Download hypercalcemia

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• Commonly encountered in Practice
• Diagnosis often is made incidentally
• The most common causes are primary
hyperparathyroidism and malignancy
• Diagnostic work-up includes measurement
of serum calcium, intact parathyroid
hormone (I-PTH), h/o any medications
• Hypercalcemic crisis is a life-threatening
emergency
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• Most often asymptomatic – Incidental Dx
• Mild Hypercalcemia is asymptomatic
• Most important cause is hyper parathyroid
• DD is needed to decide the treatment
• Optimal step by step evaluation is a must.
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• 98% of the body calcium is in the skeleton
• Only 2% is circulation and only half of this
is free calcium (ionized Ca++)
• This only is physiologically active
• The reminder 1% is bound to proteins
• Direct measurement of free Calcium ??
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Parathyroid Hormone
1,25 DHC or Vitamin D3
Calcitonin
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 Bone Resorption
 Intestinal Absorption
 Renal Excretion
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(1,000 mg/day)
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Hormone
PTH
Effect
Bone
Increases
Indirect
 Ca  Po4
Osteoclasts via Vit. D
No direct
Vitamin D3  Ca  Po4
action
Calcitonin
Gut
Kidney
Ca reab
Po4 exr.
 Ca  Po4 No direct
absorption effect
Inhibits
No direct
 Ca  Po4
Osteoclasts effect
Ca & Po4
excretion
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Corrected total calcium (mg%) =
[(Measured total calcium mg%) +
{(4.4 - measured albumin g%) x 0.8}]
Example:
[12.0 + {(4.4 – 2.4) x 0.8}] =
[ 12.0 + (2 x 0.8)] = 12.0 + 1.6 = 13.6 mg%
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Supplements
Vitamin D 2
Calcitriol (Active)
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Vitamin D is a steroid hormone
From dietary sources
Action of Sunlight on skin
Successive hydroxylations of Cholecalciferol
25 hydroxylation in the Liver
25 hydroxy Cholecalciferol
Second hydroxylation in the Kidney at first position
1,25 dihydroxy Cholecalciferol
Active Vitamin D (Calcitriol)
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PTH
Calcitriol (D)
Calcitonin
• 4 PT glands
• 84 AA
hormone
• Low Ca
stimulates it
• Active bone
formation
• Main effect is
on the Gut
• PTH  Vit. D
• Para follicular
C of Thyroid
• 34 AA hormone
• On Kidney
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Critical - > 14 mg %
Moderate - 12 to 14 mg %
Mild – 10.4 to 11.9 mg %
Normal – 8.5 to 10.3 mg %
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PTHrP
Calcitriol
PTH
Ca++
 Ca
at GIT
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PTH
Vitamin D
Genetic
 Ca++
Endocrine
Malignancy
Medicines
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• More than 90 percent of hypercalcemia cases are
Primary hyperparathyroidism and malignancy
• These conditions must be differentiated early
to provide optimal treatment & accurate prognosis
• Humoral hypercalcemia of malignancy implies a very
limited life expectancy — only a matter of weeks
• Primary hyperparathyroidism has a benign course.
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• Primary hyperparathyroidism
• Sporadic, familial, associated with
Multiple Endocrine Neoplasia (MEN I or II)
• Tertiary hyperparathyroidism
• Associated with chronic renal failure
• PTH  due to Vitamin D deficiency
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• Vitamin D intoxication
• Iatrogenic Vitamin D injections
• Usually 25-hydroxyvitamin D2 in
over-the-counter supplements
• Granulomatous disease –
Sarcoidosis, Berylliosis, Tuberculosis
• Hodgkin’s lymphoma
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• Humoral hypercalcemia of malignancy
(mediated by PTHrP) – common cause
• Solid tumors, especially lung, head and
neck squamous cancers
• Renal Cell Carcinoma (RCC)
• Local osteolysis (mediated by cytokines)
• Multiple Myeloma
• Breast cancer
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• Thiazide diuretics (usually mild) - common
• Lithium for depressive illnesses
• Milk-alkali syndrome (calcium + antacids)
• Vitamin A intoxication (including
analogs used to treat acne)
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• Hyperthyroidism
• Adrenal insufficiency
• Acromegaly
• Pheochromocytoma
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• Familial hypocalciuric hypercalcemia (FHH)
mutated calcium-sensing receptor gene
• Immobilization, with high bone turnover
(e.g., Paget’s disease, bedridden child)
• Recovery phase of Rhabdomyolysis
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• SKELETON
• KIDNEY
• GIT
STONES
BONES
MOANS
GROANS
• CNS
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Renal “stones”
• Nephrolithiasis
• Nephrogenic Diabetes Insipidus
• Dehydration
• Nephrocalcinosis
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Skeleton “bones”
• Bone pains
• Arthritis
• Osteoporosis
• Osteitis fibrosa cystica in HPTH
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Abdominal “Moans”
• Nausea, vomiting
• Severe anorexia, weight loss
• Constipation (not relieved by Rx.)
• Abdominal pain (vague and diffuse)
• Pancreatitis
• Peptic ulcer disease
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Psychological “Groans”
• Impaired concentration
• Impaired memory, Depression
• Confusion, stupor, coma
• Lethargy and severe fatigue
• Extreme muscle weakness
• Corneal calcification (band keratopathy)
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Cardiovascular
• Hypertension, Increased risk of CHD
• ECG changes of shortened QT interval, PR
prolonged, QRS widened, ST , Bradycardia
• Cardiac arrhythmias; Vascular calcification
Others
• Itching (Generalized Pruritus)
• Keratitis, conjunctivitis
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Normal calcium
? Suspect
 Calcium
Serum
Calcium
Hypocalcemia
8.5 to 10.3
> 10.3 mg %
< 8.0 mg %
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High/Normal
Pri PTH
Medications
Vit D Toxicity
> 10.3 mg%
I-PTH
Suppressed
Milk Alkali
Cancers/
Lymphoma
Suppressed
PTHrP
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Low or
Normal
PTHrP
Low or
Normal
Endocrine
1, 25 Vit. D
If Low
Cancer
If High
Lymphoma
Low – FHH
High
24 hr. urine
calcium
N or 
Sestamibi
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• Increased screening for serum Ca++ and
• Wider availability of I-PTH assay
• 80% of cases single parathyroid adenoma
• Usually benign adenoma or hyperplasia
• Rarely parathyroid cancer
• High PTH in the setting of hypercalcemia
• Slowly progressive – Sestamibi N-scan
• 25% require surgery – RLN paralysis
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64 yrs male - “hyper parathyroid storm”
with a serum calcium level of 16.4 mg%
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• Serum calcium level > 12 mg % at any time
• Episodes of hyper parathyroid crisis
• Marked hypercalciuria (urinary Ca++ > 400 mg /day)
• Nephrolithiasis; Impaired renal function
• Osteitis fibrosa cystica – Thinning of cortical bone
• Reduced bone density by DEXA scan (Z score < 2)
• Classic neuromuscular symptoms, Proximal muscle
weakness and atrophy, Hyper reflexia and ataxia
• Age younger than 50 years
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• 25 OH - Vitamin D2 is the supplemental Vit D
• Level of 25 OH – Vitamin D3 is to be measured
• Macrophages in the granulomas, lymphomas
cause extra renal conversion of 25 OH form to
the1,25 hydroxy derivative –the active Calcitriol
• PTH levels are suppressed; Calcitriol levels 
• Stop the offending use of Vitamin D
• Glucocorticoids – for over one month or more
• Manage hypercalcemia vigorously
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• Most commonly mediated by systemic PTHrP
• Humoral Hypercalcemia of malignancy
• PTHrP mimics the bone & renal effects of PTH
• Normal Calcitriol and suppressed PTH levels
• Excessive bone lysis due to primary or bone
secondaries can cause hypercalcemia
• MM and metastatic Br Ca present in this way.
• In Osteolytic hypercalcemia, SAP is markedly 
• Hodgkin’s lymphoma –  production of Calcitriol
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• Thiazide diuretics increase renal calcium
resorption and cause mild hypercalcemia
• Resolves after discontinuing the drug
• Thiazide unmasks hyperparathyroidism
• Milk–alkali syndrome – Ca + Antacids
• Lithium –  the set point for PTH 
• Excess Vitamin A -  bone resorption and
causes hypercalcemia.
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• FHH – Familial Hypocalciuric Hypercalcemia
• AD – 100% penetrance – Ca-R gene mutation
• Moderate hypercalcemia with normal/  PTH
• 24 hour urinary calcium is very low
• No benefit from parathyroidectomy
• High bone turnover in Paget’s disease or
prolonged immobilization
• Recovery phase of Rhabdomyolysis
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• Ca <12 but > 10.3 mg% – no appreciable
clinical benefit – they need evaluation
• Any patient with Serum Ca > 12 mg%
should be aggressively treated
• Ca > 14 mg% is Hypercalcemic crisis
• Always correct the Ca value for Sr Albumin
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I.V. Saline
Hydration
& Diuresis
GlucoCorticoids
Bisphosphonates
Calcitonin
I.M/S.C.
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• Vigorous I.V. Nacl Diuresis – N Saline
• Adequate hydration – urine out put must be
maintained 200 ml/hour = 5 L /day
• The safest and most effective treatment of
Hypercalcemic crisis is saline rehydration
• Once the urine out put is maintained – give I.V.
Furosemide – a loop diuretic in low doses of 10
to 20 mg
• ERT - might be beneficial in PMW – new RCT
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• In severe hypercalcemia refractory to
saline diuresis
• Calcitonin (Zycalcit, Miacalcin) 6 -8 U/kg
IM/SC (400 i.u) given every six hours.
• This treatment has a rapid onset but short
duration of effect
• Patients develop tolerance to the calciumlowering effect of Calcitonin.
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• Zoledronic acid (Zometa) - 4 mg IV diluted in
100 ml of N Saline - over at least 15’ once a M
• Pamindronate (Pamidria) - 60 mg IV infusion
over 4 h initial – repeated after a month
• Etidronate (Didronel) - 7.5 mg/kg IV over 4 h
daily for 3-7 d; dilute in at least 250 ml of
sterile N Saline
• They inhibit bone resorption, inhibit the
Osteoclastic activity.
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• Dialysis for refractory Hypercalcemic crisis
• Parathyroidectomy for adenomas
• Rx. of the underlying cause – Eliminate drugs
• Plicamycin (Mithracin) 25 mcg/kg/d IV for 4 d
• Gallium nitrate (Ganite) 100 mg/m2/d IV for
5 days in 1 L of NS or 5% Dextrose
• Cinacalcet (Sensipar) - 30 mg PO od –
(increases sensitivity of calcium sensing receptor)
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• Hypercalcemia is often asymptomatic
• Screen all suspected by doing Sr Calcium
• If elevated, do I-PTH and follow algorithm
• 90% Hyperparathyroidism and malignancy
• Vitamin D toxicity is an important cause
• Thiazide diuretics common cause, Vitamin A
• Adequate hydration - N Saline + Furosemide
• Calcitonin + Zoledronic acid main stay of Rx.
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