| disease | Primary Hyperparathyroidism |
| alias | Hyperparathyroidism, Hyperparathyroidism |
Hyperparathyroidism, abbreviated as HPT.
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 in normal glandular tissue, while larger ones can measure several centimeters in diameter. Adenomas have a complete capsule, often with 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 involves a single gland, and multiple adenomas are rare. Adenomas can also occur in ectopic parathyroid glands, such as in the mediastinum, thyroid, or behind the esophagus.
2. Hyperplasia and hypertrophy In recent years, cases caused by chief cell hyperplasia have been found to be more common (accounting for about 15%). In hyperplasia and hypertrophy, all four glands are usually affected, with irregular shapes and no capsule. The glands generally show no cystic changes, hemorrhage, or necrosis. The cellular tissue is primarily composed of large water-clear cells, interspersed with fat cells. Due to the compression of surrounding tissue in the hyperplastic area, a pseudocapsule may form, which can be mistaken for an adenoma.
3. Carcinoma Tumor cell infiltration, nuclear division, and metastasis are observed in the capsule, blood vessels, and surrounding tissues.
(3) Ectopic deposition of calcium salts The kidneys are important organs for excreting calcium salts. Changes in urine concentration and acidity during excretion can often lead to multiple urinary stones. Calcium salt deposition may occur in the renal tubules or interstitial tissues. Furthermore, calcium salt deposition can also occur in the lungs, pleura, submucosal blood vessels of the gastrointestinal tract, skin, myocardium, and other areas.
Excessive secretion of parathyroid hormone mobilizes calcium from bones into the bloodstream, leading to hypercalcemia, while the renal tubules reduce 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 sustained action of excessive parathyroid hormone causes widespread bone resorption and decalcification. The breakdown of bone matrix increases urinary excretion of metabolic products such as mucoproteins and hydroxyproline, leading 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, further stimulating increased parathyroid hormone secretion (secondary hyperfunction in non-tumor tissues). Although osteoclast mobilization dominates in this disease, osteoblast activity also compensatorily increases, often resulting in elevated serum alkaline phosphatase levels.
bubble_chart Clinical Manifestations
This disease is more common in individuals aged 20 to 50, with a higher incidence in females than males. The onset is slow, with some cases discovered due to recurrent kidney stones, some presenting primarily with bone pain, some exhibiting neurological dysfunction due to hypercalcemia, and others 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 excessive calcium stimulating gastric membrane secretion of gastrin. If accompanied by gastrinoma of the pancreas, such as in Zollinger-Ellison syndrome, peptic ulcers may become refractory. Some patients may also experience recurrent pancreatitis, the cause of which is unclear but may be due to calcium salt deposition in the pancreas leading to pancreatic duct obstruction.
2. Muscular System Muscles in the limbs become lax and hypotonic, 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 kidney stones is also high, typically between 60% and 90%. Clinically, renal colic, hematuria, or secondary urinary tract infections may occur. Repeated episodes can lead to kidney damage or even renal failure. The kidney 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 calcium salt deposition in the kidney medulla, are diagnostically significant. Calcium salt deposition in renal tubules and medullary tissue can lead to renal failure. Among general kidney stone patients, about 2–5% are caused by this disease.
(2) Skeletal Symptoms In the initial 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 swelling or cystic changes). Height may decrease, and pathological fractures may occur, eventually confining the patient to bed.
(3) Other Syndromes A few patients may exhibit psychiatric symptoms such as hallucinations or paranoia. Multiple endocrine neoplasia type I (gastrinoma, pituitary tumor, with parathyroid adenoma, 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
X-ray examination:
The main changes observed on X-ray films are: ① subperiosteal cortical resorption and decalcification, ② cystic changes are less common, ③ fracture and/or deformity. Systemic skeletal changes such as decalcification, fractures, and deformities in the pelvis, skull, spine, or long and short bones are common in this disease. However, subperiosteal cortical resorption on the medial side of the phalanges, spotty decalcification of the skull, resorption of the alveolar bone plate, and bone cyst formation are characteristic lesions (positive rate 80%) that aid 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 gland. X-rays may also reveal multiple recurrent urinary stones and nephrocalcinosis, both of which are valuable for diagnosis.
Laboratory tests:
(1) Blood
1. In the early stages, 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. In early cases, the increase in blood calcium is relatively mild and may fluctuate, so repeated measurements are necessary. It is extremely rare for blood calcium to remain consistently 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 levels, and the weight of the parathyroid tumor.
2. Blood phosphorus is mostly below 1.0 mmol/L (3.0 mg/dl), but its diagnostic significance is less than that of elevated calcium, especially in advanced cases with reduced renal function, where phosphorus excretion is impaired 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 surgery, and ② hypercalcemia requiring further investigation. Among pathologically confirmed primary hyperparathyroidism cases, 90% of patients have significantly elevated serum iPTH and calcium levels compared to normal values. 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 set of normal serum values: 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 approach is to use a two-site immunoradiometric assay (IRMA) to measure intact PTH, which has good clinical correlation, is unaffected by kidney disease, and can effectively distinguish 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 set of normal serum values: winter 13.2 ± 3.8 ng/ml, summer 18.9 ± 6.5 ng/ml.
5. Serum alkaline phosphatase: In cases presenting solely with urinary stones, it may be normal in the early stages, but in those with bone disease, 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) levels increase when bone resorption and bone turnover are elevated. In this disease, serum TRAP often increases several-fold. If surgical treatment is successful, it can significantly decrease within 1 to 2 weeks postoperatively, even returning to normal levels. A group of normal values at Peking Union Medical College Hospital was 7.2±1.9 IU/L.
(II) Urine Increased excretion of calcium and phosphorus in urine. This is primarily due to increased glomerular filtration of calcium in the kidneys as a result of hypercalcemia, leading to higher urinary calcium levels. After three days on 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. If tested under a regular diet, urinary calcium in this condition often exceeds 250mg. However, urinary calcium excretion can be influenced by many factors, such as vitamin D levels, sunlight exposure, 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 serving as a more sensitive indicator of bone resorption.
(III) Cortisol Suppression Test Large doses of glucocorticoids have an anti-vitamin D effect (inhibiting intestinal calcium absorption, among others) and can reduce hypercalcemia caused by conditions such as sarcoidosis, vitamin D intoxication, multiple myeloma, metastatic cancer, or hyperthyroidism. However, they have no effect on hypercalcemia caused by this disease. The method involves oral administration of hydrocortisone at 50mg, three times daily, for 10 days.
One should suspect this condition if any of the following characteristics are present: ① recurrent active urinary stones or renal calcium salt deposition; 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
The primary treatment for this condition is surgery. Drug therapy may be considered only in cases of extremely mild hypercalcemia (below 2.9 mmol/L or 11.5 mg/dl), or when surgery is contraindicated due to advanced age, frailty (e.g., grade III renal failure), or other factors.
(1) Localization of Parathyroid Tumors: During initial surgery, an experienced surgeon 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 primarily used for patients who require re-exploration due to failed initial surgery caused by ectopic tumors or other complexities.
(2) Surgical Exploration and Treatment: During exploration, all four glands must be meticulously identified to avoid surgical failure. Intraoperative frozen section analysis is essential. For adenomas, the tumor should be excised while preserving one normal gland. For hyperplasia, three glands should be removed, and approximately 50% of the fourth gland should be excised. Ectopic glands, often located in the mediastinum, can usually be traced along the branches of the inferior thyroid artery without sternotomy. Successful surgery corrects serum parathyroid hormone levels and abnormal calcium and phosphorus metabolism. Blood phosphorus levels typically normalize quickly postoperatively, while blood calcium levels may take 1–3 days to return to normal. In patients with significant bone disease, excessive calcium and phosphorus deposition in demineralized bones may cause hypocalcemia (5–8 mg/dl) within 1–3 days post-surgery, leading to recurrent lip numbness and limb convulsions. Intravenous administration of 10% calcium gluconate (10 ml, 2–3 times daily) may be required, with doses sometimes reaching 100 ml or 30–50 ml diluted in 500–1000 ml of 5% glucose solution for IV infusion. Symptoms usually improve within 3–5 days. Persistent hypocalcemia beyond one month suggests possible permanent hypoparathyroidism, necessitating vitamin D supplementation. If convulsions persist despite normalized calcium levels, magnesium supplementation should also be considered (see hypoparathyroidism for details). Postoperative calcium and phosphorus levels typically normalize within a week, but alkaline phosphatase may remain elevated during bone repair. Recurrence requires repeat surgery.
(3) Cimetidine: This drug inhibits PTH synthesis and/or secretion, 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: Postoperative management of bone disease and urinary stones is essential for functional recovery: ① For bone lesions, a high-protein, high-calcium, and high-phosphorus diet with calcium supplementation (3–4 g daily) is recommended. ② Urinary stones should be actively expelled or surgically removed if necessary.
During differential diagnosis, it is essential to exclude other causes of hypercalcemia and secondary hyperparathyroidism. For instance, 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, but these are generally suppressible by cortisol. In contrast, the hypercalcemia of this disease is not suppressible. Serum alkaline phosphatase is typically elevated in this condition but remains normal in myeloma. Additionally, secondary hyperparathyroidism must be distinguished.
