NORD gratefully acknowledges Marcella Donovan Walker, MD, MS, Associate Professor of Medicine, Columbia University, College of Physicians and Surgeons, for assistance in the preparation of this report.
Primary hyperparathyroidism is a condition in which the parathyroid glands produce too much parathyroid hormone and the calcium level in the blood becomes elevated. The parathyroid glands are part of the endocrine system, the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. Endocrine glands release hormones that regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital processes including regulating heart rate, body temperature and blood pressure as well as cell differentiation and growth and also in modulation of several metabolic processes. There are four tiny parathyroid glands found in the neck. They are about the size of a pea. Parathyroid hormone (along with vitamin D) is the main regulator of the level of calcium in the blood. It also affects the blood phosphorus level, bone growth and bone cell activity. Most individuals with primary hyperparathyroidism do not develop symptoms (asymptomatic) or only extremely mild symptoms. Primary hyperparathyroidism mainly affects the skeleton and the kidneys, but the heart, gastrointestinal, and nervous system can sometimes be involved. About 80-85% of the time, the disorder is caused by a benign tumor called an adenoma that is usually found in one of the four parathyroid glands.
Asymptomatic Primary Hyperparathyroidism
The most common presentation of primary hyperparathyroidism is when doctors find high levels of calcium in the blood, but no associated symptoms. This is also called asymptomatic hypercalcemia. Some individuals with asymptomatic primary hyperparathyroidism reported fatigue, weakness, mild depression, or mild cognitive dysfunction such as mild issues with concentration or memory. Whether these are caused by the condition or reversible with surgery is not clear. They may also have bone loss (low bone mineral density) and silent kidney stones and spine fractures detected by imaging. Eventually, asymptomatic primary hyperparathyroidism can progress and individuals may develop symptoms seen in the classic form.
Classic Primary Hyperparathyroidism
A characteristic finding of primary hyperparathyroidism is the development of calcium stones in the kidneys (nephrolithiasis). This has occurred with less and less frequency in the United States in recent years. Nephrolithiasis can cause low back pain in the area of the kidneys (renal colic) and pain in the lower back and lower abdomen. Sometimes, kidney damage can develop, and the kidneys may function less efficiently than they should (chronic renal insufficiency).
Affected individuals may lose bone mineral density, which can contribute to thinning and weakening of bones (osteoporosis). Affected individual can be prone to fractures of bones and can experience bone pain.
Primary hyperparathyroidism can cause a form of bone disease called osteitis fibrosa cystica. However, this is rarely seen in the United States (less than 2% of individuals) and other developed countries. Affected individuals are prone to fractures and there may be other skeletal abnormalities and bone pain or tenderness in the affected areas. Osteitis fibrosa cystica occurs in advanced disease.
A variety of nonspecific symptoms have been associated with classical primary hyperparathyroidism. Nonspecific means that the symptoms are common to many different disorders. These symptoms include unintended weight loss, vomiting, nausea, constipation, drinking lots of water (polydipsia), and urinating frequently (polyuria). Some affected individuals experience weakness and fatigue.
Many individuals with primary hyperparathyroidism have reported neuropsychiatric symptoms including depression, irritability, psychosis, and decreased social interaction. There may be cognitive dysfunction, which means there may be problems with concentration or memory or individuals may experience a lack of mental clarity (“brain fog”).
Sometimes, primary hyperparathyroidism may be associated with cardiovascular disease including high blood pressure (hypertension), irregular heart rhythms (arrhythmias), enlargement and thickening of the left lower chamber of the heart (ventricular hypertrophy), and hardening due to calcium buildup (calcification) of blood vessels and valves of the circulatory system. Generally, cardiovascular disease has been reported in people with severe primary hyperparathyroidism. Much about the relationship between primary hyperparathyroidism and cardiovascular is not fully understood (e.g. 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 influence each other.
This condition is characterized by high parathyroid hormone but normal blood calcium levels. Symptoms associated with this form of primary hyperparathyroidism include kidney stones, bone loss, and fragile bones that may be prone to fracture (osteoporosis). Much about the disorder remains unknown or not completely understood. Some researchers believe the normocalcemic form may be an early or mild form of classic primary hyperparathyroidism.
Parathyroid (Hypercalcemic) Crisis
Parathyroid crisis is a rare complication of primary hyperparathyroidism. Affected individuals develop severe hypercalcemia that is life-threatening. Symptoms can include changes in mental status, bone disease, dehydration, and kidney stones. Sometimes, nausea, vomiting, and severe abdominal pain. Some individuals with hypercalcemia or mild hyperparathyroidism develop parathyroid crisis later on. In other individuals, a parathyroid crisis can be the first sign of the disorder.
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 it is possible for more adenomas to form in multiple parathyroid glands. An adenoma causes the affected gland to become overactive. Multiple gland hyperplasia accounts for about 6-12%. This condition is characterized by enlargement of multiple parathyroid glands because of an increased reproduction rate of their cells. Multiple gland hyperplasia occurs randomly (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 instances they appear to occur sporadically and there is usually no family history of the disorder. Sometimes, genetic factors can play a role in the development of primary hyperparathyroidism. In sporadic forms, these genetic variations occur after the fertilization of the embryo and are acquired not inherited (somatic mutation). Various genetic changes (e.g. rearrangements, mutations, etc.) have been described in parathyroid adenomas.
In inherited forms of primary hyperparathyroidism, variations in both oncogenes and tumor suppressor genes have both been identified with greater frequency than in the general population. Oncogenes cause out-of-control growth when either one of the paired copies (alleles) is defective. Tumor suppressor genes normally limit or stop the growth of cells. These variations are passed on from the parents or occur randomly with no previous family history (de novo mutation).
Primary hyperparathyroidism can be seen as part of a larger genetic disorder including multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2A, hyperparathyroidism jaw tumor syndrome, or familial isolated primary hypercalcinemia. These are extremely rare disorders. (For more information, choose the specific disorder name as your search term in the NORD Rare Disease Database.)
Individuals who have received irradiation to the head and neck region appear to be at a greater risk of developing primary hyperparathyroidism, often 20 to 40 years after exposure.
The parathyroid glands release hormones in response to low calcium levels. In primary hyperparathyroidism, they release the hormones when the body doesn’t need calcium (overactivity). The increased levels of parathyroid hormone cause the bones to release more calcium into the blood, leading to the elevated calcium levels (hypercalcemia). The signs and symptoms of primary hyperparathyroidism develop because of elevated parathyroid hormone levels and hypercalcemia. Calcium is a mineral that is stored in bones. It is important for the health of bones and teeth. Calcium also plays a role in the cardiovascular system, muscle contractions, blood clotting, and transmitting nerve signals. Vitamin D also helps to regulate calcium and is sometimes deficient in individuals with primary hyperparathyroidism.
Estimates of the incidence and prevalence of primary hyperparathyroidism in the Western world varies. Most of people with the disorder, more 80% in the Western world, do not have any symptoms (asymptomatic). Individuals with symptoms, particularly severe symptoms, are a rarer occurrence in developed countries. Primary hyperthyroidism can occur at any age, but is most likely to affect individuals over 50. The incidence is highest among individuals of African-American heritage, followed by Caucasians. Women are affected about three times more often than men. According to one estimate, about 100,000 people in the United States develop primary hyperparathyroidism each year.
A diagnosis of primary hyperparathyroidism is based primarily upon blood and urine tests. A thorough clinical evaluation that assesses symptoms and family history as well as a variety of specialized tests is also performed to determine the cause, effects on the skeleton and kidney and the need for surgery. Individuals with kidney stones may be suspected of having primary hyperparathyroidism.
Clinical Testing and Workup
Routine blood tests that assess for lots of conditions (biochemical screening) can reveal elevated levels of calcium. Excessive levels of calcium are characteristic of the disorder, but can be due to other causes. Assays, which are tests that can measure the amount of a substance, can be conducted to determine the levels of parathyroid hormone in the blood. Elevated levels of calcium and parathyroid hormone indicates a diagnosis of primary hyperparathyroidism.
Normocalcemic hyperparathyroidism is usually diagnosed in people with low bone density when circulating parathyroid hormone levels are tested and found to be high and there are normal levels of calcium. Causes of secondary normocalcemic hyperparathyroidism such as vitamin D deficiency or renal disease among others must be ruled out in these situations.
A test known as dual energy x-ray absorptiometry (DXA) is recommended to measure bone mineral density. During this exam, a person lies on a table and a robotic arm is passed over the area to be examined. A narrow beam of low dose x-rays is used to measure bone density. Spine x-rays are also recommended in some individuals to detect silent spine fractures.
Sometimes, CT scans or an ultrasound can be used to detect silent kidney stones. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An ultrasound uses reflected sound waves to create pictures of internal organs and other structures. An ultrasound is a test that uses high frequency sounds waves to create pieces of organs and tissues of the body. This device produces sound waves which bounce back (or echo) and are recorded and then converted into images by a computer.
A blood test may be given specifically to look for vitamin D deficiency. A 24-hour urine collection is recommended to assess the levels of calcium and certain other chemicals. This can help doctors determine the health of the kidneys and the risk of kidney stone formation.
Surgery is the main treatment option for primary hyperparathyroidism. Watchful waiting and medications may also have a role in treatment in some patients.
Surgical removal of the parathyroid glands (parathyroidectomy) is the only potential cure for primary hyperparathyroidism. Surgery, when performed by an experienced parathyroid surgeon, can successfully cure this disorder in 95% of individuals. The preferred surgical technique for one affected parathyroid gland is minimally-invasive parathyroidectomy, which is an out-patient procedure. The surgeon will make a small incision in the neck, which allows the affected gland to be taken out. This procedure is proceeded by imaging techniques to identify and locate the affected parathyroid gland first. The minimally-invasive procedure is becoming more wide-spread.
A more extensive procedure is called bilateral neck exploration. During this procedure, a surgeon identifies all four parathyroid glands to determine which one(s) are affected at the time of surgery. This procedure involves making an incision, usually in the middle to lower portion 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 parathyroid glands that appear affected. This surgery is highly successful, but is more invasive. Bilateral neck exploration is used when the affected parathyroid gland cannot be identified by imaging before surgery or when multiple glands are affected. This procedure is also known as open parathyroidectomy, standard parathyroidectomy, and conventional parathyroidectomy.
Imaging techniques including ultrasound, sestamibi scan and others such as high resolution CT are used to determine which parathyroid glands are affected and to aid the surgeon during surgery. A sestamibi parathyroid scan uses sestamibi, which is a radioactive compound. This compound is injected into the affected individual and is eventually absorbed by overactive parathyroid glands. The compound is visible using a special camera and the overactive parathyroid glands can be identified.
Surgery is recommended for all individuals with symptomatic primary hyperparathyroidism (those have constitutional symptoms related to high calcium such as nausea and vomiting etc., those who develop kidney stones, those who have fractures related to the condition and those with osteitis fibrosa cystica). Surgery may also be beneficial for patients with asymptomatic disease without any contraindications.
There are published guidelines, the Fourth International Workshop on Asymptomatic Primary Hyperparathyroidism, that many doctors use to determine whether individuals with asymptomatic primary hyperparathyroidism should be treated by watchful waiting or surgery. Watchful waiting means that an asymptomatic person will be periodically monitored by physicians to detect if primary hyperthyroidism becomes symptomatic or is causing silent damage to the kidneys or skeleton. Surgery may be considered in individuals with normocalcemic hyperparathyroidism if patients become hypercalcemic and have other indications for surgery; surgery may also be considered when there is disease progression regardless of hypercalcemia. Everyone including asymptomatic individuals should have a consultation with an endocrinologist (hormone specialist) to learn about the condition’s risks and treatment options.
Affected individuals with mild hyperparathyroidism who do not have surgery should be regularly monitored to determine whether the disease has progressed. Dehydration should be avoided by drinking plenty of fluids and avoiding diuretics, which are drug that increases the rate of urination. These individuals should receive monitoring on kidney function and assessments of bone mineral density to detect any decline or changes.
Medications can be used to treat some individuals with primary hyperparathyroidism who are not having surgery. Bisphosphonates, a class of drugs that can prevent bone loss, can be used to treat osteoporosis. Calcimimetics are medications that mimics the action of calcium on tissues and can ‘trick’ the parathyroid glands to produce less parathyroid hormone.
The U.S. Food and Drug Administration has approved cinacalcet (Sensipar®) for the treatment of individuals with primary hyperparathyroidism who have severe hypercalcemia and are unable to undergo surgery, and in individuals whose hyperparathyroidism occurs because of parathyroid carcinoma. The drug is also approved for hyperparathyroidism secondary to chronic kidney disease. Cinacalcet is a type of calcimimetic.
Vitamin D deficiency should be treated cautiously by vitamin D supplementation. The optimal dose or regimen of vitamin D supplementation for individuals with primary hyperparathyroidism is not known.
Affected individuals should avoid becoming dehydrated as this can lead to an increase in calcium. This can occur when a person becomes dehydrated because of nausea and vomiting when sick. Affected individuals who become dehydrated should seek medical attention.
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