Overview of the disease
A group of clinical syndromes caused by overproduction of parathyroid hormone, mainly manifested as bone pain, bone deformity, pathological fracture, polydipsia, polyuria, hematuria, etc. This disease is mainly caused by overproduction of parathyroid hormone, different types of hyperparathyroidism treatment varies, including drug treatment and surgical treatment.
Definition
Hyperparathyroidism, or hyperparathyroidism for short, is a clinical syndrome caused by excessive secretion of parathyroid hormone (PTH) by the parathyroid glands, which is mainly characterized by hypercalcemia, hypophosphatemia, hypercalciuria, hyperuricosuria.
Classification
Classification is based on the cause of the disease and can be divided into the following three types.
Primary hyperparathyroidism (PHPT)
Abbreviation: primary hyperparathyroidism.
It is caused by overproduction of PTH due to primary lesions in the parathyroid tissue.
The most common pathology is a single parathyroid adenoma, with a few cases of parathyroid hyperplasia or parathyroid carcinoma.
Secondary hyperparathyroidism (SHPT)
Abbreviated secondary hyperparathyroidism.
It is often caused by various reasons of hypocalcemia which stimulates the parathyroid glands to hyperplasia and hypertrophy and secretion of excessive PTH.
It is seen in chronic kidney disease, osteochondrosis, intestinal malabsorption syndrome, vitamin D deficiency and hydroxylation disorders.
Tertiary hyperparathyroidism
Abbreviation: tertiary hyperparathyroidism.
It is caused by the development of functionally autonomous hyperplasia or tumors that autonomously secrete too much PTH on the basis of secondary hyperparathyroidism due to persistent stimulation of the gland.
It is common in chronic kidney disease and after kidney transplantation.
Pathogenesis
Primary hyperparathyroidism is a common endocrine disease, and there is a lack of data on its incidence or prevalence in China.
Some foreign studies have reported that the prevalence of primary hyperparathyroidism is as high as 1 /500~1,000 [1].
Primary hyperparathyroidism is more common in women, with a male-to-female ratio of about 1: 3, and most patients are postmenopausal women [1].
The detection rate of hyperparathyroidism is increasing, and the proportion of asymptomatic patients is also increasing, reaching 50% to 80% [2].
Etiology
Causes
Primary hyperparathyroidism
Hyperparathyroidism is caused by overproduction of parathyroid hormone due to parathyroid adenomas, hyperplasia, or adenocarcinoma, but the exact etiology is unclear.
Adenoma
Adenomas account for about 80% to 90% of cases, single parathyroid adenomas account for about 85% of cases, and multiple adenomas are rare, accounting for about 5% of cases.
Hyperplasia
About 10%～15%, often all four glands are involved.
Adenocarcinoma
Parathyroid adenocarcinoma accounts for less than 1% of cases.
Secondary hyperparathyroidism
Vitamin D deficiency
Lowering of blood calcium due to decreased intestinal calcium absorption, which stimulates parathyroid glands to proliferate and secrete excessive hormones.
Diseases of stomach, intestines, liver, gallbladder and pancreas
Causes malabsorption of fat-soluble vitamin D, causing low blood calcium.
Chronic kidney disease, renal insufficiency
During renal insufficiency, blood phosphorus is increased, blood calcium is decreased, and PTH concentration is increased.
There may also be metabolic disorders of vitamin D activation, decreased formation of 1,25-dihydroxyvitamin D (1,25-(OH)2D), which affects intestinal calcium absorption and aggravates the tendency to hypocalcemia.
Long-term phosphorus salt deficiency and hypophosphatemia
Renal tubular acidosis lesions such as Fanconi syndrome, genetically related hypophosphatemia or chronic aluminum hydroxide administration.
Pseudohypoparathyroidism.
The parathyroid glands can be stimulated by low blood calcium and high blood phosphorus due to inadequate PTH effects.
Calcitonin
Excess calcitonin can be caused by medullary thyroid carcinoma, for example, which can also stimulate the parathyroid glands.
Others
Such as pregnancy, breastfeeding, and cortisolism can also cause secondary hyperparathyroidism.
Tertiary hyperparathyroidism
It develops on the basis of secondary hyperparathyroidism.
If the parathyroid glands overreact to various stimulating factors, or the glands are subjected to persistent stimulation and continue to proliferate beyond their physiological needs, some of the proliferative tissue in the glands transforms into adenomas, which can autonomously secrete excessive amounts of PTH.
Symptoms
The disease may cause a series of clinical manifestations, which are similar for all types of hyperparathyroidism and may involve multiple systems of the body, as follows.
Non-specific symptoms
Weakness, fatigue, weight loss and loss of appetite.
Main Symptoms
Skeletal symptoms
Often manifested as generalized, diffuse, gradually aggravating bone and joint pain, and bone pain in weight-bearing parts of the skeleton is more prominent, such as the lower limbs and lumbar vertebrae.
Patients with a longer course of the disease may develop skeletal deformities, including thoracic collapse, scoliosis, pelvic deformity, and curvature of the limbs.
There may also be shortening of height, spontaneous fractures, reduced mobility, restricted movement, loose or lost teeth, etc.
Urinary system symptoms
Thirsty, excessive drinking, polyuria, renal colic, hematuria, gravel-like stones in the urine, etc. may occur.
Also prone to recurrent urinary tract infections, there may be frequent urination, urinary urgency, urinary pain and so on.
Digestive system symptoms
There may be poor appetite, nausea, vomiting, dyspepsia, constipation, epigastric pain, black stools and other symptoms.
Some hypercalcemia patients may be accompanied by acute and chronic pancreatitis, which may include epigastric pain, nausea, vomiting, poor appetite and diarrhea.
Cardiovascular symptoms
Hypertension is the most common cardiovascular manifestation, which may include dizziness, head swelling, headache, etc. A few patients may have tachycardia.
A few patients may have tachycardia or bradycardia, and patients with severe hypercalcemia may have obvious cardiac arrhythmias, such as atrioventricular block.
Neuromuscular symptoms
Patients with hypercalcemia may have apathy, depression, irritability, slow response, memory loss, and in severe cases, even hallucinations, mania and coma.
Easy to appear limb fatigue, muscle weakness, mainly manifested in the proximal extremities of the main muscle strength decline.
Some patients also show muscle pain, muscle atrophy, tendon reflexes are weakened.
Psychosomatic symptoms
There may be lethargy, drowsiness, depression, neuroticism, decreased social interaction ability, and even cognitive impairment.
Blood system symptoms
Some patients can be combined with anemia, especially patients with long course of the disease or parathyroid cancer patients, and may have fatigue, pallor, whitening of eyelids and so on.
Other metabolic symptoms
Easy to have premature aging, patients may also have dry mouth, polydipsia, polyuria, abnormal skin sensation, etc. due to high blood calcium.
Complications
Parathyroid crisis
Parathyroid crisis is caused by severe hypercalcemia (usually >3.5 mmol/L).
There is usually a history of hyperparathyroidism and hypercalcemia for many years, and parathyroid crisis often occurs when symptoms worsen with dehydration (e.g., recurrent vomiting, diarrhea, etc.), surgery, ingestion of large amounts of calcium, and bleeding or rupture of a cystic parathyroid adenoma.
There may be weakness, anorexia, nausea, vomiting, polyuria, water loss, collapse, and altered mental status, even coma.
Consultation
Department of Medicine
Endocrinology
If physical examination reveals elevated blood calcium, decreased blood phosphorus, bone pain, bone deformity, or abnormal glucose metabolism, it is recommended to consult a doctor promptly.
Cardiovascular Medicine
When bradycardia, arrhythmia, etc. occur, it is recommended to consult a doctor in time.
Urology
When urinary frequency, urgency, pain in urination, hematuria, stones in urine, etc. occur, it is recommended to consult a doctor in time.
Emergency Department
When there is severe hypercalcemia, weakness, drop in blood pressure, drowsiness, coma, etc., it is recommended to seek medical treatment immediately.
Preparation for medical treatment
Preparation for medical consultation: registration, preparation of documents, common problems
Tips for seeking medical treatment
Wear loose-fitting clothes that are easy to put on and take off for the doctor’s examination.
Preparation Checklist
Symptom list
Pay particular attention to the time of onset of symptoms and special signs and symptoms.
Is there bone pain? Where is the bone pain?
Are there any bone deformities, shortening of stature?
Is there irritable thirst, excessive drinking, excessive urination?
Is there frequent, urgent, painful or bloody urination?
Is there apathy, depression, irritability, unresponsiveness, memory loss?
Any loss of appetite, bloating, nausea, vomiting, constipation, abdominal pain?
How long have the above symptoms lasted?
List of medical history
Does anyone in the family have hyperparathyroidism?
Is there any history of vitamin D deficiency?
Any history of gastrointestinal, hepatobiliary, or pancreatic disease?
Is there a history of chronic kidney disease or post kidney transplant?
Is there a history of bone fractures?
Checklist
Test results of the last six months, which can be brought to the doctor’s office
Laboratory tests: blood calcium, blood phosphorus, urinary calcium, urinary phosphorus, blood PTH, serum alkaline phosphatase, blood creatinine ( Cr) and urea nitrogen ( BUN) levels, blood vitamin D, cortisol suppression test, etc.
Imaging tests: skeletal X-ray, bone imaging, renal pelvis X-ray, radionuclide examination, parathyroid ultrasound, CT or MRI.
Medication list
Medication used in the last 3 months, if available in a box or package, bring it with you to the doctor’s office
Bisphosphonates/Alendronate, etc.
Estrogens/estrogen, estradiol, etc.
Selective estrogen receptor modulators/Raloxifene, etc.
Calcimimetics/Cinacalcet, etc.
Diagnosis
Diagnosis is based on
Medical History
Patients with hyperparathyroidism may have a history of the following.
Presence of a history of recurrent or active urinary stones or renal calcium salts deposition disease.
Osteoporosis of undetermined cause, especially with subperiosteal bone cortical resorption and/or alveolar bone plate resorption and bone cyst formation.
“Giant cell tumors” of the long bones, ribs, jaws, or clavicles, especially if multiple.
Unexplained nausea, vomiting, peptic ulcers, persistent constipation or recurrent pancreatitis.
Unexplained psychoneurologic symptoms, especially with thirst, polyuria and bone pain.
Persons with a positive family history and mothers of children with neonatal tetany.
Those who develop hypercalcemia with prolonged use of lithium preparations.
Hypercalciuria with or without hypercalcemia.
Hypercalcemia with or without calcium supplementation, vitamin D preparations, or thiazide diuretics.
Clinical manifestations
Mainly includes symptoms of hypercalcemia, skeletal lesions and urinary tract lesions.
Symptoms of hypercalcemia: there may be neuromuscular symptoms such as apathy, lethargy, personality change, mental retardation, memory loss, easy fatigue, etc., and digestive symptoms such as loss of appetite, nausea, vomiting, abdominal distension, abdominal pain, constipation and acid reflux.
Skeletal lesions: there may be extensive bone and joint pain and pressure pain, and there may be bone deformities, such as shoulder joint sagging, hunchback, short height, rib cage and pelvis collapsing with “chicken breast”, and so on.
Urinary symptoms: polyuria, renal colic, hematuria, urine gravel, etc.
Laboratory tests
Serum calcium
Increased blood calcium is the most meaningful for diagnosis.
Blood calcium should be regarded as a suspected case if it is repeatedly >2.7mmol/L (10.8mg/dl), and >2.8mmol/L (11.2mg/dl) is of greater significance.
When determining blood calcium levels, attention should be paid to the use of serum albumin level correction, serum albumin concentration of less than 40 g / L (4 g / dl), every 10 g / L (1.0 g / dl) caused by a decrease in blood calcium levels 0. 20mmol / L (0.8 mg / dl).
Free Calcium
In normal subjects, the blood free calcium level is (1.18 ± 0.05) mmol/L. The results are more useful than total calcium for diagnosis.
The results are more sensitive than total calcium in diagnosing hypercalcemia and are not affected by albumin levels.
Serum phosphorus
Most <1.0 mmol/L, but less diagnostic than blood calcium.
Blood phosphorus may be elevated in renal insufficiency or high phosphorus intake.
Serum alkaline phosphatase
May be normal early on in those presenting with urinary calculi alone, but is almost always increased to varying degrees in those with skeletal lesions.
Urinary calcium and phosphorus
Most patients have increased urinary calcium excretion, with 24-h urinary calcium >250 mg in women and >300 mg in men, or 24-h urinary calcium excretion >4 mg/kg.
Urinary phosphorus excretion increases, but urinary phosphorus is affected by factors such as diet and renal tubular function.
Blood creatinine (Cr) and urea nitrogen (BUN) levels.
Cr and BUN levels are elevated in patients with hyperparathyroidism associated with dehydration or renal damage.
Blood Parathyroid Hormone (PTH)
Measurement of PTH is essential for the diagnosis of hyperparathyroidism.
The diagnosis of primary hyperparathyroidism is considered when the patient has hypercalcemia with blood PTH levels that are above normal or in the high normal range.
If there is only an increase in blood calcium without an increase in PTH, one needs to be wary of hypercalcemia due to malignancy or other causes.
Blood PTH may also be markedly elevated in patients with secondary hyperparathyroidism, but most have normal or low blood calcium and a few have elevated blood calcium.
Blood Vitamin D
Excess PTH can cause higher than normal blood levels of 1,25-dihydroxyvitamin D3 (1,25(OH) 2D3).
Urinary hydroxyproline excretion measurement
Urinary hydroxyproline excretion is increased and normal values in adults are usually in the range of (20±11) mg/d.
Cortisol inhibition test
Cortisol 50~100mg/d or prednisone 30mg/d (in 2~3 times) for 10 days.
Serum calcium does not decrease in patients with primary hyperparathyroidism, and may decrease in other causes of hypercalcemia such as carcinoid tumors, nodular disease, vitamin D intoxication, and multiple myeloma.
Selective thyroid venous blood sampling for PTH measurement
It is an invasive localization test for primary hyperparathyroidism.
Blood is taken from different sites (e.g. superior, middle and inferior thyroid veins, thymic vein, vertebral vein), and peripheral blood is collected as a control, and a 1.5 to 2-fold elevation of blood PTH is meaningful.
Intraoperative PTH monitoring
Rapid intraoperative measurement of changes in PTH levels allows intraoperative determination of whether hyperfunctioning parathyroid tissue has been removed.
Before removing the last hyperfunctioning parathyroid tissue, peripheral blood was taken as the preoperative PTH value, and the PTH level was measured in peripheral blood at 5, 10, and 15 min after the resection, and a decrease of 50% or more in PTH within 10 min after the operation suggested that the hyperfunctioning tissue had been removed.
Imaging
Bone X-ray
Bone abnormalities such as osteoporosis, osteochondrosis, osteosclerosis, subperiosteal resorption and cystic degeneration of bone can be seen in the X-ray film of the patient.
Bone imaging
It is a nuclear medicine functional imaging technique with high sensitivity to reflect bone lesions and can detect lesions earlier than other radiologic examinations.
Mild primary hyperparathyroidism may appear normal on bone imaging.
In severe primary hyperparathyroidism, the typical features of metabolic bone disease, such as “black skull”, “beading”, and “necktie sign” can be seen on bone imaging.
Renal pelvis X-ray
X-rays are the most commonly used imaging test of the urinary system, and may reveal urinary tract stones or calcium deposits in the renal parenchyma.
Ultrasound of parathyroid glands
Ultrasound is an effective tool for preoperative localization of hyperparathyroidism.
Ultrasound sonograms may show parathyroid adenoma, parathyroid hyperplasia, and parathyroid adenocarcinoma.
Ultrasound-guided measurement of PTH in parathyroid lesions
Helps to determine whether the lesion is of parathyroid origin.
It provides an effective preoperative diagnostic method for those who are unable to locate the lesion on preoperative imaging and those who have recurrence of primary hyperparathyroidism and need to re-localize the lesion for surgery.
Radionuclide examination
99mTc-MIBI ( 99mTc-Methoxyisobutylisocyanide) is the most widely used tracer for parathyroid imaging.
After intravenous injection of 99mTc-MIBI 740-1110 MBq (20-30 mCi), early and delayed visualization of the thyroid gland is obtained at 10-30 min and 1.5-2.5 h, respectively.
Typical hyperfunctioning parathyroid tissue images were early phase and delayed phase.
CT and MRI
CT and MRI are helpful in localizing parathyroid lesions but are not currently the imaging methods of choice for parathyroid lesions.
CT and MRI are mainly used to determine the exact location of the lesion, the relationship between the lesion and surrounding structures, and the morphologic features of the lesion itself.
Differential diagnosis
Malignant tumors
Both have elevated blood calcium, but malignant tumors such as lung, liver, thyroid, kidney, adrenal gland, prostate, breast and ovarian tumors cause hypercalcemia through bone metastatic destruction or secretion of humoral factors, and clinically have the characteristic manifestations of the primary tumor, and the blood PTH level is normal or reduced.
Familial low urinary calcium hypercalcemia
All can lead to elevated blood calcium, but familial hypocalcemic hypercalcemia has normal or higher than normal blood PTH, normal or lower than normal blood phosphorus, mildly increased serum calcium, decreased urinary calcium, usually asymptomatic, and does not require treatment, is genetically related, and has a family history of inheritance.
Hyperthyroidism
All can lead to elevated blood calcium, but hyperthyroidism is excessive thyroid hormone leading to increased bone resorption, some patients may have mild hypercalcemia, increased urinary calcium, accompanied by osteoporosis, clinically there is a corresponding manifestation of hyperthyroidism, the blood PTH level is normal or reduced.
Treatment
Aim of treatment: control hypercalcemia, remove the cause of the disease, and control the development of the disease.
Treatment principle: The treatment methods are different between each type of hyperparathyroidism, mainly including surgery, drug treatment and so on.
Primary hyperparathyroidism
Surgery
Surgery is the preferred treatment for primary hyperparathyroidism.
Indications for surgery
Patients with symptomatic primary hyperparathyroidism.
Asymptomatic primary hyperparathyroidism in combination with any of the following conditions
Hypercalcemia, with calcium 0.25 mmol/L (1 mg/dL) above the upper limit of normal.
Renal impairment with creatinine clearance below 60 ml/min.
Bone mineral density values 2.5 standard deviations below peak bone mass (T-value < -2.5) at any site and/or fragility fractures.
Age less than 50 years.
Patient is not available for routine follow-up.
No contraindications to surgery and clear localization of the lesion.
Postoperative monitoring and follow-up
Regular postoperative follow-up visits should be conducted once every 3-6 months, and can be gradually extended to once a year if the condition is stabilized.
Follow-up observation includes symptoms, signs, blood calcium, blood phosphorus, bone conversion index, PTH, creatinine, urinary calcium and bone density.
Medication
For patients with primary hyperparathyroidism who are inoperable or refuse to undergo surgery, drug treatment and long-term follow-up can be considered. If severe hypercalcemia or even hypercalcemic crisis occurs, it should be treated in time.
Treatment of hypercalcemia
The most fundamental way to treat hypercalcemia is to remove the cause of the disease. The treatment of hypercalcemia depends on the blood calcium level and clinical symptoms.
Usually, patients with mild hypercalcemia and no clinical symptoms do not require special treatment. Patients with moderate hypercalcemia who develop signs and symptoms require aggressive treatment.
When blood calcium is >3.5 mmol/L, effective measures should be taken immediately to reduce the blood calcium level, regardless of whether there are clinical symptoms.
The principles of treatment for hypercalcemia include volume expansion, promotion of urinary calcium excretion, and inhibition of bone resorption.
The first step is to replenish the extracellular fluid volume with saline, usually 0.9% sodium chloride injection, which should be used with caution in elderly patients and patients with cardiac and renal insufficiency.
After the extracellular fluid volume is replenished, furosemide can be used intravenously to promote urinary calcium excretion.
Bisphosphonates: Intravenous use of bisphosphonates is the most effective method of controlling hypercalcemia, and the ones currently used in China are pamidronate, zoledronic acid and ibandronate.
Calcitonin: Calcitonin has a fast onset of action and fewer adverse effects, but its effect is not as significant as that of bisphosphonates. Therefore, calcitonin is mostly used in patients with hypercalcemia crisis, and it is used in the transition period before the onset of bisphosphonate drugs. Commonly used drugs include salmon calcitonin and eel calcitonin.
Long-term treatment
Long-term drug therapy for patients who cannot or will not undergo surgery is as follows.
Bisphosphonates/Bisphosphonates can inhibit bone resorption and reduce bone loss, commonly used drugs are alendronate.
Estrogen/Short-term estrogen replacement therapy is mainly used for postmenopausal patients with primary hyperparathyroidism who have no contraindications to estrogen and do not have elevated blood calcium concentrations, and commonly used drugs include conjugated estrogen and estradiol.
Selective estrogen receptor modulators: mainly used in the treatment of postmenopausal osteoporosis, commonly used drugs are raloxifene.
Calcimimetic compounds: for those who cannot undergo surgery but have obvious symptoms of hypercalcemia or significantly elevated blood calcium, cinacalcet is a kind of calcimimetic compound currently used.
Secondary hyperparathyroidism
The treatment of secondary hyperparathyroidism focuses on the primary disease and consists of medication and surgery.
Pharmacologic treatment
For simple vitamin D deficiency, supplementation of appropriate amount of vitamin D to correct blood phosphorus and calcium abnormalities.
For hypophosphatemia and impaired vitamin D metabolism due to renal tubular lesions, supplementation of neutral phosphate and combined application of vitamin D, or osteotriol are appropriate.
For secondary hyperparathyroidism due to chronic renal insufficiency, the following treatments are available.
Application of vitamin D preparations to increase intestinal calcium absorption.
Oral calcium supplements or increasing calcium levels in the dialysis solution.
Oral aluminum hydroxide or aluminum carbonate to decrease phosphorus absorption and lower blood phosphorus.
Oral propranolol or metformin to inhibit PTH secretion.
Surgical treatment
Indications
Surgery can be considered if any one of the indications for surgery is met.
Severe intractable hyperphosphatemia.
Severe secondary hyperparathyroidism on dialysis (PTH > 800 to 1000 pg/mL without hypocalcemia) that has been ineffective for more than 12 months in response to combination therapy (combination of cinacalcet, phosphorus binders, and vitamin D analogs).
Patients with PTH levels higher than 500 pg/mL, with calcific defenses in the skin, and in whom medications are not immediately effective.
Development of complications associated with secondary hyperparathyroidism, such as tendon rupture, severe bone pain, or refractory anemia.
Contraindications
Severe skeletal deformities and osteoporosis.
Comorbid systemic diseases such as severe cardiac, pulmonary and cerebral dysfunction.
Severe coagulation disorders.
Surgical Procedures
There are 3 main types, i.e. total parathyroidectomy + autotransplantation, subtotal parathyroidectomy, and total parathyroidectomy.
Tertiary hyperparathyroidism
Tertiary hyperparathyroidism develops on the basis of secondary hyperparathyroidism, and treatment should include parathyroid exploration and subtotal resection.
Prognosis
Cure
With early diagnosis and aggressive treatment, most patients have a favorable prognosis, while a few may develop hypercalcemic crisis, which can be life-threatening.
Patients may develop recurrent urinary stones, infections, and even renal failure.
Hazards
Patients may have bone pain, osteoporosis, spontaneous fracture, etc., affecting normal work and life.
Repeated urinary tract infections and stones may occur, and even renal failure.
Hypercalcemic crisis may occur, and there may be polyuria, irritable thirst, polydipsia, dehydration, drowsiness, or even coma, which may jeopardize the patient’s life.
Daily
Daily management
Drink plenty of water. It is recommended to avoid high-calcium diet by eating less or no food with high calcium content, such as shrimp skin and sesame paste.
Avoid bumping to avoid fracture.
Take rest and have a regular routine.
Follow the doctor’s instructions to standardize the use of medication, do not increase or decrease the dose or stop the medication by yourself.
Disease monitoring
During the treatment period, you need to regularly monitor the levels of blood calcium, blood phosphorus, urinary calcium, urinary phosphorus, blood PTH, and adjust the dosage of medication under the guidance of the doctor, do not adjust the dosage on your own.
You need to pay attention to your own situation, if there is an aggravation of bone pain, recurrent urinary tract infections (painful urination, hematuria), etc., you need to consult a doctor in time.
Follow-up review
Under the guidance of the doctor, the levels of blood calcium, blood phosphorus, urine calcium, urine phosphorus and blood PTH should be monitored to guide the adjustment of drug dosage and the evaluation of treatment effect.
Prevention
Eat a sensible diet with a combination of meat and vegetables, drink more milk and other dairy products.
Drink plenty of water and avoid high calcium diet.
Ensure adequate sunlight exposure.
For patients with chronic kidney disease, gastrointestinal disorders, and long-term phosphorus salt deficiency, aggressive treatment is needed for these primary causes.