Disorders of the Parathyroid Gland and Calcium Homeostasis¶

Chapter 422 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 422

Key Clinical Points¶

Primary hyperparathyroidism (PHPT) is the most common cause of asymptomatic hypercalcemia in adults; incidence in the US is ~50 per 100,000 person-years.
Vitamin D deficiency is diagnosed by 25(OH)D levels, not 1,25(OH)D; 1,25(OH)D may remain normal in severe deficiency due to PTH stimulation.
Looser's zones (pseudofractures) are radiolucent lines seen in osteomalacia/Vitamin D deficiency, typically in the scapula, pelvis, and femoral neck.
Familial hypocalciuric hypercalcemia (FHH) is a benign condition caused by loss-of-function mutations in CaSR (FHH1), Gα11 (FHH2), or AP2S1 (FHH3).
PTH(1-34) is the biologically active fragment; C-terminal fragments (e.g., PTH(7-84)) are inactive but may be detected by older assays.
Calcitonin has limited physiological significance in humans but is used for severe hypercalcemia and Paget's disease, and serves as a marker for medullary thyroid carcinoma.
MEN 1 involves hyperparathyroidism, pituitary tumors, and pancreatic tumors (Zollinger-Ellison); MEN 2A involves pheochromocytoma, medullary thyroid carcinoma, and hyperparathyroidism.
The VITAL trial showed that daily small doses of vitamin D (400 IU) prevent fractures/falls, while large intermittent bolus doses increase fracture risk.
Severe hypercalcemia (≥3.7–4.5 mmol/L; 14.8–18.0 mg/dL) is a medical emergency; levels >3.2 mmol/L (12.8 mg/dL) risk calcification in kidneys, skin, vessels, lungs, heart, and stomach.
Parathyroid carcinoma is rare; mutations in CDC73 (HRPT2) are associated with HPT-JT syndrome and parathyroid carcinoma.

DEFINITION & OVERVIEW¶

• Parathyroid Physiology: - Four parathyroid glands produce PTH, the primary regulator of calcium homeostasis. - Mechanism: PTH acts on bone (calcium/phosphate release) and kidneys (increased calcium reabsorption in distal tubules; increased phosphate excretion in proximal tubules). - Indirect Action: PTH stimulates renal production of 1,25(OH)D to increase intestinal calcium absorption. • PTH Structure & Synthesis: - PTH is an 84-amino-acid single-chain peptide (preproPTH → pro-PTH → mature PTH(1-84)). - Active Fragment: PTH(1-34) is the biologically active portion; C-terminal fragments are inactive. • Regulation of Secretion: - Controlled by a negative feedback loop via CaSR (sensing calcium) and vitamin D (nuclear receptor). - Hypocalcemia increases transcriptional activity; 1,25(OH)D suppresses PTH gene transcription. • PTHrP (Parathyroid Hormone-Related Peptide): - Responsible for most cases of humoral hypercalcemia of malignancy (HHM). - Shares the PTH1R receptor with PTH but lacks C-terminal homology. • Calcitonin: - Peptide hormone with hypocalcemic properties; limited physiological significance in humans. - Clinical use: Marker for medullary thyroid carcinoma; treatment for severe hypercalcemia and Paget's disease. • Hypercalcemia Severity Thresholds: - Symptomatic Range: Typically more common at calcium levels >2.9–3.0 mmol/L (11.6–12.0 mg/dL). - Medical Emergency: ≥3.7–4.5 mmol/L (14.8–18.0 mg/dL) can lead to coma and cardiac arrest. - Calcification Risk: >3.2 mmol/L (12.8 mg/dL) leads to calcification in kidneys, skin, vessels, lungs, heart, and stomach.

EPIDEMIOLOGY¶

• Incidence: Approximately 50 per 100,000 person-years in the United States. • Demographics: Primarily a disease of postmenopausal women. • Clinical Context: - Asymptomatic hypercalcemia is usually due to primary hyperparathyroidism (PHPT) in adults. - If asymptomatic hypercalcemia persists for >1 year, malignancy is unlikely.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Solitary Adenomas: - Cause of ~80% of cases; typically benign neoplasms. - Rare instances of parathyroid carcinoma (associated with CDC73/HRPT2 mutations). • Hereditary Syndromes: - MEN 1 (Wermer's): Hyperparathyroidism, pituitary tumors, and pancreatic tumors (Zollinger-Ellison syndrome). - MEN 2A: Pheochromocytoma, medullary thyroid carcinoma, and hyperparathyroidism. - MEN 4: Caused by mutations in the CDKN1B gene (p27 cyclin-dependent kinase inhibitor). • Genetic Defects: - MEN1 Mutation: Located on chromosome 11q13; loss of tumor suppressor MENIN. - CDC73 Mutation: Located on chromosome 1q21-31; encodes parafibromin; associated with HPT-JT syndrome and parathyroid carcinoma. - CaSR Mutations: - FHH (Familial Hypocalciuric Hypercalcemia): Loss-of-function mutations in CaSR (FHH1), Gα11 (FHH2), or AP2S1 (FHH3). - NSHPT (Neonatal Severe Hyperparathyroidism): Homozygous loss-of-function mutations in CaSR; typically lethal if untreated. - MAX Gene: Mutations associated with familial forms of pheochromocytoma/paraganglioma.

CLINICAL FEATURES¶

• Symptoms of Hypercalcemia: - Fatigue, depression, mental confusion, anorexia, nausea, vomiting, constipation. - Renal: Increased urine output, reversible renal tubular defects. - Cardiac: Short QT interval, cardiac arrhythmias. • Radiologic Features (Vitamin D Deficiency): - Pediatric: Widened/expanded growth plate (rickets), 'rachitic rosary' at costochondral junctions. - Adults: Decreased cortical thickness and increased radiolucency of the skeleton. - Looser's Zones (Pseudofractures): Radiolucent lines where large arteries contact bone; typically seen in scapula, pelvis, and femoral neck. • Clinical Features of Hypocalcemia: - PTHrP Mutations: Reduced growth, delayed tooth eruption, premature growth plate closure, reduced adult height. - PTH1R Mutations: Heterozygous inactivating mutations cause delayed tooth eruption.

DIFFERENTIAL DIAGNOSIS¶

• Parathyroid-Related Causes: - Primary hyperparathyroidism, FHH, and lithium therapy. • Malignancy-Related Causes: - Osteolytic Metastases: Breast cancer, multiple myeloma, lymphoma. - Humoral Mediation: Squamous cell carcinoma of the lung, kidney, breast. - 1,25(OH)D-mediated: Lymphoma, ovarian dysgerminoma. • Vitamin D-Related Causes: - Vitamin D intoxication; Granulomatous disease (sarcoidosis); mutations in 24-hydroxylase or sodium-dependent phosphate co-transporters. • High Bone Turnover Causes: - Hyperthyroidism, immobilization, thiazides, Vitamin A intoxication, fat necrosis. • Renal Failure-Associated Causes: - Tertiary hyperparathyroidism, aluminum toxicity, milk-alkali syndrome.

DIAGNOSTIC APPROACH¶

Initial Assessment:
Confirm serum calcium and albumin to rule out false positives.
Evaluation of Hypercalcemia (Decision Pathway):
Step 1: Determine Duration.
If Acute or Unknown duration:
Measure PTH levels.
PTH High → 1° Hyperparathyroidism / Consider MEN syndromes.
PTH Low → Perform Screening (e.g., PTHrP assay).
Screen Negative → Other causes (Granulomatous disease, FHH, Milk-alkali syndrome, Medications [lithium, thiazides], Immobilization, Vit D/E intoxication, Adrenal insufficiency, Hyperthyroidism).
Screen Positive → Consider malignancy; PTHrP assay; Clinical evaluation.
If Chronic duration (months):
Measure PTH levels.
PTH High → Hyperparathyroidism or MEN syndromes (consider FHH).
PTH Low → Other causes (Granulomatous disease, FHH, Milk-alkali syndrome, Medications, Immobilization, Vit D/E intoxication, Adrenal insufficiency, Hyperthyroidism).
Genetic Screening:
Identify CaSR mutations for FHH; CDC73 for HPT-JT syndrome; GNAS for Pseudohypoparathyroidism.

MANAGEMENT & TREATMENT¶

Vitamin D Deficiency Management:
Standard Treatment: 400 IU daily (based on VITAL trial) to prevent fractures/falls.
Advanced Cases (Impaired 1α-hydroxylation):
Calcitriol (1,25(OH)D): 0.25–0.5 μg/d.
Doxercalciferol: 2.5–5 μg/d.
Alfacalcidol: 0.25–1.0 μg/d.
Surgical Management of PHPT:
Indication for Surgery (Table 2):
Serum calcium >1 mg/dL above normal.
BMD by DXA: T score < -2.5 at any site.
Vertebral fracture identified on x-ray or VFA.
Management of Severe Hypercalcemia (Table 4):
IV Hydration (Normal Saline): Rapid action; essential for rehydration.
Pamidronate: 1–2 days onset; 10–14 days to weeks duration; risk of fever, hypophosphatemia, hypocalcemia.
Denosumab: - 1–2 days onset; >3 weeks duration; strongest antiresorptive; risk of severe hypocalcemia.
Dialysis: Used for renal failure or immediate reversal of life-threatening hypercalcemia (action in hours).
Calcitonin Therapy:
Used as an adjunct in severe hypercalcemia or for Paget's disease.

COMPLICATIONS & PROGNOSIS¶

• Hypercalcemic Parathyroid Crisis: - Rapid development of marked dehydration and coma. • Long-term Follow-up: - Monitor for renal insufficiency (especially if phosphate is high). - Adynamic bone disease in children leads to impaired growth and increased fracture risk in adults. • Hypercalcemia Complications: - Fatigue, depression, mental confusion, anorexia, nausea, vomiting, constipation. - Renal: Reversible tubular defects, increased urine output. - Cardiac: Short QT interval, arrhythmias.

SPECIAL CONSIDERATIONS¶

• Pediatric Considerations: - Vitamin D deficiency leads to rickets (widened growth plates) and rachitic rosary. - PTHrP mutations lead to premature growth plate closure and reduced height. • Genetic Syndromes: - FHH: Benign; caused by CaSR, Gα11, or AP2S1 mutations. - Pseudohypoparathyroidism (PHP): - PHP1A: Resistance to PTH due to Gsα deficiency; includes Albright's hereditary osteodystrophy (AHO). - PPHP: Mutation on maternal allele → normal response to PTH but still presents with AHO features. - Jansen’s Metaphysial Chondrodysplasia: Gain-of-function in PTH1R. - Acrodysostosis: Can occur with or without hormonal resistance (mutations in PRKAR1A, PDE4D, or PDE3A).

KEY PEARLS & CLINICAL TRAPS¶

• Diagnostic Clues: - Serum Calcium >3.2 mmol/L (12.8 mg/dL) → risk of organ calcification. - 25(OH)D is the standard for Vitamin D deficiency diagnosis; 1,25(OH)D may be normal in severe deficiency. - Looser's zones are specific to osteomalacia/Vitamin D deficiency. • Exclusion Criteria: - If hypercalcemia is chronic (>1 year), malignancy is unlikely. • Clinical Pearls: - Calcitonin from salmon is 10–100 times more potent than mammalian forms. - Serum calcium and 25(OH)D should be monitored annually in patients not undergoing surgery (Table 3).

Reference Tables¶

Harrison's 22e, p.3275

I. Parathyroid-Related
A. Primary hyperparathyroidism
1. Adenoma(s)
2. Multiple endocrine neoplasia
3. Parathyroid carcinoma
4. Ectopic production of parathyroid hormone (PTH)
5. Exogenous administration of PTH or analogues
B. Lithium therapy
C. Familial hypocalciuric hypercalcemia
II. Malignancy-Related
A. Tumors with osteolytic metastases (breast, multiple myeloma, lymphoma,
etc.)
B. Solid tumor with humoral mediation of hypercalcemia (squamous cell
carcinoma of the lung, kidney, breast, and others)
C. 1,25(OH)D-mediated hypercalcemia of malignancies (lymphoma, ovarian
2
dysgerminoma, etc.)
III. Vitamin D–Related
A. Vitamin D intoxication
B. ↑ 1,25(OH)D; sarcoidosis and other granulomatous diseases, lymphoma
2
C. ↑ 1,25(OH)D; impaired 1,25(OH)D metabolism due to biallelic
2 2
24-hydroxylase mutations or increased 1,25(OH)D synthesis due to
2
inactivating biallelic mutations involving the renal sodium-dependent
phosphate co-transporters
IV. Associated with High Bone Turnover
A. Hyperthyroidism
B. Immobilization
C. Thiazides
D. Vitamin A intoxication
E. Fat necrosis
V. Associated with Renal Failure
A. Tertiary hyperparathyroidism
B. Aluminum intoxication and adynamic bone disease
C. Milk-alkali syndrome

TABLE 422-2 Guidelines for Surgery in Asymptomatic Primary Hyperparathyroidism PARAMETER Serum calcium Renal¶

Harrison's 22e, p.3278

PARAMETER	GUIDELINE
Serum calcium	>1 mg/dL above normal
Skeletal	BMD by DXA: T score <–2.5 at any site Vertebral fracture by x-ray or VFA

TABLE 422-3 Guidelines for Monitoring in Patients with Primary Hyperparathyroidism Who Do Not Undergo Parathyroidectomy…¶