Hypercalcemia secondary to Primary Hyperparathyroidism

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Hypercalcemia secondary to Primary
Hyperparathyroidism

• Emily Kingsley, MD
• Med-Peds II

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• 90 of cases of hypercalcemia are due to
  hyperparathyroidism and malignancy
• HyperPTH asymptomatic with chronic
  hypercalcemia, postmenopausal woman, normal
  physical examination, family history of
  hyperparathyroidism, and evidence of multiple
  endocrine neoplasia
• Malignancy Higher concentrations of and more
  rapid increases in serum calcium and subsequently
  are more symptomatic
• Ambulatory Healthy patients, usually due to
  primary hyperparathyroidism
• Hospital Usually due to malignancy

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Primary Hyperparathyroidism

• Usually due to parathyroid adenoma
• Typically have only small elevations in serum
  calcium concentrations (less than 11 mg/dL) and
  sometimes values are high-normal
• May require multiple measurements
• Parathyroid crisis uncommon but acute onset of
  severe, symptomatic hypercalcemia

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Secondary HyperPTH

• Seen in severe chronic kidney disease
• Usually low or normal serum calcium values
• Few with hypercalcemia have decreased bone
  turnover
• Tertiary HyperPTH Parathyroid hyperplasia to
  autonomous overproduction of PTH

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Malignancy

• Mechanism of increased bone resorption depends on
  the cancer
• Bony mets direct induction of osteolysis by
  tumor cells through the use of cytokines (TNF,
  IL-1)
• Nonmetastatic solid tumors PTHrP
• Lymphoma PTH-independent extrarenal production
  of calcitriol from mononuclear cells
• Hypercalcemia with values above 13mg/dL
• Unusual in hyperparathyroidism

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Other causes of hypercalcemia

• Thyrotoxicosis usu. mild hypercalcemia
• Immobilization
• Paget disease of bone
• Hypervitaminosis A
• Hypervitaminosis D
• Calcitriol used with renal failure has short half
  life
• Calcidiol has longer half life so symptomatic
  pts. may need steroids and bisphosphonate
• Sarcoidosis, Wegeners granulomatosis

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• Milk Alkali Syndrome can occur in the setting of
  excess calcium carbonate supplementation to treat
  osteoporosis or dyspepsia
• Lithium increased secretion of PTH due to an
  increase in the set point at which calcium
  suppresses PTH release
• Thiazide diuretics
• Pheochromocytoma
• Adrenal insufficiency
• Theophylline toxicity
• Familial hypocalciuric hypercalcemia
  loss-of-function mutation in the calcium-sensing
  sensor on the parathyroid cells and in the
  kidneys

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Clinical Manifestations

• Ranges from asymptomatic to obtundation and coma
• Mild hypercalcemia (calcium lt12 mg/dl)
  Asymptomatic or nonspecific symptoms
  (constipation, fatigue, and depression)
• Moderate hypercalcemia (calcium 12 to 14 mg/dL)
• may be well-tolerated chronically
• Acute rise to these concentrations may cause
  marked symptoms polyuria, polydipsia,
  dehydration, anorexia, nausea, muscle weakness,
  and changes in sensorium.
• Severe hypercalcemia (calcium gt14 mg/dL)
  progression of symptoms

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Bones, stones, moans, and groans

• NEURO/PSYCH
• Anxiety
• Depression
• Cognitive dysfunction
• Lethargy
• Stupor
• Coma
• GI
• Constipation
• Anorexia
• Nausea
• Pancreatitis
• Peptic ulcer disease
• MSK
• Bone pain
• Profound muscle weakness

• CARDIAC
• Shortening of the QT interval
• Bradycardia
• Hypertension
• RENAL
• Polyuria decr. concentration in distal tub.
• Nephrolithiasis
• Acute/Chronic renal insuffic.
• Serum calcium of 12 to 15 mg/dL can lead to a
  reversible fall in GFR from direct renal
  vasoconstriction
• Long-standing hypercalcemia and hypercalciuria
  Calcification, degeneration, and necrosis of the
  tubular cells ?Tubular atrophy and interstitial
  fibrosis and calcification (nephrocalcinosis).

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Assessment
Normal or
Primary HyperPTH
Calcium
PTH
PTHrP Vitamin D levels TSH SPEP/UPEP Vitamin A
levels
Malignancy Vit D intoxication Granulomatous dis.

• Correction for the measured calcium concentration
  in hypoalbuminemia
• Ca Serum Ca 0.8 (Normal Albumin Pt
  Albumin)

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Haden, ST, Brown, EM, Hurwitz, S, et al. The
effects of age and gender on parathyroid hormone
dynamics. Clin Endocrinol 2000 52329.
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• 25-OH Vitamin D Usually due to ingestion
• 1,25-OH Vitamin D Ingestion, granulomatous
  diseases, lymphoma, primary hyperparathyroidism
• Increased Recommend CXR ? Sarcoidosis, Lymphoma

Granulomatous dis. Milk Alkali
Syndrome Vitamin D intoxication Metastatic
bone dis. Thyrotoxicosis
Immobilization
Normal or
Phosphate
HyperPTH PTHrP malignancy -Inhibition of renal
proximal tubular Phosphate resorption
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Treatment of Hypercalcemia

• Degree of hypercalcemia and rate of rise
  determine symptoms and urgency of treatment
• Calcium gt14mg/dL Require treatment regardless of
  symptoms
• Calcium 12-14mg/dL
• Chronically maybe be tolerated
• Acutely may lead to AMS

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Ways to Correct Hypercalcemia

• Isotonic Saline
• Treats volume depletion from calcium-induced
  urinary salt wasting
• Increases renal perfusion and urinary calcium
  clearance
• Administration Initial rate of 200-300ml/hr
  adjusted for urinary output of 100ml/h
• Limited in those with cardiac or renal disease
• Should be discontinued with development of edema
• Goal Euvolemia
• Rarely normalizes calcium level

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• Bisphosphonates
• Analogs of inorganic pyrophosphate that absorb to
  the surface of bone hydroxyapatite inhibiting
  calcium release by interfering with
  osteoclast-mediated bone resorption
• More potent than Saline and Calcitonin
• Administration IV Zoledronic acid preferred due
  to potency and short administration time (15
  min.)
• Single dose due to risk of osteonecrosis of jaw
  with repeat doses
• Effect Seen in 2-4 DAYS

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• Calcitonin
• Decrease bone reabsorption by interfering with
  osteoclast maturation
• Increase renal calcium excretion
• Administration IM or subcut, nasal not effective
• Effect Rapid with lowering within 4-6 HOURS
• Decreases the serum calcium up to a maximum of 1
  to 2 mg/dL
• Efficacy limited to 48 HOURS

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• Glucocorticoids
• Useful with calcidiol ingestion
• Useful with hypercalcemia from increased
  calcitriol production seen in granulomatous
  disease and lymphoma
• Decreases calcitriol production by activated
  mononuclear cells in the lung and lymph nodes
• Administration 20-40mg/day
• Effect Seen in 2-5 days

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• Dialysis
• Indications
• Severe hypercalcemia (18 to 20 mg/dL) with
  neurologic symptoms
• Limited use of IV hydration
• Renal insufficiency
• Heart failure

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In Sum

• Mild (lt12mg/dl) No therapy
• Avoid thiazide diuretic, lithium, calcium
  ingestion (gt1000mg/day), volume depletion,
  prolonged bedrest
• Moderate (12-14mg/dl) Treat if symptomatic or an
  acute rise
• Severe (gt14mg/dl) IV saline (immediate effect),
  calcitonin (immediate effect), bisphosphonate
  (delayed but most effective)
• Primary hyperparathyroidism Parathyroidectomy

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And the calcium lived happily ever after

• (What would a Med-Peds presentation
• be without a Sponge Bob reference?!?!)

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HUNGRY BONE SYNDROME

• Develops in those with bone disease
  preoperatively due to a chronic increase in bone
  resorption from high levels of PTH
• Sudden withdrawal of PTH causes increased
  osteoblast-mediated bone formation and marked net
  increase in bone uptake of calcium, phosphate,
  and magnesium
• Syndrome most likely to be present if if the
  serum calcium concentration lt8.5 mg/dL and the
  serum phosphate concentration lt3.0 mg/dL on the
  3rd postoperative day

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• Hypocalcemia
• Tetany, seizures, heart failure
• Treatment
• Oral calcium (2 to 4 g per day) Between meals to
  avoid phosphate binding
• IV calcium With rapid reduction in serum calcium
  OR symptoms related to hypocalcemia OR plasma
  calcium concentration below 7.5 mg/dL
• Hypophosphatemia With significant bone disease
• Replacement only in severe hypoPO4 (below 1
  mg/dL) Combines with calcium to further reduce
  calcium concentration
• BUT with lack of severe bone disease See
  increase in phosphate due to reversal of
  PTH-induced phosphate loss in the urine
• Hypomagnesemia
• Can contribute refractory hypocalcemia by
  diminishing PTH secretion and inducing PTH
  resistance
• Hyperkalemia

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THANK YOU!
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References

• Bilezikian, J. Clinical review 51 Management of
  hypercalcemia. J Clin Endocrinol Metab 1993 77
  1445-1449.
• Haden, ST, Brown, EM, Hurwitz, S, et al. The
  effects of age and gender on parathyroid hormone
  dynamics. Clin Endocrinol 2000 52329.
• Marx, S. Hyperparathyroid and hypoparathyroid
  disorders. N Engl J Med 2000 343 1863-1875.
• Up-To-Date. www.utdol.com