Hyperparathyroidism (hyperparathyroidism) can be classified as primary, secondary, triphasic, or pseudohypoparathyroidism. Primary hyperparathyroidism is caused by excessive synthesis and secretion of parathyroid hormone (PTH) due to a lesion (tumor or hyperplasia) of the parathyroid glands themselves, leading to hypercalcemia and hypophosphatemia through their effects on bone and kidney. The clinical features are recurrent kidney stones, peptic ulcers, psychiatric changes and extensive bone resorption. In recent years, a number of patients have been detected in time due to routine measurement of serum calcium. These patients are often asymptomatic except for hypercalcemia and elevated serum PTH.
Secondary hyperparathyroidism is caused by hypocalcemia due to various causes, which stimulates the parathyroid glands to hypertrophy and secrete excessive PTH, commonly due to renal insufficiency, osteochondrosis, small intestinal malabsorption, and vitamin D deficiency and hydroxylation disorders. In secondary hyperparathyroidism, some of the hyperplastic tissues are transformed into adenomas due to persistent stimulation of the glands, and they secrete excessive PTH on their own. Pseudohyperparathyroidism refers to the secretion of PTH-like peptides by certain malignant tumors (e.g., lung, liver, kidney, ovary, etc.), resulting in hypercalcemia, called concomitant tumor hypercalcemia.
Etiology and pathogenesis
Primary hyperparathyroidism is caused by excessive secretion of parathyroid hormone due to parathyroid adenoma, hyperplasia or adenocarcinoma, of which adenoma accounts for about 85% of the total, while parathyroid cancer is rare (<2%). Some patients are part of a familial multiple endocrine neoplasia MEN, which is autosomal dominant and has a clear tendency to run in families. Recent studies have suggested that different types of MEN have different genetic defects. The MEN-1 gene is located on the long arm of chromosome 11, band 11q13, while the MEN2 gene is located on the long arm of chromosome 10, band 10q11.2, and is a RET proto-oncogene whose expression product is ret protein.
Pathological changes
The pathological changes are as follows.
I. Parathyroid gland Lesions can be divided into three types.
Adenomas account for about 80% or more. Small adenomas are buried in the normal gland, while large ones can be several centimeters in diameter. Adenomas have an intact envelope and often have cystic changes, hemorrhage, necrosis or calcification. The majority of the tumor tissue is composed of primary cells, but it may also be composed of clear cells, with no residual adipocytes found within the adenoma. The lesion involves one gland in 90% of cases, and multiple adenomas are rare. Adenomas can also occur in the thoracic mediastinum, in the thyroid gland or in the ectopic parathyroid glands behind the esophagus.
Hyperplasia has been found in recent years to be caused by an increase in the number of principal cell hyperplasia cases (about 15% of cases). In hyperplasia, all four glands are often involved, with irregular shape and no envelope. There are usually no changes in the gland such as cysts, hemorrhage or necrosis, and the cellular tissue is dominated by large watery clear cells with interstitial fat cells. Due to the compression of tissues around the hyperplastic area, the formation of a pseudo-envelope is easily mistaken for adenoma. 3. There are tumor cell infiltration, nuclear partitioning and metastasis in the envelope, blood vessels and surrounding tissues of the carcinoma.
The main lesions of bones are osteoclastic or osteoblastic increase, bone resorption, bone decalcification of different degrees, and connective tissue hyperplasia constituting fibrous osteitis. In severe cases, it causes multifocal cyst-like lesions and “brown tumor”, and is prone to pathological fractures and deformities. Calcification in neonatal tissues is rare. Skeletal lesions, mainly bone resorption, are systemic in nature. The distribution of bone disease is more obvious in the finger bones, skull, mandible, spine and pelvis. In addition, osteosclerosis and other changes may occur.
The kidney is an important organ for excretion of calcium salts, and multiple urinary calculi can occur due to changes in urinary concentration and acidity during excretion. Calcium deposits can occur in the renal tubules or interstitial tissue. Calcium deposits may also occur in the lung, pleura, gastrointestinal submucosa, skin, and myocardium.
Pathophysiology
PTH is secreted in large amounts by the parathyroid glands, causing the release of bone calcium into the bloodstream and causing hypercalcemia; PTH also promotes the conversion of 25(OH)D3 to the more active 1,25(OH)2D3 in the kidney, which promotes intestinal calcium absorption and further aggravates hypercalcemia. At the same time, renal tubular reabsorption of inorganic phosphorus is reduced, urinary phosphorus excretion is increased, and blood phosphorus is reduced. Due to the autonomy of the tumor, excessive blood calcium cannot inhibit the secretion of parathyroid PTH, so blood calcium continues to increase. If the renal function is intact, the urinary calcium excretion will increase and high urinary calcium will appear. Therefore, patients with hyperparathyroidism show hypercalcemia with hypophosphatemia, high urinary calcium and high urinary phosphorus. The breakdown of bone matrix and increased urinary excretion of metabolites such as mucin and hydroxyproline lead to the formation of urinary stones or renal calcium deposits (nephmealcinosis), which increase the load on the kidneys and affect renal function, even leading to renal insufficiency. Due to the continuous increase of PTH, it can cause extensive bone resorption and decalcification, and in severe cases, fibrocystic osteitis (brown tumor). High blood calcium levels can also lead to calcium deposition in soft tissues, resulting in migratory calcification in the lungs, pleura, gastrointestinal submucosa, skin, and, in the case of tendons and cartilage, pain in the joints.
PTH also inhibits renal tubular reabsorption of bicarbonate, making the urine alkaline and further contributing to the formation of kidney stones. It can also cause hyperchloremic acidosis, which reduces plasma albumin binding to calcium and increases free calcium, exacerbating the symptoms of hypercalcemia. High concentration of calcium ions can stimulate secretion of gastrin, increase secretion of gastric acid by gastric wall cells, and form hyperacidic multiple gastroduodenal ulcers; activation of pancreatic ductal endothelial proteasome, causing self-digestion and oxidative stress reaction of the pancreas, and acute pancreatitis.
In patients with primary hyperparathyroidism, urinary cAMP is often increased, mainly due to the action of large amounts of PTH on renal tubular epithelial cells, but the administration of exogenous PTH often fails to further increase urinary phosphorus and urinary cAMP. This can be used as a diagnostic test for this disease.
Patients with this disease, especially those with severe bone resorption or fibrocystic osteitis, often have increased serum alkaline phosphatase, suggesting increased osteoblast activity. These patients have increased urinary hydroxyproline excretion, the latter being a major component of the bone matrix. Increased serum alkaline phosphatase and increased urinary hydroxyproline excretion suggest increased bone turnover.
Clinical presentation
The disease is most common in adults aged 20 to 50 years, with a significant increase in incidence after the age of 40 years, and is approximately twice as common in women as in men. The onset of the disease is slow, and the clinical manifestations can be varied, from repeated kidney stones to bone pain as the main manifestation, to neurological syndrome with high blood calcium, to multiple endocrine adenomatosis, to no symptoms at all. The main clinical manifestations of the disease can be attributed to the following aspects.
I. Hypercalcemia The symptoms caused by increased blood calcium can affect several systems.
1, the central nervous system can appear memory reduction emotional instability, mild personality changes, depression, drowsiness, sometimes due to the non-specific symptoms, patients can be misdiagnosed as neurological disorders.
2, the neuromuscular system can appear tiredness, weakness of the limbs, proximal muscles, muscle atrophy, often accompanied by electromyography abnormalities, clinically can be misdiagnosed as primary neuromuscular disease. The severity of neurological symptoms is related to the degree of hypercalcemia. When serum calcium exceeds 3 mmol/L, symptoms are likely to occur. In severe cases, significant psychiatric symptoms such as hallucinations, mania, and even coma may occur.
3. The digestive system may show loss of appetite, bloating, indigestion, constipation, nausea and vomiting; it may cause acute pancreatitis; it may also cause intractable peptic ulcer. In addition to the duodenal bulb, ulcers may occur in the gastric sinus, post-duodenal bulb and even in the descending, transverse or upper jejunum segments of the duodenum. Soft tissue calcification affecting tendons and cartilage can cause nonspecific arthralgia. Skin itching can be caused by calcium salt deposition in the skin.
Bone pain may occur in the early stages of the skeletal system, mainly in the low back, hip, ribs and extremities, with localized pressure pain. In the later stage, the main manifestation is fibrocystic osteitis, which may appear as skeletal deformity and pathological fracture, short stature, walking difficulties, or even bedridden. In addition to diffuse decalcification, there may be subperiosteal cortical resorption of the medial phalanges and speckled decalcification of the skull on X-ray, which is diagnostic of the disease. In addition, there may be multiple fractures and alveolar bone resorption. The early stage of the disease may only show an increase in bone turnover, bone resorption exceeding bone formation, and a gradual decrease in bone mineral.
Long-term hypercalcemia in the urinary system can affect the concentration function of the renal tubules, resulting in polyuria, nocturia, thirst, etc. Calcification of the renal parenchyma can also occur. Kidney stones are mainly composed of calcium oxalate and calcium phosphate. Recurrent episodes of renal colic with blood reception may occur. Stones may be bilateral and may increase in size within a short period of time. Urinary stones can induce urinary tract infection or cause urinary tract obstruction, and if left untreated, can evolve into chronic renal meningo-nephritis, further affecting kidney function. Renal calcium deposits may lead to gradual impairment of renal function and finally may cause renal insufficiency.
Other patients with hyperparathyroidism may have a family history and are often part of multiple endocrine adenomatosis (MEN). It can coexist with pituitary tumors and insulinocytoma, or with pheochromocytoma and medullary thyroid carcinoma, or MEN2. Sometimes, patients with a family history of hyperparathyroidism may have no other endocrine gland disease, but are often the result of parathyroid hyperplasia.
Laboratory and other tests
I. Blood
Blood calcium is mostly elevated in the early stages and is the most meaningful for diagnosis. If blood calcium repeatedly exceeds 2.7 mmol/L (10.8 mg/dl) several times, it should be regarded as a suspected case, and exceeding 2.8 mmol/L (11.0 mg/dl) is more significant. The increase in blood calcium in early cases is mild and can be volatile, so it should be measured repeatedly several times. Blood calcium is often maintained at normal levels, which is extremely rare in this disease. However, in renal insufficiency, blood calcium often decreases after blood phosphorus rises. There is a parallel relationship between blood calcium concentration and serum parathyroid hormone concentration and parathyroid tumor weight.
2. Most of the blood phosphorus is less than 1.0mmol/L (3.0mg/dl), but the diagnostic significance is less than that of increased calcium, especially in advanced cases of renal hypoplasia, where phosphorus excretion is difficult and blood phosphorus can be raised.
3. Serum parathyroid hormone measurement of serum iPTH as well as blood calcium can classify patients into two groups: (i) primary hyperparathyroidism requiring surgical treatment, and (ii) high calcium causes requiring further examination. In pathologically confirmed primary hyperparathyroidism, serum iPTH and calcium are significantly higher than normal in 90% of patients. In secondary hyperparathyroidism, blood iPTH may also be significantly increased, but most of the calcium is normal or low. In a domestic group, the normal serum values are 23.5±0.12 in winter and 19.2±7.7 pg/ml in summer. PTH can be measured by radioimmunoassay (RIA), which mainly determines the middle or carboxy end of PTH, an inactive fragment that is clinically relevant but can be interfered with by renal insufficiency. Therefore, we are now striving to use the two-site immunoradiometric (IRMA) method to determine the whole molecule of PTH, which has good clinical correlation and the results are not interfered by renal disease, and can well distinguish between normal, parathyroid, primary hyperparathyroidism and tumor-induced hypercalcemia.
4. Plasma 1,25(OH)2D Excess PTH in this disease can excite renal 1a-hydroxylase activity and increase plasma 1,25(OH)2D levels. The normal value of serum in domestic group: 13.2±3.8ng/ml in winter, 18.9±6.5ng/ml in summer. 5. Serum alkaline phosphatase in those who simply show urinary calculi, the early stage can be normal, but those who have bone disease manifestations, almost all have different degrees of increase, more than 12 gold units, sometimes up to 70 gold units or more.
6, serum anti-tartaric acid phosphatase (tartrate resistance acid phosphatase, TRAP) in bone resorption and bone conversion increased, serum TRAP concentration increased. In this disease, serum TRAP often increases exponentially, and if the surgical treatment is successful, it can drop significantly within 1 to 2 weeks after surgery, and even reach normal. The normal value of a group at Peking Union Medical College Hospital is 7.2±1.9IU/L.
Second, urinary urinary calcium and phosphorus excretion increased. Mainly because of the increase in renal tubular filtration after high blood calcium, urinary calcium also increased. After 3 days on a low-calcium diet (daily calcium intake below 150 mg), 24-hour urinary calcium excretion can still be above 200 mg, while in normal subjects it is below 150 mg; if performed under a normal diet, urinary calcium in this disease often exceeds 250 mg. However, urinary calcium excretion can be affected by many factors such as the strength of vitamin D and sunlight exposure and the presence of urinary calculi, so a specific analysis should be made when estimating the significance of urinary calcium. The urine should be acidified at the time of collection to avoid precipitation of calcium salts affecting the results. If there is a urinary tract infection, proteinuria, pusuria, and hematuria are also found. In addition, increased excretion of cAMP and hydroxyproline in urine can be found, and the latter is a more sensitive indicator of bone resorption.
Cortisol suppression test is a large number of glucocorticoids with anti-vitamin D effect (inhibit intestinal absorption of calcium, etc.), which can reduce excessive calcium caused by nodular disease, vitamin D toxicity, multiple myeloma, metastatic carcinoma or hyperthyroidism, but has no effect on the excessive calcium caused by this disease. The method is oral hydrocortisone 50mg 3 times a day for 10 days.
IV. X-ray examination.
The main changes seen on X-rays are.
(i) subperiosteal cortical resorption and decalcification.
(ii) cyst-like changes are less common.
(iii) fractures and/or deformities.
Systemic skeletal changes such as decalcification, fractures and deformities in the pelvis, skull, spine or long and short bones are common in this disease, but subperiosteal cortical resorption in the medial aspect of the finger bones, speckled decalcification in the skull, resorption of the alveolar bone plate and bone cyst formation are the favored lesions (80% positive rate), which help to diagnose the disease. In a few patients, osteosclerosis and ectopic calcification may be seen, and this polymorphic change in the bone may be related to the action of parathyroid hormone on osteoclasts and osteoblasts, the compensatory effect of calcitonin and the intermittent activity of the diseased glands.