Hyperparathyroidism (HPT) can be classified into three types: primary, secondary, and tertiary. Primary hyperparathyroidism results from abnormalities in the parathyroid tissue (tumor or hyperplasia) that lead to excessive synthesis and secretion of parathyroid hormone (PTH), causing elevated calcium levels and decreased phosphate levels in the blood. Secondary hyperparathyroidism refers to excessive PTH secretion driven by hypocalcemia from various causes, commonly seen in renal insufficiency, vitamin D deficiency, or malabsorption in the intestine. Tertiary hyperparathyroidism arises from prolonged and intense stimulation of the parathyroid glands in secondary hyperparathyroidism, evolving into autonomous hyperplasia or adenomas that secrete excessive PTH independently. This is mainly observed in patients with chronic renal insufficiency, after kidney transplantation, or those on long-term phosphate therapy. This section focuses on primary hyperparathyroidism.
Epidemiology
Studies suggest that the incidence of primary hyperparathyroidism is approximately 1 in 1,000 to 1 in 500 individuals, with a female-to-male ratio of about 3:1. It occurs predominantly in postmenopausal women. While most cases are sporadic, in some patients, it may be part of a familial disorder. Primary hyperparathyroidism is a key clinical manifestation of multiple endocrine neoplasia (MEN).
Etiology and Pathology
The histopathology of hyperparathyroidism includes parathyroid adenoma, hyperplasia, and carcinoma. The etiology remains unknown in most cases.
Adenoma
Adenomas account for approximately 80–85% of cases, with most being solitary adenomas, while multiple adenomas are less common. These adenomas originate from chief cells of the parathyroid gland and may result from cellular mutations. They are generally small in size and enclosed by an intact capsule. Distinguishing adenomas from hyperplasia can sometimes be challenging histologically.
Hyperplasia
Hyperplasia accounts for about 15% of cases and typically involves all parathyroid glands, although one gland may be more prominently enlarged. Chronic renal failure, which leads to hypocalcemia, hyperphosphatemia, and reduced levels of 1,25-(OH)2D3 in the serum, is a common cause of parathyroid gland hyperplasia. Gross morphology often reveals irregularly shaped glands without capsules, but pseudocapsules can sometimes form around the hyperplastic tissue, potentially leading to misdiagnosis as multiple adenomas.
Carcinoma
Parathyroid carcinoma constitutes less than 1% of cases. Differentiating between carcinoma and adenoma in the early stages can be difficult. Definitive histological features of carcinoma include evidence of vascular invasion, perineural invasion, capsular penetration with growth into adjacent tissue, and/or metastasis.
Pathophysiology
The hallmark of primary hyperparathyroidism is inappropriate PTH secretion relative to blood calcium levels. PTH exerts direct effects on the bones and kidneys and exerts indirect effects on intestinal epithelial cells, collectively leading to increased blood calcium levels.
In the bones, excess PTH stimulates bone resorption, releasing calcium into the bloodstream and causing hypercalcemia. Initially, hypercalcemia may be intermittent, and most patients experience only mild hypercalcemia (2.7–2.8 mmol/L), which may progress to more pronounced levels. The autonomous nature of the tumor prevents high calcium levels from suppressing PTH secretion, resulting in persistent hypercalcemia. Chronic elevation of PTH leads to extensive bone resorption and decalcification, and severe cases may develop fibrous cystic osteitis (brown tumors). Excessive calcium levels can also result in metastatic calcification, with calcium deposition in soft tissues causing joint pain and other symptoms.
In the kidneys, PTH promotes the conversion of 25-(OH)D3 to its more active form, 1,25-(OH)2D3. This enhances intestinal calcium absorption, aggravating hypercalcemia. Increased calcium filtered by the glomeruli leads to elevated urinary calcium excretion. Additionally, PTH inhibits tubular reabsorption of inorganic phosphate, increasing urinary phosphate excretion and causing hypophosphatemia. PTH also facilitates the breakdown of bone matrix, increasing urinary excretion of mucoproteins and hydroxyproline, which predispose patients to urinary stones (commonly calcium oxalate stones) or nephrocalcinosis. These changes can add to the kidney's workload, impair kidney function, and, in severe cases, result in renal insufficiency. PTH also inhibits bicarbonate reabsorption in the renal tubules, producing an alkaline urinary pH that further promotes kidney stone formation and causes hyperchloremic acidosis. This acidosis increases free calcium levels, exacerbating hypercalcemia-related symptoms.
In addition, elevated calcium concentrations can stimulate the secretion of gastrin, which in turn increases gastric acid secretion and contributes to the formation of multiple gastric and duodenal ulcers. High calcium levels in the ducts of the pancreas can also activate trypsinogen, leading to acute pancreatitis.
Clinical Manifestations
The main clinical manifestations of this condition can be categorized as follows:
Hypercalcemia
The manifestations of hypercalcemia involve multiple systems and are related to the degree, speed, duration of calcium elevation, and the patient's tolerance. Many patients with mild hypercalcemia caused by primary hyperparathyroidism exhibit no obvious symptoms.
Central Nervous System
Symptoms may include memory loss, emotional instability, apathy, and personality changes.
Neuromuscular System
Fatigue and muscle weakness, especially in the proximal muscles, may occur. Prolonged weakness can lead to muscle atrophy, often accompanied by abnormal electromyography findings.
Digestive System
Symptoms may include loss of appetite, constipation, nausea, and emesis. Approximately 5% of patients experience episodes of acute or chronic pancreatitis. Unlike typical pancreatitis, which is associated with reduced calcium levels, pancreatitis with normal or elevated calcium levels may suggest the possibility of primary hyperparathyroidism. Persistent, multiple peptic ulcers may also occur.
Soft Tissue Calcification
This can affect tendons and cartilage, resulting in nonspecific joint pain.
Skin
Calcium salt deposition in the skin may lead to pruritus.
Severe cases may develop severe hypercalcemia (serum calcium >3.5 mmol/L) accompanied by significant dehydration, hallucinations, agitation, or even coma, posing a life-threatening condition that requires urgent management.
Skeletal System
Bone pain may occur early, primarily in the lower back, hips, ribs, and limbs, with localized tenderness. In advanced stages, classical signs of fibrous cystic osteitis may develop, most commonly presenting as subperiosteal bone resorption at the distal phalanges and skull, bone cysts, brown tumors in long bones, osteoporosis, and fractures. These changes can result in bone deformities, difficulty walking, and even immobility.
Urinary System
Apart from hypercalcemia, nephrolithiasis is the most common complication of primary hyperparathyroidism, occurring in approximately 20% of patients. Chronic hypercalcemia can impair renal tubular concentrating ability, leading to symptoms such as polyuria, nocturia, and excessive thirst. Calcium deposition in the renal parenchyma, recurrent renal colic, and hematuria may occur. Kidney stones can lead to urinary tract infections or obstruction and may progress to chronic pyelonephritis, further impairing renal function. Nephrocalcinosis can cause gradual renal function decline and, in severe cases, renal insufficiency.
Other Manifestations
Family history may be present in patients with primary hyperparathyroidism, especially as part of multiple endocrine neoplasia (MEN), which is inherited in an autosomal dominant pattern. It can occur alongside pituitary tumors and pancreatic islet cell tumors in MEN1 or pheochromocytomas and medullary thyroid cancer in MEN2A, with the latter often presenting with milder and less frequent primary hyperparathyroidism. Approximately one-third of patients fall into the asymptomatic category, exhibiting only nonspecific symptoms or none at all, with the condition often detected through routine blood calcium testing.
Laboratory and Auxiliary Examinations
Blood Tests
Serum calcium (total calcium) levels show persistent or fluctuating elevation, necessitating repeated measurements if required. When serum albumin levels fall below 40 g/L, the serum calcium level decreases by 0.2 mmol/L for every 10 g/L drop in albumin. For patients with hypoalbuminemia, serum calcium needs to be corrected based on albumin levels using the following formula:
Adjusted Serum Calcium (mmol/L) = Measured Serum Calcium + 0.02 × [40 - Serum Albumin (g/L)].
Serum ionized calcium measurement is more sensitive for diagnosing hypercalcemia and is not affected by albumin levels.
Serum phosphate levels are generally low, but may not decrease in cases of renal insufficiency. Serum alkaline phosphatase levels are often elevated, especially in patients with significant skeletal involvement. Increased serum chloride levels may occur, potentially accompanied by metabolic acidosis.
Urine Tests
Urinary calcium levels typically increase with elevated serum calcium. However, since PTH enhances renal tubular calcium reabsorption, urinary calcium may not significantly rise when serum calcium elevation is mild. Urinary phosphate levels are often elevated, though dietary factors limit its diagnostic utility compared to urinary calcium.
Serum PTH Measurement
Serum PTH measurement directly reflects parathyroid gland function. Intact PTH (1–84 amino acids) is the primary diagnostic indicator for primary hyperparathyroidism. The analysis of both PTH and serum calcium levels is useful for distinguishing between primary and secondary hyperparathyroidism.
X-Ray Imaging
X-ray findings correlate with the severity and duration of the disease. Typical features include generalized osteopenia and diffuse demineralization. Skull radiographs may show a "salt-and-pepper" or granular pattern. Subperiosteal bone resorption, most commonly at the phalanges, appears as irregular serrated edges on the cortical bone. Fibrous cystic osteitis presents as radiolucent areas of various sizes, often affecting long bones. Abdominal radiographs may reveal kidney or ureteral stones and renal calcification.
Bone Mineral Density (BMD) Measurement and Bone Ultrasound Speed Analysis
Results typically demonstrate bone loss and reduced bone strength.
Diagnosis and Differential Diagnosis
Qualitative Diagnosis of Hyperparathyroidism
The diagnosis of hyperparathyroidism can generally be established based on the patient's history, clinical manifestations of hypercalcemia, urinary tract stones, and skeletal abnormalities, combined with laboratory findings of coexisting hypercalcemia and elevated PTH levels (excluding normocalcemic primary hyperparathyroidism). Laboratory findings often also include hypophosphatemia, elevated serum alkaline phosphatase levels, and increased urinary calcium levels.
Localization Diagnosis of Hyperparathyroidism
After a qualitative diagnosis, localization is determined using neck ultrasound, radionuclide imaging (e.g., 99mTc-MIBI scanning), or neck and mediastinal CT scans. Accurate localization is important for surgical treatment.
Differential Diagnosis
Hyperparathyroidism must be differentiated from other causes of hypercalcemia:
Malignancies
Certain tumors (e.g., lung or kidney cancer) secrete PTH-related protein (PTHrP), which binds to PTH receptors and exerts effects similar to PTH, resulting in hypercalcemia and hypophosphatemia. In these cases, serum PTH levels are typically low, and patients usually exhibit signs of an underlying primary malignancy.
Other Causes of Hypercalcemia
Diseases such as sarcoidosis or vitamin D toxicity typically result in normal or decreased serum PTH levels. Prolonged immobilization or the use of lithium or thiazide diuretics can also cause mild hypercalcemia, which resolves after discontinuing the offending agent. Familial hypocalciuric hypercalcemia should be screened in young asymptomatic patients or those with only mildly elevated PTH levels.
Secondary Hyperparathyroidism
Serum PTH levels may be markedly elevated in secondary hyperparathyroidism, but serum calcium levels tend to be low. This condition often occurs in chronic renal failure or vitamin D deficiency.
Metabolic Bone Diseases
Conditions like osteoporosis and osteomalacia should also be considered in the differential diagnosis.
Treatment
Surgery is the preferred treatment for primary hyperparathyroidism, although medical therapy may be an alternative for elderly or frail individuals who cannot undergo surgery.
Surgical Treatment
Surgical indications include symptomatic primary hyperparathyroidism, absence of surgical contraindications, and well-localized lesions. Surgery is also recommended for asymptomatic primary hyperparathyroidism if any of the following are present:
- Hypercalcemia exceeding the upper limit of normal by 0.25 mmol/L (1 mg/dL).
- Renal impairment, as indicated by a creatinine clearance rate below 60 mL/min.
- Bone mineral density more than 2.5 standard deviations below the peak bone mass (T-score < -2.5) and/or fragility fractures.
- Age below 50 years.
- Inability or unwillingness to comply with regular follow-up.
Surgical removal of the adenoma is the optimal treatment for this condition. Successful surgery leads to normalization of serum calcium and PTH levels in the short term, although postoperative hypocalcemia may occur. Calcium and vitamin D supplementation is required to manage hypocalcemia. Severe symptoms such as tetany may necessitate intravenous administration of 10–20 mL of 10% calcium gluconate. Potential complications of parathyroid surgery include recurrent laryngeal nerve injury and permanent hypoparathyroidism.
Medical Treatment
For patients not undergoing surgery, those with surgical failure, or those unable to tolerate surgery, adequate hydration is essential. Thiazide diuretics and prolonged immobilization should be avoided.
Bisphosphonates
These inhibit osteoclast activity, reduce bone resorption, lower serum calcium levels, and help prevent or partially reverse bone loss associated with hyperparathyroidism.
Cinacalcet
As a calcium-sensing receptor modulator, cinacalcet binds to the transmembrane region of the calcium-sensing receptor, activating its pathways to reduce PTH secretion and lower serum calcium levels.
Cimetidine
This agent inhibits the synthesis and/or secretion of PTH, but its use is limited.
Management of Hypercalcemic Crisis
Hypercalcemic crisis, defined as serum calcium >3.5 mmol/L, represents a life-threatening condition requiring urgent intervention.
Fluid Replacement
The first step in treatment involves rehydration with large volumes of normal saline. Fluid replacement corrects dehydration and facilitates the renal excretion of calcium through sodium excretion. Fluid deficits require close monitoring of electrolytes and cardiovascular status, with daily fluid administration of 4–6 liters depending on the degree of dehydration.
Bisphosphonates
Examples include intravenous administration of pamidronate (60 mg diluted in 1,000 mL of normal saline or 5% glucose solution, given as a single dose) or zoledronate (4 mg over 15–30 minutes). Serum calcium normalizes in approximately 90% of patients within 3–5 days, with effects lasting 1–3 weeks.
Furosemide
Intravenous injection of 40–60 mg promotes calciuresis but may also result in magnesium and potassium loss, necessitating supplementation. Thiazide diuretics should be avoided.
Calcitonin
This suppresses bone resorption and is given as a subcutaneous or intramuscular injection at 2–8 U/(kg·day). However, tolerance to calcitonin may develop rapidly in 24–48 hours.
Dialysis
Hemodialysis or peritoneal dialysis effectively reduces serum calcium levels. Treatment is relatively safe when serum calcium levels drop below 3.0 mmol/L.
Glucocorticoids
Intravenous administration of hydrocortisone or dexamethasone may also be used.
Prognosis
For patients who undergo successful surgery, hypercalcemia and hyperparathyroidism correct, and the formation of new urinary stones ceases. Bone pain begins to subside within 1–2 weeks postoperatively, with significant symptom improvement occurring within 6–12 months. Bone structural repair may take 1–2 years or longer.