Hyperparathyroidism

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Hyperparathyroidism is overactivity of the parathyroid glands resulting in excess production of parathyroid hormone (PTH). The parathyroid hormone monitors calcium and phosphorus levels and helps to maintain these levels. Overactivity of one or more of the parathyroid glands causes high calcium levels (hypercalcemia) and low levels of phosphorus in the blood. Hyperparathyroidism was first described and treated in the 1930s by Fuller Albright of Massachusetts General Hospital, working at the Mallinckrodt General Clinical Research Center.

In 1880, Ivar Sandström, a Swedish anatomist, described parathyroids in human following 50 autopsies. In 1924, James Bertram Collip, a Canadian biochemist, discovered and extracted parathyroid hormone and treated tetany with the help of parathyroid extract along with Douglous B Leitch. In 1925, Felix Mandl, a viennese surgeon performed first parathyroidectomy to treat a patient suffering from osteitis fibrosa cystica. In 1959, Howard Rasmussen and Lyman C. Craig at the Rockefeller Institute for Medical Research purified parathyroid hormone. They also isolated the active polypeptide (parathormone B) from bovine parathyroid gland and gave its tentative formula in 1961.

Hyperparathyroidism can be classified according to origin of defect into primary, secondary and tertiary. Primary hyperparathyroidism results from a hyperfunction of the parathyroid glands themselves. There is oversecretion of PTH due to adenoma, hyperplasia or, rarely, carcinoma of the parathyroid glands. Secondary hyperparathyroidism is due to increase in secretion of parathyroid hormone from a secondary process. Tertiary hyperparathyroidism is a state of excessive secretion of parathyroid hormone (PTH) after a long period of secondary hyperparathyroidism and resulting in hypercalcemia even after treatment of secondary hyperparathyroidism..

Hyperparathyroidism is an increase in serum parathyroid hormone. Normally, parathyroid hormone increases serum calcium and magnesium concentration, and decreases serum phosphate concentration. Secretion of parathyroid hormone from parathyroid gland is stimulated by low serum calcium. Parathyroid glands have calcium-sensing receptors responsible for sensing extracellular ionized calcium. Calcium and magnesium provides a negative feedback for secretion of parathyroid hormone. Primary hyperparathyroidism is due to increase in secretion of parathyroid hormone from a primary process in parathyroid gland.Majority of times, increase in secretion of parathyroid hormone is the result of parathyroid adenoma (85%). Calcium-sensing receptor expression is reduced in parathyroid adenoma resulting in an increase in calcium sensing set point. In minority of cases, development of primary hyperparathyroidism is the result of multiple genetic mutations. Genes involved in the pathogenesis of primary hyperparathyroidism include calcium-sensing receptor gene, HRPT2 gene (CDC73 gene), Cyclin D1 gene (CCND1)/PRAD1 gene, MEN1 gene, and RET gene. Secondary hyperparathyroidism is due to increase in secretion of parathyroid hormone from a secondary process, most commonly due chronic renal failure. Fibroblast growth factor 23 (FGF-23) concentration increases in chronic renal failure which plays a central role in regulation of phosphate, vitamin D homeostasis and pathogenesis of secondary hyperparathyroidism. Majority of times, tertiary hyperparathyroidism occurs in patients after renal transplantation.Patients with secondary hyperparathyroidism continues to have elevated parathyroid hormone even after renal transplantation. Classically, there is hyperplasia of all four of parathyroid gland. On gross pathology, parathyroid adenoma is a soft, tan nodule which is well-circumscribed by a delicate capsule. Typically, cut surface of parathyroid adenoma is smooth, soft, and reddish brown in color. It should be differentiated from normal parathyroid gland tissue which is yellow-brown color. Parathyroid hyperplasia usually involves multiple glands. Bones and kidney are also commonly involved in hyperparathyroidism. Hypercalcemia due to hyperparathyroidism may cause metastatic calcification in many organs including lungs, heart, blood vessels, stomach. Chief cells are predominant in parathyroid adenoma on microcopy. Adenoma is seperated from a rim of non-neoplastic tissue on the edge by a fibrous capsule. Endocrine atypia (cells with bizarre and pleomorphic nuclei) is often seen in parathyroid adenoma. It should not be mistaken as a sign of malignancy. Majority of times, hyperplasia of chief cells is observed in parathyroid hyperplasia. It may be diffuse or multinodular. Cytologic details are unreliable for diagnosis of parathyroid carcinoma.

Hyperparathyroidism is caused by an increase in concentration of parathyroid hormone in serum. There are three type of hyperparathyroidism including primary, secondary and tertiary hyperparathyroidism. There are an array of different causes for all types of hyperparathyroidism. Most common cause of primary hyperparathyroidism is parathyroid adenoma (85%) followed by parathyroid hyperplasia (15%), and parathyroid carcinoma (5%). Most common cause of secondary hyperparathyroidism is chronic renal failure and vitamin D deficiency. Most common cause of tertiary hyperparathyroidism is post renal transplantation.

There are three types of hyperparathyroidism (primary, secondary, and tertiary) and should be differentiated between each other. Hyperparathyroidism should be differentiated from other causes of hypercalcemia. Causes of hypercalcemia other than hyperparathyroidism include familial hypocalciuric hypercalcemia, hypercalcemia related to malignancy, medication-induced hypercalcemia, hypercalcemia due to nutritional disorders, and hypercalcemia related to granulomatous diseases.

Primary hyperparathyroidism is the 3rd most common endocrine disorder. Highest incidence of primary hyperparathyroidism is in post-menopausal women.The incidence of primary hyperparathyroidism is approximately 0.4 to 21.6 per 100,000 person years. The prevalence of primary hyperparathyroidism is approximately .01 to .07 per 100,000 individuals. The incidence of primary hyperparathyroidism increases with age. Primary hyperparathyroidism usually affects individuals of African-American race. Women are more commonly affected by primary hyperparathyroidism than men. The women to men ratio is approximately 3 to 1. Difference in gender specific incidence of primary hyperparathyroidism becomes more pronounced with advancing age. There is insufficient data on epidemiology and demographics of secondary and tertiary hyperparathyroidism.

Common risk factors in the development of primary hyperparathyroidism include postmenopausal women, age group 50-60 year, family history of hyperparathyroidism, and history of familial syndromes. Common risk factors in the development of secondary hyperparathyroidism in chronic renal failure include high serum phosphorus expression levels, low serum creatinine expression levels, low serum calcium expression levels, female gender, and hypertension. Common risk factors in the development of tertiary hyperparathyroidism post renal transplantation include elderly individuals and longer duration of dialysis.

There is insufficient evidence to recommend routine screening for hyperparathyroidism.

Primary hyperparathyroidism usually develops in the fifth decade of life, in post-menopausal women and starts as asymptomatic hypercalcemia in presence of increased parathyroid hormone. If left untreated, some of patients with primary hyperparathyroidism may commonly develop marked hypercalcemia, marked hypercalciuria, cortical bone demineralization and nephrolithiasis.

Secondary hyperparathyroidism arise in the early course of chronic renal failure. As renal failure progress, secondary hyperparathyroidism becomes more notable. If left untreated, secondary hyperparathyroidism carries an increased risk of vascular calcification with increasing age and duration of dialysis in patients.

Tertiary hyperparathyroidism usually develops in post renal transplant patients. If left untreated, tertiary hyperparathyroidism in post renal transplant patients may carry the risk of amyloid deposition, calciphylaxis, destructive or erosive spondyloarthropathy, osteonecrosis, and musculoskeletal infections.

Hyperparathyroidism leads to a variety of complications in various organ systems depending on the type of hyperparathyroidism.

Prognosis is all types hyperparathyroidism is generally good after proper treatment.

The majority of patients with primary hyperparathyroidism are asymptomatic. Asymptomatic primary hyperparathyroidism patient is expected to develop signs and symptoms, but most of the patients does not becomes symptomatic with time. The hallmark of primary hyperparathyroidism is asymptomatic hypercalcemia. The classic signs and symptoms of primary hyperparathyroidism are present in a few individuals and are summarized by the mnemonic painful bones, kidney stones, abdominal groans, psychic moans, and fatigue overtones.The majority of patients with secondary hyperparathyroidism have a history of either chronic renal failure or long term vitamin D deficiency.The majority of patients with tertiary hyperparathyroidism have a history of renal transplantation.

Physical examination of patients with hyperparathyroidism is usually unremarkable. Patients may have physical findings due to severe hypercalcemia and other complications of hyperparathyroidism.

An elevated serum calcium on routine biochemical screening in a asymptomatic patient should raise the suspicion of primary hyperparathyroidism. An elevated concentration of serum calcium with elevated parathyroid hormone level is diagnostic of primary hyperparathyoidism. Most consistent laboratory findings associated with the diagnosis of secondary hyperparathyroidism include elevated serum parathyroid hormone level and low to normal serum calcium. An elevated concentration of serum calcium with elevated parathyroid hormone level in post renal transplant patients is diagnostic of tertiary hyperparathyoidism. Measurement of total serum calcium with automatic techniques has similar or even more reliability than serum ionized calcium measurement. Method of choice for measuring intact parathyroid hormone include Immunoradiometric assay (IMRA) or Immunochemiluminescent assay (ICMA). 24-Hour urinary calcium excretion is used to seperate the patients with familial hypocalciuric hypercalcemia and typical primary hyperparathyroidism. Serum 1,25-dihydroxy vitamin D (calcitriol) concentration are significantly lower in familial hypocalciuric hypercalcemia than primary hyperparathyroidism.

There are no ECG findings associated with hyperparathyroidism. However, an ECG may be helpful in the diagnosis of cardiac complications of hyperparathyroidism.

X-ray is helpful in diagnosis of hyperparathyroidism. Finding in primary hyperparathyroidism includes subperiosteal bone resorption, endoosteal bone resorption, subchondral resorption, subligamentous resorption, intracortical resorption, osteopenia, brown tumors, salt and pepper sign in the skull (pepper pot skull), and chondrocalcinosis. X-ray is the preferred imaging for diagnosis of secondary hyperparathyroidism as majority of findings are radiological. Findings in secondary and tertiary hyperparathyroidism are often associated with the osteosclerosis of renal osteodystrophy, and the osteomalacia of vitamin D deficiency and includes subperiosteal bone resorption, subchondral resorption, subligamentous resorption, severe osteopenia, osteosclerosis, brown tumor, amyloid deposition, soft tissue and vascular calcification, superior and inferior rib notching, and osteonecrosis.

Good quality preoperative evaluation favors post operative results. 4-dimentional CT scan is an investigation for preoperative localizing of hyper-functioning parathyroid gland. 4D-CT is significantly more sensitive than Tc-99m sestamibi scintigraphy and ultrasound for precise (quadrant) localization of hyper-functioning parathyroid glands. 4D-CT is required to be performed with three phases including non-contrast, arterial, and delayed phase imaging. 4D-CT provides extremely detailed images of neck in multiple planes and enables the visualization of difference in hyper-functioning parathyroid gland compared with normal parathyroid glands and other structures in the neck on the basis on perfusion characteristics ( rapid uptake and washout). 4D-CT is particularly useful in cases of re-operation. The major disadvantage of 4D-CT is significant radiation exposure associated with scanning the patient multiple times.

MRI may be helpful in the post-operative evaluation of hyper functioning parathyroid glands, particularly in patients with recurrent or persistent hyperparathyroidism. MRI has similar sensitivity and positive predictive value as Tc-99m sestamibi scintigraphy for post-operative detection of hyper-functioning parathyroid glands. MRI with gadolinium and fat suppression is used for detection of ectopic parathyroid adenoma (particularly those located in mediastinum).

Neck ultrasound is used for preoperative localization of hyper-functioning parathyroid gland. Neck ultrasound alone is not a sensitive investigation for this purpose. Neck ultrasound along with Tc-99m sestamibi scintigraphy is most common used diagnostic modality for preoperative localization of hyper-functioning parathyroid gland.

Imaging modalities may be helpful in preoperative localization of hyper-functioning parathyroid glands. This includes both non-invasive and invasive modalities. Non-invasive imaging modalities for preoperative localization of hyper-functioning parathyroid glands include Tc-99m sestamibi scintigraphy (sestamibi or MIBI), single photon emission computed tomography (SPECT), positron emission tomography (PET). Invasive modalities used for preoperative localization of hyper-functioning parathyroid glands include selective arteriography and angiography. Dual energy X-ray absorptiometry is helpful in detecting low bone mineral density (BMD) caused by hyperparathyroidism.

Other diagnostic study useful for preoperative localization of hyper-functioning parathyroid glands include super selective venous sampling. Another diagnostic study include measurement of intraoperative parathyroid hormone (IOPTH) by using a modified sensitive assay (immunoradiometric assay). IOPTH is beneficial for predicting long term surgical outcomes.

Surgical therapy is preferred over medical therapy in hyperparathyroidism. However medical therapy is considered in a few circumstances. Patients with primary hyperparathyroidism who do not undergo parathyroidectomy should be monitored for the potential progression of disease. Monitoring includes serum calcium, skeletal monitoring, and renal monitoring. Medical management of primary hyperparathyroidism includes nutritional supplements and pharmacotherapy. Nutritional supplements includes elemental calcium supplements and vitamin D analogs. Pharmacotherapy includes bisphosphonates, calcimimetics, and estrogen receptor-targeted therapy. Medical management of secondary hyperparathyroidism includes calcimimetics, vitamin D analogues, and phosphate binders/phosphate restriction. Medical management of tertiary hyperparathyroidism includes calcimimetics.

Surgery is the mainstay of treatment for hyperparathyroidism. Symptomatic hyperparathyroidism is an indication for surgery. However, there are guidelines for surgery in asymptomatic primary hyperparathyroidism. Surgery for hyperparathyroidism is parathyroidectomy which includes bilateral neck exploration and minimally invasive parathyroidectomy. Most commonly done surgery for hyperparathyroidism is minimally invasive parathyroidectomy (MIP). There are various types of MIP. MIP provides excellent postoperative cure rates comparable to bilateral neck exploration (BNE) with less complications than BNE. This is due to precise preoperative localization of hyper-functioning parathyroid gland and use of intraoperative parathyroid hormone (IOPTH) monitoring for predicting post-surgical success (postoperative normocalcemia).

Effective measures for the primary prevention of secondary hyperparathyroidism in chronic kidney disease include aggressive management of hyperphosphatemia in early stages of chronic kidney disease and prevention and treatment of vitamin D deficiency in stage 3 & 4 chronic kidney disease. There are no established measures for the primary prevention of primary hyperparathyroidism and tertiary hyperparathyroidism.

Secondary prevention of primary hyperparathyroidism includes monitoring for potential progression of disease in patients who do not undergo parathyroidectomy. There are guidelines for monitoring of patients with asymptomatic hyperparathyroidism not undergoing parathyroidectomy. Effective measures for secondary prevention of secondary hyperparathyroidism include maintain adequate nutrition, proper intake of vitamin D and/or sufficient sunlight exposure, and adequate physical activity. Effective measures for secondary prevention of tertiary hyperparathyroidism include early detection and treatment of hyperparathyroidism by either calcimimetics or parathyroidectomy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

In 1880, Ivar Sandström, a Swedish anatomist, described parathyroids in human following 50 autopsies. In 1924, James Bertram Collip, a Canadian biochemist, discovered and extracted parathormone and treated tetany with the help of parathyroid extract along with Douglous B Leitch. In 1925, Felix Mandl, a viennese surgeon performed first parathyroidectomy to treat a patient suffering from suffering from osteitis fibrosa cystica. In 1959, Howard Rasmussen and Lyman C. Craig at the Rockefeller Institute for Medical Research purified parathyroid hormone. They also isolated the active polypeptide (parathormone B) from bovine parathyroid gland and gave its tentative formula in 1961.

• The oldest known case of hyperparathyroidism was found in a cadaver from a Early Neolithic cemetery in southwest Germany.^[1]
• In 1852, Sir Richard Owen, Hunterian Professor and Conservator of the Museum in the Royal College of Surgeons of England, described parathyroids in rhinoceros.^[2]
• In 1880, Ivar Sandström, a Swedish anatomist, described parathyroids in human following 50 autopsies. He found two parathyroid glands bilaterally in 43 out of 50 autopsies.^[3]
• In 1891, Friedrich van Rechlinghausen, a German pathologist described ‘osteitis fibrosa cystica‘ (the parathyroid cystic bone disease).^[3]
• In 1909, William George MacCallum and Carl Voegtlin, demonstrated association between parathyroid gland, calcium, and tetany.^[4]
• In 1924, James Bertram Collip, a Canadian biochemist, discovered and extracted parathormone.^[5]
• In 1932, L. I. Pugsley and Hans Selye, described the histological changes in the bone due to parathyroid hormone action and calcium metabolism in rat experiments. ^[6]
• In 1948, Nigel Ashworth Barnicot, an English anthropologist described the association between parathyroid hormone and bone resorption.^[7]
• In the same year, Iftakhar Jahan and Robert F. Pitts described effect of parathyroid hormone in decreasing calcium and magnesium excretion.^[8]
• In 1959, Howard Rasmussen and Lyman C. Craig at the Rockefeller Institute for Medical Research purified parathyroid hormone.^[9] They also isolated the active polypeptide (parathormone B) from bovine parathyroid gland and gave its tentative formula in 1961.^[10]

• In 1925, James Bertram Collip along with Douglous B Leitch, was the first who treated tetany with the help of parathyroid extract. They names the extract as parathyrin.^[11]
• In 1925, Felix Mandl, a viennese surgeon, was the first who performed parathyroidectomy to treat a patient suffering from osteitis fibrosa cystica.^[12]

• Garry Shandling, a famous comedian suffered from hyperparathyroidism.^[13]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Hyperparathyroidism can be classified according to origin of defect into primary, secondary and tertiary.

Hyperparathyroidism can be classified according to origin of defect into primary, secondary and tertiary.

• Primary hyperparathyroidism is due to over activity of the parathyroid glands themselves. The most important causes of oversecretion of parathyroid hormone include:
• Adenoma
• Hyperplasia
• Carcinoma of the parathyroid glands

Secondary hyperparathyroidism is due to increase in secretion of parathyroid hormone from a secondary process.

Tertiary hyperparathyroidism is a state of excessive secretion of parathyroid hormone (PTH) after a long period of secondary hyperparathyroidism and resulting in hypercalcemia even after treatment of secondary hyperparathyroidism.

Hyperparathyroidism

Primary hyperparathyroidism

Secondary hyperparathyroidism

Tertiary hyperparathyroidosm

•Parathyroid adenoma •Parathyroid hyperplasia •Parathyroid carcinoma

•Chronic renal failure •Vitamin D deficiency

•Post-renal transplantation

Template:WH Template:WS ​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Hyperparathyroidism is an increase in serum parathyroid hormone. Normally, parathyroid hormone increases serum calcium and magnesium concentration, and decreases serum phosphate concentration. Secretion of parathyroid hormone from parathyroid gland is stimulated by low serum calcium. Parathyroid glands have calcium-sensing receptors responsible for sensing extracellular ionized calcium. Calcium and magnesium provides a negative feedback for secretion of parathyroid hormone. Primary hyperparathyroidism is due to increase in secretion of parathyroid hormone from a primary process in parathyroid gland. Majority of times, increase in secretion of parathyroid hormone is the result of parathyroid adenoma (85%). Calcium-sensing receptor expression in reduced in parathyroid adenoma resulting in an increase in calcium sensing set point. In minority of cases, development of primary hyperparathyroidism is the result of multiple genetic mutations. Genes involved in the pathogenesis of primary hyperparathyroidism include calcium-sensing receptor gene, HRPT2 gene (CDC73 gene), Cyclin D1 gene (CCND1)/PRAD1 gene, MEN1 gene, and RET gene. Secondary hyperparathyroidism is due to increase in secretion of parathyroid hormone from a secondary process, most commonly due chronic renal failure. Fibroblast growth factor 23 (FGF-23) concentration increases in chronic renal failure which plays a central role in regulation of phosphate vitamin D homeostasis and pathogenesis of secondary hyperparathyroidism. Majority of times, tertiary hyperparathyroidism occurs in patients after renal transplantation.Patients with secondary hyperparathyroidism continues to have elevated parathyroid hormone even after renal transplantation. Classically, there is hyperplasia of all four of parathyroid gland. On gross pathology, parathyroid adenoma is a soft, tan nodule which is well-circumscribed by a delicate capsule. Typically, cut surface of parathyroid adenoma is smooth, soft, and reddish brown in color. It should be differentiated from normal parathyroid gland tissue which is yellow-brown color. Parathyroid hyperplasia usually involves multiple glands. Bones and kidney are also commonly involved in hyperparathyroidism. Hypercalcemia due to hyperparathyroidism may cause metastatic calcification in many organs including lungs, heart, blood vessels, stomach. Chief cells are predominant in parathyroid adenoma on microcopy. Adenoma is seperated from a rim of non-neoplastic tissue on the edge by a fibrous capsule. Endocrine atypia (cells with bizarre and pleomorphic nuclei) is often seen in parathyroid adenoma. It should not be mistaken as a sign of malignancy. Majority of times, hyperplasia of chief cells is observed in parathyroid hyperplasia. It may be diffuse or multinodular. Cytologic details are unreliable for diagnosis of parathyroid carcinoma.

The effect of parathyroid hormone on mineral metabolism is as follows:^[1][2]

• Effect of parathyroid hormone on inorganic phosphate metabolism:
  • Increases excretion of inorganic phosphate from kidney resulting in decreased serum concentration of phosphate.
• Effect on parathyroid hormone on calcium metabolism:
  • Direct effect:
    • Increased resorption of bones.
    • Decreases excretion from kidney.
  • Indirect effect:
    • Increases conversion of inactive 25-hydroxy vitamin D to the active 1,25-dihydroxy vitamin D which increases absorption of calcium from gut. Decreased phosphate concentration also increases this conversion process. Vitamin D shows synergism with parathyroid hormone action on bone.
    • Decreased serum inorganic phosphate concentration prevents precipitation of calcium phosphate in bones.
  • Both these direct and indirect mechanism results in an increased serum calcium concentration.
• Effect of parathyroid hormone on magnesium concentration:
  • Decreases excretion of magnesium resulting in increased serum magnesium concentretion.

Effect of minerals and vitamin D on parathyroid hormone:

• Decrease in serum calcium concentration stimulates parathyroid hormone.
• Calcium provides negative feedback on parathyroid hormone.
• Magnesium provides negative feedback on parathyroid hormone.
• Vitamin D decreases the concentration of parathyroid hormone.

Parathyroid hormone

Kidney

Bone

Decreased excretion of magnesium

Increasead conversion of inactive 25-hydroxy vitamin D to the active 1,25-dihydroxy vitamin D

Increase excretion of inorganic phosphate

Decrease excretion of calcium

Increased resorption of bone

Increased serum concentration of magnesium

Increased absorption of calcium from gut

Decreased serum concentration of inorganic phosphate

Prevents precipitation of calcium phosphate in bones

Increased serum concentration of calcium

• Calcium-sensing receptors are present on parathyroid glands. They are a type of 7-transmembrane receptors in G-protein coupled receptors superfamily of receptors.^[3]
• Calcium-sensing receptors sense change in extracellular concentration of ionized calcium.^[4]
• Calcium-sensing receptor expression in reduced in primary hyperparathyroidism (parathyroid adenoma) and secondary hyperparathyroidism.^[5]
• This reduced expression of receptor causes an increases in calcium sensing set point.^[6]
• This in turn leads to increase in secretion of parathyroid hormone in presence on normal serum concentration of extracellular ionized calcium.

• Primary hyperparathyroidism is due to increase in secretion of parathyroid hormone from a primary process in parathyroid gland.
• Majority of times, increase in secretion of parathyroid hormone is the result of parathyroid adenoma (85%). Other causes of increase in secretion of parathyroid hormone includes parathyroid hyperplasia (15%) and parathyroid carcinoma (5%).^[7]
• Calcium-sensing receptor expression in reduced in parathyroid adenoma resulting in an increase in calcium sensing set point.^[5][6]
• In parathyroid hyperplasia, an increase in cell number causes increased secretion of parathyroid hormone.

• Secondary hyperparathyroidism is due to increase in secretion of parathyroid hormone from a secondary process, most commonly due chronic renal failure. Other causes include vitamin D deficiency, severe calcium deficiency.^[8]
• Chronic renal failure leads to high serum inorganic phosphate and low serum calcium and deficiency of active form of vitamin D (1,25-dihydroxy vitamin D/calcitriol)
• This leads to continuous stimulation of parathyroid glands resulting down-regulation of parathyroid vitamin D receptors and calcium-sensing receptors.
• Fibroblast growth factor 23 (FGF-23) concentration increases in chronic renal failure which plays a central role in regulation of phosphate vitamin D homeostasis.
• Elevated FGF-23 expression down-regulates remaining 25(OH)-1-hydroxylase enzyme. 25(OH)-1-hydroxylase enzyme is responsible for conversion of inactive 25-hydroxy vitamin D into active 1,25-dihydroxy vitamin D (calcitriol). This aggravates the deficiency of active vitamin D.
• These all factors leads to hyperplasia of parathyroid gland.

Chronic renal failure

Elevated serum inorganic phosphate concentration

Elevated FGF-23

Decreased calcitriol

Decreaed serum calcium concentration

Continuous stimulation of parathyroid gland

Downregulation of parathyroid vitamin D receptors and calcium-sensing receptors

Parathyroid hyperplasia

Increased secretion of parathyroid hormone

The mechanism of fibroblast growth factor 23 (FGF-23) in chronic renal disease and development of secondary hyperparathyroidism is as follows:^[8]

• FGF-23 is a hormone produced in the osteocytes and osteoblasts.
• Its production is increased due to high serum phosphate and high calcitriol.
• FGF-23 binds and activates a receptor called fibroblast growth factor receptor 1 (FGFR1).
• FGFR1 is functional when co-expressed with the Klotho transmembrane protein, as a Klotho-FGF receptor complex.
• FGF-23 reduces the expression of type II sodium phosphate co-transporters (NaPi-2a and NaPi-2c) decreasing phosphate reabsorption in proximal tubules.
• In chronic renal failure, as a result, phosphate absorption is increased in proximal tubules due to effect of FGF-23 as well as increased parathyroid hormone. This is responsible for normal serum phosphate levels in majority of patients until the glomerular filtration rate (GFR) falls below 20 ml/min.
• As chronic renal failure progresses, these negative feedback loops are impaired leading to deranged phosphate homeostasis.
• FGF-23 have direct and indirect effect on parathyroid hormone.
  • Direct effect: In normal parathyroid gland, FGF-23 decreases synthesis of parathyroid hormone through the mitogen-activated protein kinase (MAPK) pathway.^[9] FGF-23 increases expression of the parathyroid calcium-sensing receptor and the vitamin D receptor, and reduces cellular proliferation.^[10]
  • Indirect effect: Increased synthesis of parathyroid hormone by decreasing synthesis of calcitriol.
• FGF-23 fails to activate mitogen-activated protein kinase pathway in hyperplastic parathyroid gland secondary to chronic renal failure.^[10]

• Majority of times, tertiary hyperparathyroidism occurs in patients after renal transplantation.^[11]
• Patients with secondary hyperparathyroidism continues to have elevated parathyroid hormone even after renal transplantation.
• Patients with secondary hyperparathyroidism and long term hypocalcemia tends to have hyperplasia of chief cells of parathyroid gland and increased secretion of parathyroid hormone.
• The primary disorder in secondary hyperparathyroidism is chronic renal failure in majority of patients. After correction of chronic renal failure by renal transplant, the hyperplastic parathyroid gland fails to resolve and continues to secrete excess amount of parathyroid hormone.
• Clasically, there is hyperplasia of all four of parathyroid gland.

The development of primary hyperparathyroidism is the result of multiple genetic mutations in minority of cases. Genes involved in the pathogenesis of primary hyperparathyroidism include calcium-sensing receptor gene, HRPT2 gene (CDC73 gene), Cyclin D1 gene (CCND1)/PRAD1 gene, MEN1 gene, and RET gene.

• Calcium-sensing receptor gene mutation:^[12]
  • Calcium-sensing receptor (CSR) gene is present on chromosome 3q.
  • Few individuals carries an inherited mutation in the extracellular calcium-sensing receptor gene.
  • The first identified mutation in CSR gene is a point mutation in which phenylalanine is replaced with leucine at codon 881 of CSR gene.^[13]
  • This mutation reduces the activity of calcium-sensing receptor.
  • This mutation can be heterozygous or homozygous.
  • Individuals carrying heterozygous mutation have familial hypocalciuric hypercalcemia (FHH) or familial benign hypercalcemia. FHH is characterized by parathyroid dependent hypercalcemia and decreased responsiveness of parathyroid and kidney to hypercalcemia.
  • Individuals carrying homozygous mutation have neonatal severe hyperparathyroidism. Neonatal severe hyperparathyroidism is characterized by marked parathyroid hyperplasia.
• Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism are transmitted in autosomal dominant pattern.

• HRPT2 gene(CDC73 gene) mutations:^[14]
  • HRPT2 gene code for parafibromin protein.
  • HRPT2 gene mutations are found in a type of familial hyperparathyroidism, hyperparathyroidism-jaw tumor (HPT-JT) syndrome.
  • HRTP2 gene mutations increases risk of parathyroid carcinoma.
• Cyclin D1 gene (CCND1)/PRAD1 gene:^[15][16]
  • PRAD1 (parathyroid adenoma 1) is a protooncogene located on chromosome 11q13.
  • Cyclin D1 gene translocation and oncogene action observed in 8% of adenomas.
  • Cyclin D1 gene overexpression is observed in 20% to 40% of parathyroid adenomas.
• MEN1 gene:^[15][17]
  • MEN 1 ics a tumor supressor gene on chromosome 11q13.
  • Somatic loss of single MEN1 allele is observed in 25% to 40% of sporadic parathyroid adenomas.
• RET gene:^[18]
  • RET gene is a proto-oncogene.
  • RET proto-oncogene is associated with multiple endocrine neoplasia type 2 (MEN 2).
  • MEN2A caries increased risk of parathyroid adenoma and/or parathyroid hyperplasia.
• CDNK1B gene:^[19]
  • CDNK1B mutation causes Multiple endocrine neoplasia type 4 (MEN 4).
  • Parathyroid tumors are found along with anterior pituitary, gonadal, adrenal, and renal tumors in MEN 4 syndrome.
  • CDNK1B encodes for the cyclin-dependent kinase inhibitor p27kip1.

The conditions associated with hyperparathyroidism include:^{[20][21][22][12][14][17][23][24][25][26][27][28]}

• Brown tumor
• Chronic renal failure
• Depression
• Familial hypocalciuric hypercalcemia
• Hyperparathyroid-jaw tumor syndrome
• Hypertension
• Multiple endocrine neoplasia type 1
• Multiple endocrine neoplasia type 2A
• Multiple endocrine neoplasia type 4
• Neonatal severe hyperparathyroidism
• Osteitis fibrosa cystica
• Osteoporosis
• Osteomalacia
• Osteoarthritis
• Pancreatitis

• On gross pathology, parathyroid adenoma is a soft, tan nodule which is well-circumscribed by a delicate capsule.^[29]
• Most commonly, parathyroid adenoma is present in single gland. Some times multiple glands are involved.
• If single gland is involved, the other glands may shrink due to negative feedback.
• Majority of times, parathyroid adenoma weight ranges between 0.5 gram to 5 gram.
• Typically, cut surface of parathyroid adenoma is smooth, soft, and reddish brown in color. It should be differentiated from normal parathyroid gland tissue which is yellow-brown color.^[30]
• The tissue of parathyroid gland that is not involved in parathyroid adenoma is typically atrophied and compressed. Fat component of normal parathyroid tissue is also observed.
• On rare occasion, parathyroid adenoma may be cystic.

• Parathyroid hyperplasia usually involves multiple glands.^[29]
• The combine weight of all hyperplastic gland is usually less than 1 gram.

• On gross pathology, parathyroid carcinoma may range from a well circumscribed lesion to invasive neoplasm.^[29]
• Sometimes, it may be difficult to differentiate from parathyroid adenoma.
• One parathyroid gland enlarges in parathyroid carcinoma, consisting gery-white and irregular mass.
• Sometimes, mass of single parathyroid carcinoma becomes more than 10 gram in weight.

• There is erosion of bone martix and bone resorption due to increase in osteoclastic activity.^[29][31]
• Most common site is metaphysis of long tubular bones.
• There is increased osteoblastic activity along with bone resorption leading to formation of new bone trabeculae.
• As severity increases, there is gross thinning of cortex and increase in amount of fibrous tissue in marrow along with multiple foci of hemorrhage and cysts. The condition is called osteitis fibrosa cystica.
• Sometimes there is development of masses due to aggregation of osteoclasts, reactive giant cells and hemorrhagic debris. This may be confused with neoplasm. This is called brown tumor of hyperparathyroidism.

Hypercalcemia due to hyperparathyroidism may lead to formation of nephrolithiasis as well as nephrocalcinosis.[32]

• Hypercalcemia due to hyperparathyroidism may cause metastatic calcification in many organs including lungs, heart, blood vessels, stomach.^[29][33]

• Chief cells are predominant in parathyroid adenoma on microcopy.
• In majority of cases, a few nests of larger oxyphil cells are also present.
• Adenoma is seperated from a rim of non-neoplastic tissue on the edge by a fibrous capsule.
• Chief cells present in adenoma larger than normal chief cells and shows greater variability on nuclear size.
• Endocrine atypia (cells with bizarre and pleomorphic nuclei) is often seen in parathyroid adenoma. It should not be mistaken as a sign of malignancy.
• Mitotic figures are rarely present.
• Parathyroid adenoma has incospicuous adipose tissue when compared with normal parathyroid gland.

• 
  Intermediate/Low magnification micrograph of parathyroid adenoma. H&E stain. Features: Single cell population forming a single mass. Thin capsule. No adipose tissue. +/-Glandular architecture (which may lead to confusion with thyroid tissue). Normal parathyroid gland with prominent adipose tissue is seen on the right of the image. – Source: Wikipedia
• 
  High magnification micrograph of a parathyroid adenoma. H&E stain. Features: Single cell population forming a single mass. Thin capsule. No adipose tissue. +/-Glandular architecture (which may lead to confusion with thyroid tissue). Normal parathyroid gland with prominent adipose tissue is seen on the right of the image. – Source:wikipeida
• 
  Histopatholgical image of parathyroid adenoma in a patient with primary hyperparathyroidism. Hematoxylin and eosin stain. – Source: Wikipedia
• 
  Histopatholgical image of parathyroid adenoma in a patient with primary hyperparathyroidism. Hematoxylin and eosin stain. – Source: Wikipedia
• 
  Histopatholgical image of parathyroid adenoma in a patient with primary hyperparathyroidism. – Source: Wikipedia

• Majority of times, hyperplasia of chief cells is observed. It may be diffuse or multinodular.
• In minority of cases, there is accumulation of glycogen in cytoplasm resulting in abundant clear cytoplasm. This condition is called “water-clear cell hyperplasia”.
• Adipose tissue is in incospicuous in hyperplastic foci, same as adenoma.

• 
  Micrograph showing a parathyroid hyperplasia (H&E stain) on intermediate magnification.Parathyroid adenoma is a clinicopathologic diagnosis. The histology is nonspecific. –Source: Wikimedia commons
• 
  Micrograph showing a parathyroid hyperplasia (H&E stain) on high magnification.Parathyroid adenoma is a clinicopathologic diagnosis. The histology is nonspecific. – Source: Wikimedia commons
• 
  Hyperplasia of parathyroid gland HE-staining, 20× magnification. Source: Wikipedia. Biomedcentral For original file click here.Creative Commons lisence

• Cytologic details are unreliable for diagnosis of parathyroid carcinoma.
• Definitive diagnostic criteria include invasion of surrounding tissue and metastasis.
• About one third of cases have local recurrence and another one third have distant metastasis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Hyperparathyroidism is caused by an increase in concentration of parathyroid hormone in serum. There are three type of hyperparathyroidism including primary, secondary and tertiary hyperparathyroidism. There are an array of different causes for all types of hyperparathyroidism. Most common cause of primary hyperparathyroidism is parathyroid adenoma (85%) followed by parathyroid hyperplasia (15%), and parathyroid carcinoma (5%). Most common cause of secondary hyperparathyroidism is chronic renal failure and vitamin D deficiency. Most common cause of tertiary hyperparathyroidism is post renal transplantation.

Hyperparathyroidism causes can be divided based on the hyperthyroidism category.

Causes of primary hyperparathyroidism are as follows:

Life threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. There are no life threatening causes of primary hyperparathyroidism.

• Parathyroid adenoma^[1]
  • Usually single gland affected
  • Sometimes multiple gland affected

• Parathyroid hyperplasia
• Parathyroid carcinoma
• Familial isloated hyperparathyroidism
• Radiation exposure (due to development of parathyroid adenoma or parathyroid hyperplasia)^[2][3][4]
• Celiac disease^[5][6]

• Calcium-sensing receptor gene mutation^[7]
• HRPT2 gene mutations (hyperparathyroidism-jaw tumor (HPT-JT) syndrome) ^[8]
• Cyclin D1 gene (CCND1)/PRAD1 gene translocation or overexression (parathyroid adenoma)^[9][10]
• MEN1 gene (Multiple endocrine neoplasia type 1)^[9][11]
• RET gene mutations (multiple endocrine neoplasia type 2A)^[12]

Causes of secondary hyperparathyroidism are as follows:

• Chronic renal failure (leading to parathyroid hyperplasia)^[13]
• Vitamin D deficiency^[14]

• Severe calcium deficiency^[15]
• Gastric bypass surgery, particularly roux-en-Y gastric bypass (RYGBP)^[16]
• Malabsorption syndrome^[17]

Causes of tertiary hyperparathyroidism are as follows:

• Chronic renal failure (leading to parathyroid hyperplasia)
• Renal transplant patients^[18]

• Long standing celiac disease^[5]
• Long standing hypocalcemia^[19]
  • Chronic dialysis
  • Gastrointestinal malabsorption

Cardiovascular	No underlying causes
Chemical/Poisoning	No underlying causes
Dental	Hyperparathyroidism-jaw tumor syndrome
Dermatologic	No underlying causes
Drug Side Effect	No underlying causes
Ear Nose Throat	No underlying causes
Endocrine	Parathyroid adenoma, parathyroid hyperplasia, parathyroid carcinoma, neonatal severe primary hyperparathyroidism, familial isolated hyperparathyroidism, Familial hypocalciuric hypercalcemia
Environmental	No underlying causes
Gastroenterologic	Celiac disease, gastric bypass surgery, malabsorption syndrome
Genetic	Familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism
Hematologic	No underlying causes
Iatrogenic	Gastric bypass surgery, radiation exposure
Infectious Disease	No underlying causes
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	Vitamin D deficiency, severe calcium deficiency
Obstetric/Gynecologic	No underlying causes
Oncologic	Hyperparathyroidism-jaw tumor syndrome, parathyroid adenoma,parathyroid carcinoma, multiple endocrine neoplasia type 1 (MEN 1), multiple endocrine neoplasia type 2A (MEN 2A), multiple endocrine neoplasia type 4 (MEN 4)
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte	Chronic renal failure, renal transplant, severe calcium deficiency
Rheumatology/Immunology/Allergy	Celiac disease
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

There are three types of hyperparathyroidism (primary, secondary, and tertiary) and should be differentiated between each other. Hyperparathyroidism should be differentiated from other causes of hypercalcemia. Causes of hypercalcemia other than hyperparathyroidism include familial hypocalciuric hypercalcemia, hypercalcemia related to malignancy, medication-induced hypercalcemia, hypercalcemia due to nutritional disorders, and hypercalcemia related to granulomatous diseases.

There are three types of hyperparathyroidism (primary, secondary, and tertiary) and should be differentiated between each other. Hyperparathyroidism should be differentiated from other causes of hypercalcemia. Causes of hypercalcemia include:

• Parathyroid related
  • Hyperparathyroidism
    • Primary hyperparathyroidism
    • Secondary hyperparathyroidism
    • Tertiary hyperparathyroidism
  • Familial hypocalciuric hypercalcemia
• Non-parathyroid related
  • Malignancy
    • Humoral hypercalcemia of malignancy
    • Osteolytic tumors
    • Production of calcitriol by tumors
    • Ectopic parathyroid hormone production
  • Medication-induced
    • Thiazide diuretics
    • Lithium
  • Nutritional
    • Milk-alkali syndrome
    • Vitamin D toxicity
  • Granulomatous disease
    • Sarcoidosis
  • Surgical
    • Immobization

Differential diagnosis of hyperparathyroidism on the basis of hypercalcemia
Disorder		Mechanism of hypercalcemia	Clinical features	Laboratory findings				Imaging & diagnostic modalities
				PTH	Calcium	Phosphate	Other findings
Hyperparathyroidism	Primary hyperparathyroidism	Increase in secretion of parathyroid hormone (PTH) from a primary process in parathyroid gland. Parathyroid hormone causes increase in serum calcium.	Usually asymptomatic Hypercalcemia detected on routine biochemical panel	↑	↑	↓/Normal	Normal/↑ calcitriol	Findings of bone resorption: X-ray Dual energy X-ray absorptiometry (DXA) Preoperative localization of hyperfunctioning parathyroid gland: Non-Invasive Tc-99m sestamibi scintigraphy Neck ultrasound 4D-CT SPECT(P-SPECT) PET MRI Invasive: Super sensitive venous sampling Selective arteriography Angiography Predicting post-operative success: Intraoperative parathyroid hormone monitoring
	Secondary hyperparathyroidism	Increase in secretion of parathyroid hormone (PTH) from a secondary process. Parathyroid hormone causes increase in serum calcium after long periods.	May present with history of: Chronic renal failure Vitamin D deficiency	↑	↓/Normal	↑	—
	Tertiary hyperparathyroidism	Continuous elevation of parathyroid hormone (PTH) even after successful treatment of the secondary cause of elevated parathyroid hormone. Parathyroid hormone causes increase in serum calcium.	Usually present with history of kidney transplant Usually hyperplasia of all four parathyroid glands	↑	↑	↑	—
Familial hypocalciuric hypercalcemia		This is a genetic disorder caused my mutation in calcium-sensing receptor gene.	A benign condition Does not require treatment	Normal/↑	Normal/↑	—	—	Urinary calcium/creatinine clearance ratio
Malignancy[1][2]	Humoral hypercalcemia of malignancy[3][4][5][6]	Tumor cells secretes parathyroid hormone-related protein (PTHrP) which has similar action as parathyroid hormone.	Most common cause of malignancy related hypercalcemia Usually present with solid tumors	—	↑	↓/Normal	↑ PTHrP Normal/↑ calcitriol	Chest X-ray CT scan MRI
	Osteolytic tumors[7][8]	Multiple myeloma produces osteolysis of bones causing hypercalcemia. Osteolytic metasteses can cause bone resorption causing hypercalcemia.	Commonly present in multiple myeloma and breast cancer	↓	↑	—	—	DXA X-ray Mammography Ultrasound ESR Serum protein electrophoresis
	Production of calcitirol[9]	Some tumors has ectopic activity of 1-alpha-hydroxylase leading to increased production of calcitriol. Calcitriol is active form of vitamin D and causes hypercalcemia.	Commonly present in lymphomas and in some ovarian germ cell tumors	—	↑	—	↑ Calcitriol	CT scan MRI
	Ectopic parathyroid hormone[10]	Some tumors leads to ectopic production of parathyroid hormone.	In rare instances, small cell carcinoma of lung may produce hypercalcemia by this process	↑	↑	↓/Normal	Normal/↑ calcitriol	Chest X-ray CT scan MRI
Medication induced	Lithium[11]	Lithium lowers urinary calcium and causes hypercalcemia. Lithium has been reported to cause an increase in parathyroid hormone and enlargement if parathyroid gland after weeks to months of therapy.	History of mood disorder	↑	↑	—	—	Lithium levels
	Thiazide diuretics[12]	Thiazide diuretics lowers urinary calcium excretion and causes hypercalcemia.	History of cardiac disorder Rarely causes hypercalcemia	—	↑	—	—	—
Nutritional	Milk-alkali syndrome	Hypercalcemia is be caused by high intake of calcium carbonate.	History of High milk intake Excess calcium intake for treating: Osteoporosis Dyspepsia May lead to metabolic alkalosis and renal insufficiency.	—	↑	—	↓ calcitriol	Renal function tests
	Vitamin D toxicity[13][14][15]	Excess vitamin D causes increased absorption of calcium from intestine causing hypercalcemia.	History of: Excess intake vitamin D Excess milk fortified with vitamin D[16] Topical application of vitamin D analogue calcipotriol[17]	—	↑	—	↑ Vitamin D (calcidiol and/or calcitriol)	—
Granulomatous disease	Sarcoidosis[18]	Hypercalcemia is causes by endogeous production of calcitriol by disease-activated macrophages.	History of: Cough Dyspnea Chest pain Tiredness or weakness Fever Weight loss	—	↑	—	↑ Calcitriol ↑ ACE levels	Chest X-ray Biopsy

Disease	Gene	Chromosome	Differentiating Features	Components of MEN			Diagnosis
				Parathyroid	Pitutary	Pancreas
von Hippel-Lindau syndrome	Von Hippel–Lindau tumor suppressor	3p25.3	Angiomatosis,  Hemangioblastomas, Pheochromocytoma,  Renal cell carcinoma, Pancreatic cysts (pancreatic serous cystadenoma) Endolymphatic sac tumor, Bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women)	–	–	+	Clinical diagnosis In hereditary VHL, disease techniques such as Southern blotting and gene sequencing can be used to analyse DNA and identify mutations.
Carney complex	PRKAR1A	17q23-q24	Myxomas of the heart Hyperpigmentation of the skin (lentiginosis) Endocrine (ACTH-independent Cushing’s syndrome due to primary pigmented nodular adrenocortical disease)	–	–	–	Clinical diagnosis
Neurofibromatosis type 1	RAS	17	Scoliosis Learning disabilities Vision disorders Cutaneous lesions Epilepsy.	–	–	–	Prenatal Chorionic villus sampling or amniocentesis can be used to detect NF-1 in the fetus. Postnatal Cardinal Clinical Features” are required for positive diagnosis. Six or more café-au-lait spots over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals. Two or more neurofibromas of any type or 1 plexiform neurofibroma Freckling in the axillary (Crowe sign) or inguinal regions Optic glioma Two or more Lisch nodules (pigmented iris hamartomas) A distinctive osseous lesion such as sphenoid dysplasia, or thinning of the long bone cortex with or without pseudarthrosis.
Li-Fraumeni syndrome	TP53	17	Early onset of diverse amount of cancers such as Sarcoma Cancers of Breast Brain Adrenal glands	–	–	–	Criteria Sarcoma at a young age (below 45) A first-degree relative diagnosed with any cancer at a young age (below 45) A first or second degree relative with any cancer diagnosed before age 60.
Gardner’s syndrome	APC	5q21	Multiple polyps in the colon  Osteomas of the skull Thyroid cancer, Epidermoid cysts, Fibromas Desmoid tumors	–	–	–	Clinical diagnosis Colonoscopy
Multiple endocrine neoplasia type 2	RET	–	Medullary thyroid carcinoma (MTC) Pheochromocytoma Primary hyperparathyroidism	+	–	–	Hypercalcemia Hypophosphatemia, Elevated parathyroid hormone, Elevated norepinephrine Criteria Two or more specific endocrine tumors Medullary thyroid carcinoma Pheochromocytoma Parathyroid hyperplasia
Cowden syndrome	PTEN	–	Hamartomas	–	–	–	PTEN mutation probability risk calculator
Acromegaly/gigantism	–	–	Enlargement of the hands, feet, nose, lips and ears, and a general thickening of the skin Hypertrichosis Hyperpigmentation Hyperhidrosis Carpal tunnel syndrome.	–	+	–	An elevated concentration of serum growth hormone (GH) and insulin-like growth factor 1(IGF-1) levels is diagnostic of acromegaly.
Pituitary adenoma	–	–	Visual field defects classically bitemporal hemianopsia Increased intracranial pressure Migraine Lateral rectus palsy	–	+	–	Elevated serum level of prolactin Elevated or decreased serum level of adrenocorticotropic hormone (ACTH) Elevated or decreased serum level of growth hormone (GH) Elevated or decreased serum level of thyroid-stimulating hormone (TSH) Elevated or decreased serum level of follicle-stimulating hormone (FSH) Elevated or decreased serum level of luteinizing hormone (LH)
Hyperparathyroidism	–	–	– Kidney stones Hypercalcemia, Constipation Peptic ulcers Depression	+	–	–	An elevated concentration of serum calcium with elevated parathyroid hormone level is diagnostic of primary hyperparathyroidism. Most consistent laboratory findings associated with the diagnosis of secondary hyperparathyroidism include elevated serum parathyroid hormone level and low to normal serum calcium. An elevated concentration of serum calcium with elevated parathyroid hormone level in post renal transplant patients is diagnostic of tertiary hyperparathyoidism.
Pheochromocytoma/paraganglioma	VHL RET NF1   SDHB  SDHD	–	Characterized by Episodic hypertension Palpitations Anxiety Diaphoresis Weight loss	–	–	–	Increased catecholamines and metanephrines in plasma (blood) or through a 24-hour urine collection.
Adrenocortical carcinoma	p53 Retinoblastoma h19 Insulin-like growth factor II (IGF-II) p57kip2	17p, 13q	Cushing syndrome (cortisol hypersecretion) Conn syndrome (aldosterone hypersecretion) virilization (testosterone hypersecretion)	–	–	–	Increased serum glucose Increased urine cortisol Serum androstenedione and dehydroepiandrosterone Low serum potassium Low plasma renin activity High serum aldosterone. Excess serum estrogen.
Adapted from Toledo SP, Lourenço DM, Toledo RA. A differential diagnosis of inherited endocrine tumors and their tumor counterparts, journal=Clinics (Sao Paulo), volume= 68, issue= 7, 07/24/2013[19]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Primary hyperparathyroidism is the 3rd most common endocrine disorder. Highest incidence of primary hyperparathyroidism is in post-menopausal women.The incidence of primary hyperparathyroidism is approximately 0.4 to 21.6 per 100,000 person years. The prevalence of primary hyperparathyroidism is approximately .01 to .07 per 100,000 individuals. The incidence of primary hyperparathyroidism increases with age. Primary hyperparathyroidism usually affects individuals of African-American race. Women are more commonly affected by primary hyperparathyroidism than men. The women to men ratio is approximately 3 to 1. Difference in gender specific incidence of primary hyperparathyroidism becomes more pronounced with advancing age. There is insufficient data on epidemiology and demographics of secondary and tertiary hyperparathyroidism.

Primary hyperparathyroidism is the 3rd most common endocrine disorder. Highest incidence of primary hyperparathyroidism is in post-menopausal women.^[1] Epidemiology and demographics of primary hyperparathyroidism is as follows:^[2]

• The incidence of primary hyperparathyroidism is approximately 0.4 to 21.6 per 100,000 person years.

• The prevalence of primary hyperparathyroidism is approximately .01 to .07 per 100,000 individuals.

• The incidence of primary hyperparathyroidism increases with age.
• In individuals age < 50 years, the incidence of primary hyperparathyroidism ranges from a low of 12 per 100,000 person years to a high of 24 per 100,000 per person years.

• Primary hyperparathyroidism usually affects individuals of African-American race.
• The incidence of primary hyperparathyroidism according to race is as follows:

Incidence of Primary hyperparathyroidism according to race
Race	Gender (incidence per 100,000 person years)
	Women	Men
African-American	92	46
White	81	29
Asian	52	28
Hispanic	49	17
Other race	25	6

• Women are more commonly affected by primary hyperparathyroidism than men. The women to men ratio is approximately 3 to 1.
• In women, the incidence of primary hyperparathyroidism ranges from a low of 34 per 100,000 person years to a high of 120 per 100,000 person years with an average incidence of 66 per 100,000 person years.
• In men, the incidence of primary hyperparathyroidism ranges from a low of 13 per 100,000 person years to a high of 36 per 100,000 person years with an average incidence of 24 per 100,000 person years.
• Difference in gender specific incidence of primary hyperparathyroidism becomes more pronounced with advancing age.

Incidence of primary hyperparathyroidism in different age group
Age group	Gender (incidence per 100,000 person years)
	Women	Men
Age < 50 years	12-24	12-24
Age 50 – 59 years	80	36
Age 70-79 years	196	95

There is insufficient data on epidemiology and demographics of secondary and tertiary hyperparathyroidism.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Common risk factors in the development of primary hyperparathyroidism include postmenopausal women, age group 50-60 year, family history of hyperparathyroidism, and history of familial syndromes. Common risk factors in the development of secondary hyperparathyroidism in chronic renal failure include high serum phosphorus expression levels, low serum creatinine expression levels, low serum calcium expression levels, female gender, and hypertension. Common risk factors in the development of tertiary hyperparathyroidism post renal transplantation include elderly individuals and longer duration of dialysis.

Common risk factors in the development of primary hyperparathyroidism include postmenopausal women, age group 50-60 year, family history of hyperparathyroidism, and history of familial syndromes.

Common risk factors in the development of secondary hyperparathyroidism in chronic renal failure include high serum phosphorus expression levels, low serum creatinine expression levels, low serum calcium expression levels, female gender, and hypertension.

Common risk factors in the development of tertiary hyperparathyroidism post renal transplantation include elderly individuals and longer duration of dialysis.

Common risk factors in the development of primary hyperparathyroidism include:

• Postmenopausal women
• Age group 50-60 years
• Family history of hyperparathyroidism
• History of familial syndromes such as multiple endocrine neoplasia type 1, type 2A or type 4; familial hypocalciuric hypercalcemia, hyperparathyroid-jaw tumor syndrome

Common risk factors in the development of secondary hyperparathyroidism in chronic renal failure include:^[1]

• High serum phosphorus expression levels
• Low serum creatinine expression levels
• Low serum calcium expression levels
• Female gender
• Hypertension

Common risk factors in the development of tertiary hyperparathyroidism post renal transplantation include:^[2]

• Elderly individuals
• Longer duration of dialysis

Less common risk factors in the development of primary hyperparathyroidism include:

• history of current or past lithium use^[3]
• Exposure to head and neck radiation

Less common risk factors in the development of secondary hyperparathyroidism in chronic renal failure include:^[1]

• Acidosis
• Anemia
• Hyperlipidemia
• Micro-inflammation (C reactive protein)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

There is insufficient evidence to recommend routine screening for hyperparathyroidism.

There is insufficient evidence to recommend routine screening for hyperparathyroidism.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Primary hyperparathyroidism usually develops in the fifth decade of life, in post-menopausal women and starts as asymptomatic hypercalcemia in presence of increased parathyroid hormone. If left untreated, some of patients with primary hyperparathyroidism may commonly develop marked hypercalcemia, marked hypercalciuria, cortical bone demineralization and nephrolithiasis.

Secondary hyperparathyroidism arise in the early course of chronic renal failure. As renal failure progress, secondary hyperparathyroidism becomes more notable. If left untreated, secondary hyperparathyroidism carries an increased risk of vascular calcification with increasing age and duration of dialysis in patients.

Tertiary hyperparathyroidism usually develops in post renal transplant patients. If left untreated, tertiary hyperparathyroidism in post renal transplant patients may carry the risk of amyloid deposition, calciphylaxis, destructive or erosive spondyloarthropathy, osteonecrosis, and musculoskeletal infections.

Hyperparathyroidism leads to a variety of complications in various organ systems depending on the type of hyperparathyroidism.

Prognosis is all types hyperparathyroidism is generally good after proper treatment.

• Primary hyperparathyroidism usually develops in the fifth decade of life, in post-menopausal women and starts as asymptomatic hypercalcemia in presence of increased parathyroid hormone.
• If left untreated, some of the patients with primary hyperparathyroidism may develop marked hypercalcemia, hypercalciuria, cortical bone demineralization and nephrolithiasis.^[1][2]

• Secondary hyperparathyroidism arise in the early course of chronic renal failure. As renal failure progress, secondary hyperparathyroidism becomes more notable.^[3]
• Secondary hyperparathyroidism leads to vascular calcification due to elevated calcium and phosphorus levels. This is strongly associated with increase in morbidity and mortality.^[4]
• If left untreated, secondary hyperparathyroidism carries an increased risk of vascular calcification with increasing age and duration of dialysis in patients.

• Tertiary hyperparathyroidism usually develops in post renal transplant patients.
• If left untreated, tertiary hyperparathyroidism in post renal transplant patients may carry the risk of amyloid deposition, calciphylaxis, destructive or erosive spondyloarthropathy, osteonecrosis, and musculoskeletal infections.^[5]

Complications involving Organ system	Complications of hyperparathyroidism
	Primary hyperparathyroidism	Secondary hyperparathyroidism	Tertiary hyperparathyroidism
Cardiaovascular complications [6][7]	Aortic and mitral valve calcification Calcific deposits in the myocardium Left ventricular hypertrophy	Impaired left ventricular diastolic function Left ventricular hypertrophy	—
Endocrine complications[8]	Pancreatitis	—	—
Gastrointestinal complications[9]	Peptic ulcer disease	—	—
Hematologic complications[10]	—	Platlet function inhibition
Metabolic complications [11][12][9][13][14][15][16]	Hypercalcemic crisis Osteomalacia	Metabolic syndrome	Calciphylaxis
Musculo-skeletal complications [17][18][19][20][21][5]	Brown tumor Osteitis fibrosa cystica Osteoporosis	Renal Osteodystrophy Brown cysts Osteitis fibrosa cystica Osteoporosis Osteosclerosis	Musculoskeletal infections Osteonecrosis
Neurologic complications [22][23]	—	Electroencephalogram abnormalities Uremic neuropathy	—
Neuromuscular complications [24][25]	Neuropathic muscle disease	Neuropathic muscle disease	Neuropathic muscle disease
Pregnancy related complications[26]	Neonatal hypoparathyroidism	—	—
Psychiatric complications [27][28][29]	Anxiety Cognitive dysfunction including verbal memory and nonverbal abstraction Depression Irritability Lack of concentration Sleep disturbances	—	—
Renal complications [1][30][31][32]	Hypercalciuria Nephrolithiasis Nephrocalcinosis Renal insufficiency (impairement of GFR)	Renal insufficiency (impairement of GFR)	Nephrolithiasis
Rheumatologic complications [33][34][35][36]	Gout Osteoarthritis Pseudogout	—	Destructive or erosive spondyloarthropathy
System non-specific complications [37][5]	—	Metastatic calcifications	Amyloid deposition Metastatic calcifications

• Prognosis of primary hyperparathyroidism is generally excellent after parathyroidectomy.
• The complications of primary hyperparathyroidism resolves after the treatment.
• Untreated complication of primary hyperparathyroidism may be fatal.^[9]

• Effective treatment can reduce morbidity and mortality associated with uncontrolled secondary hyperparathyroidism.^[4]
• Hyperphosphatemia and metastatic calcification results due elevated product of serum calcium and serum phosphorus. Both conditions are present in patients with secondary hyperparathyroidism in presence of end stage renal disease. This leads to a significant increase in morbidity and mortality. Aggressive control of hyperphosphatemia may improve prognosis^[37]

• Prognosis of tertiary hyperparathyroidism is generally good after resection of abnormal hyperplastic gland.^[38]

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