Hyperparathyroidism

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Hyperparathyroidism
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 an increased parathyroid hormone (PTH) levels in the blood.[1] This occurs either from the parathyroid glands inappropriately making too much PTH (primarily hyperparathyroidism) or other events triggering increased production by the parathyroid glands (secondary hyperparathyroidism).[2] Most people with primary disease have no symptoms at the time of diagnosis.[3] In those with symptoms the most common is kidney stones with other potential symptoms including weakness, depression, bone pains, confusion, and increased urination.[2][4] Both types increase the risk of weak bones.[4][3]

Primary hyperparathyroidism in 80% of cases is due to a single benign tumor known as a parathyroid adenoma with most of the rest of the cases due to a multiple benign tumors.[4][2] Rarely it may be due to parathyroid cancer.[4] Secondary hyperparathyroidism typically occurs due to vitamin D deficiency, chronic kidney disease, or other causes of low blood calcium.[2] Diagnosis of primary disease is by finding a high blood calcium and high PTH levels.[4]

Primary hyperparathyroidism may be cured by removing the adenoma or overactive parathyroid glands.[2][4] In those without symptoms, mildly increased blood calcium levels, normal kidneys, and normal bone density monitoring may be all that is required. The medication cinacalcet may also be used to decrease PTH levels.[4] In those with very high blood calcium levels treatment may include large amounts of intravenous normal saline.[2] Low vitamin D levels should be corrected.[4]

Primary hyperparathyroidism is the most common form.[2] In the developed world between one and four per thousand people are affected.[3] It occurs three times more often in women than men and is typically diagnosed between the ages of 50 and 60.[4] The disease was first described in the 1700s and in the late 1800s was determined to be related to the parathyroid. Surgery as a treatment was first carried out in 1925.[5]

Signs and symptoms[edit]

Symptoms depend on whether the hyperparathyroidism is the result of parathyroid overactivity or secondary.

In primary hyperparathyroidism about 75% of people have no symptoms.[2] The problem is often picked up during blood work for other reasons via a raised calcium.[3] Many other people 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.[9] A history of acquired racquet nails (brachyonychia) may be indicative of bone resorption.[10] 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.

Cause[edit]

Radiation exposure increases the risk of primary hyperparathyroidism.[2] A number of genetic conditions including multiple endocrine neoplasia syndromes also increase the risk.[2]

Mechanism[edit]

Normal parathyroid glands measure the ionized calcium (Ca2+) concentration in the blood 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.[6]

Secondary hyperparathyroidism occurs if the calcium level is abnormally low. 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 and there is hypocalcemia. 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 the body cannot make its own vitamin D from cholesterol.[11] 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.[6][11] 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.

Diagnosis[edit]

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.

Differential diagnosis[edit]

Familial benign hypocalciuric hypercalcaemia can present with similarly lab changes.[2] In this condition the calcium creatinine clearance ratio; however, is typically under 0.01.[2]

Blood tests[edit]

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.

Nuclear medicine[edit]

A technetium sestamibi scan is a procedure in nuclear medicine that identifies hyperparathyroidism (or parathyroid adenoma).[12] It is used by surgeons to locate ectopic parathyroid adenomas, most commonly found in the anterior mediastinum.[citation needed]

Classification[edit]

Primary[edit]

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.[13][14]

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.[15][16]

Patients with bipolar disorder who are receiving long-term lithium treatment are at increased risk for hyperparathyroidism.[17] 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.[17]

Secondary[edit]

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[18] (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[edit]

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.

Treatment[edit]

Treatment depends entirely on the type of hyperparathyroidism encountered.

Primary[edit]

People with primary hyperparathyroidism who are symptomatic benefit from surgery to remove the parathyroid tumor (parathyroid adenoma). Indications for surgery are as follows:[19]

  • 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)
    • People age < 50

Surgery can rarely result in hypoparathyroidism.

Secondary[edit]

In people 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)

Calcimimetics[edit]

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.[20][21]

In the treatment of secondary hyperparathyroidism due to chronic kidney disease on dialysis calcimimetics do not appear to affect the risk of early death.[22] They do decrease the need for a parathyroidectomy but cause more issues with low blood calcium levels and vomiting.[22]

History[edit]

The oldest known case was found in a cadaver from an Early Neolithic cemetery in southwest Germany.[23]

Notes[edit]

  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”.[6][7][8]

References[edit]

  1. ^ Allerheiligen, DA; Schoeber, J; Houston, RE; Mohl, VK; Wildman, KM (15 April 1998). "Hyperparathyroidism.". American family physician. 57 (8): 1795–802, 1807–8. PMID 9575320. 
  2. ^ a b c d e f g h i j k l Fraser WD (July 2009). "Hyperparathyroidism". Lancet. 374 (9684): 145–58. doi:10.1016/S0140-6736(09)60507-9. PMID 19595349. 
  3. ^ a b c d Michels, TC; Kelly, KM (15 August 2013). "Parathyroid disorders.". American family physician. 88 (4): 249–57. PMID 23944728. 
  4. ^ a b c d e f g h i "Primary Hyperparathyroidism". NIDDK. August 2012. Retrieved 27 September 2016. 
  5. ^ Gasparri, Guido; Camandona, Michele; Palestini, Nicola (2015). Primary, Secondary and Tertiary Hyperparathyroidism: Diagnostic and Therapeutic Updates. Springer. ISBN 9788847057586. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ "Symptoms of Hyperparathyroidism and Symptoms of Parathyroid Disease.". Parathyroid.com. Norman Parathyroid Center. Retrieved 2015-12-30. 
  9. ^ Hyperparathyroidism. National Endocrine and Metabolic Diseases Information Service. May 2006.
  10. ^ 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. 
  11. ^ a b Stryer, Lubert (1995). In: Biochemistry. (Fourth ed.). New York: W.H. Freeman and Company. p. 707. ISBN 0 7167 2009 4. 
  12. ^ "Parathyroid Adenoma". 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ Marx SJ. (2011) Hyperparathyroid Genes: Sequences Reveal Answers and Questions. Endocr. Pract.
  16. ^ 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. 
  17. ^ a b Pomerantz JM (2010). "Hyperparathyroidism Resulting From Lithium Treatment Remains Underrecognized". Drug Benefit Trends. 22: 62–63. 
  18. ^ 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. 
  19. ^ Bilezikian JP, Silverberg SJ. Clinical practice. Asymptomatic primary hyperparathyroidism. N Engl J Med. 2004 Apr 22;350(17):1746-51
  20. ^ http://pi.amgen.com/united_states/sensipar/sensipar_pi_hcp_english.pdf
  21. ^ 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. 
  22. ^ 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. 
  23. ^ 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. 

External links[edit]