Primary hyperparathyroidism

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Primary hyperparathyroidism
Illu thyroid parathyroid.jpg
Thyroid and parathyroid.
Specialty Endocrinology

Primary hyperparathyroidism (or PHPT) is a medical condition where the parathyroid gland (or a benign tumor within it) produce excess amounts of parathyroid hormone (PTH). The symptoms of the condition relate to the resulting elevated serum calcium (hypercalcemia), which can cause digestive symptoms, kidney stones, psychiatric abnormalities, and bone disease.

Contents

The diagnosis is initially made on blood tests; an elevated level of calcium together with a raised (or inappropriately high) level of parathyroid hormone are typically found. To identify the source of the excessive hormone secretion, medical imaging may be performed. Parathyroidectomy, the surgical removal of one or more parathyroid glands, may be required to control symptoms.

Signs and symptoms

The signs and symptoms of primary hyperparathyroidism are those of hypercalcemia. They are classically summarized by "stones, bones, abdominal groans, thrones and psychiatric overtones". [1]

Left ventricular hypertrophy may also be seen. [3]

Other signs include proximal muscle weakness, itching, and band keratopathy of the eyes.[ citation needed ]

When subjected to formal research, symptoms of depression, pain, and gastric dysfunction seem to correlate with mild cases of hypercalcemia. [4]

Causes

The most common cause of primary hyperparathyroidism is a sporadic, single parathyroid adenoma [5] resulting from a clonal mutation (~97%). Less common are parathyroid hyperplasia [6] (~2.5%), parathyroid carcinoma (malignant tumor), and adenomas in more than one gland (together ~0.5%).Primary hyperparathyroidism is also a feature of several familial endocrine disorders: Multiple endocrine neoplasia type 1 and type 2A (MEN type 1 and MEN type 2A), and familial hyperparathyroidism.[ citation needed ]

Genetic associations include:

OMIM NameGene
145000 HRPT1 MEN1, HRPT2
145001 HRPT2 HRPT2
610071 HRPT3unknown at 2p13.3-14 [7]

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

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. [8]

Diagnosis

The diagnosis of primary hyperparathyroidism is made by blood tests.[ citation needed ]

Serum calcium levels are usually elevated, and the parathyroid hormone level is abnormally high compared with an expected low level in response to the high calcium. A relatively elevated parathyroid hormone has been estimated to have a sensitivity of 60–80% and a specificity of approximately 90% for primary hyperparathyroidism. [9]

A more powerful variant of comparing the balance between calcium and parathyroid hormone is to perform a 3-hour calcium infusion. After infusion, a parathyroid hormone level above a cutoff of 14 ng/L has a sensitivity of 100% and a specificity of 93% in detecting primary hyperparathyroidism, with a confidence interval of 80% to 100%. [10]

Urinary cAMP is occasionally measured; it is generally elevated due to activation of Gs proteins when PTH binds to its receptor. [11]

Biochemical confirmation of primary hyperparathyroidism is following by investigations to localize the culprit lesion. Primary hyperparathyroidism is most commonly due to solitary parathyroid adenoma. Less commonly it may be due to double parathyroid adenomas or parathyroid hyperplasia. Tc99 sestamibi scan of head, neck and upper thorax is the most commonly used test for localizing parathyroid adenomas having a sensitivity and specificity of 70–80%. Sensitivity falls down to 30% in case of double/multiple parathyroid adenomas or in case of parathyroid hyperplasia. Ultrasonography is also a useful test in localizing suspicious parathyroid lesions.[ citation needed ]

Normocalcemic Primary Hyperparathyroidism

Normocalcemic PHPT was first recognized in 2009 by an international panel of experts. [12] By definition these patients have normal serum calcium (though usually in the upper range) and are typically found to have elevated PTH during workup for osteoporosis. In order to diagnose normocalcemic PHPT, ionized calcium levels should be normal, and all secondary causes for secondary hyperparathyroidism (such as vitamin D deficiency and chronic kidney disease) ruled out.

Treatment

Treatment is usually surgical removal of the gland(s) containing adenomas, but medication may also be required.[ citation needed ]

Surgery

The surgical removal of one or more of the parathyroid glands is known as a parathyroidectomy; this operation was first performed in 1925. [13] The symptoms of the disease, listed above, are indications for surgery. Surgery reduces all cause mortality as well as resolving symptoms. However, cardiovascular mortality is not significantly reduced. [14]

The 2002 NIH Workshop on Asymptomatic Primary Hyperparathyroidism developed criteria for surgical intervention . The criteria were revised at the Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism . These criteria were chosen on the basis of clinical experience and observational and clinical trial data as to which patients are more likely to have end-organ effects of primary hyperparathyroidism (nephrolithiasis, skeletal involvement), disease progression if surgery is deferred, and the most benefit from surgery. The panel emphasized the need for parathyroidectomy to be performed by surgeons who are highly experienced and skilled in the operation. The Third International Workshop guidelines concluded that surgery is indicated in asymptomatic patients who meet any one of the following conditions:[ citation needed ]

Operative intervention can be delayed in patients over 50 years of age who are asymptomatic or minimally symptomatic and who have serum calcium concentrations <1.0 mg/dL (0.2 mmol/L) above the upper limit of normal, and in patients who are medically unfit for surgery[ citation needed ]

More recently, three randomized controlled trials have studied the role of surgery in patients with asymptomatic hyperparathyroidism. The largest study reported that surgery resulted in an increase in bone mass, but no improvement in quality of life after one to two years among patients in the following groups: [15]

Two other trials reported improvements in bone density and some improvement in quality of life with surgery. [16] [17]

Medications

Medications are used when surgery is not indicated or for poor surgical candidates. [18] Calcimimetics are used to reduce the amount of parathyroid hormone released by the parathyroid glands and subsequent hypercalcemia. Other medications used for PHPT includes treatments for osteoporosis such as estrogen replacement therapy, bisphosphonates or denosumab and for treatment hypercalciuria to reduce the risk for kidney stones. [19]

Epidemiology

Primary hyperparathyroidism affects approximately 1 per 1,000 people (0.1%), [20] while there are 25–30 new cases per 100,000 people per year in the United States. [21] The prevalence of primary hyperparathyroidism has been estimated to be 3 in 1000 in the general population and as high as 21 in 1000 in postmenopausal women. [22]

Primary hyperparathyroidism is associated with increased all-cause mortality. [14]

Children

In contrast with primary hyperparathyroidism in adults, primary hyperparathyroidism in children is considered a rare endocrinopathy. Pediatric primary hyperparathyroidism can be distinguished by its more severe manifestations, in contrast to the less intense manifestations in adult primary hyperparathyroidism. Multiple endocrine neoplasia is more likely to be associated with childhood and adolescent primary hyperparathyroidism. The fundamental skeletal radiologic manifestation include diffuse osteopenia, pathologic fractures and the coexistence of resorption and sclerosis at numerous sites. Skeletal lesions can be specifically bilateral, symmetric and multifocal, exhibiting different types of bone resorption. Pathologic fractures of the femoral neck and spine can potentially initiate serious complications. Because pediatric primary hyperparathyroidism is frequently associated with pathologic fractures it can be misdiagnosed as osteogenesis imperfecta. Pediatric patients with primary hyperparathyroidism are best remedied by parathyroidectomy. Early diagnosis of pediatric primary hyperparathyroidism is all-important to minimize disease complications and start off timely and relevant treatment. [23] [24]

See also

Related Research Articles

<span class="mw-page-title-main">Parathyroid gland</span> Endocrine gland

Parathyroid glands are small endocrine glands in the neck of humans and other tetrapods. Humans usually have four parathyroid glands, located on the back of the thyroid gland in variable locations. The parathyroid gland produces and secretes parathyroid hormone in response to low blood calcium, which plays a key role in regulating the amount of calcium in the blood and within the bones.

<span class="mw-page-title-main">Parathyroid hormone</span> Mammalian protein found in humans

Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine.

Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcemia. Those with a mild increase that has developed slowly typically have no symptoms. In those with greater levels or rapid onset, symptoms may include abdominal pain, bone pain, confusion, depression, weakness, kidney stones or an abnormal heart rhythm including cardiac arrest.

Disorders of calcium metabolism occur when the body has too little or too much calcium. The serum level of calcium is closely regulated within a fairly limited range in the human body. In a healthy physiology, extracellular calcium levels are maintained within a tight range through the actions of parathyroid hormone, vitamin D and the calcium sensing receptor. Disorders in calcium metabolism can lead to hypocalcemia, decreased plasma levels of calcium or hypercalcemia, elevated plasma calcium levels.

<span class="mw-page-title-main">Parathyroid chief cell</span>

Parathyroid chief cells are one of the two cell types of the parathyroid glands, along with oxyphil cells. The chief cells are much more prevalent in the parathyroid gland than the oxyphil cells. It is perceived that oxyphil cells may be derived from chief cells at puberty, as they are not present at birth like chief cells.

Hypoparathyroidism is decreased function of the parathyroid glands with underproduction of parathyroid hormone (PTH). This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany, and several other symptoms. It is a very rare disease. The condition can be inherited, but it is also encountered after thyroid or parathyroid gland surgery, and it can be caused by immune system-related damage as well as a number of rarer causes. The diagnosis is made with blood tests, and other investigations such as genetic testing depending on the results. The primary treatment of hypoparathyroidism is calcium and vitamin D supplementation. Calcium replacement or vitamin D can ameliorate the symptoms but can increase the risk of kidney stones and chronic kidney disease. Additionally, medications such as recombinant human parathyroid hormone or teriparatide may be given by injection to replace the missing hormone.

<span class="mw-page-title-main">Hyperparathyroidism</span> Increase in parathyroid hormone levels in the blood

Hyperparathyroidism is an increase in parathyroid hormone (PTH) levels in the blood. This occurs from a disorder either within the parathyroid glands or as response to external stimuli. Symptoms of hyperparathyroidism are caused by inappropriately normal or elevated blood calcium excreted from the bones and flowing into the blood stream in response to increased production of parathyroid hormone. In healthy people, when blood calcium levels are high, parathyroid hormone levels should be low. With long-standing hyperparathyroidism, the most common symptom is kidney stones. Other symptoms may include bone pain, weakness, depression, confusion, and increased urination. Both primary and secondary may result in osteoporosis.

<span class="mw-page-title-main">Pituitary adenoma</span> Tumor of the pituitary gland

Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas. Pituitary adenomas represent from 10% to 25% of all intracranial neoplasms and the estimated prevalence rate in the general population is approximately 17%.

<span class="mw-page-title-main">Parathyroidectomy</span> Surgical removal of one or more of the parathyroid glands

Parathyroidectomy is the surgical removal of one or more of the (usually) four parathyroid glands. This procedure is used to remove an adenoma or hyperplasia of these glands when they are producing excessive parathyroid hormone (PTH): hyperparathyroidism. The glands are usually four in number and located adjacent to the posterior surface of the thyroid gland, but their exact location is variable. When an elevated PTH level is found, a sestamibi scan or an ultrasound may be performed in order to confirm the presence and location of abnormal parathyroid tissue.

<span class="mw-page-title-main">Cinacalcet</span> Chemical compound

Cinacalcet, sold under the brand name Sensipar among others, is a medication used to treat primary hyperparathyroidism, tertiary hyperparathyroidism and parathyroid carcinoma. Cinacalcet acts as a calcimimetic by allosteric activation of the calcium-sensing receptor that is expressed in various human organ tissues.

<span class="mw-page-title-main">Multiple endocrine neoplasia type 1</span> Medical condition

Multiple endocrine neoplasia type 1 (MEN-1) is one of a group of disorders, the multiple endocrine neoplasias, that affect the endocrine system through development of neoplastic lesions in pituitary, parathyroid gland and pancreas. Individuals suffering from this disorder are prone to developing multiple endocrine and nonendocrine tumors. It was first described by Paul Wermer in 1954.

<span class="mw-page-title-main">Osteitis fibrosa cystica</span> Medical condition

Osteitis fibrosa cystica is a skeletal disorder resulting in a loss of bone mass, a weakening of the bones as their calcified supporting structures are replaced with fibrous tissue, and the formation of cyst-like brown tumors in and around the bone. Osteitis fibrosis cystica (OFC), also known as osteitis fibrosa, osteodystrophia fibrosa, and von Recklinghausen's disease of bone, is caused by hyperparathyroidism, which is a surplus of parathyroid hormone from over-active parathyroid glands. This surplus stimulates the activity of osteoclasts, cells that break down bone, in a process known as osteoclastic bone resorption. The hyperparathyroidism can be triggered by a parathyroid adenoma, hereditary factors, parathyroid carcinoma, or renal osteodystrophy. Osteoclastic bone resorption releases minerals, including calcium, from the bone into the bloodstream, causing both elevated blood calcium levels, and the structural changes which weaken the bone. The symptoms of the disease are the consequences of both the general softening of the bones and the excess calcium in the blood, and include bone fractures, kidney stones, nausea, moth-eaten appearance in the bones, appetite loss, and weight loss.

<span class="mw-page-title-main">Secondary hyperparathyroidism</span> Medical condition

Secondary hyperparathyroidism is the medical condition of excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia, with resultant hyperplasia of these glands. This disorder is primarily seen in patients with chronic kidney failure. It is sometimes abbreviated "SHPT" in medical literature.

<span class="mw-page-title-main">Tertiary hyperparathyroidism</span> Medical condition

Tertiary hyperparathyroidism is a condition involving the overproduction of the hormone, parathyroid hormone, produced by the parathyroid glands. The parathyroid glands are involved in monitoring and regulating blood calcium levels and respond by either producing or ceasing to produce parathyroid hormone.

<span class="mw-page-title-main">Endocrine disease</span> Disorders of the endocrine system

Endocrine diseases are disorders of the endocrine system. The branch of medicine associated with endocrine disorders is known as endocrinology.

<span class="mw-page-title-main">Parathyroid adenoma</span> Benign tumor of the parathyroid gland

A parathyroid adenoma is a benign tumor of the parathyroid gland. It generally causes hyperparathyroidism; there are very few reports of parathyroid adenomas that were not associated with hyperparathyroidism.

<span class="mw-page-title-main">Parathyroid carcinoma</span> Cancerous tumor of the parathyroid gland

Parathyroid carcinoma is a rare cancer resulting in parathyroid adenoma to carcinoma progression. It forms in tissues of one or more of the parathyroid glands.

<span class="mw-page-title-main">Parathyroid disease</span> Medical condition

Many conditions are associated with disorders of the function of the parathyroid gland. Some disorders may be purely anatomical resulting in an enlarged gland which will raise concern. Such benign disorders, such as parathyroid cyst, are not discussed here. Parathyroid diseases can be divided into those causing hyperparathyroidism, and those causing hypoparathyroidism.

Familial hypocalciuric hypercalcemia (FHH) is an inherited condition that can cause hypercalcemia, a serum calcium level typically above 10.2 mg/dL; although uncommon. It is also known as familial benign hypocalciuric hypercalcemia (FBHH) where there is usually a family history of hypercalcemia which is mild, a urine calcium to creatinine ratio <0.01, and urine calcium <200 mg/day (hypocalciuria).

<span class="mw-page-title-main">Sestamibi parathyroid scan</span> Procedure in nuclear medicine

A sestamibi parathyroid scan is a procedure in nuclear medicine which is performed to localize parathyroid adenoma, which causes Hyperparathyroidism. Adequate localization of parathyroid adenoma allows the surgeon to use a minimally invasive surgical approach.

References

  1. ↑ "Hyperparathyroidism or Hypercalcemia: "Stones, Bones, abdominal Groans, thrones and psychiatric overtones"". Time of Care. July 12, 2016. Retrieved October 18, 2023.
  2. ↑ Barreras, R. F.; Donaldson, R. M. (1967). "Role of Calcium in Gastric Hypersecretion, Parathyroid Adenoma and Peptic Ulcer". New England Journal of Medicine. 276 (20): 1122–1124. doi:10.1056/NEJM196705182762005. PMID   6024167.
  3. ↑ Stefenelli T, Abela C, Frank H, et al. (1997). "Cardiac abnormalities in patients with primary hyperparathyroidism: implications for follow-up". J. Clin. Endocrinol. Metab. 82 (1): 106–12. doi:10.1210/jcem.82.1.3666. PMID   8989242. Archived from the original on 2011-05-16. Retrieved 2007-04-27.
  4. ↑ Bargren AE, Repplinger D, Chen H, Sippel RS (2011). "Can biochemical abnormalities predict symptomatology in patients with primary hyperparathyroidism?". J Am Coll Surg. 213 (3): 410–4. doi:10.1016/j.jamcollsurg.2011.06.401. PMID   21723154.
  5. ↑ "Endocrine Pathology". Archived from the original on 2009-03-08. Retrieved 2009-05-08.
  6. ↑ "Endocrine Pathology". Archived from the original on 2009-03-07. Retrieved 2009-05-08.
  7. ↑ Warner JV, Nyholt DR, Busfield F, et al. (March 2006). "Familial isolated hyperparathyroidism is linked to a 1.7 Mb region on chromosome 2p13.3–14". J. Med. Genet. 43 (3): e12. doi:10.1136/jmg.2005.035766. PMC   2563254 . PMID   16525030.
  8. ↑ Boehm BO, Rosinger S, Belyi D, Dietrich JW (2011). "The parathyroid as a target for radiation damage". N. Engl. J. Med. 365 (7): 676–8. doi: 10.1056/NEJMc1104982 . PMID   21848480.
  9. ↑ Lepage, R.; d'Amour, P.; Boucher, A.; Hamel, L.; Demontigny, C.; Labelle, F. (1988). "Clinical performance of a parathyrin immunoassay with dynamically determined reference values". Clinical Chemistry. 34 (12): 2439–2443. doi: 10.1093/clinchem/34.12.2439 . PMID   3058363.
  10. ↑ Titon, I.; Cailleux-Bounacer, A.; Basuyau, J. P.; Lefebvre, H.; Savoure, A.; Kuhn, J. M. (2007). "Evaluation of a standardized short-time calcium suppression test in healthy subjects: Interest for the diagnosis of primary hyperparathyroidism". European Journal of Endocrinology. 157 (3): 351–357. doi:10.1530/EJE-07-0132. PMID   17766719.
  11. ↑ Jameson, J. Larry, éditeur intellectuel. (2018-08-13). Harrison's principles of internal medicine. ISBN   9781259644030. OCLC   1056749127.{{cite book}}: CS1 maint: multiple names: authors list (link)
  12. ↑ Silverberg, Shonni J.; Lewiecki, E. Michael; Mosekilde, Leif; Peacock, Munro; Rubin, Mishaela R. (February 2009). "Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop". The Journal of Clinical Endocrinology and Metabolism. 94 (2): 351–365. doi:10.1210/jc.2008-1760. ISSN   0021-972X. PMC   5393372 . PMID   19193910.
  13. ↑ Weber T, Eberle J, Messelhäuser U, et al. (2013). "Parathyroidectomy, elevated depression scores, and suicidal ideation in patients with primary hyperparathyroidism: results of a prospective multicenter study". JAMA Surg. 148 (2): 109–115. doi:10.1001/2013.jamasurg.316. PMID   23560281.
  14. 1 2 Vestergaard, P.; Mosekilde, L. (2003). "Cohort study on effects of parathyroid surgery on multiple outcomes in primary hyperparathyroidism". BMJ . 327 (7414): 530–534. doi:10.1136/bmj.327.7414.530. PMC   192894 . PMID   12958111.
  15. ↑ Bollerslev J, Jansson S, Mollerup CL, et al. (2007). "Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial". J. Clin. Endocrinol. Metab. 92 (5): 1687–92. doi: 10.1210/jc.2006-1836 . PMID   17284629.
  16. ↑ Ambrogini E, Cetani F, Cianferotti L, et al. (2007). "Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial". J. Clin. Endocrinol. Metab. 92 (8): 3114–21. doi: 10.1210/jc.2007-0219 . PMID   17535997.
  17. ↑ Rao DS, Phillips ER, Divine GW, Talpos GB (2004). "Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism". J. Clin. Endocrinol. Metab. 89 (11): 5415–22. doi: 10.1210/jc.2004-0028 . PMID   15531491.
  18. ↑ "SENSIPAR® (cinacalcet)" (PDF). Archived (PDF) from the original on 28 May 2024. Retrieved 12 July 2024.
  19. ↑ Wilhelm, Scott M.; Wang, Tracy S.; Ruan, Daniel T.; Lee, James A.; Asa, Sylvia L.; Duh, Quan-Yang; Doherty, Gerard M.; Herrera, Miguel F.; Pasieka, Janice L.; Perrier, Nancy D.; Silverberg, Shonni J.; Solórzano, Carmen C.; Sturgeon, Cord; Tublin, Mitchell E.; Udelsman, Robert (2016-10-01). "The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism". JAMA Surgery. 151 (10): 959–968. doi:10.1001/jamasurg.2016.2310. ISSN   2168-6254. PMID   27532368.
  20. ↑ Deshmukh, R. G.; Alsagoff, S. A. L.; Krishnan, S.; Dhillon, K. S.; Khir, A. S. M. (1998). "Primary hyperparathyroidism presenting with pathological fracture". Journal of the Royal College of Surgeons of Edinburgh. 43 (6): 424–427. PMID   9990797. Archived from the original on 2011-05-13. Retrieved 2011-06-18.
  21. ↑ Bilezikian, John P.; Silverberg, Shonni J. (2002). "Primary hyperparathyroidism: Epidemiology and clinical consequences". Clinical Reviews in Bone and Mineral Metabolism. 1 (1): 25–34. doi:10.1385/BMM:1:1:25. S2CID   74793206.
  22. ↑ Bolland, M. J.; Grey, A. B.; Gamble, G. D.; Reid, I. R. (2004). "Association between Primary Hyperparathyroidism and Increased Body Weight: A Meta-Analysis". Journal of Clinical Endocrinology & Metabolism. 90 (3): 1525–1530. doi: 10.1210/jc.2004-1891 . PMID   15613408.
  23. ↑ EL-Sobky TA, Ahmad KA, Samir S, EL Mikkawy DME (2016). "Primary hyperparathyroidism in a child: The musculoskeletal manifestations of a late presenting rare endocrinopathy". Egypt J Radiol Nucl Med. 47 (4): 1613–16. doi: 10.1016/j.ejrnm.2016.09.002 .{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ↑ Mallet E (2008). "Primary hyperparathyroidism in neonates and childhood. The French experience (1984–2004)". Horm Res. 69 (3): 180–8. doi:10.1159/000112592. PMID   18219222. S2CID   25046706.
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