| disease | Hyperparathyroidism |
| alias | Hyperparathyroidism |
Hyperparathyroidism is referred to as hyperparathyroidism.
bubble_chart Etiology
Primary hyperparathyroidism is caused by excessive secretion of parathyroid hormone due to parathyroid adenoma, hyperplasia, or adenocarcinoma, and its disease cause is unknown. The pathological changes are as follows:
(1) Parathyroid lesions can be divided into three types.
1. **Adenoma** accounts for approximately 80% or more. Small adenomas may be embedded within the normal gland, while larger ones can measure several centimeters in diameter. Adenomas have a complete capsule and often exhibit cystic changes, hemorrhage, necrosis, or calcification. The tumor tissue is predominantly composed of chief cells but may also consist of clear cells. Residual fat cells are not found within the adenoma. In 90% of cases, the lesion affects a single gland, and multiple adenomas are rare. Adenomas may also occur in ectopic parathyroid glands, such as in the mediastinum, thyroid, or behind the esophagus.
2. **Hyperplasia** Recent studies have shown an increase in cases caused by chief cell hyperplasia (accounting for about 15%). In hyperplasia, all four glands are usually involved, with irregular shapes and no capsule. The glands typically lack cystic changes, hemorrhage, or necrosis. The cellular composition is mainly large water-clear cells, interspersed with fat cells. Due to compression of surrounding tissue by the hyperplastic area, a pseudocapsule may form, which can be mistaken for an adenoma.
3. **Carcinoma** Tumor cell infiltration into the capsule, blood vessels, and surrounding tissues, nuclear division, and metastasis are observed.
(2) **Bone** The main pathological changes include increased osteoclast or osteoblast activity, bone resorption, and varying degrees of bone decalcification. Proliferation of connective tissue leads to fibrous osteitis. In severe cases, multicystic lesions and "brown tumors" may develop, often resulting in pathological fractures and deformities. Calcification in neonatal tissues is rare. Bone lesions, primarily characterized by resorption, are systemic. The distribution of bone disease is more pronounced in the phalanges, skull, mandible, spine, and pelvis. Additionally, osteosclerosis and other changes may occur.(3) **Ectopic calcium deposition** The kidneys are the primary organs for calcium excretion. Changes in urine concentration and acidity during excretion often lead to the formation of multiple urinary stones. Calcium deposition may also occur in renal tubules or interstitial tissues. Furthermore, calcium salts can deposit in the lungs, pleura, submucosal blood vessels of the gastrointestinal tract, skin, myocardium, and other sites.
Excessive secretion of parathyroid hormone causes calcium to be mobilized from bones into the bloodstream, leading to hypercalcemia. At the same time, the renal tubules reduce the reabsorption of inorganic phosphorus, increasing urinary phosphorus excretion and lowering blood phosphorus levels. Due to the autonomous nature of the tumor, hypercalcemia fails to suppress the parathyroid glands, resulting in persistently elevated blood calcium. If renal function remains intact, increased urinary calcium excretion may slightly reduce blood calcium levels. However, the continued excessive action of parathyroid hormone leads to widespread bone resorption and decalcification, as well as the breakdown of bone matrix. Metabolic products such as mucoproteins and hydroxyproline are excreted in greater amounts in the urine, contributing to the formation of urinary calculi or nephrocalcinosis. Combined with secondary infections and other factors, renal function often suffers severe damage. In the late stage (third stage), when renal insufficiency occurs, phosphate excretion becomes inadequate, causing blood phosphorus levels to rebound while blood calcium levels may decrease. This can further stimulate increased parathyroid hormone secretion (secondary hyperfunction in tissues outside the tumor). Although osteoclast mobilization dominates this condition, osteoblast activity also increases compensatorily, often resulting in elevated serum alkaline phosphatase levels.
This disease is more common in individuals aged 20 to 50, with a higher incidence in females than males. The onset is slow, and it may be discovered through recurrent kidney stones, manifest primarily as bone pain, present with neurological Guanneng symptoms due to hypercalcemia, or be identified through multiple endocrine gland tumor diseases. Some cases remain asymptomatic throughout. The clinical manifestations can be summarized into the following four groups:
(1) Hypercalcemia and Hypophosphatemia Syndrome This is an early symptom often overlooked.
1. Digestive System Symptoms may include poor appetite, constipation, abdominal distension and fullness, nausea, and vomiting. Some patients may have duodenal ulcers, possibly due to hypercalcemia stimulating gastric membrane secretion of gastrin. If accompanied by gastrinomas, such as in Zollinger-Ellison syndrome, peptic ulcers may become refractory. Some patients may also develop recurrent pancreatitis, the cause of which is unclear but may be related to calcium salt deposition in the pancreas leading to pancreatic duct obstruction.
2. Muscular System Muscle relaxation and reduced tension in the limbs, leading to fatigue and weakness. Bradycardia and occasional arrhythmias may occur, with electrocardiograms showing shortened QT intervals.
3. Urinary System Due to excessive calcium excretion in the urine caused by hypercalcemia, patients often report polyuria, thirst, and polydipsia. The incidence of urinary stones is also high, ranging between 60–90%. Clinically, renal colicky pain, hematuria, or secondary urinary tract infections may occur. Repeated episodes can lead to renal impairment or even renal failure. The urinary stones associated with this disease are characterized by being multiple, recurrent, and bilateral, often showing progressive increases in number and size. These features, along with kidney excess calcium salt deposition, are diagnostically significant. Calcium salt deposition in renal tubules and parenchyma can lead to renal failure. Among general urinary stone patients, about 2–5% are caused by this disease.
(2) Skeletal Symptoms In the initial stage [first stage], bone pain may occur in the back, spine, hips, ribs, or limbs, accompanied by tenderness. The lower limbs may become unable to bear weight, leading to difficulty walking, often misdiagnosed as arthritis or muscular disorders. Over time, skeletal deformities may develop (some patients may also exhibit localized bone protrusions or cystic changes). Height may decrease, and pathological fractures may occur, eventually confining the patient to bed.
(3) Other Syndromes A few patients may develop psychiatric symptoms such as hallucinations or paranoia. Multiple endocrine neoplasia type I (gastrinomas, pituitary tumors, with parathyroid adenomas, sometimes accompanied by gastrointestinal carcinoid tumors, known as Wermer syndrome) or type II (Sipple syndrome: pheochromocytoma, medullary thyroid carcinoma with hyperparathyroidism) may also occur.
bubble_chart Auxiliary Examination
(1) Blood
1. Early-stage blood calcium is mostly elevated, which is most significant for diagnosis. If blood calcium repeatedly exceeds 2.7 mmol/L (10.8 mg/dl), it should be considered a suspected case; exceeding 2.8 mmol/L (11.0 mg/dl) is even more significant. The degree of blood calcium elevation in early cases is relatively mild and may fluctuate, so repeated measurements are necessary. It is extremely rare for blood calcium to consistently remain at normal levels in this disease. However, when renal insufficiency occurs, blood phosphorus rises and blood calcium often decreases. There is a parallel relationship between blood calcium concentration, serum parathyroid hormone (PTH) concentration, and the weight of parathyroid tumors.
2. Blood phosphorus is mostly below 1.0 mmol/L (3.0 mg/dl), but its diagnostic significance is not as strong as elevated calcium, especially in advanced-stage cases with impaired renal function, where phosphorus excretion is difficult and blood phosphorus may increase.
3. Serum parathyroid hormone measurement: Measuring serum iPTH and blood calcium can divide patients into two groups: (1) primary hyperparathyroidism requiring surgical treatment, and (2) hypercalcemia requiring further investigation. Among pathologically confirmed primary hyperparathyroidism cases, 90% of patients have significantly higher serum iPTH and calcium levels than normal. If only blood calcium is elevated while iPTH remains largely unchanged, cancer or other causes of hypercalcemia should be considered. In secondary hyperparathyroidism, blood iPTH may also be significantly elevated, but blood calcium is mostly normal or low. A domestic reference range for serum iPTH: winter 23.5 ± 0.12, summer 19.2 ± 7.7 pg/ml.
PTH measurement can be performed using radioimmunoassay (RIA), primarily targeting the mid-region or carboxyl-terminal of PTH, which are inactive fragments. Although this correlates well clinically, it can be affected by renal insufficiency. Therefore, the current preferred method is the two-site immunoradiometric assay (IRMA) to measure intact PTH, which has good clinical correlation, is unaffected by kidney disease, and effectively distinguishes between normal, hypoparathyroidism, primary hyperparathyroidism, and tumor-induced hypercalcemia.
4. Plasma 1,25(OH)2D: In this disease, excessive PTH can stimulate renal 1α-hydroxylase activity, leading to increased plasma 1,25(OH)2D levels. A domestic reference range for serum 1,25(OH)2D: winter 13.2 ± 3.8 ng/ml, summer 18.9 ± 6.5 ng/ml.
5. Serum alkaline phosphatase may be normal in early cases presenting solely with urinary stones, but in cases with bone disease manifestations, it is almost always elevated to varying degrees, exceeding 12 King-Armstrong units and sometimes reaching over 70 King-Armstrong units.
6. Serum tartrate-resistant acid phosphatase (TRAP): When bone resorption and turnover are increased, serum TRAP concentration rises. In this disease, serum TRAP often increases several-fold. If surgical treatment is successful, it can significantly decrease within 1–2 weeks postoperatively, even returning to normal. A reference range from Peking Union Medical College Hospital is 7.2 ± 1.9 IU/L.
(II) Urine Increased excretion of calcium and phosphorus in urine. This is primarily due to the elevated blood calcium levels leading to increased filtration by the renal tubules, resulting in higher urinary calcium. Even after three days of a low-calcium diet (daily calcium intake below 150mg), the 24-hour urinary calcium excretion in patients can still exceed 200mg, whereas in normal individuals, it remains below 150mg. Under a regular diet, urinary calcium in this condition often surpasses 250mg. However, urinary calcium excretion can be influenced by many factors, such as vitamin D levels, sunlight exposure intensity, and the presence of urinary stones, so the significance of urinary calcium should be analyzed contextually. When collecting urine, it should be acidified to prevent calcium salt precipitation from affecting the results. If there is a urinary tract infection, findings may also include proteinuria, pyuria, and hematuria. Additionally, increased excretion of urinary cAMP and hydroxyproline may be observed, with the latter being a more sensitive indicator of bone resorption.
(3) Cortisol Suppression Test Large amounts of glucocorticoids have an anti-vitamin D effect (inhibiting intestinal calcium absorption, etc.), which can reduce hypercalcemia caused by sarcoidosis, vitamin D intoxication, multiple myeloma, metastatic cancer, or hyperthyroidism, but have no effect on hypercalcemia caused by this disease. The method involves oral administration of hydrocortisone 50mg, three times a day for 10 days.
(4) X-ray Examination:
The main changes observed on X-ray films are: (1) subperiosteal cortical absorption and decalcification, (2) cystic changes are less common, (3) fractures and/or deformities. Generalized skeletal decalcification, fractures, and deformities in areas such as the pelvis, skull, spine, or long and short bones are commonly seen in this disease. However, subperiosteal cortical absorption on the medial side of the phalanges, spotty decalcification of the skull, absorption of the alveolar bone plate, and bone cyst formation are characteristic lesions of this disease (positive rate of 80%), aiding in diagnosis. A few patients may also exhibit bone sclerosis and ectopic calcification. These polymorphic skeletal changes may be related to the effects of parathyroid hormone on osteoclasts and osteoblasts, compensatory calcitonin activity, and intermittent activity of the diseased glands. X-rays may also reveal multiple recurrent urinary calculi and nephrocalcinosis, both of which are valuable for diagnosis.
One should suspect this condition if any of the following characteristics are present: (1) recurrent active urinary stones or renal calcification; (2) bone resorption, decalcification, or even cyst formation, especially when involving the aforementioned predilection sites.
In addition to clinical manifestations, the key diagnostic criteria are: (1) hypercalcemia, averaging above 10.8–11.0 mg/dl; (2) elevated iPTH. As mentioned earlier, hypercalcemia accompanied by elevated iPTH, combined with clinical and X-ray findings, can confirm the diagnosis. The presence of increased urinary calcium and hypophosphatemia makes the diagnosis even more typical.
bubble_chart Treatment Measures
This disease is primarily treated with surgery. Drug therapy may be considered only in cases of extremely mild hypercalcemia (below 2.9 mmol/L or 11.5 mg/dl), or in elderly or frail patients (such as those with grade III renal failure) who are unable to undergo surgery.
(1) **Localization of Parathyroid Tumors** During the initial surgery, experienced surgeons can usually resolve the issue without the need for specialized localization tests. However, simple examinations such as barium swallow or ultrasound may be performed. Invasive localization methods, such as selective arteriography, jugular vein catheterization, and segmental sampling for iPTH concentration (samples draining the tumor contain high hormone levels), are mainly used for patients who require re-exploration due to failed initial surgery caused by ectopic tumors or other special difficulties.
(2) **Surgical Exploration and Treatment** During exploration, all four glands must be thoroughly examined to avoid surgical failure. Intraoperative frozen section analysis is necessary. If an adenoma is found, it should be excised while preserving one normal gland. In cases of hyperplasia, three glands should be removed, and approximately 50% of the fourth gland should be excised. Ectopic glands are often located in the mediastinum and can usually be traced along the branches of the inferior thyroid artery without requiring sternotomy. If the surgery is successful, serum parathyroid hormone levels and abnormal calcium and phosphorus metabolism in blood and urine can be corrected. Blood phosphorus levels typically return to normal shortly after surgery, while blood calcium levels may normalize within 1–3 days. In patients with significant bone disease, excessive calcium and phosphorus deposition in demineralized bones postoperatively may cause blood calcium to drop to dangerously low levels (5–8 mg/dl) within 1–3 days, leading to recurrent lip numbness and limb convulsions. Intravenous administration of 10% calcium gluconate (10 ml, 2–3 times daily) may be required, with some cases needing up to 100 ml or 30–50 ml diluted in 500–1000 ml of 5% glucose solution for intravenous drip. Symptoms usually improve within 3–5 days. If hypocalcemia persists for more than a month, permanent hypoparathyroidism should be suspected, and vitamin D supplementation may be necessary. If convulsions persist despite normalized blood calcium levels, magnesium supplementation should also be considered (see hypoparathyroidism for details). Postoperatively, blood calcium and phosphorus levels often normalize within a week, but alkaline phosphatase may remain elevated for an extended period during bone repair. If recurrence occurs, repeat surgery may be required.
(3) **Cimetidine** This drug can inhibit the synthesis and/or secretion of PTH, thereby reducing iPTH levels and normalizing blood calcium. However, rebound hypercalcemia may occur after discontinuation. The dosage is 300 mg, three times daily.
(4) **Other Measures** Postoperatively, further management of bone disease and urinary stones is necessary to restore function: - **Bone lesions**: A high-protein, high-calcium, and high-phosphorus diet is recommended, along with calcium salt supplementation (3–4 g daily). - **Urinary stones**: Active stone expulsion or surgical removal may be required if necessary.
During differential diagnosis, it is essential to exclude other causes of hypercalcemia and secondary hyperparathyroidism. For example, cancer, whether metastatic or not, often presents with hypercalcemia. Other conditions such as multiple myeloma, sarcoidosis, milk-alkali syndrome, vitamin D toxicity, and thiazide diuretic intoxication can also cause hypercalcemia. However, these conditions are generally suppressible by corticosteroids, whereas the hypercalcemia in this disease is not. Additionally, serum alkaline phosphatase levels are typically elevated in this disease but normal in myeloma. Furthermore, secondary hyperparathyroidism must also be distinguished.
