Hyperparathyroidism

Overview

Hyperparathyroidism is a disorder that occurs when one or more of the parathyroid glands secretes an excess amount of parathyroid hormone.1 Hyperparathyroidism is broken down into two main sub-categories: primary hyperparathyroidism and secondary hyperparathyroidism.2 In primary hyperparathyroidism, an enlargement of one or more of the parathyroid glands leads to the excess production of parathyroid hormone,2 whereas in secondary hyperparathyroidism, the overactivity of the parathyroid glands is due to a secondary condition that causes calcium loss.1 Secondary hyperparathyroidism stems from the body’s attempt to correct for low calcium levels. Both types of hyperparathyroidism can cause hypercalcemia, which can lead to a variety of health problems.2

A third characterization of hyperparathyroidism is known as normocalcemic hyperparathyroidism, which can be primary or secondary.3 In normocalcemic hyperparathyroidism, parathyroid hormone levels are elevated, but serum calcium levels are normal.3 Prognosis overall is generally good, as the primary treatment for severe cases (surgical parathyroidectomy) can permanently cure the disorder.5

Hyperparathyroidism History

The parathyroid gland was first described in 1850 by Sir Richard Owen, a professor of anatomy at the Royal College of England, who identified the gland inside an Indian rhinoceros at the London Zoo.6 The presence of these glands in humans was verified in 1887 by Ivor Sandstrom. A patient with both skeletal disease and a tumor near the parathyroid gland was described in 1904 by Max Askanazy, and in 1909, William MacCallum and Carl Voegtlin observed that hypocalcemia accompanied parathyroidectomy and that injections of parathyroid/calcium were an effective cure.6

In 1915,  Freidrich Schlagenhaufe suggested that a parathyroid tumor was responsible for bone disease rather than the reverse and that in an attempt to cure bone disease, any parathyroid enlargement should be surgically removed.6 The term hyperparathyroidism was first coined by Henry Dixon and colleagues.6 Fuller Albright conducted the most extensive work on hyperparathyroidism in the 1930s, describing parathyroid hyperplasia and differentiating between primary, secondary, and tertiary hyperparathyroidism.7 Initially diagnosed as a mainly symptomatic disease of “bones, stones, abdominal groans, and psychic moans,”6 hyperparathyroidism is now known to be largely asymptomatic in the initial stages. More comprehensive health screenings by clinicians, namely the inclusion of calcium estimation, have led to an increase in early detection and intervention.6

Etiology

There are multiple causes of both primary and secondary hyperparathyroidism. In primary hyperparathyroidism, 80% of patients will present with a single adenoma on a parathyroid gland, while 2% to 4% will have multiple adenomas. Approximately 15% of patients will have hyperplasia of all four glands, while less than 1% will have malignancy. The vast majority of adenomas are located in one of the two inferior parathyroid glands. Potential ectopic locations, which may occur in up to 10% of all cases of primary hyperparathyroidism, include the pericardium, thyroid, thymus, superior mediastinum, or behind the esophagus.5 Primary hyperparathyroidism typically develops randomly, but some people inherit a gene that can cause the disorder.2 A full list of potential causes of primary hyperparathyroidism include:5

  • Single adenoma
  • Multi-gland disease
    • Familial causes of hyperparathyroidism
      • Multiple endocrine neoplasia Type 1
      • Multiple endocrine neoplasia Type 2a
      • Hyperparathyroidism-jaw tumor syndrome
      • Familial hyperparathyroidism (chief cell parathyroid hyperplasia)
    • Parathyroid carcinoma
    • Parathyromatosis
    • Radiation treatment to the neck area1

Secondary hyperparathyroidism is most commonly caused by: vitamin D deficiency or chronic kidney disease.8 It can also be caused by severe calcium deficiency stemming from a lack of dietary calcium. This is usually due to a lack of absorption in the digestive system and is common after intestinal surgery.2 If vitamin D levels are low, or if the kidneys cannot convert vitamin D into the physiologically active 1,25-cholecalciferol,8 serum calcium levels drop, thus increasing the production of parathyroid hormone, leading to secondary hyperparathyroidism.2 Other causes of secondary hyperparathyroidism include the use of lithium, anticonvulsants, denosumab, bisphosphonates, and diuretics (thiazides).3

Long-term secondary hyperparathyroidism can cause the parathyroid glands to enlarge in some patients. As a result, the parathyroid glands begin to release parathyroid hormone on their own and become unresponsive to medical treatment. This is known as tertiary hyperparathyroidism.2

Risk Factors

While most cases are idiopathic, there are risk factors associated with the development of hyperparathyroidism. These risk factors include:

  • Being a woman, particularly one who has undergone menopause2
  • Having had prolonged, severe calcium or vitamin D deficiency2
  • Having a rare, inherited disorder (multiple endocrine neoplasia Type 1, etc.)2
  • Having had radiation treatment to the neck area1
  • Have taken lithium or other drugs associated with secondary hyperparathyroidism3
  • Having celiac disease3
  • Having chronic kidney disease8

Hyperparathyroidism Prognosis

The prognosis for hyperparathyroidism varies depending on the and the etiology, but the overall outlook is generally favorable.

Primary Hyperparathyroidism

In the United States, most cases of primary hyperparathyroidism are diagnosed asymptomatically due to an elevated serum calcium level.5 As such, appropriate measures for monitoring and intervention can take place well in advance of serious disease progression, allowing for a better prognosis. There have been studies that followed these types of patients for 15 years and determined that laboratory values remain relatively stable over time, but eventually, bone mineral density will start to decline.5 The risk of renal calculi remains increased as well. Surgical parathyroidectomy typically resolves and permanently cures the disorder. Surgery also allows for improvements in bone mineral density over time. Primary hyperparathyroidism increases the risk of cardiovascular events, and it is unclear whether treatment or surgery negates or improves the risk.5

Secondary Hyperparathyroidism

The prognosis for secondary hyperparathyroidism is generally good, although the severity of the issue causing the hyperparathyroidism is the primary indicator of patient outlook. Complications from secondary hyperparathyroidism, such as calciphylaxis, bone mineral disorders, and cardiovascular events, can significantly impact the patient, and their quality of life can be affected by muscle pain, bone pain, and fractures.8 Medical therapy is used to achieve target levels per Kidney Disease Outcomes Quality Initiative guidelines. Both calcimimetics and surgery offer improved survival in the initial stages of chronic kidney disease, but for secondary hyperparathyroidism patients on hemodialysis, surgery has not been shown to improve cardiovascular morbidity or mortality.8

However, calcimimetics have been shown to improve some outcomes, such as rates of parathyroidectomy, cardiovascular hospitalizations, fractures, and certain health-related quality of life parameters. In a case where secondary hyperparathyroidism is medically refractory, parathyroidectomy is indicated. End-stage renal disease patients on hemodialysis with secondary hyperparathyroidism can expect an increase in the incidence of parathyroidectomy as time passes, with roughly 15% of patients requiring surgery within 5 to 10 years of initiating dialysis.8

Normocalcemic primary hyperparathyroidism patients typically have a good prognosis after a parathyroidectomy. Newer, minimally invasive procedures have led to fewer complications and better outcomes due to being less intrusive, having shorter operating times, and utilizing intraoperative monitoring of serum parathyroid hormone levels.3 Normocalcemic primary hyperparathyroidism patients who undergo parathyroidectomy do require reoperation at more than double the rate of hypercalcemia hyperparathyroidism patients. They are also much more likely to develop permanent hypocalcemia postoperatively.3

Hyperparathyroidism Diagnosis & Presentation

Most cases of hyperparathyroidism are diagnosed while patients are asymptomatic, often due to elevated serum calcium levels found on routine blood tests.2 If elevated serum calcium levels are detected, parathyroid hormone levels should be tested. If these are also high, the clinician can make a diagnosis of hyperparathyroidism,9 as essentially all other causes of hypercalcemia will show low parathyroid hormone levels.5 On occasion, parathyroid hormone levels are in the upper portion of the normal range, but they should drop to low-normal or below normal in response to elevated calcium levels. This is still indicative of a hyperparathyroidism diagnosis.4 Although most patients with primary hyperparathyroidism are asymptomatic, those that do have symptoms may present with any of the following:5

  • Kidney stones
  • Bone pain
  • Muscle weakness
  • Joint pain
  • Body aches
  • Headaches
  • Osteoporosis
  • Abdominal pain
  • Loss of appetite
  • Nephrocalcinosis
  • Excessive urination
  • Tiring easily, chronic fatigue
  • Difficulty sleeping
  • Trouble concentrating
  • Depression, memory loss, or forgetfulness
  • Renal Failure
  • Hypertension
  • Increased overall cardiovascular disease
  • Cardiac arrhythmias
  • Decreased coronary artery flow reserve
  • Aortic valve calcification
  • Left ventricular hypertrophy
  • Frequent complaints of illness with no apparent cause

While most primary hyperparathyroidism patients are asymptomatic, up to 55% will have previously undiagnosed nephrocalcinosis or non-obstructing renal calculi. Of the symptomatic patients, up to 75% will present with acute renal colic or nephrolithiasis, highlighting the need for routine serum calcium testing for all patients with calcium nephrolithiasis. Hypercalciuria will also be present in about 40% of patients with primary hyperparathyroidism.5

Normocalcemic hyperparathyroidism can be primary or secondary. This disorder can be diagnosed when a patient has persistently elevated parathyroid hormone levels in combination with normal calcium levels, 25-hydroxyvitamin D levels of 30 ng/mL or more, and a glomerular filtration rate (GFR) of at least 60 mL/min.5

Physical Examinations Findings

The physical examination findings in a patient with primary hyperparathyroidism are typically normal. The physical examination can, however, help to find any abnormalities that may suggest other etiologies of hypercalcemia. Rarely are parathyroid adenomas palpable on physical examination, but the presence of a large, firm neck mass in the neck of a patient with hypercalcemia should raise suspicion of possible parathyroid carcinoma.5

In secondary hyperparathyroidism, bone remodeling and mineralization are affected, with bony skeletal deformities being secondary to bone remodeling. Clinicians may note during their physical examination of patients that they exhibit chest wall deformity and kyphoscoliosis due to abnormal mineralization and bone remodeling. Hip joints, pelvic bones, and bones of the lower extremities may also be deformed in patients with secondary hyperparathyroidism, and increased stress from weight-bearing may lead to fractures. In children, these bone deformities could lead to rickets.8

Extraosseous manifestations are also seen in some patients with secondary hyperparathyroidism, with calcifications affecting the arterial walls, periarticular tissue, cutaneous tissue, viscera, and the eye (conjunctiva and cornea). These extraosseous manifestations are responsible for intense pruritus, red-eye syndrome, and muscle weakness.8 Calciphylaxis in secondary hyperparathyroidism patients can be seen as ulceration of the skin, resulting from arterial obstruction, with cutaneous necrosis of the extremities.8

Diagnostic Workup

Patients with elevated serum calcium levels should always be asked about history of kidney stones, bone pain, myalgias or muscle weakness, use of thiazide diuretics, ingestion of calcium or vitamin D supplements, symptoms of depression, or other symptoms associated with the multiple etiologies of hypercalcemia.5 If primary hyperthyroidism is diagnosed at an early age, a familial syndrome should be considered. This is also the case if there is a family history of hypercalcemia, pancreatic islet cell tumors, pituitary adenomas, pheochromocytomas, or medullary thyroid cancer.5 On blood tests, hypercalcemia and hypophosphatemia are highly suggestive of hyperparathyroidism, but the definitive test is having both elevated calcium and parathyroid hormone levels.

If a patient is borderline for hyperparathyroidism but has low vitamin D levels, the 25-hydroxyvitamin D level should be raised to at least 30 ng/mL for at least three months in order to rule out vitamin D deficiency.5 If a patient is taking known hypercalcemic drugs, such as thiazide and lithium, then the regimen should be halted for three to six months, if possible. After the allotted time has passed, retesting of serum calcium and parathyroid hormone levels are needed to help confirm a diagnosis. The clinician can exclude familial hypocalciuric hypercalcemia with a 24-hour urine calcium determination (<100 mg calcium/24  hours) or by a low calcium/creatinine excretion ratio, typically less than .02. Familial hypocalciuric hypercalcemia may present as early as age 30, but essentially never after age 50.5

A patient that takes biotin (vitamin B-7) should discontinue use, followed by a retest of parathyroid hormone levels, as biotin supplementation can interfere with parathyroid hormone assays. Immunochemiluminometric or immunoradiometric assays are the recommended serum intact parathyroid tests, as they readily discriminate between primary hyperparathyroidism and malignancy-related hypercalcemia.5 It should be noted that it is uncommon for clinically occult malignancies to cause hypercalcemia, and most patients with malignancy-associated hypercalcemia have already been diagnosed with cancer, or their cancer is readily diagnosable upon evaluation.5

Blood Tests

  • Total serum calcium
  • Parathyroid hormone
  • Corrected serum calcium; corrected calcium = measured calcium + 0.8 x (4.0 – albumin) (calcium measured in mg/dL; albumin measured in g/dL)
  • Ionized calcium, if there are concerns regarding the accuracy of the corrected calcium
  • Phosphate, hypercalcemia with hypophosphatemia is highly suggestive of hyperparathyroidism
  • 25-hydroxyvitamin D
  • Urine calcium and creatinine
  • BUN and creatinine
  • Alkaline phosphatase (ALP) and osteocalcin, as ALP in hyperparathyroidism is usually elevated
  • Sclerostin (a bone formation regulator), usually suppressed in primary hyperparathyroidism
  • Serum albumin

Imaging Tests

  • Parathyroid nuclear medicine (Tc-Sestamibi) scans and neck ultrasonography are standard imaging tests for finding and confirming hyperfunctioning parathyroid glands, with Tc-Sestamibi scans generally considered the most sensitive and specific. However, due to the potential for false-test results they are not considered definitively diagnostic and should not be ordered unless there are plans for surgery
  • Single-photon emission computed tomography (SPECT) used in conjunction with Tc-Sestamibi scans fand neck ultrasonography can enhance the sensitivity of parathyroid imaging scans
  • Imaging to screen for renal calcifications or urolithiasis (KUB, renal ultrasound, or non-contrast CT scan)
  • Bone densitometry (DEXA) scans, including measurement at the distal 1/3 radius, which is preferentially affected in hyperparathyroidism patients
  • EKG
  • Localization studies for potential surgical patients5

The results from these tests, combined with a thorough review of the patient’s medications, should suffice to differentiate between the types of hyperparathyroidism.3

Differential Diagnosis

There are many potential differential diagnoses for hyperparathyroidism, including:

  • Chronic kidney disease
  • Vitamin D deficiency3
  • Vitamin D intoxication5
  • Hyperthyroidism5
  • Hypercalciuria3
  • Malignancy-related hypercalcemia5
  • Granulomatous diseases5
  • Thiazide therapy5
  • Treatment with lithium5
  • Bisphosphonates and denosumab usage3
  • Milk-alkali syndrome5
  • Adrenal insufficiency5
  • Vitamin A intoxication5

Hyperparathyroidism Management

There are multiple treatment options available for patients with hyperparathyroidism. These include surgery, pharmacotherapy, and non-operative surveillance. The determination of the treatment plan should be based on the individual circumstances of the case, including the etiology, health and age of the patient, and severity of symptoms or disease.9

Primary Hyperparathyroidism

Surgery

This is the definitive treatment for cases of primary hyperparathyroidism, although monitoring may be the more appropriate option for some patients, especially if they are older and have mild symptoms and no significant complications.5 If the patient has decreased bone mineral density or recurring kidney stones, surgery is the treatment of choice. A successful parathyroidectomy typically results in permanent normalization of both parathyroid hormone and serum calcium levels. It also leads to a dramatic improvement in bone mineral density throughout the body.

After a successful parathyroid surgery, patients will have a reduced risk of kidney stones and fractures, as bone mineral density, microstructure, and strength all improve. The improvement in bone mineral density persists at least 15 years, and these benefits are seen in all successful parathyroidectomy patients, even if they did not meet the criteria for surgery. However, there is no substantial clinical evidence that parathyroidectomy will benefit neurocognitive function or cardiovascular events in primary hyperparathyroidism patients.5

The criteria for surgery in primary hyperparathyroidism are as follows:5

  • All patients who are symptomatic
  • Asymptomatic patients who meet the following guidelines:
    • Age younger than 50 years
    • History of fractures
    • Osteoporosis on DEXA scan (T-score <-2.5 at any site)
    • Serum calcium is more than 1 mg/dL above the upper limit of normal
    • GFR less than 60 mL/min
    • Hypercalciuria with urine calcium greater than 400 mg/24 hours
    • Vertebral compression fracture on imaging
    • Evidence of renal calcifications, nephrocalcinosis, or urinary stones
    • Electively for all hyperparathyroidism patients, even if they do not meet any of the above criteria and have no medical contraindications

In most centers, minimally invasive parathyroidectomy is the preferred surgery for primary hyperparathyroidism. If done by experienced parathyroid surgeons, the success rate exceeds 95%.5 Intraoperative parathyroid hormone measurements are highly recommended during the procedure to help successfully control parathyroid hormone levels and verify the efficacy of the surgery. As the half-life of parathyroid hormone is roughly four minutes, the parathyroid hormone level should drop by at least 50% in the first 10 to 20 minutes after successful excision and should normalize within 30 minutes.5

Pharmacotherapy

Primary hyperparathyroidism patients who are not surgical candidates may benefit from pharmacotherapy management of primary hyperparathyroidism. Calcium intake should not be restricted, and patients with 25-hydroxyvitamin D levels less than 30 ng/mL should receive supplementation starting at 1000 IU per day.5 Oral phosphates can reduce serum calcium levels up to 1 mg/dL; however, since phosphates can increase parathyroid hormone levels, they are no longer utilized for long-term medical management of primary hyperparathyroidism. Estrogen therapy for postmenopausal patients has been shown to increase bone mineral density but does not cause changes to calcium or parathyroid hormone levels. Again, concerns over chronic estrogen use keep this from being recommended for long-term management. Oral bisphosphonates and denosumab can help control hypercalcemia and increase bone mineral density in hyperparathyroidism patients with osteoporosis or osteopenia. Calcimimetics, such as cinacalcet, significantly lower serum calcium and parathyroid hormone but do not increase bone density. The use of combination therapy involving calcimimetics and bisphosphonates or denosumab is reasonable for increasing bone mineral density and controlling serum calcium and parathyroid hormone levels, although there are only limited studies on this approach.5

If monitoring is the selected course of action, periodic testing of serum and urine calcium levels, bone densitometry, and renal function is required. Calcium and parathyroid hormone blood tests should be done every six months, and 24-hour urine measurements and DEXA scans should be completed annually. Surgery should be recommended if complications develop or if the hypercalcemia worsens.5

Secondary Hyperparathyroidism

Pharmacotherapy

The management of secondary hyperparathyroidism should focus on abnormal phosphocalcic metabolism, as maintaining serum calcium, phosphorus, parathyroid hormone, and vitamin D levels is key to long-term treatment. The US National Kidney Foundation (NKF) proposed the Kidney Disease Outcomes Quality Initiative guidelines, and established targets for calcium, phosphorus, and parathyroid hormone biomarkers to lower mortality related to secondary hyperparathyroidism. Phosphate binders, vitamin D supplementation, and calcimimetics are often used in patients with chronic kidney disease.8

Surgery

If pharmacotherapy is unsuccessful or refractory, parathyroidectomy is an option. Other indications for surgery in secondary hyperparathyroidism patients include:8

  • Calciphylaxis
  • Refractory pruritus
  • Severe hypercalcemia
  • Severe hyperphosphatemia
  • Anemia hyporesponsive to erythropoietin
  • Parathyroid hormone levels more than 800 pg/mL, occurring for more than 6 months despite medical therapy
  • Extraskeletal calcification

Monitoring

Regardless of the specific type of hyperparathyroidism or the treatment option used, monitoring will be required to ensure successful management of the disease. As hypercalcemia can affect many organs, the condition is best managed by an interprofessional team that includes an endocrinologist, urologist, radiologist, surgeon, and internist.5 Hyperparathyroidism patients who are being treated medically are recommended to undergo annual testing of serum calcium and creatinine levels, annual or bi-annual DEXA scans, and occasional monitoring of parathyroid hormone and vitamin D levels. The frequency of testing for any of these biomarkers may vary based on the initial results and the specific treatment used.5 If monitoring is the selected course of action, periodic testing of serum and urine calcium levels, bone densitometry, and renal function is required. Calcium and parathyroid hormone blood tests should occur every six months, and 24-hour urine measurements and DEXA scans should be completed annually. Surgery should be recommended if complications develop or the hypercalcemia worsens.5

Calcimimetic usage can have side effects such as hypocalcemia, arrhythmias, QT prolongation, nausea, worsening heart failure, and convulsions.8 Phosphate binders can be calcium-containing or calcium-free; however, calcium-containing phosphate binders can increase vascular and soft tissue calcification and are associated with lower survival. If these are used for treatment, close monitoring of soft tissue and vascular calcification is recommended. Primary hyperparathyroidism increases the risk of a cardiovascular event, and it is unclear whether treatment improves or eliminates this risk. As such, the clinician should also monitor for cardiovascular risk factors in patients diagnosed with hyperparathyroidism.5

Hyperparathyroidism Complications

Complications of hyperparathyroidism include:

  • Fractures
  • Bone pain
  • Loss of bone mineral density
  • Higher risk of urinary stones
  • Gastrointestinal disturbances
  • Psychological issues
  • Increased risk of cardiovascular disease5

Surgical intervention for the disease can cause another complication, known as hungry bone syndrome or bone hunger.8 This syndrome is described as a period of profound, severe, and prolonged hypocalcemia that initiates immediately following parathyroidectomy. While a drop in serum calcium levels is expected after surgery, it should resolve within four days. It is considered hungry bone syndrome if severe hypocalcemia persists for more than four days.Symptoms of severe hypocalcemia include arrhythmias, seizures, numbness, paresthesias, cardiomyopathy, and laryngospasms.5

Hungry bone syndrome can persist for months or even years, and the likelihood of it developing increases as the duration and severity of hyperparathyroidism rise.5 It is more common in patients with secondary hyperparathyroidism from renal failure and chronic dialysis than from primary hyperparathyroidism; however, the severity of the hungry bone syndrome is generally less than after primary hyperparathyroidism surgery.5 Treatment for hungry bone syndrome may be needed for up to a year after surgery and generally includes high oral doses of supplemental calcium and vitamin D, although intravenous calcium supplementation may be required in some patients.5

Guidelines

References

1. Hyperparathyroidism | Cleveland Clinic. Cleveland Clinic. Published 2016. Accessed August 30, 2022.
2. Hyperparathyroidism – Symptoms and causes. Mayo Clinic. Published 2019. Accessed August 30, 2022.
3. Rajkumar V, Levine SN. Normocalcemic Hyperparathyroidism. In: StatPearls. NCBI Bookshelf version. Published 2022. Accessed August 30, 2022.
4. National Institute of Diabetes and Digestive and Kidney Diseases. Primary Hyperparathyroidism | NIDDK. Published June 17, 2019. Accessed August 30, 2022.
5. Pokhrel B, Levine SN. Primary Hyperparathyroidism. In: StatPearls. NCBI Bookshelf version. Published 2020. Accessed August 30, 2022.
6. Dorairajan N, Pradeep PV. Vignette Hyperparathyroidism: Glimpse Into Its History. International Surgery. 2014;99(5):528-533. doi:10.9738/INTSURG-D-13-00225.1
7. Kalra S, Baruah M, Sahay R, Sawhney K. The history of parathyroid endocrinology. Indian Journal of Endocrinology and Metabolism. 2013;17(2):320. doi:10.4103/2230-8210.109703
8. Muppidi V, Meegada SR, Rehman A. Secondary Hyperparathyroidism. In: StatPearls. NCBI Bookshelf version. Published 2020. Accessed August 30, 2022.
9. Hyperparathyroidism – Diagnosis and treatment. Mayo Clinic. Published 2019. Accessed August 30, 2022.

Author Bio

Jonathan Poole is a freelance writer and copy-editor with a BSc in Exercise Science living in West Lafayette, IN. When not writing, he owns and operates a fitness training company, Unstoppable Athletes. More information regarding his training business can be found here: https://www.unstoppableathletes.com