Primary hyperparathyroidism: what is it, causes, symptoms, treatment

What is primary hyperparathyroidism?

Primary hyperparathyroidism (PGPT) is a condition in which the parathyroid glands produce too much parathyroid hormone and the level of calcium in the blood rises. The parathyroid glands are part of the endocrine system, a network of glands that release hormones into the bloodstream, from where they travel to various areas of the body. The endocrine glands secrete hormones that regulate chemical processes (metabolism) that affect the functions of various organs and activities within the body.

Hormones are involved in many vital processes, including the regulation of heart rate, body temperature and blood pressure, as well as cell differentiation and growth, and modulation of certain metabolic processes. There are four tiny parathyroid glands on the neck. They are about the size of a pea. Parathyroid hormone (along with 

vitamin D) is the main regulator of blood calcium levels. It also affects blood phosphorus levels, bone growth, and bone cell activity.

Most people with primary hyperparathyroidism develop no symptoms or only very mild symptoms. Primary hyperparathyroidism mainly affects the skeleton and kidneys, but sometimes the heart, gastrointestinal tract, and nervous system can be affected. In about 80–85% of cases, PGPT is caused by a benign tumor called an adenoma, which is usually found in one of the four parathyroid glands.

Signs and symptoms

- Asymptomatic primary hyperparathyroidism.

The most common manifestation of primary hyperparathyroidism is when doctors find high levels of calcium in the blood but no accompanying symptoms. It is also called asymptomatic hypercalcemia. Some people with asymptomatic PGPT have reported fatigue, weakness, mild depression or mild cognitive dysfunction, such as mild problems with concentration or memory. Patients may also have bone loss (low bone mineral density) and "silent" stones in the kidneys and spinal fractures found on imaging. Eventually, asymptomatic primary hyperparathyroidism can progress and people can develop the symptoms seen in the classic form of PHPT.

- Classic primary hyperparathyroidism.

A characteristic feature of primary hyperparathyroidism is the formation of calcium kidney stones (nephrolithiasis). Kidney stones can cause lower back pain in the kidney area (renal colic) and pain in the lower abdomen. Sometimes kidney damage may develop, and the kidneys may function less efficiently than they should (chronic renal failure).

People who are sick can lose bone mineral density, which can contribute to thinning and weakening of bones (osteoporosis). The patient may be predisposed to bone fractures and may experience bone pain.

PGPT can cause a form of bone disease called osteitis cystic fibrosis. However, it is rare. Patients are prone to fractures and may have other skeletal abnormalities and bone pain or tenderness in the affected areas. Cystic fibrous osteitis occurs with progressive disease.

Many nonspecific symptoms are associated with classic primary hyperparathyroidism. Nonspecific means that the symptoms are common to many different diseases. These symptoms include:

• unintentional weight loss;
• vomiting;
• nausea;
• constipation;
• unnaturally strong, unquenchable thirst (polydipsia);
• Frequent urination (polyuria)

Some people who are affected experience weakness and fatigue.

Many people with primary hyperparathyroidism have reported neuropsychiatric symptoms, including depression, irritability, psychosis, and decreased social interaction. Cognitive dysfunction is possible, which means that there may be problems with concentration or memory, or people may experience a lack of mental clarity ("brain fog").

Sometimes PGPT can be associated with cardiovascular disease, including high blood pressure (arterial hypertension), irregular heart rhythms (arrhythmias), enlargement and thickening of the left lower heart chamber (ventricular hypertrophy) and induration due to calcium accumulation (calcification) of vessels and valves circulatory system. Generally, cardiovascular disease has been reported in people with severe primary hyperparathyroidism. Much is not fully understood about the relationship between primary hyperparathyroidism and cardiovascular disease (eg, the underlying cause of cardiovascular problems, their response to treatment, etc.). Research is ongoing to better understand these two conditions and how they interact or affect each other.

- Normocalcemic primary hyperparathyroidism.

This condition is characterized by high levels of parathyroid hormone but normal blood calcium levels. Symptoms associated with this form of primary hyperparathyroidism include kidney stones, bone loss, and fragile bones that can be prone to fractures (osteoporosis). Much of this disease remains unknown or not fully understood. Some researchers believe that the normocalcemic form of PGPT may be an early or mild form of classic PGPT.

- Crisis of the parathyroid gland (hypercalcemia).

Parathyroid crisis is a rare complication of primary hyperparathyroidism. Patients develop severe, life-threatening hypercalcemia. Symptoms may include changes in mental status, bone disease, dehydration and kidney stones. Sometimes nausea, vomiting, and severe abdominal pain. Some people with hypercalcemia or mild hyperparathyroidism later develop a hypercalcemic crisis (acute parathyroid failure). In other people, a hypercalcemic crisis may be the first sign of illness.

Causes and risk factors

The most common cause of primary hyperparathyroidism is a tiny, benign tumor called an adenoma. Usually one adenoma forms in one of the four parathyroid glands, but more adenomas are possible in several parathyroid glands. Parathyroid adenoma causes excessive activity of the affected gland. Multiple glandular hyperplasia is about 6-12%. This condition is characterized by an increase in several parathyroid glands due to the increased rate of reproduction of their cells. Multiple glandular hyperplasia occurs occasionally (sporadically) or as part of a larger genetic syndrome. Double adenomas account for about 2-5%.

Researchers do not know why adenomas form in the parathyroid glands. In most cases, they occur sporadically, and usually there is no family history of the disease. Sometimes, genetic factors can play a role in the development of PGPT. In sporadic forms, these genetic variations occur after fertilization of the embryo and are not acquired by inheritance (somatic mutation). With parathyroid adenomas, various genetic changes are observed (for example, rearrangements, mutations, etc.).

In inherited forms of primary hyperparathyroidism, variations in both oncogenes and tumor suppressor genes are detected with a higher frequency than in the general population. Oncogenes cause uncontrolled growth when one of the paired copies (alleles) is defective. Tumor suppressor genes usually restrict or stop cell growth. These variations are passed on from parents or occur at random, without a family history (new mutation).

PGPT can be seen as part of a larger genetic disorder, including multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2A, hyperparathyroidism syndrome with jaw tumor, or familial isolated primary hypercalcemia. These are extremely rare violations.

People who have received radiation in the head and neck area are at greater risk of developing primary hyperparathyroidism, often 20-40 years after radiation exposure.

The parathyroid glands release hormones in response to low calcium levels. In PGPT, they release hormones when the body does not need calcium (increased activity). Elevated parathyroid hormone levels cause bones to release more calcium into the bloodstream, resulting in elevated calcium levels (hypercalcemia). The signs and symptoms of primary hyperparathyroidism develop due to elevated parathyroid hormone levels and hypercalcemia. Calcium is a mineral that is stored in bones. It is essential for healthy bones and teeth. Calcium also plays an important role in the cardiovascular system, muscle contractions, blood clotting, and nerve signaling. Vitamin D also helps regulate calcium and is sometimes lacking in people with PHPT.

Affected populations

Estimates of the incidence and prevalence of primary hyperparathyroidism in the world differ. The majority of people with this condition, more than 80% in the world, do not have any symptoms. People with symptoms, especially severe ones, are less common in developed countries. Primary hyperthyroidism can occur at any age, but most often affects people over the age of 50. The incidence is highest among people of African American descent, followed by Caucasians. Women are affected about three times more often than men.

The incidence of PGPT is 20-200 new observations per 100,000 population. In the United States, about 100,000 cases are reported annually, which is 15.4 per 100,000, and among the elderly - 150 cases per 100,000 people. In Europe, the rate is higher, with an average of 300 cases per 100,000 people.

Symptomatic disorders

Some of the signs or symptoms of the following conditions may be similar to those of primary hyperparathyroidism (PHPT). Comparisons can be useful for differential diagnosis.

• Familial hypocalciuric hypercalcemia - a genetic disorder in which there is a variation in the gene that encodes a protein that determines the level of calcium in the blood (calcium receptor). Sometimes the variation is in another gene. As with primary hyperparathyroidism, blood calcium levels are elevated. The parathyroid hormone is usually in the upper normal range. People with this condition have higher blood calcium levels than normal in the general population, and this is “normal” for their body. Familial hypocalciuric hypercalcemia is distinguished from primary hyperparathyroidism by low urinary calcium, family history, and, in some cases, genetic testing. Surgery does not cure and is almost never indicated for familial hypocalciuric hypercalcemia.
• Isolated familial hyperparathyroidism - a rare genetic disease characterized by increased activity of the parathyroid glands. People have elevated blood calcium levels, which can cause weakness, fatigue, high blood pressure, kidney stones, and weakened bones that are prone to fractures (osteoporosis). Familial isolated hyperparathyroidism is caused by gene variation including genes MEN1, CDC73 and CASR, and is diagnosed when there are no other associated endocrine gland diseases other than HGPT. These variations are inherited in an autosomal dominant manner. Sometimes the underlying cause is unknown and no variation can be found in these genes, suggesting that variations in other genes could cause familial isolated hyperparathyroidism.
• Parathyroid carcinoma - a rare form of cancer that affects the parathyroid glands. It accounts for about 1% or less of people with primary hyperparathyroidism. Patients usually have very high blood calcium levels (hypercalcemia) and may experience fatigue, weakness, constipation, depression, and confusion. They can also experience bone pain, fractures and kidney stones. Most people with this cancer have a gene variant CDC73. Parathyroid carcinoma can occur on its own or as part of a larger genetic disorder. Surgery to remove the affected parathyroid tissue is the main treatment option. Medication to lower blood calcium is also sometimes used in conjunction with surgery.
• Secondary hyperparathyroidism refers to people who have hyperparathyroidism (high levels of parathyroid hormone with normal blood calcium levels) is caused by another disorder. This could include chronic kidney disease, lack of calcium in the diet, malabsorption and severe vitamin D deficiency. In some cases, secondary hyperparathyroidism is reversible when the underlying cause is treated.

Diagnostics

The diagnosis of HGPT is based primarily on blood and urine tests. In addition, a thorough clinical assessment of symptoms and family history is carried out, as well as a number of specialized tests to determine the cause, effects on the skeleton and kidneys, and the need for surgical interference. Primary hyperparathyroidism may be suspected in people with kidney stones.

- Analyzes and examinations.

Routine blood tests that evaluate a variety of conditions (biochemical screening) can show elevated calcium levels. Excessive calcium levels are common in the disorder, but may be due to other causes. Tests that can measure the amount of a substance can be done to determine the level of parathyroid hormone in the blood. Elevated levels of calcium and parathyroid hormone indicate a diagnosis of primary hyperparathyroidism.

Normocalcemic primary hyperparathyroidism is usually diagnosed in people with low bone density, when high circulating parathyroid hormone levels are tested and found to be normal calcium. In these situations, the causes of secondary normocalcemic hyperparathyroidism, such as vitamin D deficiency or renal failure.

A technique known as dual energy X-ray absorptiometry (DXA) is recommended for measuring bone mineral density. During this examination, a person lies down on a table and a robotic arm passes over the area to be examined. A narrow beam of low-energy X-rays is used to measure bone density. For some patients, an X-ray of the spine is recommended to detect hidden fractures of the spine.

Sometimes computed tomography or ultrasound scans can be used to detect "silent" kidney stones. Computed tomography uses a computer and X-rays to create images of specific tissue structures, showing cross sections of specific tissue structures. Ultrasound uses reflected sound waves to create images of internal organs and other structures. Ultrasound is a study that uses high-frequency sound waves to create parts of organs and tissues of the body. This device creates sound waves that are reflected and recorded and then converted into images using a computer.

A blood test may be done specifically to check for vitamin D deficiency. A 24-hour urine collection is recommended to assess levels of calcium and certain other chemicals. This can help doctors determine the condition of the kidneys and the risk of kidney stones.

Standard treatments

Surgery is the main treatment option for primary hyperparathyroidism. Watchful waiting and the use of drugs can also play a role in the treatment of some patients.

- Surgical intervention.

Surgical removal of the parathyroid glands (parathyroidectomy) is the only possible cure for primary hyperparathyroidism. An operation performed by an experienced surgeon can successfully cure the disease in 95% of people. The preferred surgical method for affecting one affected parathyroid gland is minimally invasive parathyroidectomy, which is performed on an outpatient basis. The surgeon will make a small incision in the neck that will remove the affected gland. This procedure is performed using imaging techniques to primarily identify and localize the affected parathyroid gland. The minimally invasive procedure is becoming an increasingly common method of therapy.

A more extensive procedure is called an open parathyroidectomy. During this procedure, the surgeon identifies all four parathyroid glands in order to determine which ones are affected during surgery. This procedure involves an incision, usually in the middle and lower part of the neck. The skin is folded back and the muscles are separated so that the surgeon can see each parathyroid gland. A biopsy, which involves cutting out a small sample of tissue and viewing the sample under a microscope, is performed on any affected parathyroid glands. This surgery is very successful but more invasive. Open parathyroidectomy is used when the affected parathyroid gland cannot be visualized prior to surgery or when multiple glands are affected.

Methods are used to identify the affected parathyroid glands and to assist the surgeon during the operation imaging, including ultrasound, technetrile scintigraphy, and other techniques such as high computed tomography permissions. Technetril scintigraphy of the parathyroid glands uses technetril, a radioactive compound. This compound is injected into the patient and ultimately absorbed by the overactive parathyroid glands. The connection is visible with a special camera and overactive parathyroid glands can be identified.

Surgery is recommended for all patients with symptomatic HHPT (those with constitutional symptoms associated with high calcium levels, such as nausea, vomiting, etc., in those who develop kidney stones, who have fractures associated with this disease, and in patients with cystic fibrous osteitis). The operation can also be useful for asymptomatic patients without any contraindications.

Patients with mild hyperparathyroidism who have not undergone surgery should be monitored regularly to determine if the disease is progressing. Avoid dehydration by drinking plenty of fluids and avoiding diuretics that increase the frequency of urination. These patients should be monitored for kidney function and bone mineral density assessments to detect any decrease or change.

- Medicines.

Medications can be used to treat some people with primary hyperparathyroidism who have not undergone surgery. Bisphosphonates, a class of drugs that can prevent bone loss, can be used to treat osteoporosis. Calcimimetics are drugs that mimic the effects of calcium on tissues and can trick the parathyroid glands into producing less parathyroid hormone.

Cinacalcet (Mimpara®) is approved by the FDA for the treatment of people with primary hyperparathyroidism who suffer from severe hypercalcemia and cannot undergo surgery, as well as people whose hyperparathyroidism occurs due to parathyroid carcinoma glands. It is also approved for hyperparathyroidism secondary to chronic kidney disease. Cinacalcet is a type of calcimimetic.

Vitamin D deficiency should be treated with caution by adding vitamin D to the diet. The optimal dose or regimen of vitamin D for people with HPPT is not known.

Patients should avoid dehydration, as this can lead to an increase in calcium levels. This can happen when a person becomes dehydrated due to nausea and vomiting during illness. People who are dehydrated should seek medical attention.