Author:
Rami A.Ahmed
JenniferYee
Description
- Parathyroid hormone (PTH) excess with symptoms owing to PTH actions, including:
- Decreases urinary Ca2+ loss
- Increases urinary PO42− loss
- Stimulates vitamin D conversion from 25(OH)-D to 1,25(OH)-D in kidney
- Liberates Ca2+ and PO42− from bone
- Hypercalcemia is the primary metabolic finding
- Hypercalciuria from hypercalcemia (despite decreased urinary loss) produces increased magnesium loss in urine
- Hypomagnesemia (due to negative feedback to prevent hypercalcemia):
- 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 (parathyroid single benign 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
Signs and Symptoms
Stones, bones, abdominal groans, and psychiatric moans
ALERT |
- Hypercalcemic crisis (most often due to primary hyperparathyroidism):
- Oliguria, anuria
- Mental obtundation
- Anorexia, nausea, vomiting
|
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
- Decreased urinary output
Essential Workup
- Calcium level
- Albumin:
- 40-45% of calcium is bound to albumin
- Elevated albumin = falsely elevated total calcium level with a normal ionized/free calcium level
- Low albumin = falsely lowered total calcium level with an elevated ionized/free calcium level
- Evaluate for symptoms of hypercalcemia, especially impending parathyroid storm (hypercalcemic crisis - oliguria, anorexia, nausea, vomiting, obtundation progressing to coma)
- Review history for medication ingestion (see Differential Diagnosis)
- 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
- Albumin
- Chest radiograph (for signs of decompensated CHF/malignancy/bilateral hilar adenopathy of sarcoidosis)
- Phosphorus
- Electrolytes, BUN, creatinine
- Sedimentation rate
- Alkaline phosphatase
- Magnesium
- Thyroid-stimulating hormone (TSH)
- CBC
Diagnostic 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/PO42− 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:
- 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 for decompensated CHF risk during IV hydration
- Granulomatous disease or evaluate for malignancy if cause of hypercalcemia is uncertain
- To evaluate for bilateral hilar adenopathy of sarcoidosis if cause of hypercalcemia is uncertain
Diagnostic Procedures/Surgery
Definitive treatment is parathyroidectomy to treat and establish cause of hyperparathyroidism
Differential Diagnosis
- PTH elevation:
- 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
- Vitamin D deficiency causing secondary hyperparathyroidism
- Granulomatous diseases:
- Immobilization:
- Associated with Paget disease
- Drug induced:
- Thiazide diuretics
- Lithium
- Aluminum-containing antacids
- Tamoxifen
- Estrogens
- and rogens
- Vitamin A
Prehospital
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:
- Start with vigorous intravenous hydration with 0.9% NS at minimum of 250 mL/hr unless risk of decompensated 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 decompensated CHF:
- Blocks calcium reabsorption in loop of Henle
- 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 stand ard fashion:
- 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/hr depending on patient's propensity to develop decompensated 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 - use often described in conjunction with bisphosphonate therapy:
- Test dose: Intradermal 0.1 mL of 10 U/mL solution recommended
- Initial dose: 4 U/kg SC q12h
- Bisphosphonates - best described in use with cancer-related hypercalcemia
- Pamidronate (a bisphosphonate):
- 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 (a bisphosphonate): 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 b.i.d (calcimimetic for secondary hyperparathyroidism or parathyroid carcinoma)
Disposition
Admission Criteria
- Corrected calcium >14 mg/dL
- Symptomatic hypercalcemia
- Evidence of abnormal cardiac rhythm or conduction
Discharge Criteria
- Does not meet admission criteria
- Able to maintain adequate oral 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)
- AhmadS, KuragantiG, SteenkampD. Hypercalcemic crisis: A clinical review . Am J Med. 2015;128(3):239-245.
- BenjaminIJ, GriggsRC, WingEJ, et al. and reoli and Carpenter's Cecil Essentials of Medicine. 9th ed.Philadelphia, PA: Saunders; 2015.
- GoldmanL, SchaferAI, eds. Goldman-Cecil Medicine. 25th ed.Philadelphia, PA: Elsevier; 2015.
- JamalSA, MillerPD. Secondary and tertiary hyperparathyroidism . J Clin Densitom. 2013;16(1):64-68.
- KhanAA. Medical management of primary hyperparathyroidism . J Clin Densitom. 2013;16(1):60-63.
- MarcocciC, CetaniF. Primary hyperparathyroidism . N Engl J Med. 2011;365(25):2389-2397.
See Also (Topic, Algorithm, Electronic Media Element)
Hypoparathyroidism