Hyperparathyroidism

Hyperparathyroidism (HPT) is characterized by abnormally high parathyroid hormone (PTH) levels in the blood due to parathyroid gland overactivity. HPT is further classified based on the underlying cause: primary HPT (pHPT), secondary HPT (sHPT), or tertiary HPT (tHPT). pHPT is characterized by elevated PTH and calcium levels and is usually caused by parathyroid adenomas or hyperplasia, or, in rare cases, parathyroid carcinomas. Although pHPT is often asymptomatic, symptoms such as bone pain, gastric ulcers, and kidney stones may be present in severe or untreated cases. sHPT is characterized by high PTH and low calcium levels and may be caused by chronic kidney disease (CKD), vitamin D deficiency, insufficient calcium intake, or malabsorption. sHPT is also called reactive HPT, as the increase in PTH production is a physiological response to hypocalcemia rather than an abnormality of the parathyroid glands. If sHPT and elevated serum PTH levels persist, tHPT may develop, resulting in a shift from low to high serum calcium levels. Diagnostics and classification involve evaluating calcium, PTH, and phosphate levels, and, in the case of sHPT, identifying the underlying cause (e.g., CKD). Surgery is the primary treatment option for most patients with pHPT or tHPT. Patients who do not undergo surgery can be managed with either calcimimetics or, if osteoporosis is present, bisphosphonates. In sHPT, management focuses on treating the underlying cause.

All forms of HPT are characterized by elevated PTH levels (or inappropriately normal levels ). See also “Calcium homeostasis.”

pHPT develops as a result of hyperplasia of the parathyroid glands. sHPT develops as a result of decreased levels of calcium in the blood (reactive HPT).

Hypercalcemic crises can occur in primary and tertiary HPT.

Epidemiology

• Lifetime incidence: 1/80
• Sex: ♀ > ♂ (3:1)
• Age: Most cases occur after age 50 years. ^[4]
• Prevalence: ∼ 0.1–0.5% ^[5]

Etiology ^[1]

• Parathyroid gland adenoma (∼ 85%): benign tumor of the parathyroid glands ^[2]
• Hyperplasia or multiple adenomas (∼ 15%) ^[1]
• In rare cases:
  • Carcinomas (∼ 0.5%) ^[2][3]
  • Idiopathic
• Multiple endocrine neoplasia type 1 or 2
• Medication: lithium or thiazide diuretics ^[2][6]

Pathophysiology

• Overproduction of PTH by parathyroid chief cells
• Effect of PTH on bone → ↑ bone resorption → ↑ release of calcium phosphate → ↑ calcium levels
  • Induces RANKL expression in osteoblasts → binding of RANKL to RANK on osteoclasts → activation of osteoclasts
  • Induces IL-1 expression in osteoblasts → activation of osteoclasts
• Effect of PTH on the kidneys → ↑ phosphate excretion (phosphaturia)

Clinical features

Patients with pHPT are usually asymptomatic. Symptomatic patients often have clinical features of hypercalcemia.

• General: weakness
• Cardiovascular system
  • Left ventricular hypertrophy
  • Arterial hypertension
  • Shortened QT interval
• Urinary tract
  • Nephrolithiasis, nephrocalcinosis
  • Abdominal/flank pain
  • Polyuria, polydipsia
• Musculoskeletal system
  • Bone, muscle, and joint pain
  • Pseudogout
• Digestive tract
  • Lack of appetite → weight loss
  • Nausea, constipation
  • Gastric or duodenal ulcers
  • Acute pancreatitis
• Psychological symptoms: : depression, fatigue, anxiety, sleep disorders

The majority of patients are asymptomatic.

"Stones, bones, abdominal groans, thrones, and psychiatric overtones!"

Diagnostics ^[2][7]

Approach

• Consider pHPT in patients with hypercalcemia.
• Obtain laboratory studies to confirm hypercalcemia and assess for elevated intact PTH levels.
• Evaluate for features of hypercalcemia
• Determine surgical eligibility using detailed patient history and laboratory and imaging findings.
• Consider genetic counseling referral if there is suspicion for an inherited condition based on the patient's family history. ^[7]

Laboratory studies ^[2][7]

• Diagnostic confirmation: both results must be present on two separate occasions, ≥ 2 weeks apart ^[2]
  • ↑ Serum calcium
  • ↑ Serum intact PTH (or inappropriately normal)
• Additional studies: for patients with confirmed pHPT
  • Serum creatinine and estimated GFR: to evaluate for renal dysfunction
  • 25-hydroxyvitamin D: to assess for deficiency ^[2]
  • Phosphate: may be low ^[2]
  • ALP: high as a result of bone turnover
  • 24-hour urinary calcium and creatinine ^[3][7]
    • ↑ Ca/Cr clearance ratio (> 0.02): suggests pHPT and is a risk factor for nephrocalcinosis and nephrolithiasis
    • ↓ Ca/Cr clearance ratio (< 0.01): suggests familial hypocalciuric hypercalcemia, which can mimic pHPT

A normal PTH level does not exclude pHPT. PTH should be low in patients with hypercalcemia, therefore, a normal PTH level would suggest pHPT.

Routine imaging studies ^[2][7]

Obtain in all patients with confirmed pHPT to evaluate for renal and skeletal manifestations.

• Skeletal evaluation
  • Assess for osteoporosis, osteopenia, and fragility fractures.
  • Preferred modality: dual-energy x-ray absorptiometry (DXA) including vertebral fracture assessment (VFA) ^[8]
  • Alternative: vertebral x-ray (to assess for spinal fragility fractures)
• Renal imaging
  • Assess for nephrolithiasis and/or nephrocalcinosis.
  • Options include abdominal CT without contrast, renal ultrasound, and abdominal x-ray.

Additional imaging studies

• Neck imaging ^[7]
  • For surgical planning to determine the location of the abnormal glands and evaluate for concomitant thyroid disease
  • Options include ultrasound neck and nuclear imaging, i.e., Tc-99m sestamibi scan.
• X-ray is not routinely indicated; potential findings include:
  • Decreased BMD
  • Cortical thinning: especially prominent in the phalanges of the hand; manifests as acroosteolysis (a subperiosteal pattern of bone resorption) ^[9]
  • Salt and pepper skull: granular decalcification manifesting as diffusely distributed lytic foci on imaging of the calvarium ^[9]
  • Features of osteitis fibrosa cystica

Parathyroid imaging is used for surgical planning but is not indicated for initial diagnosis. ^[2][7]

Differential diagnoses

• Other causes of PTH-mediated hypercalcemia: i.e., tHPT, familial hypocalciuric hypercalcemia
• Causes of non-PTH-mediated hypercalcemia: e.g., hypercalcemia of malignancy, granulomatous disorders

Management ^[2][7]

Approach

Management should be guided by a specialist.

• Provide treatment for hypercalcemia.
• Refer all symptomatic patients and eligible asymptomatic patients for surgical evaluation.
• For patients who do not undergo surgery:
  • Start pharmacotherapy.
  • Monitor for complications.

Parathyroidectomy is curative in ∼ 98% of patients and therefore is indicated for most patients with pHPT. ^[2]

Start immediate hypercalcemia treatment (e.g., IV fluids, calcitonin, and bisphosphonates) for patients with a serum calcium level > 14 mg/dL (> 3.5 mmol/L).

Surgical therapy ^[2][7]

• Indications: symptomatic patients, and asymptomatic patients who fulfill any of the following criteria
  • Age < 50 years
  • Hypercalcemia: serum calcium level > 1 mg/dL above the ULN
  • Renal involvement
    • Estimated GFR < 60 mL/minute
    • Hypercalciuria
    • Nephrolithiasis or nephrocalcinosis on imaging
  • Skeletal involvement
    • Reduced BMD (T-score ≤ -2.5 at any site)
    • Vertebral fracture
• Procedures ^[7]
  • Solitary adenoma: minimally invasive parathyroidectomy of the affected gland
  • Hyperplasia: total parathyroidectomy (removal of all four glands) with reimplantation of half a gland in easily accessible muscle
  • Carcinoma: tumor resection (with removal of the ipsilateral thyroid lobe and enlarged lymph nodes)

Pharmacotherapy ^[2]

• Calcimimetics (e.g., cinacalcet)
  • Mechanism of action: increases the sensitivity of calcium-sensing receptors in parathyroid glands to circulating Ca²⁺ → inhibition of PTH release
  • Indications
    • Parathyroid carcinoma with hypercalcemia
    • pHPT and severe hypercalcemia in patients who do not undergo parathyroidectomy ^[2]
    • sHPT in patients with CKD who are on dialysis
  • Adverse effects include hypocalcemia, nausea, vomiting, and diarrhea.
  • Contraindications: hypocalcemia
• Bisphosphonates (e.g., alendronate): for patients with osteopenia or osteoporosis
• Denosumab: alternative to bisphosphonates
• Vitamin D supplementation
  • For patients with vitamin D deficiency or insufficiency
  • Goal 25-hydroxyvitamin D level > 30 ng/mL

Low vitamin D levels further stimulate the parathyroid glands, which increases PTH secretion, leading to an increased risk of complications from pHPT. ^[7]

Monitoring ^[2]

• Indication: patients who do not undergo parathyroid surgery
• Imaging studies (every 1–2 years)
  • DXA with VFA to assess BMD
  • Renal imaging (e.g., abdominal CT without contrast, renal ultrasound) to assess for nephrolithiasis and/or nephrocalcinosis
• Laboratory studies (yearly)
  • Serum calcium, 25-hydroxyvitamin D, creatinine, estimated GFR
  • 24-hour urine calcium

Complications

• Osteitis fibrosa cystica (OFC): a rare skeletal disorder seen in advanced hyperparathyroidism characterized by replacement of calcified bone with fibrous tissue
  • Most commonly seen in primary hyperparathyroidism but can also occur in secondary hyperparathyroidism
  • ↑ PTH → ↑ RANK ligand expression → activation of osteoclasts → bone resorption, cortical bone destruction, and fibrous tissue deposition
  • Features include bone pain, subperiosteal thinning, and bone cysts; multiple bone cysts in the skull may result in a salt and pepper skull (pepper pot) appearance on x-ray.
  • In advanced OFC, large, cystic, vascular cavities with a tumor-like appearance on x-ray and a brown color due to hemosiderin deposition (brown tumors) can form in long bones.
• Hungry bone syndrome ^[10]
  • Definition: A complication of parathyroidectomy characterized by severe hypocalcemia despite normal or elevated PTH levels
  • Diagnosis
    • Severe or symptomatic hypocalcemia and/or hypocalcemia that persists for > 4 days postoperatively ^[10]
    • Can also manifest with hypophosphatemia, hypomagnesemia, and hyperkalemia
  • Management
    • Frequent postoperative monitoring and serum calcium, phosphate, and magnesium supplementation
    • For more information, see “Treatment of hypocalcemia.”
  • Prevention: Consider preoperative calcium supplementation, calcitriol, and low-dose IV pamidronate 1–2 days before surgery for high-risk patients. ^[10]

Etiology

• Secondary hyperparathyroidism
  • Chronic kidney disease (most frequent cause)
  • Malnutrition
  • Vitamin D deficiency (e.g., reduced exposure to sunlight, nutritional deficiency, liver cirrhosis)
  • Cholestasis
• Tertiary hyperparathyroidism: caused by persistent sHPT

Pathophysiology

• Secondary hyperparathyroidism: ↓ calcium and/or ↑ phosphate blood levels → reactive hyperplasia of the parathyroid glands → ↑ PTH secretion ^[11]
  • Chronic kidney disease → impaired renal phosphate excretion → ↑ phosphate blood levels→ ↑ PTH secretion
  • In addition, CKD → ↓ biosynthesis of active vitamin D → ↓ intestinal calcium resorption and ↓ renal calcium reabsorption → hypocalcemia → ↑ PTH secretion
• Tertiary hyperparathyroidism: chronic renal disease → refractory and autonomous secretion of PTH → hypercalcemia
• Renal disease: secondary or tertiary hyperparathyroidism → renal osteodystrophy → bone lesions

Clinical features

• Symptoms related to the underlying cause of sHPT or tHPT (commonly CKD)
• Clinical features of hypocalcemia or features of hypercalcemia
• Bone pain and increased risk of fractures
• Osteitis fibrosa cystica
• Rugger-jersey spine sign

Diagnostics ^[3][12][13]

Approach

• Consider sHPT in patients with hypocalcemia and an associated underlying condition (e.g., CKD, vitamin D deficiency).
• Consider tHPT in patients with long-standing sHPT who develop hypercalcemia.
• Imaging studies are not routinely indicated.
• See also “Diagnostics" in “CKD-MBD.”

Laboratory studies ^[12]

• Diagnostic confirmation
  • ↑ PTH and ↓ calcium: sHPT
  • ↑ PTH (or inappropriately normal) and ↑ calcium: tHPT
• Additional studies: to support the diagnosis and assess for modifiable factors
  • Phosphate
    • ↓ Phosphate: sHPT not caused by CKD
    • Normal or ↑ phosphate: sHPT caused by CKD
    • ↑ Phosphate: tHPT
  • ↑ ALP: sign of bone turnover
  • ↑ Creatinine and ↓ vitamin D: signs of CKD-MBD

Differential diagnoses

• Other causes of hypercalcemia
• Other causes of hypocalcemia
• Other causes of hyperphosphatemia

Treatment ^[11][12]

• Treatment of the underlying condition
  • See “Management of chronic kidney disease” and “CKD-MBD.”
  • In patients with vitamin D deficiency: Supplement with vitamin D analogues (e.g., ergocalciferol).
• Treatment of complications, e.g.:
  • Hyperphosphatemia
    • Dietary phosphorus restriction (e.g., no soft cheese or nuts)
    • Consider phosphate binders (e.g., if dietary restriction alone is unsuccessful).
  • Hypercalcemia: may include IV fluids, diuretics, calcitonin, and bisphosphonates
• Calcimimetics ^[12]
  • For treatment of sHPT in patients with CKD who are on dialysis
  • Consider for patients with tHPT (off-label).
• Parathyroidectomy ^[1][14]
  • Consider for sHPT refractory to medical therapy.
  • Mainstay of treatment for tHPT