Hyperparathyroidism

Hyperparathyroidism (HPT) is characterized by abnormally high parathyroid hormone (PTH) levels in the blood due to overactivity of the parathyroid glands. It is differentiated into three types based on the underlying cause: primary HPT (pHPT), secondary hyperparathyroidism (sHPT), and tertiary hyperparathyroidism (tHPT). pHPT is characterized by elevated parathyroid hormone and calcium levels and is usually caused by parathyroid adenomas (or, in rare cases, by parathyroid carcinomas). Although often asymptomatic, symptoms such as bone pain, gastric ulcers, and/or kidney stones may emerge in severe cases. sHPT is characterized by high parathyroid hormone and low calcium levels and may be caused by kidney failure, vitamin D deficiency, or malabsorption. sHPT is also called reactive HPT, as the increase in (parathyroid) hormone production is a physiological response to hypocalcemia and not caused by an abnormality of the parathyroid glands. If sHPT and elevated parathyroid hormone blood levels persist, tHPT may develop, resulting in a shift from low to high calcium blood levels. Hyperparathyroidism is diagnosed and classified by evaluating calcium, phosphorus, and parathyroid hormone levels and, in the case of sHPT, evaluating the underlying disease (e.g., creatinine in chronic kidney disease). Surgery is the primary treatment option for symptomatic patients and asymptomatic patients who meet certain criteria. Patients who are not surgical candidates are managed with either calcimimetics or, if osteoporosis is present, bisphosphonates. In sHPT, treatment of the underlying disease is the focus.

All forms of hyperparathyroidism are characterized by elevated PTH levels.

• Primary hyperparathyroidism (pHPT): Hypercalcemia results from abnormally active parathyroid glands.
• Secondary hyperparathyroidism (sHPT): Hypocalcemia results in reactive overproduction of PTH.
• Tertiary hyperparathyroidism (tHPT): Hypercalcemia results from untreated sHPT, with continuously elevated PTH levels.

• Lifetime incidence: 1/80
• Sex: ♀ > ♂ (3:1)
• Age: Most cases occur after age 50 years. ^[1]
• Prevalence: ∼ 0.1–0.5% ^[2]

Epidemiological data refers to the US, unless otherwise specified.

Primary hyperparathyroidism

• Parathyroid gland adenoma (∼ 85%): benign tumor of the parathyroid glands
• Hyperplasia and multiple adenomas (∼ 15%)
• In rare cases, carcinomas ; (∼ 0.5%) or idiopathic
• MEN type 1 or 2
• Lithium ^[3]

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

Physiological secretion of PTH

• See “Calcium homeostasis.”

Pathologically increased secretion of PTH

• Primary hyperparathyroidism: 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)
• Secondary hyperparathyroidism: ↓ calcium and/or ↑ phosphate blood levels → reactive hyperplasia of the parathyroid glands → ↑ PTH secretion ^[4]
  • 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
• See “Familial hypocalciuric hypercalcemia (FHH).”

pHPT develops due to hyperplasia of the parathyroid glands. sHPT develops due to decreased levels of calcium in the blood (reactive HPT).

Primary hyperparathyroidism

• Nonspecific: weakness
• Cardiovascular system
  • Left ventricular hypertrophy
  • Arterial hypertension
  • Shortened QT interval
• Kidney
  • 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!"

Secondary and tertiary hyperparathyroidism

• Symptoms related to the underlying cause of sHPT (commonly renal failure)
• Bone pain and increased risk of fractures

Laboratory studies of hyperparathyroidism

• Measurement of 25-hydroxyvitamin D ^[5]

Hypercalcemic crises may occur in primary and tertiary HPT.

Imaging

• X-ray: decreased bone mineral density, but usually an incidental finding, as x-ray is not a routine diagnostic tool ; ^[5]
  • Cortical thinning: especially prominent in the phalanges of the hand (acroosteolysis)
  • Salt-and-pepper skull: granular decalcification ^[6]
  • Rugger-jersey spine sign: Alternating low and high density in the vertebrae produces a banded pattern, similar to a striped rugby jersey. ^[7]
  • 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 can demonstrate as 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.
• Ultrasound/nuclear imaging (Tc99m-sestamibi scan): only performed prior to surgery to determine the exact location of the abnormal glands

Primary hyperparathyroidism

Surgical

• Indications
  • Symptomatic patients
  • Asymptomatic patients who meet at least one of the following criteria:
    • Age < 50 years
    • Serum calcium level more than 1 mg/dL higher than the normal upper limit
    • Impaired renal function (eGFR < 60 mL/min)
    • Increased calcium excretion (> 400 mg/day) in combination with an increased risk for nephrolithiasis
    • Evidence of nephrolithiasis or nephrocalcinosis via imaging
    • Reduced bone mineral density (T-score < -2.5 at lumbar spine, total hip, femoral neck, or distal third of the radius, or preexisting asymptomatic vertebral fracture)
• Procedures
  • Parathyroidectomy
    • In cases of solitary adenoma
    • Only the respective gland is removed.
    • Complication: hungry bone syndrome
      • Characterized by severe hypocalcemia despite a normal or increased serum concentration of parathyroid hormone
      • In addition to hypocalcemia, patients can also develop hypophosphatemia, hypomagnesemia, and hyperkalemia.
  • Total parathyroidectomy ; ^[8]
    • In cases of hyperplasia
    • All four glands are removed. ^[5]
  • Tumor resection
    • In cases of carcinoma
    • Includes removal of ipsilateral thyroid lobe and enlarged lymph nodes

Pharmacotherapy ^[9]

• Calcimimetics (e.g., cinacalcet)
  • Mechanism of action: modulation of calcium-sensitive receptor (CaSR) in parathyroid glands → ↑ sensitivity of the receptor to circulating Ca²⁺ → inhibition of PTH release
  • Indication
    • Primary hyperparathyroidism after failed parathyroidectomy
    • Hypercalcemia in hemodialysis patients with secondary hyperparathyroidism due to CKD
    • Parathyroid carcinoma with hypercalcemia
  • Adverse effects
    • Gastrointestinal: nausea, vomiting, diarrhea
    • Hypocalcemia
  • Contraindications
    • Hypocalcemia
  • Interactions: strong inhibition of CYP2A6
• Bisphosphonates: In patients with osteoporosis
• Avoid lithium and thiazide diuretics.
• For treatment of acute hypercalcemia, see “Calcium homeostasis.”

Secondary hyperparathyroidism ^[4]

• Treat the underlying condition (e.g., see “Treatment” in “Chronic kidney disease”) and focus on treating hyperphosphatemia
  • Dietary phosphorus restriction (e.g., no soft cheese, nuts)
  • If dietary restriction alone is unsuccessful, add phosphate binders.
• In case of vitamin D deficiency: substitute with ergocalciferol

Phosphate binders

• Agent: sevelamer
• Mechanism of action: binds phosphate in the gut (sevelamer is nonabsorbable) → ↓ phosphate absorption → ↓ serum phosphate → ↓ PTH
• Indication: hyperphosphatemia caused by chronic kidney disease
• Adverse effects
  • Gastrointestinal: nausea, vomiting, diarrhea, constipation, pain
  • Hypophosphatemia
  • Fatigue
  • Joint pain

Tertiary hyperparathyroidism

• Similar to pHPT