Disorders of the Parathyroid Gland and Calcium Homeostasis¶
Chapter 422 | Part 12: Endocrinology
KEY CLINICAL POINTS¶
- Parathyroid hormone (PTH) regulates calcium homeostasis by increasing bone resorption, renal calcium reabsorption, and intestinal calcium absorption.
- Hyperparathyroidism is the most common cause of hypercalcemia, characterized by excessive PTH secretion leading to bone resorption, renal calcium wasting, and secondary hypercalcemia.
- Vitamin D deficiency is a major cause of hypocalcemia, with treatment involving calcium supplementation, vitamin D analogs, and addressing underlying causes like malabsorption or renal failure.
- Pseudohypoparathyroidism (PHP) involves resistance to PTH action, often with Albright's hereditary osteodystrophy (AHO) features, and is caused by mutations in GNAS gene.
- Management of hypercalcemia includes hydration, bisphosphonates, calcitonin, and addressing underlying causes like malignancy or vitamin D toxicity.
1. DEFINITION & OVERVIEW¶
Parathyroid hormone (PTH) is the primary regulator of calcium homeostasis. Primary hyperparathyroidism (PHPT) is characterized by excessive PTH secretion due to parathyroid adenoma, hyperplasia, or carcinoma, leading to hypercalcemia. Secondary hyperparathyroidism occurs due to chronic hypocalcemia or low phosphate, while tertiary hyperparathyroidism develops in chronic renal failure patients with autonomous PTH secretion. Hypoparathyroidism results from PTH deficiency, causing hypocalcemia and hyperphosphatemia.
Table 422-1: Classification of Causes of Hypercalcemia¶
| I. Parathyroid-Relat ed | II. Malignancy-Relat ed | III. Vitamin D–Related | IV. Associated with High Bone Turnover | V. Associated with Renal Failure |
|---|---|---|---|---|
| Primary hyperparathyroidism | Tumors with osteolytic metastases | Vitamin D intoxication | Hyperthyroidism | Tertiary hyperparathyroidism |
| Laleboparathyroidis m | PTHrP-producing tumors | Vitamin D deficiency | Thiazides | Aluminum intoxication |
| Lithium-induced | Lymphomas | Malabsorption | Immobilization | Milk-alkali syndrome |
| Familial hypocalciuric hypercalcemia | Sarcoidosis | Renal tubular acidosis | Vitamin A toxicity | Chronic kidney disease |
1.1 PTH Physiology¶
PTH acts on bone, kidney, and intestine to increase calcium release, reabsorption, and absorption. It upregulates 1 α -hydroxylase to activate vitamin D, enhancing intestinal calcium uptake. PTH also stimulates phosphate excretion via renal tubules.
1.2 Calcium Regulation¶
Calcium homeostasis is maintained by PTH, vitamin D, and calcitonin. PTH increases bone resorption, renal calcium reabsorption, and intestinal calcium absorption. Vitamin D enhances intestinal calcium uptake, while calcitonin inhibits bone resorption.
2. EPIDEMIOLOGY¶
PHPT is common in older adults, with prevalence increasing with age. Hypercalcemia is more prevalent in postmenopausal women and individuals with chronic kidney disease. Hypoparathyroidism is rare, with an estimated incidence of 1 in 100,000. Pseudohypoparathyroidism (PHP) has an incidence of 1 in 10,000, with PHP1A being the most common subtype.
Table 422-2: Guidelines for Hypercalcemia Management¶
| Severity | Treatment | Monitoring |
|---|---|---|
| Mild (<3.7 mmol/L) | Hydration, calcium restriction | Serum calcium, PTH, phosphate |
| Moderate (3.7–4.5 mmol/L) | Hydration, bisphosphonates | Electrolytes, renal function |
| Severe (>4.5 mmol/L) | IV fluids, calcitonin, dialysis | Continuous monitoring, ECG |
2.1 Hypercalcemia¶
Hypercalcemia is more common in older adults, especially those with chronic kidney disease, malignancy, or vitamin D toxicity. Malignancy-related hypercalcemia is often due to osteolytic tumors or paraneoplastic syndromes.
2.2 Hypocalcemia¶
Hypocalcemia is more prevalent in individuals with chronic kidney disease, vitamin D deficiency, or parathyroid dysfunction. Severe hypocalcemia can occur in acute pancreatitis or after parathyroidectomy.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Hyperparathyroidism is caused by parathyroid adenoma (80%), hyperplasia (10%), or carcinoma (1%). PTH resistance due to GNAS mutations causes pseudohypoparathyroidism (PHP). Vitamin D deficiency leads to hypocalcemia via reduced intestinal absorption. Secondary hyperparathyroidism occurs due to chronic hypocalcemia or renal failure, while tertiary hyperparathyroidism is autonomous in end-stage renal disease.
Table 422-3: PTH and Vitamin D Deficiency¶
| Condition | Cause | Clinical Features |
|---|---|---|
| Vitamin D Deficiency | Dietary insufficiency, sun exposure | Hypocalcemia, hypophosphatemia, rickets |
| Vitamin D Resistance | Genetic mutations (e.g., CYP27B1) | Hypocalcemia, hyperphosphatemia, rickets |
| Secondary Hyperparathyroidism | Chronic hypocalcemia/renal failure | Hypercalcemia, osteitis fibrosa |
3.1 PTH Regulation¶
PTH secretion is regulated by serum calcium, phosphate, and vitamin D. Low calcium or high phosphate stimulates PTH release, while vitamin D inhibits it. PTH also upregulates 1 α -hydroxylase to activate vitamin D.
3.2 Vitamin D Metabolism¶
Vitamin D is converted to 25(OH)D in the liver and then to 1,25(OH)2D in the kidney. 1,25(OH)2D enhances intestinal calcium absorption and renal calcium reabsorption. Defects in these steps cause rickets or osteomalacia.
4. CLINICAL FEATURES¶
Hypercalcemia presents with fatigue, polyuria, constipation, and renal stones. Severe cases may cause confusion, coma, or cardiac arrhythmias. Hypocalcemia manifests as tetany, muscle spasms, and seizures. Pseudohypoparathyroidism (PHP) includes AHO features like short stature, brachydactyly, and intellectual disability.
Table 422-4: Therapies for Severe Hypercalcemia¶
| Treatment | Onset of Action | Duration of Action | Advantages | Disadvantages |
|---|---|---|---|---|
| IV hydration with normal saline | Hours | During infusion | Rehydration invariably needed | Volume overload |
| Pamidronate | 1–2 days | 10–14 days | High potency | Fever, hypophosphatemia |
| Zoledronate | 1–2 days | >3 weeks | Sustained effect | Same as pamidronate |
| Denosumab | 1–2 days | >3 weeks | Strongest antiresorptive | Severe hypocalcemia |
4.1 Hypercalcemia Symptoms¶
Symptoms include polyuria, polydipsia, constipation, fatigue, and renal stones. Severe cases may present with confusion, coma, or cardiac arrhythmias. PTH levels are elevated despite hypercalcemia.
5. DIFFERENTIAL DIAGNOSIS¶
Hypercalcemia differentials include malignancy (e.g., multiple myeloma), vitamin D toxicity, sarcoidosis, and hyperthyroidism. Hypocalcemia differentials include vitamin D deficiency, hypoparathyroidism, renal failure, and hypomagnesemia. Pseudohypoparathyroidism (PHP) must be distinguished from true hypoparathyroidism using PTH levels and response to exogenous PTH.
Table 422-5: Functional Classification of Hypocalcemia¶
| Type | Cause | Clinical Features |
|---|---|---|
| PTH-Related | Hypoparathyroidism, PHP | Hypocalcemia, hyperphosphatemia, AHO |
| Vitamin D–Related | Vitamin D deficiency, resistance | Hypocalcemia, rickets, osteomalacia |
| Others | Chronic kidney disease, drug-induced | Hypocalcemia, secondary hyperparathyroidism |
5.1 Hypercalcemia Differentials¶
Malignancy-related hypercalcemia is due to osteolytic tumors or paraneoplastic syndromes. Vitamin D toxicity causes hypercalcemia via increased intestinal absorption. Sarcoidosis and tuberculosis may lead to hypercalcemia due to increased 1 α -hydroxylase activity.
5.2 Hypocalcemia Differentials¶
Hypocalcemia can result from vitamin D deficiency, hypoparathyroidism, renal failure, or hypomagnesemia. Pseudohypoparathyroidism (PHP) is diagnosed by PTH resistance and AHO features.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnosis of hypercalcemia involves measuring serum calcium, PTH, and vitamin D levels. PTH levels are elevated in PHPT but suppressed in malignancy-related hypercalcemia. Hypocalcemia is diagnosed with low serum calcium and elevated PTH in hypoparathyroidism. Imaging studies like X-ray or CT may reveal bone abnormalities or tumors.
Table 422-6: Classification of Pseudohypoparathyroidism (PHP)¶
| Type | Hypercalcemia | cAMP Response to PTH | Serum PTH | AHO | Other Hormone Resistance |
|---|---|---|---|---|---|
| PHP1A | Yes | fl | › | Yes | Yes |
| PHP1B | Yes | fl | › | No | Yes |
| PPHP | No | Normal | Normal | Yes | No |
| PHP2 | Yes | Normal | › | No | No |
6.1 Laboratory Tests¶
Serum calcium, phosphate, PTH, vitamin D, and alkaline phosphatase levels are essential. 24-hour urine calcium and phosphate excretion help differentiate hyperparathyroidism from other causes.
6.2 Imaging¶
X-ray or CT can detect bone resorption, renal stones, or tumors. Bone densitometry assesses osteoporosis in secondary hyperparathyroidism.
7. MANAGEMENT & TREATMENT¶
Treatment of hypercalcemia includes hydration, bisphosphonates, calcitonin, and addressing underlying causes. Hypocalcemia is managed with calcium and vitamin D supplementation. Pseudohypoparathyroidism (PHP) requires PTH analogs or calcitriol. Surgical removal of parathyroid adenomas is indicated for PHPT with severe symptoms.
Table 422-7: PTH and Vitamin D Deficiency¶
| Condition | Cause | Treatment |
|---|---|---|
| Vitamin D Deficiency | Dietary insufficiency, sun exposure | Calcium and vitamin D supplementation |
| Vitamin D Resistance | Genetic mutations (e.g., CYP27B1) | Calcitriol or PTH analogs |
| Secondary Hyperparathyroidism | Chronic hypocalcemia/renal failure | Calcium, vitamin D, and phosphate binders |
7.1 Hypercalcemia Management¶
Mild hypercalcemia is treated with hydration and calcium restriction. Severe cases require bisphosphonates, calcitonin, or dialysis. Malignancy-related hypercalcemia may respond to glucocorticoids or chemotherapy.
7.2 Hypocalcemia Management¶
Hypocalcemia is treated with oral or intravenous calcium and vitamin D. Severe cases may require intravenous calcitriol. Pseudohypoparathyroidism (PHP) is managed with PTH analogs or calcitriol.
8. PROGNOSIS & COMPLICATIONS¶
PHPT can lead to osteoporosis, renal stones, and cardiovascular complications. Hypoparathyroidism may cause tetany, seizures, and cardiac arrhythmias. Pseudohypoparathyroidism (PHP) is associated with AHO features and increased risk of osteomalacia. Severe hypercalcemia can cause renal failure, cardiac arrhythmias, or coma.
Table 422-8: Complications of Hypercalcemia¶
| Complication | Cause | Management |
|---|---|---|
| Renal Stones | Hypercalcemia | Hydration, calcium restriction |
| Cardiac Arrhythmias | Hypercalcemia | Calcium restriction, bisphosphonates |
| Coma | Severe hypercalcemia | Dialysis, calcitonin |
8.1 Complications of PHPT¶
Long-term complications include osteoporosis, renal stones, and cardiovascular disease. Tertiary hyperparathyroidism in CKD patients may lead to autonomous PTH secretion and renal failure.
8.2 Complications of Hypoparathyroidism¶
Hypocalcemia can cause tetany, seizures, and cardiac arrhythmias. Severe hypocalcemia may lead to laryngospasm or cardiac arrest.
9. SPECIAL CONSIDERATIONS¶
Pregnancy, pediatric, and elderly patients require tailored management. Hypoparathyroidism in pregnancy may require higher vitamin D doses. Children with PHP may need PTH analogs. Elderly patients with CKD require careful calcium and phosphate management to prevent hypercalcemia or hypocalcemia.
Table 422-9: Management in Special Populations¶
| Population | Considerations |
|---|---|
| Pregnancy | Higher vitamin D and calcium intake, calcitriol/PTH analogs |
| Pediatrics | AHO features, PTH analogs, calcium/vitamin D supplementation |
| Elderly | Careful calcium/phosphate management, CKD monitoring |
9.1 Pregnancy¶
Pregnancy increases calcium demands, requiring higher vitamin D and calcium intake. Hypoparathyroidism in pregnancy may require calcitriol or PTH analogs to prevent fetal complications.
9.2 Pediatrics¶
Children with PHP may present with AHO features and require PTH analogs. Hypoparathyroidism in children is managed with calcium and vitamin D supplementation.
10. KEY POINTS & CLINICAL PEARLS¶
Key points include: PTH regulates calcium homeostasis, PHPT is the most common cause of hypercalcemia, and hypoparathyroidism is rare but requires calcium and vitamin D supplementation. Pseudohypoparathyroidism (PHP) is diagnosed by PTH resistance and AHO features. Treatment of hypercalcemia includes hydration, bisphosphonates, and addressing underlying causes.
10.1 Clinical Pearls¶
- PTH levels are elevated in PHPT but suppressed in malignancy-related hypercalcemia. 2. Vitamin D deficiency is a common cause of hypocalcemia. 3. Pseudohypoparathyroidism (PHP) requires PTH analogs or calcitriol. 4. Severe hypercalcemia may require dialysis or calcitonin.