Primary Hyperparathyroidism and Nephropathy
Introduction
Introduction to primary hyperparathyroidism and nephropathy Primary hyperparathyroidism (primary hyperparathyroidism) is due to hyperplasia of the parathyroid gland itself, adenoma or adenocarcinoma caused by the synthesis and secretion of parathyroid hormone (PTH), through Its effects on bone and kidney lead to high blood calcium, low blood phosphorus, increased urinary calcium and phosphorus excretion, kidney stones and bone damage, resulting in a series of clinical manifestations. Primary hyperparathyroidism is a parathyroid adenoma, hyperplasia of hyperplasia or adenocarcinoma caused by excessive secretion of PTH, due to excessive secretion of parathyroid hormone, calcium from bone mobilization to blood circulation, causing hypercalcemia; Reduced inorganic phosphorus reabsorption, increased urinary phosphorus excretion, decreased blood phosphorus, elevated blood calcium can not inhibit parathyroid glands, increased PTH effect, cause extensive bone resorption and decalcification, bone matrix decomposition, mucin, hydroxyl Metabolites such as proline increase excretion from the urine, form kidney stones or nephrocalcinosis, and secondary infections cause serious damage to kidney function. When renal insufficiency occurs, phosphate cannot be fully discharged. The blood phosphorus concentration will rebound, while the blood calcium can be reduced, and it can stimulate the secretion of parathyroid glands. This is called secondary hyperparathyroidism. Because of the high calcium level, calcium is excreted from the urine, resulting in renal parenchymal calcium. Salt deposition, urinary stones occur, the incidence rate is 60% to 90%, clinically have renal colic, hematuria and secondary urinary tract infections, as well as frequent urination, urgency and dysuria. basic knowledge Sickness ratio: 0.05% Susceptible people: no special people Mode of infection: non-infectious Complications: urinary tract infection
Cause
Primary hyperparathyroidism and etiology of nephropathy
Gene mutation (30%):
The etiology of this disease has not yet been fully elucidated, and is most likely related to genetic mutations. Several family surveys have been reported in the literature, all of which are autosomal dominant, and have been found in recent years in parathyroid adenomas and multiple endocrine neoplasias. (MEN) In the type I parathyroid hyperplasia cells, the q13 gene of the 11th pair has recombination and deletion.
Radiation exposure (20%):
Radiation exposure may also cause disease. According to a group of neck X-ray radiotherapy patients, the incidence of PHPT and parathyroid tumors increased by 10 times, parathyroid hormone secretion parathyroids (parathyroidsrrl hormon PTH), PTH is an important hormone regulating the environmental stability of human calcium and phosphorus. PTH is secreted by the main cells of the parathyroid gland. The molecular weight is 9500D, which is a polypeptide consisting of 84 amino acids. The intact PTH molecule is cleaved in the kidney and liver. It is a two-part fragment of the amino terminus and the carboxy terminus. The former is biologically active, while the latter is absent. The intact PTH or its amino acid fragment acts on the bone and the renal tubules, producing biological effects and being extinguished. The main target organ of PTH is bone. With the kidneys.
Pathological changes (20%):
Primary hyperparathyroidism is a parathyroid adenoma, hyperplasia of hyperplasia or adenocarcinoma caused by excessive secretion of PTH, due to excessive secretion of parathyroid hormone, calcium from bone mobilization to blood circulation, causing hypercalcemia; Reduced inorganic phosphorus reabsorption, increased urinary phosphorus excretion, decreased blood phosphorus, elevated blood calcium can not inhibit parathyroid glands, increased PTH effect, cause extensive bone resorption and decalcification, bone matrix decomposition, mucin, hydroxyl Metabolites such as proline increase excretion from the urine, form kidney stones or nephrocalcinosis, and secondary infections cause serious damage to kidney function. When renal insufficiency occurs, phosphate cannot be fully discharged. The blood phosphorus concentration will rebound, while the blood calcium can be reduced, and it can stimulate the secretion of parathyroid glands. This is called secondary hyperparathyroidism. Because of the high calcium level, calcium is excreted from the urine, resulting in renal parenchymal calcium. Salt deposition, urinary stones occur, the incidence rate is 60% to 90%, clinically have renal colic, hematuria and secondary urinary tract infections, as well as frequent urination, urgency and dysuria.
The characteristics of urinary stones caused by this disease are multiple, recurrent and bilateral; stones gradually increase, increase and other activities, blood calcium in patients with urinary calculi exceeds 2.62mmol / L should be further examined and determined Whether it is a kidney stone caused by hyperparathyroidism.
Prevention
Primary hyperparathyroidism and prevention of kidney disease
The following conditions in PHPT are critical signs, and should be quickly corrected for high blood calcium, and strive for early surgery.
1. Signs of severe hypercalcemia such as blood calcium >3.5mmol/L (14mg/dl), as well as neuropsychiatric symptoms, long-term hypercalcemia, such as kidney stones, renal failure, fibrous cystic osteitis , hunchback, shortened height, false clubbing (indicating that the end of the phalanx has severe osteitis).
2. There are severe myopathy, metastatic calcification (including lung, kidney, blood vessels, joint calcification and banding keratopathy, "red eyes" caused by deposition of calcium phosphate in the conjunctiva), anemia (excessive PTH can induce bone marrow Fibrosis and hematopoietic function are reduced. In general, the prevention of this disease should be adequately rested during the onset of illness, avoid fatigue, and exercise properly during the stable period. Also pay attention to prevent colds, keep personal hygiene clean, prevent all kinds of infections, and pay attention to diet. Conditioning, diet should be regular, generally use high-calorie, rich in sugar, protein and vitamin diet; to relieve bad mood or unnecessary psychological burden, enhance confidence in the fight against disease.
Complication
Primary hyperparathyroidism and complications of nephropathy Complications, urinary tract infections
Due to the destruction of renal tubular structure, the disease is complicated by repeated urinary tract infections, which eventually leads to a decrease in renal units and an irreversible renal failure.
Symptom
Primary hyperparathyroidism and symptoms of nephropathy Common symptoms Hyperparathyroidism hyperactivity, limbs, weakness, polyuria, nausea, depression, loss of appetite, complex urinary tract infection, indigestion, bloating
The onset is slow, the clinical manifestations are diverse, and some patients can be asymptomatic.
1. Systemic manifestations of hypercalcemia can affect multiple systemic lesions.
(1) Central nervous system: memory loss, emotional instability, mild personality changes, depression, lethargy, hallucinations, arrogance, coma.
(2) Neuro-muscle system: burnout, weakness of limbs, proximal muscles, muscle atrophy, digestive system, peptic ulcer, pancreatitis, etc. As a result of decreased muscle tone, it can cause bloating, constipation, loss of appetite, indigestion, nausea, vomiting, etc.
(3) Soft tissue: non-specific joint pain.
(4) Skin: Itchy skin.
(5) skeletal system: early bone pain, especially the lower back, hip, ribs, limbs, local bone tenderness, other extrarenal manifestations of multiple parts of calcification, such as cartilage and blood vessels, calcification of soft tissue around the joints, eyes Calcification (discussed in banded keratopathy), or calcification of the conjunctiva, can cause high calcium crisis when severe hypercalcemia, and pseudo gout, anemia and high blood pressure.
2. The performance of kidney disease
(1) Kidney stones: Kidney stones are the most common single complaint in patients with symptomatic primary hyperparathyroidism. About 5% of patients with hyperparathyroidism have kidney stones, while those with kidney stones are caused by primary hyperparathyroidism. About 5%, mostly multiple kidney stones, kidney stones often consist of calcium phosphate or calcium oxalate, recurrent kidney stones found in 60% to 70% of patients; kidney stones can cause urinary tract obstruction and complex urinary tract infections Repeated episodes, severe cases may cause renal damage, kidney colic, gross hematuria or microscopic hematuria, with nausea, vomiting and other systemic symptoms.
(2) Renal calcification: extensive calcium phosphate complex deposition in the kidney causes renal calcification, renal calcification refers to renal medullary calcification, caused by long-term hypercalcemia and dehydration, and ultimately severe cases can lead to progressive chronic renal failure, can also Calcification occurs in other parts, such as cartilage and blood vessels and soft tissue calcification around the joints. This is more common in secondary hyperparathyroidism caused by renal failure. Eye calcification is characterized by banded keratopathy or deposition in the conjunctiva. visible.
(3) Kidney concentrating function damage: due to long-term hypercalcemia affecting the renal medulla, leading to renal dysfunction, polyuria and decreased blood volume, and due to the large amount of calcium in the urine to solute diuresis, patients often perform Dry mouth, polydipsia, polydipsia, and more urine.
(4) Bone lesions: mainly manifested as osteoporosis and bone resorption. The periosteum, skull and alveolar bone plate of the finger bone are good sites. When the disease course is long or severe, cystic fibrous osteitis can be developed. Brown tumors and bone cysts are prone to pathological fractures. Typical bone lesions are cystic fibrosis. Percutaneous bone biopsy shows typical narrowing of cortical width, increased bone formation and bone resorption surface, and bone demineralization on X-ray. Subperiosteal absorption of the humerus, long bone brown tumor and bone cyst, skull-like shadow, tooth hard layer disappeared, advanced fibrocystic osteitis, skeletal deformity and pathological fracture, which may cause difficulty in walking, even in bed Some patients have bone cysts, which are manifested as local bone bulges.
In recent years, the bone density meter has been used to detect the decrease in the density of long bone cortex in patients with hyperparathyroidism. However, the X-ray examination is still normal at this time, so the former is a sensitive detection technique.
Examine
Primary hyperparathyroidism and nephropathy
The laboratory tests for parathyroidism mainly include the following:
1. Increased blood calcium The normal value of total calcium in the blood is 2.25 ~ 2.75mmol / L (9 ~ 11mg / dl), almost all patients with hyperparathyroidism have increased blood calcium, rare "blood calcium normal parathyroid" In fact, blood calcium is intermittently increased, and should be repeatedly measured. If PHPT is accompanied by vitamin D deficiency, rickets, renal insufficiency, pancreatitis and rare parathyroid adenoma necrosis, there is no high calcium. Blood.
2. The normal value of blood phosphorus to reduce blood phosphorus is 0.97~1.45mmol/L (3~4.5mg/dl). Because PTH can inhibit the reabsorption of phosphorus by renal tubules and increase the phosphorus excretion of kidney, the blood of typical PHPT Phosphorus is reduced, but due to various factors such as diet, age and renal function, only half of the patients in PHPT have decreased serum phosphorus, and the rest of the patients have normal low limit. If chronic renal failure occurs in the later stage of the disease, Blood phosphorus can be normal or even high, but blood phosphorus>1.83mmol/L does not support the diagnosis of PHPT. Hypercalcemia with hypophosphatemia supports the diagnosis of PHPT, which can be based on hypercalcemia caused by bone metastasis of malignant tumor. Identification of patients with normal or elevated blood phosphorus.
3. Urinary calcium increased urinary calcium normal value is 50 ~ 62.5mmol / 24h (200 ~ 250mg / 24h), renal calcium threshold is 0.175 ~ 2.0mmol / L (7 ~ 8mg / dl), so hypercalcemia often followed Increased urinary calcium, because PTH can promote the reabsorption of calcium by renal tubules, resulting in high urinary calcium in hyperparathyroidism compared with other high calcium caused by hypercalcemia, urinary calcium excretion is best in urine Calcium clearance rate / creatinine clearance ratio calculation, hypercalcemia patients with urinary calcium <60mmol / 24h, support the diagnosis of PHPT.
4. The urinary phosphorus increased the normal value of urinary phosphorus was 22.448mmol/24h (0.71.5g/24h). In patients with PHPT, the reabsorption of phosphorus (TRP) by renal tubules decreased (<83%), and the phosphorus in urine increased. However, if the blood phosphorus is significantly reduced in this patient, the absolute value of phosphorus excretion in urine can be reduced to the normal range, while the relative value is still high, and there is hypophosphatemia and urine phosphorus >19.2mmol/24h (0.6g/24h). , has a diagnostic value for this disease.
5. Radioimmunoassay of PTH in blood The normal value of plasma iPTH is 100-500pg/ml. The iPTH of parathyroidism can be increased or at the normal high limit. Compared with the blood calcium value of the same blood sample, the relative value is significantly increased. PTH in blood increases in parallel with blood calcium; PTH in blood is negatively correlated with blood calcium in secondary hyperparathyroidism; iPTH is extremely low or undetectable in hypercalcemia caused by parathyroidism However, PTH in the blood does not distinguish the primary atopic (heterologous) PTH syndrome. In recent years, the intermediate fragment of PTH44-68 has been measured by sensitive radioimmunoassay, which greatly improves the sensitivity of diagnosis, high calcium. Hyperemia with elevated PTH is the most important direct basis for the diagnosis of PHPT, but it should be noted that in renal failure, due to the dysfunction of the carboxy-terminal fragment of PTH35-84, the measurement results may be abnormally increased, and high blood calcium and lower PTH may exclude PHPT.
6. Urinary cyclic adenosine monophosphate (cAMP) increased in normal urine total cAMP was 1.83 ~ 4.55nmol / dl, PTH can bind to specific receptors in renal tubular epithelial cells, so that cAMP production increased, so urine cAMP increased It is the basis for indirect diagnosis of parathyroidism.
7.1,25-(OH)2D3 determination of PTH can activate 1-hydroxylase in the renal tubules, increasing the 1,25-(OH)2D3 produced by the kidneys. Most patients with hyperparathyroidism, especially those with increased urinary calcium and kidney stones, are increased. , but this measurement can overlap with normal people.
8. Mild hyperchloremia acidosis PTH can directly inhibit the reabsorption of bicarbonate by renal tubules, and hypophosphatemia can also inhibit the reabsorption of bicarbonate, so hyperparathyroidism can be complicated by high blood chlorine. Acidosis, hypercalcemia in non-parathyroidism promotes renal tubular reabsorption of bicarbonate, which can cause hypochlore alkalosis. Hyperchlorinated acidosis of hyperparathyroidism is mostly in parathyroidectomy. After recovery, but occasionally in the first few days after surgery, metabolic acidosis, but worse, may be associated with postoperative renal function deterioration, phosphate depletion, release of H during bone remineralization, or functional recovery of residual parathyroid tissue, etc. related.
9. Blood alkaline phosphatase, tartrate-resistant acid phosphatase and urinary hydroxyproline increase reflect the activity of osteoblasts, osteoclasts and bone turnover, respectively, often with osteoporosis Parallel, this is related to the accelerated rate of bone turnover.
10. Other laboratory tests The following tests have reference value for the diagnosis of parathyroidism and renal damage:
(1) Blood potassium and blood magnesium can be reduced: this is related to the decrease in concentration function caused by renal lesions of hyperparathyroidism.
(2) Phosphorus clearance test (CP): Patients with hyperparathyroidism often >15 ml/min, but the sensitivity of this test is poor.
(3) Calcium tolerance test and calcium inhibition test: After normal person calcium transfusion (intravenous rapid infusion of 180mg calcium is equivalent to 10% calcium gluconate 20m1), PTH is obviously inhibited, and even can not be measured, urine phosphorus release is reduced, uP The /uCr ratio was lower than that before calcium transfusion, and most of the PTH in patients with hyperparathyroidism was autocrine. PTH did not decrease or decreased after calcium transfusion, but it was still higher than the normal low limit; urinary phosphorus decreased not significantly (<20%) or even Still rising, this measurement helps in the diagnosis of light early PHPT.
(4) Low calcium test: After a low calcium diet in patients with hyperparathyroidism, the urinary calcium is still >50 mmol/24 h (200 mg/24 h).
(5) Phosphorus test (phosphorus deprivation test): normal people give low-phosphorus diet, while taking aluminum hydroxide, blood phosphorus is reduced and intestinal calcium absorption is increased, thereby inhibiting the secretion of PTH, reducing urinary phosphorus, and significant uP/uCr Reduced, the blood calcium of patients with hyperparathyroidism increased significantly and urinary phosphorus did not decrease, uP/uCr did not change significantly, urinary calcium>62.5mmol/24h (250mg/24h), the test is suitable for blood calcium at the normal high limit Hey patients.
(6) glucocorticoid inhibition test: first measure blood calcium twice as a control, then oral prednisone 10mg, once every 8 hours, even for 10 days, while measuring blood calcium, once every other day; parathyroidism patients There was no significant reduction in blood calcium, and hypercalcemia in hyperparathyroidism was significantly lower in blood calcium after taking glucocorticoids.
(7) urine routine examination: visible proteinuria, hematuria, increased urinary calcium, increased urinary phosphorus, increased urinary cyclic adenosine monophosphate (cAMP).
11. X-ray examination varies greatly with the length of the disease and the severity of the disease. It can be changed from mild decalcification to complete disappearance of bone and increased fibrous tissue. The following X-ray signs are diagnostically significant:
(1) Subperiosteal absorption of long bones, the most characteristic of the subclavian bone resorption and the subperiosteal bone resorption of the temporal side, followed by the reductive decalcification or streaked bone resorption at the distal end of the clavicle.
(2) Alveolar bone plate bone absorption, but the specificity is poor, can also be caused by periodontal disease.
(3) The bone absorption of the skull is a ground-glass-like or "black-and-white speckled" worm-like image, which is more diagnostic if the edges of the inner and outer bone plates are blurred.
(4) fibrous osteitis and cystic changes, the bone is frosted glass, small cysts appear under the cortex, larger cysts can make the cortical bone expand spherical or oval, similar to osteoclast-like structure, this Bone damage often invades the frontal bone to form a "brown tumor."
(6) The vertebrae are flattened or fishbone, and the intervertebral space is widened.
(7) Obvious bone decalcification, softening and fibrosis, which can cause fractures and deformities. Chinese scholars have found that there are many X-ray signs and pseudo-fractures of osteoporosis in the parathyroid bone disease. Calcium and vitamin D intake are insufficient.
(8) X-ray manifestations of the kidney: kidney stones are 20% to 40%, mostly bilateral, and the calcium deposits in the renal parenchyma account for about 10%, mostly diffuse.
(9) ectopic calcification: less common, can occur in the kidney, burs, joint cartilage and other parts.
12. The location of the diagnosis of parathyroid glands is variable and the number and size are varied. According to various reports, ectopic parathyroid glands range from 3% to 39%. Common variant sites include mediastinal upper part, thyroid gland, pharynx and esophagus. After the thymus or thyroid gland, it can be seen in the carotid bifurcation, other parts of the mediastinum or pericardium. Therefore, it is important for a small number of patients who failed the first surgical exploration to make a localization diagnosis before reoperation. The following may be selected as appropriate. Special inspection.
(1) Ultrasound examination of the neck: The high-resolution B-ultrasound probe has a diagnostic accuracy of more than 80%, but it is not easy to find adenomas with a diameter less than 1 cm and an ectopic parathyroid gland.
(2) CT scan: ectopic PHPT syndrome caused by mediastinal adenoma with diameter greater than 1 cm and malignant tumor can be detected.
(3) Radionuclide examination: 125I, 99mTc, 201TI and 75Sc methionine scan, more than 80% of lesions can be found.
(4) Selective venous intubation blood sampling PTH: PTH was measured by the lateral neck and mediastinal cannula, and the concentration of PTH in the drainage vein and peripheral blood was compared. The former was significantly higher than the latter, suggesting that the side had parathyroid glands. Adenoma, if there is no significant difference in PTH values between the upper and lower venous blood of the bilateral parathyroid glands, suggesting that the hyperplasia or lesions are in the mediastinum, the correct rate of diagnosis is above 80%.
Diagnosis
Diagnosis of primary hyperparathyroidism and diagnosis of nephropathy
Diagnostic criteria
Early mild parathyroidism is often asymptomatic or has only non-specific symptoms, depending on the determination of ions or repeated determination of total calcium in the blood, bone densitometry and calcium inhibition tests for the determination of parathyroid function. Typical PHPT is high. The clinical manifestations of the blood calcium group, as well as bone and kidney, can exist alone or in combination; if the blood calcium is increased, the blood phosphorus is lowered, the urinary calcium is increased, the renal tubular reabsorption of phosphorus is lowered, and the X-ray examination has bone resorption. And the characteristic manifestations of dissolution, kidney ultrasound and X-ray examination found that the diagnosis of the disease should be considered, if necessary, blood PTH and various biochemical tests reflecting the function of the parathyroid gland, but slow renal damage and bone disease, It is often difficult to cause the patient and doctor's attention and delay diagnosis. Conversely, pseudohypercalcemia caused by laboratory factors can also cause misdiagnosis and should be noted.
Differential diagnosis
1. Identification of hypercalcemia should be caused by other causes
(1) thiazide diuretic: This medicine can increase the effect of PTH on bone and kidney, and reduce the excretion of urinary calcium, thus causing mild hypercalcemia, but if the blood calcium is significantly increased after administration, after stopping the drug Blood calcium can not be quickly reduced, and mild hyperparathyroidism should be suspected.
(2) Vitamin D poisoning: Vitamin D poisoning can promote the absorption of intestinal calcium and bone and cause high blood calcium. The diagnosis depends on the intake history of vitamin D (generally > 10,000 U / d), accompanied by high blood phosphorus and mild Metabolic alkalosis, glucocorticoid inhibition test helps to identify, in conditions, the blood concentration of vitamin D or its hydroxylate can be determined.
(3) Hypercalcemia caused by malignant tumors: Hypercalcemia caused by malignant tumors, which is the most common type of hypercalcemia in the differential diagnosis of hyperparathyroidism. Especially, multiple myeloma is most likely to be confused with PHPT. The patient has extensive osteolytic bone destruction, bone pain, hypercalcemia, high urinary calcium and renal dysfunction, but alkaline phosphatase is normal or only slightly elevated, blood phosphorus is normal, blood PTH is normal or decreased, and The specific immunoglobulin is increased, the protein in the urine is mostly positive, the erythrocyte sedimentation rate is increased, the bone marrow biopsy has myeloma cells, and many other malignant tumors (commonly include lung, breast, liver, kidney, adrenal gland, prostate, ovary, etc.) Malignant tumors can occur with osteolytic metastases, and are also prone to increased serum calcium, but limbs are particularly vulnerable to invasion at the distal end. In addition, there is a type of pseudoparathyroidism due to the secretion of PTH-like substances by tumor cells (measured iPTH increased) ), growth factor (TGF8), prostaglandin, interleukin-2 (IL-2), osteoclast activating factor (OAF) or 1,25-(OH)2D3 and other humoral factors, causing hypercalcemia, but not dissolution Bone bone metastasis, generally normal or reduced blood chlorine, can be light Metabolic alkalosis, often anemia and elevated ESR fast, fast progression, the primary tumor has local and systemic symptoms, after resection of the primary tumor calcium return to normal.
(4) idiopathic hypercalciuria: this disease has a significant increase in urinary calcium, but blood calcium is normal.
(5) familial benign hypercalcemia: characterized by asymptomatic or mild hypercalcemia, hypermagnesemia, hypocalciuria, normal or low serum PTH, which is not uncommon in recent years. Is an autosomal dominant hereditary disease, this disease due to renal-derived cAMP high sensitivity to PTH, may be a form of functional hyperparathyroidism, although clinically similar to PHPT high blood calcium, hypophosphatemia, urinary phosphorus and Urinary cAMP increased, but the patient's calcium and magnesium clearance rate is lower than PHPT, urinary calcium is mostly <2.5mmol / 24h (100mg / 24h); only a small number of patients with urinary calcium secondary to high blood calcium is high, and There are multiple calcium oxalate combinations, but there are few hypercalcemia syndromes, no bone damage to parathyroidism, normal or reduced PTH in the blood, normal or hyperplasia of the parathyroid glands, and should not be mistaken for parathyroidectomy. .
(6) should be related to the identification of bone diseases: metabolic bone disease such as osteoporosis, rickets, renal osteodystrophy, fibrous dysplasia of bone, osteoarthritis (Paget disease), etc. It can be identified by the characteristics of biochemistry and X-ray.
(7) Identification of kidney performance or kidney disease due to other causes.
2. Exclusion of secondary hyperparathyroidism (Table 1) is generally not difficult.
