercalcemia and
dehydration, we started Infusion normal saline with proper
maintenance of intake output chart. Later added Tab.
Frusemide 40mg (1 + 0 + 0).
After correction of dehydration, her serum Ca2+ started to
decline and become 9.9 mg/dl (Corrected) and remained stable
through out the hospital stay.
Other supportive management was given, as well management
of cellulitis was also done.
Injectable bisphosphonate therapy was advised after resolving
of the cellulitis during discharge (DOR).
Patient party has been advised to do Sestamibi scan as early as
possible and come to follow up for definitive management.
30. Brief case summary (2):
Mrs. Rezina Anju, 71 years old patient with h/o DM, HTN,
Hypothyroidism on replacement got admitted with
complaints of:
altered behavior, decreased talk and response for 8
days
h/o fecal and urinary incontinence.
On Drug history: Patient was receiving both calcium and
vitamin –D (Calcitriol) as a part of osteoporosis treatment
but was not having regular follow up.
On Examination, Patient was clinically stable with normal
vitals. Generalized weakness was present. Planter was
equivocal. Focal neurological signs were absent.
31. Investigations:
On routine investigations:
S. Calcium Level: 10.8mg/dl (Corrected: 11.4mg/dl)
S. TP: 73.3 gm/L. S. Albumin: 32.6 gm/L
ALP: 74 U/L
Vitamin – D Level: Report pending.
S. Creatinine: 0.9mg/dl
BMD: Osteoporosis. T Score – 2.9 on Femur (Done Previously)
ECG: Normal Sinus Rhythm
Other investigations reveals normal findings.
CT Scan of Brain: Left cerebral infract. Peri and paraventricular
white matter ischemic changes. Mild Degenerative cortical
atrophy of brain.
32. Diagnosis & management
Diagnosis: DM, HTN, Hypothyroidism (on replacement),
Ischemic Stroke, Dementia, Hypercalcemia (Iatrogenic)
Management: Calcium and Vitamin – D supplementation
has been stopped. Neurology consultation was taken for
Ischemic Stroke. Conservative management has been
advised.
During discharge, Patient has been advised to come after
1 week on follow up with S. Vit-D level and Ca2+.
33. Brief case summary (3):
Md. Zahirul Islam khan, 55 years old patient with h/o DM for 10
years and CKD for 2 years got admitted in Endocrinology dept. of
BIRDEM with complaints of:
Generalized weakness for last 2 months.
Multiple joint pain for 2 months.
High blood sugar for 2 months.
Patient gives history of multiple episodes of acute and chronic
pancreatitis since 2013. That time his S. Ca2+ was also above
normal range but it was not properly evaluated.
2 months back, he has suffered from chikungunya fever. For joint
pain, uncontrolled DM and weakness, he got admitted in a hospital
outside BIRDEM, where he was ultrasonologically diagnosed as a
case of nephrocalcinosis with pancreatic calculi. On evaluation,
He was diagnosed as a case of hypercalcemia with
hyperparathyroidism. For further management, he was referred to
BIRDEM Endocrinology department.
34. Clinical examination
[Patient is currently under treatment on our dept. (Bed: 1240)]
On general examination, Patient is ill looking his body built is
below average.
Anemia: +
BP: 110/60 mmHg, Pulse: 88b/m, regular. R/R: 18b/m, Temp:
N.
Edema: ++
Bed side albumin: +, Acetone: Nil.
Thyroid gland: Not palpable
Fundus: Appears normal.
Gross muscle wasting present. Muscle power is 4/5 in all limbs.
Jerks are slightly diminished.
Metatarsal joint tenderness present.
No features of acromegaly, visual difficulty.
Rest of the findings are normal.
35. Investigations:
S. Total Calcium 12.6mg/dL. Corrected Ca2+: 13.27 mg/dL
S. Total Protein: 66.1 gm/L. S. Albumin: 29.1 g/L.
S. PO4 : 2.4 mg/dL.
ALP: 188 U/L
iPTH: 751 pg/ml
S. Creatinine: 2.8 mg/dL (eGFR: 25.22).
24 hour urinary calcium: report pending
ECG: Short QT interval. 384 ms. Left ventricular
hypertrophy. Sinus rhythm.
USG of W/A: Suggestive of pancreatic calculi with dilated
PD. Nephropathy. Suggestive of left renal calculi. Mild
splenomegaly.
USG of neck: Bilateral Nodular goiter.
X-ray both hand: Osteopenia
X-ray skull: Osteopenia, No Lytic Lesion. Sella turcica
appears to be enlarged.
Urinary bence jones protein: Negative
36. Investigations (Cont):
DEXA: Pending
Vitamin-D level: Report Pending
Sestamibi scan: Pending
For evaluation of MEN Syndrome:
ACTH: 5.0 pg/ml
Basal Cortisol: 425 nmol/L
S. TSH: 1.19 uIU/mL
FT4: 14.31 pmol/L
S. Prolactin: Pending
MRI of sella and parasellar region: Pending.
37. Diagnosis & management
Working Diagnosis: DM, Hyperparathyroidism (? Primary),
Hypercalcemia, Post Chikungunya Arthritis, CKD (Stage – 4)
Management: For management of severe hypercalcemia and
dehydration, we started infusion normal saline along with
injection frusemide (40mg in each liter) to maintain forced
diuresis with careful monitoring of renal function.
Injectable albumin has been advised for correction of
hypoalbuminemia.
Serum Calcium level initially decreased then again increase
(14.2mg/dL).
Inj. Calcitonin (100u) S/C BD has been advised with careful
monitoring of Ca2+ along with hydration. (Also per advise of
Nephrology consultation)
Inj. Bisphosphonate is yet to be advised after careful
assessment of risk benefit ratio.
38. References:
Greenspan's Basic and Clinical Endocrinology, 9E
Endocrinology Secrets 6E
UpToDate online, Management of Hypercalcemia.
Medscape.com
