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 “.”
Overview of hyperparathyroidism 
|Primary hyperparathyroidism (pHPT)||Secondary hyperparathyroidism (sHPT)||Tertiary hyperparathyroidism (tHPT)|
|Laboratory studies in hyperparathyroidism||Calcium (ionized calcium or corrected calcium)|| || || |
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|Phosphate|| || || |
|Alkaline phosphatase|| |
|Treatment||Surgical therapy|| || || |
|Medical management|| |
Hypercalcemic crises can occur in primary and tertiary HPT.
- Lifetime incidence: 1/80
- Sex: ♀ > ♂ (3:1)
- Age: Most cases occur after age 50 years. 
- Prevalence: ∼ 0.1–0.5% 
- Parathyroid gland adenoma (∼ 85%): benign tumor of the parathyroid glands 
- Hyperplasia or multiple adenomas (∼ 15%) 
- In rare cases:
- Multiple endocrine neoplasia type 1 or 2
- Medication: lithium or thiazide diuretics 
- Overproduction of PTH by parathyroid chief cells
- Effect of PTH on bone → ↑ bone resorption → ↑ release of calcium phosphate → ↑ calcium levels
- Effect of PTH on the kidneys → ↑ phosphate excretion (phosphaturia)
Patients with pHPT are usually asymptomatic. Symptomatic patients often have .
- General: weakness
- Cardiovascular system
- Urinary tract
- Musculoskeletal system
- Digestive tract
- Psychological symptoms: : depression, fatigue, anxiety, sleep disorders
The majority of patients are asymptomatic.
"Stones, bones, abdominal groans, thrones, and psychiatric overtones!"
- Consider pHPT in patients with hypercalcemia.
- Obtain laboratory studies to confirm hypercalcemia and assess for elevated intact PTH levels.
- Evaluate for
- 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. 
Laboratory studies 
- Diagnostic confirmation: both results must be present on two separate occasions, ≥ 2 weeks apart 
Additional studies: for patients with confirmed pHPT
- Serum creatinine and : to evaluate for renal dysfunction
- 25-hydroxyvitamin D: to assess for deficiency 
- Phosphate: may be low 
- ALP: high as a result of bone turnover
- 24-hour urinary calcium and creatinine 
Routine imaging studies 
Obtain in all patients with confirmed pHPT to evaluate for renal and skeletal manifestations.
- Skeletal evaluation
- Renal imaging
Additional imaging studies
- Neck imaging 
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) 
- Salt and pepper skull: granular decalcification manifesting as diffusely distributed lytic foci on imaging of the calvarium 
- Features of
Parathyroid imaging is used for surgical planning but is not indicated for initial diagnosis. 
- Other causes of : i.e., tHPT,
- Causes of : e.g., , granulomatous disorders
Management should be guided by a specialist.
- Provide .
- Refer all symptomatic patients and eligible asymptomatic patients for surgical evaluation.
- For patients who do not undergo surgery:
- Start pharmacotherapy.
- Monitor for complications.
Surgical therapy 
- Indications: symptomatic patients, and asymptomatic patients who fulfill any of the following criteria
- 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)
Calcimimetics (e.g., cinacalcet)
- Mechanism of action: increases the sensitivity of calcium-sensing receptors in parathyroid glands to circulating Ca2+ → inhibition of PTH release
- 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
- Indication: patients who do not undergo parathyroid surgery
- Imaging studies (every 1–2 years)
- Laboratory studies (yearly)
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 (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 
- Definition: A complication of parathyroidectomy characterized by severe hypocalcemia despite normal or elevated PTH levels
- Prevention: Consider preoperative calcium supplementation, calcitriol, and low-dose IV pamidronate 1–2 days before surgery for high-risk patients. 
- Secondary hyperparathyroidism
- Tertiary hyperparathyroidism: caused by persistent sHPT
- Secondary hyperparathyroidism: ↓ calcium and/or ↑ phosphate blood levels → reactive hyperplasia of the parathyroid glands → ↑ PTH secretion 
- Tertiary hyperparathyroidism: chronic renal disease → refractory and autonomous secretion of PTH → hypercalcemia
- Renal disease: secondary or tertiary hyperparathyroidism → → bone lesions
- Symptoms related to the underlying cause of sHPT or tHPT (commonly CKD)
- Bone pain and increased risk of fractures
- 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 “ .”
Laboratory studies 
- Diagnostic confirmation
- Additional studies: to support the diagnosis and assess for modifiable factors
- Treatment of the underlying condition
- Treatment of complications, e.g.:
- Calcimimetics