HYPERCALCEMIA

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HYPERCALCEMIA

• Dr R V S N Sarma., M.D., M.Sc.,
• Consultant Physician and Chest Specialist

visit www.drsarma.in
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Hypercalcemia

• 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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Important Issues

• 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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Physiology of Calcium

• 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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Calcium Homeostasis
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Calcium Homeostasis
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Calcium Metabolism
(1,000 mg/day)
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How They control Ca Levels
Hormone Effect Bone Gut Kidney
PTH ? Ca ? Po4 Increases Osteoclasts Indirect via Vit. D Ca reab Po4 exr.
Vitamin D3 ? Ca ? Po4 No direct action ? Ca ? Po4 absorption No direct effect
Calcitonin ? Ca ? Po4 Inhibits Osteoclasts No direct effect Ca Po4 excretion
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Corrected Serum Calcium

• 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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Vitamin D Metabolism
Supplements Vitamin D 2
Calcitriol (Active)
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Formation of Calcitriol
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Calcium Homeostasis
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Hypercalcemia Grading
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Hypercalcemia
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Causes of Hypercalcemia
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The Two Important Causes

• 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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Parathyroid hormone-related

• 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-related

• Vitamin D intoxication
• Iatrogenic Vitamin D injections
• Usually 25-hydroxyvitamin D2 in
• over-the-counter supplements
• Granulomatous disease
• Sarcoidosis, Berylliosis, Tuberculosis
• Hodgkins lymphoma

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Malignancy

• 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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Medications

• 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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Endocrine Diseases

• Hyperthyroidism
• Adrenal insufficiency
• Acromegaly
• Pheochromocytoma

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Genetic and Other disorders

• Familial hypocalciuric hypercalcemia (FHH)
• mutated calcium-sensing receptor gene
• Immobilization, with high bone turnover (e.g.,
  Pagets disease, bedridden child)
• Recovery phase of Rhabdomyolysis

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Hypercalcemia - Clinical
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Clinical Features

• Renal stones
• Nephrolithiasis
• Nephrogenic Diabetes Insipidus
• Dehydration
• Nephrocalcinosis

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Clinical Features

• Skeleton bones
• Bone pains
• Arthritis
• Osteoporosis
• Osteitis fibrosa cystica in HPTH

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Clinical Features

• 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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Clinical Features

• 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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Clinical Features contd

• 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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Algorithmic Approach
Normal calcium
Hypocalcemia
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Algorithmic Approach
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Algorithmic Approach
Endocrine
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Serum Ca and I-PTH
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Hyperparathyroidism

• 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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Sestamibi Nuclear Scan
64 yrs male - hyper parathyroid storm with a
serum calcium level of 16.4 mg
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Criteria for Surgery

• Serum calcium level gt 12 mg at any time
• Episodes of hyper parathyroid crisis
• Marked hypercalciuria (urinary Ca gt 400 mg
  /day)
• Nephrolithiasis Impaired renal function
• Osteitis fibrosa cystica Thinning of cortical
  bone
• Reduced bone density by DEXA scan (Z score lt 2)
• Classic neuromuscular symptoms, Proximal muscle
  weakness and atrophy, Hyper reflexia and ataxia
• Age younger than 50 years

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Vitamin D Related

• 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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Hypercalcemia of Malignancy

• 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 ?
• Hodgkins lymphoma ? production of Calcitriol

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Medications and Hypercalcemia

• Thiazide diuretics increase renal calcium
• resorption and cause mild hypercalcemia
• Resolves after discontinuing the drug
• Thiazide unmasks hyperparathyroidism
• Milkalkali syndrome Ca Antacids
• Lithium ? the set point for PTH ?
• Excess Vitamin A - ? bone resorption and
• causes hypercalcemia.

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Other Causes of Hypercalcemia

• 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 Pagets disease or
  prolonged immobilization
• Recovery phase of Rhabdomyolysis

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Treatment

• Ca lt12 but gt 10.3 mg no appreciable clinical
  benefit they need evaluation
• Any patient with Serum Ca gt 12 mg should be
  aggressively treated
• Ca gt 14 mg is Hypercalcemic crisis
• Always correct the Ca value for Sr Albumin

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The Four Rx Modalities
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Hydration and Diuresis

• 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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Calcitonin

• 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
  calcium-lowering effect of Calcitonin.

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Bisphosphonates

• 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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Other Rx Options

• 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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Take Home Points

• 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.