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".{{cite web | title=Hyperparathyroidism or Hypercalcemia: "Stones, Bones, abdominal Groans, thrones and psychiatric overtones" | website=Time of Care | date=July 12, 2016 |url=https://www.timeofcare.com/hyperparathyroidism-or-hypercalcemia-stones-bones-abdominal-groans-thrones-and-psychiatric-overtones/ | access-date=October 18, 2023}}

• "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. The peptic ulcers can be an effect of increased gastric acid secretion by hypercalcemia.{{Cite journal | last1 = Barreras | first1 = R. F. | last2 = Donaldson | first2 = R. M. | doi = 10.1056/NEJM196705182762005 | title = Role of Calcium in Gastric Hypersecretion, Parathyroid Adenoma and Peptic Ulcer | journal = New England Journal of Medicine | volume = 276 | issue = 20 | pages = 1122–1124 | year = 1967 | pmid = 6024167}}
• "Thrones" refers to polyuria and constipation
• "Psychiatric overtones" refers to effects on the central nervous system. Symptoms include lethargy, fatigue, depression, memory loss, psychosis, ataxia, delirium, and coma.

Left ventricular hypertrophy may also be seen.{{cite journal |vauthors=Stefenelli T, Abela C, Frank H, etal |title=Cardiac abnormalities in patients with primary hyperparathyroidism: implications for follow-up |journal=J. Clin. Endocrinol. Metab. |volume=82 |issue=1 |pages=106–12 |year=1997 |pmid=8989242 |doi=10.1210/jcem.82.1.3666 |url=http://jcem.endojournals.org/cgi/content/full/82/1/106 |doi-access= |access-date=2007-04-27 |archive-date=2011-05-16 |archive-url=https://web.archive.org/web/20110516205230/http://jcem.endojournals.org/cgi/content/full/82/1/106 |url-status=live |url-access=subscription }}

Other signs include proximal muscle weakness, itching, and band keratopathy of the eyes.{{citation needed|date=October 2021}}

When subjected to formal research, symptoms of depression, pain, and gastric dysfunction seem to correlate with mild cases of hypercalcemia.{{cite journal|vauthors=Bargren AE, Repplinger D, Chen H, Sippel RS | title=Can biochemical abnormalities predict symptomatology in patients with primary hyperparathyroidism? | journal=J Am Coll Surg | year= 2011 | volume= 213 | issue= 3 | pages= 410–4 | pmid=21723154 | doi=10.1016/j.jamcollsurg.2011.06.401}}

The most common cause of primary hyperparathyroidism is a sporadic, single parathyroid adenoma{{cite web |url=http://library.med.utah.edu/WebPath/ENDOHTML/ENDO044.html |title=Endocrine Pathology |access-date=2009-05-08 |archive-date=2009-03-08 |archive-url=https://web.archive.org/web/20090308095554/http://library.med.utah.edu/WebPath/ENDOHTML/ENDO044.html |url-status=live }} resulting from a clonal mutation (~97%). Less common are parathyroid hyperplasia{{cite web |url=http://library.med.utah.edu/WebPath/ENDOHTML/ENDO043.html |title=Endocrine Pathology |access-date=2009-05-08 |archive-date=2009-03-07 |archive-url=https://web.archive.org/web/20090307223624/http://library.med.utah.edu/WebPath/ENDOHTML/ENDO043.html |url-status=live }} (~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|date=August 2020}}

Genetic associations include:

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|date=October 2021}}

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.{{cite journal |vauthors=Boehm BO, Rosinger S, Belyi D, Dietrich JW |title=The parathyroid as a target for radiation damage |journal=N. Engl. J. Med. |volume=365 |issue=7 |pages=676–8 |year=2011 |pmid=21848480 |doi=10.1056/NEJMc1104982 |doi-access=free }}

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.[http://www.clinchem.org/cgi/reprint/34/12/2439.pdf] {{Cite journal | last1 = Lepage | first1 = R. | last2 = d'Amour | first2 = P. | last3 = Boucher | first3 = A. | last4 = Hamel | first4 = L. | last5 = Demontigny | first5 = C. | last6 = Labelle | first6 = F. | title = Clinical performance of a parathyrin immunoassay with dynamically determined reference values | journal = Clinical Chemistry | volume = 34 | issue = 12 | pages = 2439–2443 | year = 1988 | doi = 10.1093/clinchem/34.12.2439 | pmid = 3058363| doi-access = free }}

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%.{{Cite journal | last1 = Titon | first1 = I. | last2 = Cailleux-Bounacer | first2 = A. | last3 = Basuyau | first3 = J. P. | last4 = Lefebvre | first4 = H. | last5 = Savoure | first5 = A. | last6 = Kuhn | first6 = J. M. | title = Evaluation of a standardized short-time calcium suppression test in healthy subjects: Interest for the diagnosis of primary hyperparathyroidism | journal = European Journal of Endocrinology | volume = 157 | issue = 3 | pages = 351–357 | year = 2007 | pmid = 17766719 | doi = 10.1530/EJE-07-0132| doi-access = }}

Normocalcemic PHPT, the unusual occurrence of PHPT not being associated with elevated serum calcium levels, was first recognized in 2009 by an international panel of experts.{{Cite journal |last1=Silverberg |first1=Shonni J. |last2=Lewiecki |first2=E. Michael |last3=Mosekilde |first3=Leif |last4=Peacock |first4=Munro |last5=Rubin |first5=Mishaela R. |date=February 2009 |title=Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop |journal=The Journal of Clinical Endocrinology and Metabolism |volume=94 |issue=2 |pages=351–365 |doi=10.1210/jc.2008-1760 |issn=0021-972X |pmc=5393372 |pmid=19193910}} 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.

Urinary cAMP is occasionally measured; it is generally elevated due to activation of G_s proteins when PTH binds to its receptor.{{Cite book|title=Harrison's principles of internal medicine|last=Jameson, J. Larry, éditeur intellectuel.|isbn=9781259644030|oclc=1056749127|date = 2018-08-13}}

Biochemical confirmation of primary hyperparathyroidism is following by investigations to localize the culprit lesion. Primary hyperparathyroidism is most commonly caused by a solitary parathyroid adenoma or parathyroid hyperplasia. Infrequently, the condition is caused by double or multiple parathyroid adenomas that can be present on more than one parathyroidal gland or even occur elsewhere. Scintigraphic or single-photon emission computed tomography (SPECT) imaging with the radiotracer ^99mTc-sestamibi of head, neck and upper thorax is the first-line nuclear imaging modality 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.

In cases where ^99mTc-sestamibi scintigraphy or SPECT delivers inconclusive results, other imaging modalities and tracers can be applied. For detection of multiple parathyroid adenomas, positron emission tomography (PET) using the radiopharmaceutical ⁶⁸Ga-Trivehexin{{cite journal | vauthors = Quigley NG, Steiger K, Hoberueck S, Czech N, Zierke MA, Kossatz S, Pretze M, Richter F, Weichert W, Pox C, Kotzerke J, Notni J | display-authors = 6 | title = PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the "Cancer Integrin" αvβ6 with Ga-68-Trivehexin | journal = European Journal of Nuclear Medicine and Molecular Imaging | volume = 49 | issue = 4 | pages = 1136–1147 | date = March 2022 | pmid = 34559266 | doi = 10.1007/s00259-021-05559-x | doi-access = free | pmc = 8460406 }} has demonstrated a higher detection rate (94.1%) than ^99mTc-sestamibi imaging (58.8%).{{cite journal | vauthors = Kuyumcu S, Denizmen D, Has-Simsek D, Poyanli A, Uzum AK, Buyukkaya F, Isik EG, Onder S, Aksakal N, Ozkan ZG, Sanli Y | display-authors = 6 | title = ⁶⁸Ga-Trivehexin PET/CT: a promising novel tracer for primary hyperparathyroidism | journal = European Journal of Nuclear Medicine and Molecular Imaging | volume = 51 | issue = 13 | pages = 3912–3923 | date = July 2024 | pmid = 39028425 | doi = 10.1007/s00259-024-06846-z | doi-access = free | pmc = 11527967 }}

Ultrasonography is also a useful test in localizing suspicious parathyroid lesions.{{citation needed|date=October 2021}}

Treatment is usually surgical removal of the gland(s) containing adenomas, but medication may also be required.{{citation needed|date=October 2021}}

The surgical removal of one or more of the parathyroid glands is known as a parathyroidectomy; this operation was first performed in 1925.{{cite journal |vauthors=Weber T, Eberle J, Messelhäuser U |title=Parathyroidectomy, elevated depression scores, and suicidal ideation in patients with primary hyperparathyroidism: results of a prospective multicenter study| journal=JAMA Surg. |volume=148 |issue=2 |pages=109–115 |year=2013 |doi=10.1001/2013.jamasurg.316|pmid=23560281|display-authors=etal|doi-access= }} 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.

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|date=October 2021}}

• Serum calcium concentration of 1.0 mg/dL (0.25 mmol/L) or more above the upper limit of normal
• Creatinine clearance that is reduced to <60 mL/min
• Bone density at the hip, lumbar spine, or distal radius that is more than 2.5 standard deviations below peak bone mass (T score <-2.5) and/or previous fragility fracture
• Age less than 50 years

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|date=October 2021}}

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:{{cite journal |vauthors=Bollerslev J, Jansson S, Mollerup CL, etal |title=Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial |journal=J. Clin. Endocrinol. Metab. |volume=92 |issue=5 |pages=1687–92 |year=2007 |pmid=17284629 |doi=10.1210/jc.2006-1836|doi-access=free }}

• Untreated, asymptomatic primary hyperparathyroidism
• Serum calcium between 2.60 and 2.85 mmol/liter (10.4–11.4 mg/dL)
• Age between 50 and 80 yr
• No medications interfering with Ca metabolism
• No hyperparathyroid bone disease
• No previous operation in the neck
• Creatinine level < 130 μmol/liter (<1.47 mg/dL)

Two other trials reported improvements in bone density and some improvement in quality of life with surgery.{{cite journal |vauthors=Ambrogini E, Cetani F, Cianferotti L, etal |title=Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial |journal=J. Clin. Endocrinol. Metab. |volume=92 |issue=8 |pages=3114–21 |year=2007 |pmid=17535997 |doi=10.1210/jc.2007-0219|doi-access=free }}{{cite journal |vauthors=Rao DS, Phillips ER, Divine GW, Talpos GB |title=Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism |journal=J. Clin. Endocrinol. Metab. |volume=89 |issue=11 |pages=5415–22 |year=2004 |pmid=15531491 |doi=10.1210/jc.2004-0028|doi-access=free }}

Medications are used when surgery is not indicated or for poor surgical candidates.{{cite web |title=SENSIPAR® (cinacalcet) |url=https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Sensipar/sensipar_pi_hcp_english.pdf |access-date=12 July 2024 |archive-date=28 May 2024 |archive-url=https://web.archive.org/web/20240528090715/https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Sensipar/sensipar_pi_hcp_english.pdf |url-status=live }} 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.{{Cite journal |last1=Wilhelm |first1=Scott M. |last2=Wang |first2=Tracy S. |last3=Ruan |first3=Daniel T. |last4=Lee |first4=James A. |last5=Asa |first5=Sylvia L. |last6=Duh |first6=Quan-Yang |last7=Doherty |first7=Gerard M. |last8=Herrera |first8=Miguel F. |last9=Pasieka |first9=Janice L. |last10=Perrier |first10=Nancy D. |last11=Silverberg |first11=Shonni J. |last12=Solórzano |first12=Carmen C. |last13=Sturgeon |first13=Cord |last14=Tublin |first14=Mitchell E. |last15=Udelsman |first15=Robert |date=2016-10-01 |title=The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism |url=https://doi.org/10.1001/jamasurg.2016.2310 |journal=JAMA Surgery |volume=151 |issue=10 |pages=959–968 |doi=10.1001/jamasurg.2016.2310 |pmid=27532368 |issn=2168-6254|url-access=subscription }}

Primary hyperparathyroidism affects approximately 1 per 1,000 people (0.1%),{{cite journal |url=http://www.rcsed.ac.uk/journal/vol43_6/4360019.htm |first1=R. G. |last1=Deshmukh |first2=S. A. L. |last2=Alsagoff |first3=S. |last3=Krishnan |first4=K. S. |last4=Dhillon |first5=A. S. M. |last5=Khir |year=1998 |title=Primary hyperparathyroidism presenting with pathological fracture |journal=Journal of the Royal College of Surgeons of Edinburgh |volume=43 |issue=6 |pages=424–427 |pmid=9990797 |access-date=2011-06-18 |archive-url=https://web.archive.org/web/20110513032409/http://www.rcsed.ac.uk/journal/vol43_6/4360019.htm |archive-date=2011-05-13 |url-status=dead }} while there are 25–30 new cases per 100,000 people per year in the United States.{{cite journal |last1=Bilezikian |first1=John P. |first2=Shonni J. |last2=Silverberg |year=2002 |title=Primary hyperparathyroidism: Epidemiology and clinical consequences |journal=Clinical Reviews in Bone and Mineral Metabolism |volume=1 |issue=1 |pages=25–34 |doi=10.1385/BMM:1:1:25 |s2cid=74793206 }} 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.{{Cite journal | last1 = Bolland | first1 = M. J. | last2 = Grey | first2 = A. B. | last3 = Gamble | first3 = G. D. | last4 = Reid | first4 = I. R. | title = Association between Primary Hyperparathyroidism and Increased Body Weight: A Meta-Analysis | journal = Journal of Clinical Endocrinology & Metabolism | volume = 90 | issue = 3 | pages = 1525–1530 | year = 2004 | doi = 10.1210/jc.2004-1891| pmid = 15613408 | doi-access = free }}

Primary hyperparathyroidism is associated with increased all-cause mortality.{{cite journal |last1=Vestergaard |first1=P. |last2=Mosekilde |first2=L. |journal=BMJ |title=Cohort study on effects of parathyroid surgery on multiple outcomes in primary hyperparathyroidism |year=2003 |volume=327 |issue=7414 |pages=530–534 |doi=10.1136/bmj.327.7414.530 |pmc=192894 |pmid=12958111 }}

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.{{cite journal | author = EL-Sobky TA, Ahmad KA, Samir S, EL Mikkawy DME | year = 2016 | title = Primary hyperparathyroidism in a child: The musculoskeletal manifestations of a late presenting rare endocrinopathy | journal = Egypt J Radiol Nucl Med | volume = 47 | issue = 4| pages = 1613–16 | doi = 10.1016/j.ejrnm.2016.09.002 | doi-access = free }}{{cite journal | author = Mallet E | year = 2008 | title = Primary hyperparathyroidism in neonates and childhood. The French experience (1984–2004) | journal = Horm Res | volume = 69 | issue = 3| pages = 180–8 | pmid = 18219222 | doi = 10.1159/000112592 | s2cid = 25046706 }}

• Secondary hyperparathyroidism
• Tertiary hyperparathyroidism

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{{Medical resources

| DiseasesDB = 6283

| ICD10 = {{ICD10|E|21|0|e|20}}

| ICD9 = {{ICD9|252.01}}

| ICDO =

| OMIM =

| MedlinePlus = 000384

| eMedicineSubj = radio

| eMedicineTopic = 355

| MeshID = D049950

| SNOMED CT = 36348003

}}

{{Parathyroid disease}}

{{DEFAULTSORT:Primary Hyperparathyroidism}}

Category:Parathyroid disorders