DESCRIPTION

• Parathyroid hormone (PTH) excess with symptoms owing to PTH actions:
  • Decreases urinary Ca²⁺ loss
  • Increases urinary PO₄^2– loss
  • Stimulates vitamin D conversion from 25(OH)-D to 1,25(OH)-D in kidney
  • Liberates Ca²⁺ and PO₄^2– from bone
  • Hypercalcemia is the primary metabolic finding
• Hypercalciuria from hypercalcemia (despite decreased urinary loss) produces increased magnesium loss in urine
• Magnesium (negative feedback to prevent hypercalcemia causes hypomagnesaemia):
  • Cofactor in the production of PTH
  • Essential for action of PTH in target tissues
• Genetics:
  • Associated with multiple endocrine neoplasia type 1:
    • Hyperparathyroidism
    • Pancreatic islet disease
    • Pituitary disease
  • Associated with multiple endocrine neoplasia type 2:
    • Hyperparathyroidism (type 2A, rare in 2B)
    • Medullary carcinoma of the thyroid (type 2A and 2B, less virulent in type 2A)
    • Pheochromocytoma (type 2A and 2B)
    • Mucosal neuroma (type 2B)

ETIOLOGY

• Excess secretion of PTH owing to:
  • Primary hyperparathyroidism (adenoma 85%, hyperplasia 14%, carcinoma < 1%)
  • Secondary hyperparathyroidism (response to vitamin D deficiency or chronic renal failure with hyperphosphatemia):
    • Calcium is low or normal, but PTH levels are elevated

[Outline]

• DESCRIPTION
• ETIOLOGY

SIGNS AND SYMPTOMS

Stones, bones, abdominal groans, and psychiatric moans

ALERT

History

Depends on the severity and rapidity of hypercalcemia

Pediatric Considerations

• Neonate:
  • Hypotonia, weakness, and listlessness
  • Following delivery to hypoparathyroid mothers
• Hypercalcemic infants:
  • Broad forehead
  • Epicanthal folds
  • Underdeveloped nasal bridge
  • Prominent upper lip

Physical Exam

• Dehydration
• Cardiac:
  • Hypertension (even in the face of dehydration)
  • Cardiac conduction abnormalities (not proportional to degree of hypercalcemia)
  • Bradydysrhythmia
  • Bundle branch blocks
  • Complete heart block
  • Asystole
  • Short QT interval (shortened ST segment)
  • Potentiation of digitalis effects (Hypercalcemia +digoxin = digitalis toxicity)
• Neurologic:
  • Headaches
  • Decreased reflexes
  • Proximal muscle weakness
  • Dementia
  • Lethargy
  • Coma
• Psychiatric:
  • Personality changes
  • Depression
  • Inability to concentrate
  • Anxiety
  • Psychosis
• GI:
  • Anorexia, nausea, vomiting
  • Constipation
  • Peptic ulcer disease
  • Pancreatitis
• General:
  • Fatigue
  • Weight loss
  • Polyuria and polydipsia
• Musculoskeletal:
  • Gout/pseudogout
  • Bone pain, bone cysts (osteitis cystica)
  • Arthralgias
  • Chondrocalcinosis
• Renal:
  • Kidney stones
  • Nephrocalcinosis
  • Decreased renal concentrating ability

ESSENTIAL WORKUP

• Calcium level
• Albumin:
  • Elevated albumin—falsely elevated calcium level
  • Low albumin—falsely lowered calcium level
• Evaluate for symptoms of hypercalcemia, especially impending parathyroid storm (hypercalcemic crisis—anorexia, nausea, vomiting, obtundation progressing to coma).
• Review history for medication ingestion (see Differential Diagnosis below)
• No further ED workup if:
  • Asymptomatic
  • Normal ECG
  • Calcium level < 14 mg/dL when corrected for albumin
• If symptomatic with Ca²⁺ < 14 mg/dL or any patient with Ca²⁺≥14 mg/dL, check:
  • Ionized calcium
  • Chest radiograph (for CHF/malignancy)
  • Phosphorus
  • Electrolytes, BUN, creatinine
  • Sedimentation rate
  • Alkaline phosphatase
  • Magnesium
  • Thyroid-stimulating hormone (TSH)
  • CBC

DIAGNOSIS TESTS & INTERPRETATION

Lab

• Calcium correction for albumin:
  • Corrected Ca²⁺ (mg/dL) = measured Ca²⁺ (mg/dL) + 0.8 [4 – albumin (g/dL)]
  • Acidosis:
    • Decreases affinity to albumin—increases ionized (metabolically active) Ca²⁺
    • Decrease of 0.1 pH unit increases the ionized Ca²⁺ by 3–8%
• Phosphorus:
  • Low in primary hyperparathyroidism
  • Usually high in secondary hyperparathyroidism
  • Normal or high in malignancy-related hypercalcemia
• Chloride/PO₄^2– ratio:
  • > 33—hyperparathyroidism
  • < 30—malignancy
• Alkaline phosphatase:
  • Increased in 50% of patients with hyperparathyroidism
  • Normal with vitamin D excess
• Erythrocyte sedimentation rate (ESR):
  • Normal in hyperparathyroidism
  • Elevated in malignancy or granulomatous diseases
• Anemia:
  • Present with malignancy or granulomatous disease
  • Absent in hyperparathyroidism
• Magnesium:
  • Low or low normal
• PTH:
  • Elevated in primary and secondary hyperparathyroidism
• PTH-related peptide:
  • Secreted by squamous cell carcinomas of lung, head, neck; renal carcinomas, bladder carcinomas, adenocarcinomas, and lymphomas

Imaging

• Chest radiograph:
  • To assess CHF risk during IV hydration
  • Granulomatous disease or malignancy if cause of hypercalcemia is uncertain

Diagnostic Procedures/Surgery

Definitive treatment is parathyroidectomy to treat and establish cause of hyperparathyroidism

DIFFERENTIAL DIAGNOSIS

• PTH related:
  • Primary or secondary hyperparathyroidism
  • Familial hypocalciuric hypercalcemia
• Malignancy related:
  • PTH-related peptide or Ca²⁺ release from osteolytic tumor
• Vitamin D related:
  • Excess vitamin D intake or vitamin D production by granulomas
• Immobilization:
  • Associated with Paget disease
• Drug induced:
  • Thiazide diuretics
  • Lithium
  • Aluminum-containing antacids
  • Tamoxifen
  • Estrogens
  • Androgens
  • Vitamin A

[Outline]

• SIGNS AND SYMPTOMS
• ESSENTIAL WORKUP
• DIAGNOSIS TESTS & INTERPRETATION
• DIFFERENTIAL DIAGNOSIS

PRE-HOSPITAL

May present as a primarily psychiatric disorder

INITIAL STABILIZATION/THERAPY

• Cardiac monitor if:
  • Symptomatic hypercalcemia
  • Ca²⁺ level > 14 mg/dL
• Hydrate with IV 0.9% NS.
• Correct acidosis

ED TREATMENT/PROCEDURES

• Treat hypercalcemia:
  • Vigorous hydration with 0.9% NS at minimum of 250 mL/hr unless CHF:
    • Lowers calcium 1.5–2 mg/dL in 24 hr
    • Achieve urine output 100 mL/hr
  • Administer furosemide or other loop diuretic (calciuric) after adequate volume replacement or in the presence of CHF:
    • Common error: Administration of furosemide before adequate hydration
    • If urinary sodium losses exceed replacement sodium, then renal conservation measures impede calcium excretion
  • Avoid thiazide diuretics (impede calcium excretion)
  • Consider glucocorticoid administration (decreases gut absorption and increases renal excretion of Ca²⁺); most effective with vitamin D intoxication or granulomatous diseases
  • Start bisphosphonates (pamidronate or etidronate) in conjunction with primary physician (inhibits calcium mobilization from bone)
• Treat cardiac dysrhythmias in standard fashion:
  • Correct acidosis
• Determine the cause of the hypercalcemia.
• Stop all medications that may contribute to hypercalcemia
• Exercise extreme caution in the use of digoxin.
• Anticipate CHF and electrolyte imbalance with frequent reassessment of patient and monitoring of serum electrolytes and magnesium levels
• Calcitonin if unable to use hydration
• Emergent dialysis with renal failure

MEDICATION

First Line

• NS hydration: Initial 250–300 mL/h depending on patient's propensity to CHF
• Furosemide: 40 mg IV q2–4h after assurance of adequate hydration
• Prednisone: 40–60 mg PO OR Hydrocortisone: 100 mg (peds: 1–2 mg/kg) IV

Second Line

• IN CONSULTATION WITH ENDOCRINOLOGIST
• Calcitonin salmon 4 U/kg SC if saline hydration contraindicated
  • Test dose: Intradermal 0.1 mL of 10 U/mL solution recommended
  • Initial dose: 4 U/kg SC q12h
• Pamidronate:
  • If albumin-corrected Ca²⁺ level 12–13.5 mg/dL: 60 mg IV infused over 2 hr
  • If albumin-corrected Ca²⁺ level > 13.5 mg/dL: 90 mg IV over 4 hr
  • Dosage should be reduced in renal impairment and infusion time may be extended to reduce nephrotoxic potential but no formal recommendations exist (pregnancy category D – maternal benefit may outweigh fetal risk)
• Zoledronic acid: 4 mg IV over 15–30 min (first-line agent due to efficacy and convenience, but less preferred due to lack of less expensive available generic)
• Cinacalcet (Sensipar): 30 mg PO daily or BID (calcimimetic for secondary hyperparathyroidism or parathyroid carcinoma)

[Outline]

• PRE-HOSPITAL
• INITIAL STABILIZATION/THERAPY
• ED TREATMENT/PROCEDURES
• MEDICATION

DISPOSITION

Admission Criteria

• Corrected calcium > 14 mg/dL
• Symptomatic hypercalcemia
• Evidence of abnormal cardiac rhythm or conduction

Discharge Criteria

• Not meeting admission criteria
• Able to maintain adequate hydration

Issues for Referral

If diagnosis is suspected, referral to check PTH levels and response to therapy

FOLLOW-UP RECOMMENDATIONS

• If hyperparathyroidism is suspected arrange follow-up and send a PTH level
• Patient needs to be instructed to maintain hydration and stop medications associated with hypercalcemia (see the list in Differential Diagnosis)

[Outline]

• DISPOSITION
• FOLLOW-UP RECOMMENDATIONS

• The hypercalcemia of hyperparathyroidism is rarely symptomatic and Ca²⁺ level rarely > 14. (Higher levels are most frequently attributable to neoplastic disease)
• The importance of diagnosis is to prevent long-term complications
• Calcium level should be measured as ionized Ca²⁺, or corrected for albumin level
• Administration of loop diuretics prior to adequate saline hydration will worsen hypercalcemia; some experts suggest that loop diuretics may be no longer warranted for this indication

ICD9

• 252.00 Hyperparathyroidism, unspecified
• 252.01 Primary hyperparathyroidism
• 252.02 Secondary hyperparathyroidism, non-renal

ICD10

• E21.0 Primary hyperparathyroidism
• E21.1 Secondary hyperparathyroidism, not elsewhere classified
• E21.3 Hyperparathyroidism, unspecified

[Outline]

• ICD9
• ICD10

• Andreoli TE, Carpenter CCJ, Cecil RL. Andreoli and Carpenter's Cecil Essentials of Medicine. 7th ed. Philadelphia, PA:Saunders-Elsevier; 2007.
• Goldman L, Bennett JC, eds. Cecil's Textbook of Medicine. 23rd ed. Philadelphia, PA: Saunders-Elsevier; 2008.
• Jamal SA, Miller PD. Secondary and tertiary hyperparathyroidism. J Clin Densitom. 2013;16(1):64–68.
• Khan AA. Medical management of primary hyperparathyroidism. J Densitom. 2013;16(1):60–63.
• Marcocci C, Cetani F. Primary hyperparathyroidism. N Engl J Med. 2011;365:2389–2397.

See Also (Topic, Algorithm, Electronic Media Element)

Hypoparathyroidism

Rami A. Ahmed

Brad D. Gable