Secondary Hyperparathyroidism – Causes, Symptoms, Treatment

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Secondary Hyperparathyroidism/Primary hyperparathyroidism is a relatively common disorder that can cause significant renal and skeletal complications. Surgery remains the definitive treatment. However, alternative therapies may be appropriate for select patients. A basic knowledge of normal calcium homeostasis is essential in diagnosing and managing patients with hyperparathyroidism. This activity reviews the evaluation and management of primary hyperparathyroidism and highlights the role of the interprofessional team in the management of patients with this disorder.

Primary hyperparathyroidism is a relatively common disorder that may cause significant renal and skeletal complications, although most patients diagnosed in recent decades have mild degrees of hypercalcemia and are often asymptomatic. Surgery remains the definitive treatment. However, conservative observation or medical therapy may be appropriate for selected patients. A basic understanding of normal calcium homeostasis is essential in diagnosing and managing patients with hyperparathyroidism.

Types

Primary hyperparathyroidism

Primary hyperparathyroidism occurs because of some problem with one or more of the four parathyroid glands:

  • A noncancerous growth (adenoma) on a gland is the most common cause.
  • Enlargement (hyperplasia) of two or more parathyroid glands accounts for most other cases.
  • A cancerous tumor is a very rare cause of primary hyperparathyroidism.

Primary hyperparathyroidism usually occurs randomly, but some people inherit a gene that causes the disorder.

Secondary hyperparathyroidism

Secondary hyperparathyroidism is the result of another condition that lowers calcium levels. This causes your parathyroid glands to overwork to compensate for the calcium loss. Factors that may contribute to secondary hyperparathyroidism include:

  • Severe calcium deficiency. Your body may not get enough calcium from your diet, often because your digestive system doesn’t absorb the calcium from it.
  • Severe vitamin D deficiency. Vitamin D helps maintain appropriate calcium levels in the blood. It also helps your digestive system absorb calcium from your food. Your body produces vitamin D when your skin is exposed to sunlight. You also consume some vitamin D in food. If you don’t get enough vitamin D, then calcium levels may drop.
  • Chronic kidney failure. Your kidneys convert vitamin D into a form that your body can use. If your kidneys work poorly, usable vitamin D may decline and calcium levels drop, causing parathyroid hormone levels to go up. Chronic kidney failure is the most common cause of secondary hyperparathyroidism. Some medical treatments, such as vitamin D, bisphosphonates and cinacalcet, will lower PTH levels. In some people with long-term end-stage kidney disease, the parathyroid glands enlarge and begin to release PTH on their own, and PTH doesn’t go down with medical treatment. This is called tertiary hyperparathyroidism, and people with this condition may require surgery to remove parathyroid tissue.

Pathophysiology

Normal Calcium Homeostasis

Under physiologic circumstances, the concentration of calcium in the extracellular fluid is maintained within a very narrow range. Normal calcium homeostasis is dependent upon a complex set of hormonal regulatory mechanisms that include the effects of parathyroid hormone, vitamin D metabolites, and calcitonin on calcium transport in bone, kidney, and the gastrointestinal tract.

Approximately 50% of total serum calcium is protein-bound, principally to albumin. Forty-five percent is ionized, while a small proportion is complexed to anions such as phosphate and citrate. It is only the ionized calcium that is biologically active, yet most laboratories report total serum calcium levels. Measurements of ionized calcium are available. However, an approximate correction of serum calcium can be made by adjusting for differences in the serum albumin level.

Corrected calcium = Measured calcium + 0.8 x (4.0 – albumin)

Caution must be exercised in evaluating normal total serum calcium levels in patients with hypoalbuminemia. Such patients may have elevated ionized calcium levels and are truly hypercalcemic. Conversely, the ionized calcium is often normal when there is a low total calcium concentration in the presence of hypoalbuminemia.

Parathyroid Hormone

Secretion of parathyroid hormone is inversely related to the concentration of ionized calcium in the extracellular fluid. The calcium-sensing receptor (CaSR) is a G-protein coupled receptor whose activity varies with changes in the types of serum calcium. As the calcium concentration in the extracellular fluid increases, this receptor is activated and parathyroid cells decrease secretion of parathyroid hormone. Conversely, the activity of the CaSR decreases and parathyroid hormone secretion increases as calcium levels decline. Mutations that inactivate the CaSR are the etiology of familial hypocalciuric hypercalcemia (FHH), an autosomal dominant disorder characterized by increased parathyroid hormone secretion, hypercalcemia, and hypocalciuria.

Parathyroid hormone activates the parathyroid hormone receptor increasing the resorption of calcium and phosphorus from bone, enhancing the distal tubular resorption of calcium, and decreasing the renal tubular resorption of phosphorus. Also, the parathyroid hormone plays an essential role in vitamin D metabolism, activating the vitamin D 1-alpha hydroxylase, which increases the renal synthesis of 1,25-dihydroxyvitamin D.

Causes of Primary Hyperparathyroidism

PTH-dependent Causes of Hypercalcemia

  • Primary Hyperparathyroidism
    • Single adenoma
    • Multigland disease
      • Familial causes of hyperparathyroidism
        • Multiple endocrine neoplasia Type 1
        • Multiple endocrine neoplasia Type 2
        • Familial hyperparathyroidism
        • Hyperparathyroidism-jaw tumor syndrome
    • Parathyroid carcinoma
  • Familial hypocalciuric hypercalcemia, autosomal dominant inactivating mutations of the calcium-sensing receptor
  • Adverse effect of treatment with lithium

PTH Independent Causes of Hypercalcemia

  • Malignancy
  • Granulomatous diseases
  • Hyperthyroidism
  • Thiazide therapy
  • Vitamin D intoxication
  • Milk-alkali syndrome
  • Adrenal insufficiency
  • Vitamin A intoxication
  • Genetic associations include:
OMIM Name Gene
145000 HRPT1 MEN1, HRPT2
145001 HRPT2 HRPT2
610071 HRPT3 unknown at 2p13.3-14[rx]

In all cases, the disease is idiopathic but is thought to involve the inactivation of tumor suppressor genes (Menin gene in MEN1) or involve gain of function mutations (RET proto-oncogene MEN 2a).

Recently, it was demonstrated that liquidators of the Chernobyl power plant are faced with a substantial risk of primary hyperparathyroidism, possibly caused by radioactive strontium isotopes.[rx]

What are the symptoms of primary hyperparathyroidism?

The signs and symptoms of primary hyperparathyroidism are those of hypercalcemia. They are classically summarized by “stones, bones, abdominal groans, thrones, and psychiatric overtones”.

  • “Stones” refers to kidney stones, nephrocalcinosis, and diabetes insipidus (polyuria and polydipsia). These can ultimately lead to kidney failure.
  • “Bones” refers to bone-related complications. The classic bone disease in hyperparathyroidism is osteitis fibrosa cystica, which results in pain and sometimes pathological fractures. Other bone diseases associated with hyperparathyroidism are osteoporosis, osteomalacia, and arthritis.
  • “Abdominal groans” refers to gastrointestinal symptoms of constipation, indigestion, nausea, and vomiting. Hypercalcemia can lead to peptic ulcers and acute pancreatitis. Peptic ulcers can be an effect of increased gastric acid secretion by hypercalcemia.
  • “Thrones” refers to polyuria and constipation
  • “Psychiatric overtones” refer to effects on the central nervous system. Symptoms include lethargy, fatigue, depression, memory loss, psychosis, ataxia, delirium, and coma.
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These are the most common symptoms of primary hyperparathyroidism. However, each person may experience symptoms differently. Symptoms of too much calcium in the blood may include:

  • Constipation
  • Frequent urination
  • Increased thirst
  • Joint pain
  • Kidney pain (due to the presence of kidney stones)
  • Lethargy and fatigue
  • Loss of appetite
  • Muscle weakness

Other serious symptoms may include:

  • Abdominal pain
  • Depression
  • Memory loss
  • Nausea
  • Vomiting

The symptoms of primary hyperparathyroidism may look like other medical problems. Always talk with your healthcare provider for a diagnosis.

Diagnosis of Primary Hyperparathyroidism

In past decades most patients were diagnosed when they had complaints of nephrolithiasis, bone pain, or bone deformity. Now, most patients with primary hyperparathyroidism are asymptomatic, diagnosed when hypercalcemia is incidentally discovered on a chemistry profile. Patients should be asked about any history of kidney stones, bone pain, myalgias or muscle weakness, symptoms of depression, use of thiazide diuretics, calcium products, vitamin D supplements, or other symptoms associated with the multiples etiologies of hypercalcemia. A familial syndrome should be considered when primary hyperparathyroidism is diagnosed at an early age, or there is a family history of hypercalcemia, pituitary adenomas, pancreatic islet cell tumors, pheochromocytomas, or medullary thyroid cancer.

The physical examination of a patient with primary hyperparathyroidism is usually normal. However, the physical examination can be helpful in finding abnormalities that could suggest other etiologies of hypercalcemia. Parathyroid adenomas are rarely palpable on physical examination, but the presence of a large, firm mass in the neck of a patient with hypercalcemia should raise suspicion of parathyroid carcinoma.

Evaluation

Patients with primary hyperparathyroidism and other causes of PTH-dependent hypercalcemia often have frankly elevated levels of PTH, while some will have values that fall within the reference range for the general population. A normal PTH in the presence of hypercalcemia is considered inappropriate and still consistent with PTH-dependent hypercalcemia. PTH levels should be very low in those patients with PTH-independent hypercalcemia.

A comprehensive clinical evaluation complemented by routine laboratory and radiologic studies should be sufficient to establish a diagnosis of primary hyperparathyroidism in a patient with persistent hypercalcemia and an elevated serum level of parathyroid hormone. It is uncommon for clinically occult malignancies to cause hypercalcemia. Most patients with malignancy-associated hypercalcemia are known to have cancer, or cancer is readily detectable on initial evaluation, and PTH levels will be suppressed.

A review of previous medical records can often be of significant value in establishing the cause of hypercalcemia. Most patients with hyperparathyroidism have persistent or intermittent hypercalcemia for many years before a definitive diagnosis is established. Very few diseases, other than hyperparathyroidism, will allow a healthy-appearing individual to be hypercalcemic for more than a few years without becoming clinically obvious.

Bone mineral density test

Dual-energy x-ray absorptiometry, also called a DXA or DEXA scan uses low-dose x-rays to measure bone density. During the test, you will lie on a padded table while a technician moves the scanner over your body. A bone expert or radiologist will read the scan.

A woman lying on a table with a DXA scanner positioned over her abdomen.During a DXA scan, you will lie on a padded table while a technician moves the scanner over your body.

Kidney imaging tests

Doctors may use one of the following imaging tests to look for kidney stones.

Ultrasound. Ultrasound uses a device called a transducer that bounces safe, painless sound waves off organs to create an image of their structure. A specially trained technician does the procedure. A radiologist reads the images, which can show kidney stones.

Abdominal x-ray. An abdominal x-ray is a picture of the abdomen that uses low levels of radiation and is recorded on film or on a computer. During an abdominal x-ray, you lie on a table or stand up. A technician positions the x-ray machine close to your abdomen and asks you to hold your breath so the picture won’t be blurry. A radiologist reads the x-ray, which can show the location of kidney stones in the urinary tract. Not all stones are visible on an abdominal x-ray.

Computed tomography (CT) scans. CT scans use a combination of x-rays and computer technology to create images of your urinary tract. CT scans sometimes use a contrast medium—a dye or other substance that makes structures inside your body easier to see. A contrast medium isn’t usually needed to see kidney stones. For the scan, you’ll lie on a table that slides into a tunnel-shaped machine that takes the x-rays. A radiologist reads the images, which can show the size and location of a kidney stone.

Vitamin D blood test – Health care professionals test for vitamin D levels because low levels are common in people with primary hyperparathyroidism. In patients with primary hyperparathyroidism, the low vitamin D level can further stimulate the parathyroid glands to make even more parathyroid hormone. Also, a very low vitamin D level may cause a secondary form of hyperparathyroidism, which resolves when vitamin D levels are returned to normal.

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List of tests for primary hyperparathyroidism: 

  • Total calcium
  • Albumin
  • Calculation of the “corrected” serum calcium. Approximately 50% of total serum calcium is protein-bound, principally to albumin and only free or ionized fraction is biologically active. Corrected calcium = Measured calcium + 0.8 x (4.0 – albumin) (calcium measured in mg/dL; albumin measured in g/dL)
  • Ionized calcium in selected cases when there are questions about the accuracy of the corrected calcium
  • Parathyroid hormone
  • Phosphorus
  • BUN and creatinine
  • Alkaline phosphatase
  • 25-hydroxyvitamin D
  • Urine calcium and creatinine
  • Imaging to screen for renal calcifications or urolithiasis
  • Bone densitometry (DXA) including measurement at the distal 1/3 radius
  • EKG
  • Genetic testing in selected individuals if there is suspicion of a genetic syndrome
  • Parathyroid scan and neck ultrasound. These tests are not considered diagnostic because there can be false-negative results. They should not be ordered when there are no plans for surgery. They should be ordered when there are plans for surgery to assist the surgeon as a “roadmap” in localizing the enlarged parathyroid gland.

The need for other studies such as PTHrP levels, serum or urine protein electrophoresis, 1,25-dihydroxy vitamin D levels, thyroid tests, bone scans, or mammography can be individualized and are usually only needed in those with PTH-independent hypercalcemia.

Treatment of Primary Hyperparathyroidism

Drugs

Medications to treat hyperparathyroidism include the following:

  • Calcimimetics. A calcimimetic is a drug that mimics calcium circulating in the blood. The drug may trick the parathyroid glands into releasing less parathyroid hormone. This drug is sold as a cinacalcet (Sensipar). Some doctors may prescribe cinacalcet to treat primary hyperparathyroidism, particularly if surgery hasn’t successfully cured the disorder or a person isn’t a good surgery candidate. The most commonly reported side effects of cinacalcet are joint and muscle pain, diarrhea, nausea, and respiratory infection.
  • Hormone replacement therapy. For women who have gone through menopause and have signs of osteoporosis, hormone replacement therapy may help bones retain calcium. This treatment doesn’t address the underlying problems with the parathyroid glands. Prolonged use of hormone replacement therapy can increase the risk of blood clots and breast cancer. Work with your doctor to evaluate the risks and benefits to help you decide what’s best for you. Some common side effects of hormone replacement therapy include breast pain and tenderness, dizziness, and headaches.
  • Bisphosphonates. Bisphosphonates also prevent the loss of calcium from bones and may lessen osteoporosis caused by hyperparathyroidism. Some side effects associated with bisphosphonates include low blood pressure, fever and vomiting. This treatment doesn’t address the underlying problems with the parathyroid glands

Surgery remains the definitive treatment for primary hyperparathyroidism, but non-operative surveillance may be the appropriate option for some, particularly for patients who are elderly with mild hypercalcemia and no significant complications. Medical treatment with bisphosphonates or cinacalcet can be useful in selected patients. The decision of whether to recommend surgery is based on age, the degree of hypercalcemia, and the presence or absence of complications due to hyperparathyroidism. Surgery is the treatment of choice for those with recurrent kidney stones.

Since 1990, several workshops have been convened to develop guidelines to assist physicians in the management of asymptomatic hyperparathyroidism. Surgical and medical experts, internationally recognized for their experience in managing patients with hyperparathyroidism, reviewed the evidence-based medical literature and a consensus of their opinions was disseminated to the medical community. The most recent guidelines were published in 2014.

The current guidelines state that surgery should be recommended for asymptomatic primary hyperparathyroidism when:

  • Serum calcium is more than 1 mg/dL greater than the upper limit of normal
  • Age younger than 50 years
  • Osteoporosis
  • GFR less than 60 mL/min
  • Urine calcium greater than 400 mg/24 hours
  • Evidence of renal calcification or stones

Left untreated, many patients with primary hyperparathyroidism have progressive loss of cortical bone while successful surgery leads to a substantial increase in bone mineral density, an effect that can persist for up to 15 years.

For patients where observation is the selected course of action, periodic monitoring with measurement of serum and urine calcium, renal function, and bone densitometry is required. If there is worsening hypercalcemia or the development of complications, then surgery should be recommended.

Medical Treatment

Some patients who are not surgical candidates may benefit from medical management of primary hyperparathyroidism.

  • Bisphosphonates can increase bone mineral density in those with osteoporosis or osteopenia.
  • Agonists to the calcium-sensing receptor, such as cinacalcet will lower PTH and calcium levels. However, they do not increase bone density.

Surgery

Surgery to remove the overactive parathyroid gland or glands is the only sure way to cure primary hyperparathyroidism. Doctors recommend surgery for people with clear symptoms or complications of the disease. In people without symptoms, doctors follow the above guidelines to identify who might benefit from parathyroid surgery.2 Surgery can lead to improved bone density and can lower the chance of forming kidney stones.

When performed by experienced surgeons, surgery almost always cures primary hyperparathyroidism.

Surgeons often use imaging tests before surgery to locate the overactive gland or glands to be removed. The tests used most often are sestamibi, ultrasound, and CT scans. In a sestamibi scan, you will get an injection, or shot, of a small amount of radioactive dye in your vein. The overactive parathyroid gland or glands then absorb the dye. The surgeon can see where the dye has been absorbed by using a special camera.

Surgeons use two main types of operations to remove the overactive gland or glands.

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Minimally invasive parathyroidectomy. Also called focused parathyroidectomy, surgeons use this type of surgery when they think only one of the parathyroid glands is overactive. Guided by a tumor-imaging test, your surgeon will make a small incision, or cut, in your neck to remove the gland. The small incision means you will probably have less pain and a faster recovery than people who have more invasive surgery. You can go home the same day. Your doctor may use regional or general anesthesia during the surgery.

Bilateral neck exploration. This type of surgery uses a larger incision that lets the surgeon find and look at all four parathyroid glands and remove the overactive ones. If you have bilateral neck exploration, you will probably have general anesthesia and may need to stay in the hospital overnight.

Monitoring

Some people who have mild primary hyperparathyroidism may not need surgery right away, or even any surgery, and can be safely monitored.

You may want to talk with your doctor about long-term monitoring if you

  • don’t have symptoms
  • have only slightly high blood calcium levels
  • have normal kidneys and bone density

Long-term monitoring should include regular doctor visits, a yearly blood test to measure calcium levels and check your kidney function, and a bone density test every 1 to 2 years.

If you and your doctor choose long-term monitoring, you should

Next steps

Tips to help you get the most from a visit to your healthcare provider:

  • Know the reason for your visit and what you want to happen.
  • Before your visit, write down questions you want to be answered.
  • Bring someone with you to help you ask questions and remember what your healthcare provider tells you.
  • At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also, write down any new instructions your provider gives you.
  • Know why a new medicine or treatment is prescribed, and how it will help you. Also, know what the side effects are.
  • Ask if your condition can be treated in other ways.
  • Know why a test or procedure is recommended and what the results could mean.
  • Know what to expect if you do not take the medicine or have the test or procedure.
  • If you have a follow-up appointment, write down the date, time, and purpose for that visit.
  • Know how you can contact your healthcare provider if you have questions.

Parathyroid Quick Facts

  • There are 4 parathyroids glands. We all have 4 parathyroids glands.
  • Except in rare cases, parathyroid glands are in the neck behind the thyroid.
  • Parathyroids are NOT related to the thyroid (except they are neighbors in the neck).
  • The thyroid gland controls much of your body’s metabolism, but the parathyroid glands control body calcium. They have no relationship except they are neighbors.
  • Parathyroid glands make a hormone, called “Parathyroid Hormone”.
  • Doctors and labs abbreviate Parathyroid Hormone as “PTH”.
  • Just like calcium, PTH has a normal range in our blood…we can measure it to see how good or bad a job the parathyroid glands are doing.
  • All four parathyroid glands do the exact same thing.
  • Parathyroid glands control the amount of calcium in your blood.
  • Parathyroid glands control the amount of calcium in your bones.
  • You can easily live with one (or even 1/2) parathyroid gland.
  • Removing all 4 parathyroid glands will cause very bad symptoms of too little calcium (hypoparathyroidism). HypOparathyroidism is the opposite of hypERparathyroidism and it is very rare… only one page of this entire site is about hypoparathyroidism disease.
  • When parathyroid glands go bad, it is just one gland that goes bad about 91% of the time–it just grows big (develops a benign tumor) and makes too much hormone. About 8% of the time people with hyperparathyroidism will have two bad glands. It is quite uncommon for 3 or 4 glands to go bad.
  • When one of your parathyroid glands goes bad and makes too much hormone, the excess hormone goes to the bones and takes calcium out of the bones, and puts it in your blood. It’s the high calcium in the blood that makes you feel bad.
  • Everybody with a bad parathyroid gland will eventually develop bad osteoporosis–unless the bad gland is removed.
  • Parathyroids almost never develop cancer–so stop worrying about that!
  • However, not removing the parathyroid tumor and leaving the calcium high for a number of years will increase the chance of developing other cancers in your body (breast, colon, kidney, and prostate).
  • There is only ONE way to treat parathyroid problems–Surgery.
  • Mini-Surgery is now available that almost everyone can/should have. You should educate yourself about the new surgical treatments available. Do not have an “exploratory” operation to find the bad parathyroid tumor–this old-fashioned operation is too big and dangerous.

References

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