Hypercalcemia and related disorders Flashcards
What is hypercalcemia defined as?
Plasma or serum [Ca(^{2+})] > 11 mg/dL or 1 mg/dL above the normal range
Which organs can be affected by hypercalcemia?
- Kidney
- Heart
- Brain
- Peripheral nerves
- Gut
What condition is considered a pseudohypercalcemia?
High adjusted or corrected total serum [Ca(^{2+})] in an individual with elevated serum albumin concentration
When is true hypercalcemia considered?
When serum ionized [Ca(^{2+})] is elevated above normal
What are the four major groups of causes of hypercalcemia?
- Increased Ca(^{2+}) mobilization from the bone
- Increased absorption of Ca(^{2+}) from the gastrointestinal tract
- Decreased urinary excretion of Ca(^{2+})
- Medications
What is the most common cause of hypercalcemia?
Primary hyperparathyroidism (PHPT)
What is the prevalence of primary hyperparathyroidism in terms of gender?
More common in elderly women than men
What percentage of primary hyperparathyroidism cases are due to a single adenoma?
80–85%
What are the clinical presentations of primary hyperparathyroidism?
- Mild hypercalcemia (60–80%) with minimal or no symptoms
- Moderate hypercalcemia (20–25%) with nephrolithiasis
- Severe hypercalcemia (5–19%) with kidney disease, bone disease, or GI tract problems
What laboratory findings are common in primary hyperparathyroidism?
- Elevated serum PTH
- Hypercalcemia
- Hypophosphatemia
- Elevated alkaline phosphatase
- Hypercalciuria
- Elevated urinary cyclic adenosine monophosphate (cAMP)
What is the standard therapy for severe and symptomatic primary hyperparathyroidism?
Surgery
What is the specificity of the sestamibi scan for preoperative localization of parathyroid glands?
90%
What are the indications for surgery in asymptomatic primary hyperparathyroidism?
- Serum Ca(^{2+}) level > 1 mg/dL above normal
- Reduced bone mineral density (T-score < –2.5)
- Kidney issues (eGFR <60 mL/min or 24-h urine calcium >400 mg)
- Age <50 years
What specific bone condition is associated with primary hyperparathyroidism?
Osteitis fibrosa cystica
Fill in the blank: Hypercalcemia due to increased absorption of Ca(^{2+}) from the GI tract can be caused by _______.
Granulomatous diseases, Vitamin D intoxication, Milk-alkali syndrome
True or False: Hypercalcemia can be caused by medications other than thiazide diuretics.
True
What are some specific causes of hypercalcemia related to medications?
- Lithium
- Vitamin D
- Vitamin A
- Growth hormone
- Estrogens/antiestrogens
- Theophylline
- Immune checkpoint inhibitors
What role does primary hyperparathyroidism play in the general population?
It is the most underlying and leading cause of hypercalcemia
What laboratory tests are used to diagnose primary hyperparathyroidism?
Serum parathyroid hormone (PTH) and electrolytes
What is a common complication of severe hypercalcemia in primary hyperparathyroidism?
Nephrolithiasis (kidney stones)
Fill in the blank: The binding of Ca(^{2+}) to globulins increases due to elevated _______.
Globulin levels
What is the mechanism of hypercalcemia associated with familial hypercalcemic hypocalciuria?
Inactivating mutations of Ca(^{2+}) sensing receptor (CaSR)
What are the guidelines for monitoring patients with asymptomatic PHPT who do not undergo parathyroid surgery?
- Serum [Ca²⁺] annually. 2. Dual-energy x-ray absorptiometry every 1–2 yr (3 sites). 3. eGFR and creatinine annually.
If kidney stones are suspected, a 24-h biochemical stone profile and kidney imaging by x-ray, ultrasound, or CT is performed.
What vitamin D level should be maintained in asymptomatic patients with PHPT who refuse surgery?
Vitamin D (25(OH)D₃) levels should be maintained >30 ng/mL.
Some evidence indicates that this level may reduce PTH in these patients.
What are the four classes of medications available for patients with PHPT who are not surgical candidates?
- Ca²⁺-sensing receptor (CaSR) agonist—cinacalcet.
- Bisphosphonates.
- Combination therapy with cinacalcet and bisphosphonate or denosumab.
- Estrogens and progestins.
- Selective estrogen modulator—raloxifene.
What is Multiple Endocrine Neoplasia (MEN) Type 1 characterized by?
Tumors of the parathyroid, anterior pituitary, and pancreas.
Parathyroid tumors are more prevalent and caused by mutations in the tumor suppressor gene encoding menin.
What is the genetic cause of MEN Type 2a?
Mutations in the RET proto-oncogene.
What is Jansen’s Disease also known as?
Pseudohypoparathyroidism.
What are the characteristics of Familial Hypocalciuric Hypercalcemia (FHH)?
- Mild hypercalcemia.
- Hypermagnesemia.
- Hypocalciuria (calcium/creatinine clearance ratio < 0.01).
- Hypophosphatemia.
- Normal to slightly elevated PTH levels.
What is the treatment approach for asymptomatic patients with Familial Hypocalciuric Hypercalcemia?
No treatment is necessary unless there are complications like relapsing pancreatitis.
What is Neonatal Severe Hyperparathyroidism?
A homozygous form of FHH characterized by life-threatening hypercalcemia and massive hyperplasia of the parathyroid glands.
What causes Lithium-Induced Hypercalcemia?
Decreased sensitivity of the parathyroid gland to Ca²⁺ and stimulation of PTH secretion by Lithium.
What are the management options for Lithium-Induced Hypercalcemia?
- Discontinuation of Lithium.
- Use of calcimimetics.
- Parathyroidectomy.
What is secondary hyperparathyroidism?
Appropriate increase in PTH secretion in response to hypocalcemia, usually occurring in chronic kidney disease (CKD) G4–G5.
What differentiates tertiary hyperparathyroidism from secondary hyperparathyroidism?
Tertiary hyperparathyroidism persists despite adequate treatment and occurs in CKD G5 patients and those on dialysis.
What is the main characteristic of Milk (Calcium)-Alkali Syndrome?
Triad of hypercalcemia, metabolic alkalosis, and some degree of kidney insufficiency.
What factors contribute to the generation and maintenance of hypercalcemia in Milk-Alkali Syndrome?
- Sufficient intake of Ca²⁺ over several days.
- Decreased glomerular filtration rate (GFR).
- Hypercalcemia-induced nephrogenic diabetes insipidus (DI).
- Increased kidney reabsorption of Ca²⁺.
What is the second leading cause of hypercalcemia?
Malignancy
Occurs in 20–30% of patients with hypercalcemia.
What are the most common malignancies associated with hypercalcemia?
- Lung (35%)
- Breast (25%)
- Hematologic (14%)
- Other organs (3–7%)
These percentages indicate the frequency of each type of malignancy associated with hypercalcemia.
What are the four types of hypercalcemia associated with malignancy?
- Humoral hypercalcemia of malignancy
- Local osteolytic hypercalcemia
- 1,25(OH)₂D₃ (calcitriol)-secreting lymphomas
- Ectopic hyperparathyroidism
What is humoral hypercalcemia of malignancy characterized by?
80% occurrence with minimal or absent bone metastases and primarily caused by PTH-related peptide (PTHrP)
Associated tumors include squamous cell cancers, breast cancer, renal cell cancer, and others.
What is the role of PTH-related peptide (PTHrP) in hypercalcemia?
Responsible for hypercalcemia in >80% of tumors, interacts with PTH-PTHrP receptor, increases bone resorption and Ca²⁺ reabsorption in kidneys
PTHrP also causes hypophosphatemia.
Which cytokines are involved in hypercalcemia caused by tumors?
- IL-1
- IL-6
- IL-8
- TNF-α
- Macrophage inflammatory peptide
- PTHrP
These cytokines activate osteoclasts leading to bone resorption.
How do lymphoma cells contribute to hypercalcemia?
By increasing 1α-hydroxylase activity, converting 25-hydroxyvitamin D₃ to 1,25(OH)₂D₃, which increases intestinal Ca²⁺ absorption and bone resorption.
What is ectopic hyperparathyroidism?
A rare condition where tumors ectopically produce PTH, leading to hypercalcemia
Commonly associated with small cell lung cancer and adenocarcinoma.
What are the biochemical profiles used to identify the cause of malignancy-induced hypercalcemia?
- PTHrP: ↑, PTH: ↓/UD, 25(OH)D₃: N, 1,25(OH)₂D₃: N/↓, Phosphate: ↓
- 1,25(OH)₂D₃: ↓, PTH: ↓, Phosphate: ↓
- PTH: ↓, PTH: ↑, Phosphate: ↓
↑ indicates increase, ↓ indicates decrease, N indicates normal, UD indicates undetectable.
What is the clinical manifestation of hypercalcemia in the general system?
Weakness, malaise, tiredness
What are the cardiac manifestations of hypercalcemia?
Short QT interval, arrhythmias, bundle branch blocks, hypertension
What common causes of hypercalcemia should be considered in critically ill patients?
- Malignancy
- Primary hyperparathyroidism
- Prolonged immobilization
- Parenteral nutrition
What is the first step in diagnosing hypercalcemia?
Confirm true hypercalcemia (ionized Ca²⁺ > normal)
What are the acute treatments for hypercalcemia?
- Hydration with normal saline
- Furosemide
- Bone resorption inhibitors (calcitonin, bisphosphonates)
- Glucocorticoids
- Dialysis
Hydration improves GFR and Ca²⁺ excretion.
What chronic treatments are available for hypercalcemia?
- Address underlying cause (e.g., parathyroidectomy, chemotherapy)
- Medications (cinacalcet, bisphosphonates, denosumab)
- Lifestyle changes (low-calcium diet, avoid vitamin D supplements)
True or False: Vitamin D overdose can lead to hypercalcemia.
True
Doses >100,000 units/day of 25-hydroxyvitamin D cause hypercalcemia.
