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Illu thyroid parathyroid.jpg
Thyroid and parathyroid.
Classification and external resources
Specialty Endocrinology
ICD-10 E21
ICD-9-CM 252.0
DiseasesDB 20710
MedlinePlus 001215
eMedicine emerg/265 med/3200
Patient UK Hyperparathyroidism
MeSH D006961

Hyperparathyroidism is inappropriate overactivity of the parathyroid glands resulting in parathyroid hormone (PTH) levels in the blood above what a normally functioning plasma ionized calcium regulator (or homeostat, or negative feedback mechanism) would produce. Hyperparathyroidism can also result if the organs that normally respond to PTH are compromised in one way or the other, thus causing the parathyroid glands to secrete very high quantities of PTH in response to the resulting unresponsively low plasma ionized calcium levels in the blood (hypocalcemia).

Normal parathyroid glands measure the ionized calcium (Ca2+) concentration in the blood plasma and secrete parathyroid hormone accordingly: if the ionized calcium rises above normal the secretion of PTH is decreased, whereas when the Ca2+ level falls, parathyroid hormone secretion is increased.[1]

In primary hyperparathyroidism, the release of parathyroid hormone into the blood is no longer determined by the current plasma Ca2+ level, but is persistently above what is appropriate. This may be due to a parathyroid adenoma, which secretes PTH independently of changes in the plasma ionized calcium concentration. This leads to hypercalcemia (abnormally high plasma calcium levels).

Secondary hyperparathyroidism occurs if the plasma ionized calcium level does not respond to changes in PTH secretion from normal glands, and therefore remains abnormally low (hypocalcemia). The normal glands respond by secreting parathyroid hormone at a persistently high rate. This typically occurs when the 1,25 dihydroxyvitamin D3 levels in the blood are low or absent. 1,25 Dihydroxyvitamin D3 (or calcitriol) is the active hormone that determines the quantity of calcium absorbed from the duodenum. Its absence therefore causes hypocalcemia, to which the parathyroid glands respond by secreting large quantities of PTH into the blood (i.e. "secondary hyperparathyroidism"). A lack of 1,25 dihydroxyvitamin D3 can result from a deficient dietary intake of vitamin D, or from a lack of exposure of the skin to sunlight, so that the body cannot make its own vitamin D from cholesterol.[2] The resulting hypovitaminosis D is usually due to a partial combination of both factors. Vitamin D3 (or cholecalciferol) is converted to 25-hydroxyvitamin D (or calcidiol) by the liver, from where it is transported via the circulation to the kidneys where it is converted into the active hormone, 1,25 dihydroxyvitamin D3.[1][2] Thus a third cause of secondary hyperparathyroidism is chronic kidney disease. Here the ability to manufacture 1,25 dihydroxyvitamin D3 is compromised, resulting in hypocalcemia. In both primary and secondary hyperparathyroidism, the high plasma PTH levels erode the skeleton, predisposing it to fractures and bone deformities, necessitating interventions to reverse the high PTH levels in the blood.[3]



Primary hyperparathyroidism results from a hyperfunction of the parathyroid glands themselves. There is oversecretion of PTH due to a parathyroid adenoma, parathyroid hyperplasia or, rarely, a parathyroid carcinoma. This disease is often characterized by the quartet stones, bones, groans, and psychiatric overtones referring to the presence of kidney stones, hypercalcemia, constipation and peptic ulcers, as well as depression, respectively.[4][5]

In a minority of cases this occurs as part of a multiple endocrine neoplasia (MEN) syndrome, either type 1 (caused by a mutation in the gene MEN1) or type 2a (caused by a mutation in the gene RET). Other mutations that have been linked to parathyroid neoplasia include mutations in the genes HRPT2, and CASR.[6][7]

Patients with bipolar disorder who are receiving long-term lithium treatment are at increased risk for hyperparathyroidism.[8] Elevated calcium levels are found in 15% to 20% of patients who have been taking lithium long-term. However, only a few of these patients have significantly elevated levels of parathyroid hormone and clinical symptoms of hyperparathyroidism. Lithium-associated hyperparathyroidism is usually caused by a single parathyroid adenoma.[8]


Secondary hyperparathyroidism is due to physiological (i.e. appropriate) secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia (low blood calcium levels). The most common causes are vitamin D deficiency[9] (caused by lack of sunlight, diet or malabsorption) and chronic kidney failure.

Lack of vitamin D leads to reduced calcium absorption by the intestine leading to hypocalcemia and increased parathyroid hormone secretion. This increases bone resorption. In chronic kidney failure the problem is more specifically failure to convert vitamin D to its active form in the kidney. The bone disease in secondary hyperparathyroidism caused by renal failure is termed renal osteodystrophy.


Tertiary hyperparathyroidism is seen in patients with long-term secondary hyperparathyroidism, which eventually leads to hyperplasia of the parathyroid glands and a loss of response to serum calcium levels. This disorder is most often seen in patients with chronic renal failure and is an autonomous activity.

Quaternary and Quintary[edit]

Quaternary and quintary are rare conditions that may be observed after surgical removal of primary hyperparathyroidism, when it has led to kidney damage that now again causes a form of secondary (quaternary) hyperparathyroidism that may itself result in autonomy (quintary) hyperparathyroidism.[10] Additionally, quaternary hyperparathyroidism may ensue from hungry bone syndrome after parathyroidectomy.[11]

Signs and symptoms[edit]

These depend entirely on whether the hyperparathyroidism is primary or secondary.

In primary hyperparathyroidism about 50% of patients have no symptoms and the problem is picked up as an incidental finding (via a raised calcium or characteristic X-ray appearances). Many other patients only have non-specific symptoms. Symptoms directly due to hypercalcemia are relatively rare, being more common in patients with malignant hypercalcemia. If present, common manifestations of hypercalcemia include weakness and fatigue, depression, bone pain, muscle soreness (myalgias), decreased appetite, feelings of nausea and vomiting, constipation, polyuria, polydipsia, cognitive impairment, kidney stones (See Foot Note[nb 1]) and osteoporosis.[14] A history of acquired racquet nails (brachyonychia) may be indicative of bone resorption.[15] Parathyroid adenomas are very rarely detectable on clinical examination. Surgical removal of a parathyroid tumor eliminates the symptoms in most patients.

In secondary hyperparathyroidism the parathyroid gland is behaving normally; clinical problems are due to bone resorption and manifest as bone syndromes such as rickets, osteomalacia and renal osteodystrophy.


Calcification in the brain due to hyperparathyroidism
Pepper & Salt, classical X-Ray appearance of hyperparathyroidisim

The gold standard of diagnosis is the parathyroid immunoassay. Once an elevated Parathyroid hormone has been confirmed, goal of diagnosis is to determine whether the hyperparathyroidism is primary or secondary in origin by obtaining a serum calcium level:

PTH serum calcium likely type
high high primary hyperparathyroidism
high low or normal secondary hyperparathyroidism

Tertiary hyperparathyroidism has a high PTH and a high serum calcium. It is differentiated from primary hyperparathyroidism by a history of chronic kidney failure and secondary hyperparathyroidism.

Intact PTH[edit]

In primary hyperparathyroidism, parathyroid hormone (PTH) levels are either elevated or "inappropriately normal" in the presence of elevated calcium. Typically PTH levels vary greatly over time in the affected patient and (as with Ca and Ca++ levels) must be retested several times to see the pattern. The currently accepted test for PTH is Intact PTH, which detects only relatively intact and biologically active PTH molecules. Older tests often detected other, inactive fragments. Even "Intact PTH" may be inaccurate in patients with renal dysfunction.

Calcium levels[edit]

In cases of primary hyperparathyroidism or tertiary hyperparathyroidism heightened PTH leads to increased serum calcium (hypercalcemia) due to:

  1. increased bone resorption, allowing flow of calcium from bone to blood
  2. reduced kidney clearance of calcium
  3. increased intestinal calcium absorption

Serum phosphate[edit]

In primary hyperparathyroidism, serum phosphate levels are abnormally low as a result of decreased renal tubular phosphate reabsorption. However, this is only present in about 50% of cases. This contrasts with secondary hyperparathyroidism, in which serum phosphate levels are generally elevated because of renal disease.

Alkaline phosphatase[edit]

Alkaline phosphatase levels are usually elevated in hyperparathyroidism. In primary hyperparathyroidism, levels may remain within the normal range, however this is 'inappropriately normal' given the increased levels of plasma calcium.

Technetium sestamibi[edit]

A sestamibi scan is a procedure in nuclear medicine that identifies hyperparathyroidism (or parathyroid adenoma).[16] It is used by surgeons to locate ectopic parathyroid adenomas, most commonly found in the anterior mediastinum.[citation needed]


Treatment depends entirely on the type of hyperparathyroidism encountered. People with primary hyperparathyroidism who are symptomatic benefit from surgery to remove the parathyroid tumor (parathyroid adenoma). Indications for surgery are as follows:[17]

  • Symptomatic hyperparathyroidism
  • Asymptomatic hyperparathyroidism with any of the following:
    • 24-hour urinary calcium > 400 mg (see Foot Note, below)
    • serum calcium > 1 mg/dL above upper limit of normal
    • Creatinine clearance > 30% below normal for patient's age
    • Bone density > 2.5 standard deviations for below peak (i.e., T-score of -2.5)
    • Patient age < 50

In patients with secondary hyperparathyroidism, the high PTH levels are an appropriate response to low calcium and treatment must be directed at the underlying cause of this (usually vitamin D deficiency or chronic kidney failure). If this is successful PTH levels should naturally return to normal levels unless PTH secretion has become autonomous (tertiary hyperparathyroidism)

Testing for hyperparathryroidism:

  • Calcium level
  • Bone density
  • Vitamin D
  • Phosphorus


A calcimimetic (such as cinacalcet) is a potential therapy for some people with severe hypercalcemia and primary hyperparathyroidism who are unable to undergo parathyroidectomy and for secondary hyperparathyroidism on dialysis.[18][19]

In the treatment of secondary hyperparathyroidism due to chronic kidney disease on dialysis calcimimetics do not appear to affect the risk of early death.[20] They do decrease the need for a parathyroidectomy but cause more issues with low blood calcium levels and vomiting.[20]


Hyperparathyroidism was first described and treated in the 1930s by Fuller Albright of Massachusetts General Hospital, working at the Mallinckrodt General Clinical Research Center. The oldest known case was found in a cadaver from an Early Neolithic cemetery in southwest Germany.[21]


  1. ^ Although parathyroid hormone (PTH) promotes the re-absorption of calcium from the renal tubular fluid, thus decreasing the rate of urinary calcium excretion, its effect is only noticeable at any given plasma ionized calcium concentration. The primary determinant of the amount of calcium excreted into the urine per day is the plasma ionized calcium concentration. Thus, in primary hyperparathyroidism the quantity of calcium excreted in the urine per day is increased despite the high levels of PTH in the blood. This is because hyperparathyroidism results in hypercalcemia, which increases the urinary calcium concentration (hypercalcuria). Renal stones are therefore often a first indication of hyperparathyroidism, especially since the hypercalcuria is accompanied by an increase in urinary phosphate excretion (a direct result of the high plasma PTH levels). Together the calcium and phosphate tend to precipitate out as water-insoluble salts, which readily form solid “stones”.[1][12][13]

See also[edit]


  1. ^ a b c Blaine J, Chonchol M, Levi M (2015). "Renal control of calcium, phosphate, and magnesium homeostasis". Clinical Journal of the American Society of Nephrology. 10 (7): 1257–72. doi:10.2215/CJN.09750913. PMID 25287933. 
  2. ^ a b Stryer, Lubert (1995). In: Biochemistry. (Fourth ed.). New York: W.H. Freeman and Company. p. 707. ISBN 0 7167 2009 4. 
  3. ^ Fraser WD (July 2009). "Hyperparathyroidism". Lancet. 374 (9684): 145–58. doi:10.1016/S0140-6736(09)60507-9. PMID 19595349. 
  4. ^ Carrol, Mary F.; David S. Schade (1 May 2003). "A Practical Approach to Hypercalcemia". American Family Physician. 67 (9): 1959–1966. his constellation of symptoms has led to the mnemonic “Stones, bones, abdominal moans, and psychic groans,” which is used to recall the signs and symptoms of hypercalcemia, particularly as a result of primary hyperparathyroidism. 
  5. ^ McConnell, Thomas H. (2007). The Nature of Disease: Pathology for the Health Professions. Lippincott Williams & Wilkins. p. 466. ISBN 9780781753173. "Stones" refers to kidney stones, "bones" to associated destructive bone changes, "groans" to the pain of stomach and peptic ulcers that occur in some cases, and "moans" to the depression that frequently accompanies the disease and is often its first and most prominent manifestation. 
  6. ^ Marx SJ. (2011) Hyperparathyroid Genes: Sequences Reveal Answers and Questions. Endocr. Pract.
  7. ^ Sulaiman L, Nilsson IL, Juhlin CC, Haglund F, Höög A, Larsson C, Hashemi J (June 2012). "Genetic characterization of large parathyroid adenomas.". Endocr Relat Cancer. 19 (3): 389–407. doi:10.1530/ERC-11-0140. PMID 22454399. 
  8. ^ a b Pomerantz JM (2010). "Hyperparathyroidism Resulting From Lithium Treatment Remains Underrecognized". Drug Benefit Trends. 22: 62–63. 
  9. ^ Zink AR, Panzer S, Fesq-Martin M, Burger-Heinrich E, Wahl J, Nerlich AG (2001). "Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications.". Endocr Rev. 22 (4): 477–501. doi:10.1210/er.22.4.477. PMID 11493580. 
  10. ^ Kaiser, W.; Schmidt G. A.; Gerlach H.. (June 1976). "Quintärer Hyperparathyreoidismus [Quintary hyperparathyroidism]". Z Gesamte Inn Med. 31 (11): 358–64. PMID 960860. 
  11. ^ Oltmann, Sarah C.; Maalouf, N. M.; Holt, S. (March 2011). "Significance of Elevated Parathyroid Hormone after Parathyroidectomy for Primary Hyperparathyroidism". Endocrine Practice. 17 (S1): 57–73. doi:10.4158/EP10324.RA. PMID 21247842. Retrieved 27 September 2011. 
  12. ^ Harrison, T.R.; Adams, R.D.; Bennett Jnr., I.L.; Resnick, W.H.; Thorn, G.W.; Wintrobe, M.M. (1958). "Metabolic and Endocrine Disorders.". In: Principles of Internal Medicine. (Third ed.). New York: McGraw-Hill Book Company. pp. 575–578. 
  13. ^ "Symptoms of Hyperparathyroidism and Symptoms of Parathyroid Disease.". Parathyroid.com. Norman Parathyroid Center. Retrieved 2015-12-30. 
  14. ^ Hyperparathyroidism. National Endocrine and Metabolic Diseases Information Service. May 2006.
  15. ^ Baran, R.; Turkmani, M.G.; Mubki, T. "Acquired Racquet Nails: a Useful Sign of Hyperparathyroidism". Wiley Online Library. Journal of the European Academy of Dermatology and Venereology. Retrieved 27 June 2014. 
  16. ^ "Parathyroid Adenoma". 
  17. ^ Bilezikian JP, Silverberg SJ. Clinical practice. Asymptomatic primary hyperparathyroidism. N Engl J Med. 2004 Apr 22;350(17):1746-51
  18. ^ http://pi.amgen.com/united_states/sensipar/sensipar_pi_hcp_english.pdf
  19. ^ Ott, SM (April 1998). "Calcimimetics–new drugs with the potential to control hyperparathyroidism". J. Clin. Endocrinol. Metab. 83 (4): 1080–2. doi:10.1210/jc.83.4.1080. PMID 9543121. 
  20. ^ a b Ballinger, AE; Palmer, SC; Nistor, I; Craig, JC; Strippoli, GF (9 December 2014). "Calcimimetics for secondary hyperparathyroidism in chronic kidney disease patients.". The Cochrane database of systematic reviews. 12: CD006254. doi:10.1002/14651858.CD006254.pub2. PMID 25490118. 
  21. ^ Zink AR, Panzer S, Fesq-Martin M, Burger-Heinrich E, Wahl J, Nerlich AG (2005). "Evidence for a 7000-year-old case of primary hyperparathyroidism". JAMA. 293 (1): 40–2. doi:10.1001/jama.293.1.40-c. PMID 15632333. 

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