Primary hyperparathyroidism
Encyclopedia
Primary hyperparathyroidism causes hypercalcemia (elevated blood calcium levels) through the excessive secretion of parathyroid hormone
(PTH), usually by an adenoma
(benign tumors) of the parathyroid gland
s.
of primary hyperparathyroidism is approximately 1 per 1,000 people (0.1%), while there are 25-30 new cases per 100,000 people per year in the United States. The prevalence
of primary hyperparathyroidism has been estimated to be 3 in 1000 in the general population and as high as 21 in 1000 in postmenopausal women. It is almost exactly three times as common in women as men.
The German description of the same symptoms is "", literally "stone, bone, and stomach-pain".
Other signs include proximal muscle weakness, itching, and band keratopathy
of the eyes.
However, when subjected to formal research, nonspecific symptoms, fatigue, musculoskeletal pain, constipation, depression, do not correlate with hypercalcemia.
Serum calcium levels are elevated, and the parathyroid hormone level is abnormally high compared with an expected low level in response to the high calcium. A relatively elevated parathyroid hormone has been estimated to have a sensitivity
of 60%-80% and a specificity
of approximately 90% for primary hyperparathyroidism.
A more powerful variant of comparing the balance between calcium and parathyroid hormone is to perform a 3 hour calcium infusion. After infusion, a parathyroid hormone level above a cutoff of 14 ng/l has a sensitivity
of 100% and a specificity
of 93% in detecting primary hyperparathyroidism, with a confidence interval
of 80% to 100%.
The serum chloride/phosphate ratio is 33 or more in most patients with primary hyperparathyroidism. However, usage of thiazide
medications have been reported to causes ratios above 33. Studies without any usage of thiazide diuretics have estimated a serum chloride/phosphate ratio to have a sensitivity of 94% or 95% and a specificity of 96% or 100%.
Urinary cAMP
is occasionally measured; this is generally elevated..
resulting from a clonal mutation (~97%). Less common are parathyroid hyperplasia (~2.5%), parathyroid carcinoma
(malignant tumor), and adenomas in more than one gland (together ~0.5%).
Primary hyperparathyroidism is also a feature of several familial endocrine disorders: Multiple endocrine neoplasia
type 1 and type 2A (MEN type 1
and MEN type 2A
), and familial hyperparathyroidism.
Genetic associations include:
In all cases, the disease is idiopathic
, but is thought to involve inactivation of tumor suppressor gene
s (Menin
gene in MEN1), or involve gain of function mutations (RET proto-oncogene
MEN 2a).
Recently, it was demonstrated that liquidator
s of the Chernobyl
power plant are faced with a substantial risk of primary hyperparathyroidism, possibly caused by radioactive strontium
isotope
s.
Primary hyperparathyroidism can also result from pregnancy
. It is apparently very rare, with only about 110 cases have so far been reported in world literature, but this is probably a considerable underestimate of its actual prevalence in pregnant women.
, which results in pain and sometimes pathological fractures. Other bone diseases associated with hyperparathyroidism are osteoporosis
, osteomalacia
, and arthritis
.
s. Bisphosphonate
s may improve bone turnover.
Newer medications termed "calcimimetics" used in secondary hyperparathyroidism are now being used in Primary hyperparathyroidism. Calcimimetics reduce the amount of parathyroid hormone released by the parathyroid glands. They are recommended in patients in whom surgery is inappropriate.
A consensus statement in 2002 recommended the following indications for surgery in asymptomatic hyperparathyroidism:
More recently, three randomized controlled trial
s have studied the role of surgery in patients with asymptomatic hyperparathyroidism. The largest study reported that surgery showed increase in bone mass, but no improvement in quality of life after one to two years among patients with:
Two other trials
reported improvements in bone density and some improvement in quality of life with surgery.
TH-One uses High Intensity Focused Ultrasound (HIFU), which is a process that allows the delivery of a large amount of acoustic energy to a confined space resulting in localized tissue necrosis.
The TH-One enables to treat primary hyperparathyroidism by ablating the adenoma. It also allows to lower in a control manner the PTH level for secondary hyperparathyroidism
patients. It is scar-less, totally non invasive.
) which activate the parathyroid calcium-sensing receptor
may offer a good alternative to surgery.
Parathyroid hormone
Parathyroid hormone , parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids...
(PTH), usually by an adenoma
Adenoma
An adenoma is a benign tumor of glandular origin. Adenomas can grow from many organs including the colon, adrenal glands, pituitary gland, thyroid, prostate, etc. Although these growths are benign, over time they may progress to become malignant, at which point they are called adenocarcinomas...
(benign tumors) of the parathyroid gland
Parathyroid gland
The parathyroid glands are small endocrine glands in the neck that produce parathyroid hormone. Humans usually have four parathyroid glands, which are usually located on the rear surface of the thyroid gland, or, in rare cases, within the thyroid gland itself or in the chest...
s.
Epidemiology
The incidenceIncidence
Incidence may refer to:* Incidence , a measure of the risk of developing some new condition within a specified period of time* Incidence , the binary relations describing how subsets meet...
of primary hyperparathyroidism is approximately 1 per 1,000 people (0.1%), while there are 25-30 new cases per 100,000 people per year in the United States. The prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
of primary hyperparathyroidism has been estimated to be 3 in 1000 in the general population and as high as 21 in 1000 in postmenopausal women. It is almost exactly three times as common in women as men.
Signs and Symptoms
The signs and symptoms of primary hyperparathyroidism are those of hypercalcemia. They are classically summarized by the mnemonic "stones, bones, abdominal groans and psychiatric moans".- "Stones" refers to kidney stones, nephrocalcinosisNephrocalcinosisNephrocalcinosis, once known as Albright's calcinosis after Fuller Albright, is a term originally used to describe deposition of calcium salts in the renal parenchyma due to hyperparathyroidism. It is now more commonly used to describe diffuse, fine, renal parenchymal calcification on radiology...
, and diabetes insipidusDiabetes insipidusDiabetes insipidus is a condition characterized by excessive thirst and excretion of large amounts of severely diluted urine, with reduction of fluid intake having no effect on the concentration of the urine. There are several different types of DI, each with a different cause...
(polyuria and polydipsia). These can ultimately lead to renal failureRenal failureRenal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
. - "Bones" refers to bone-related complications. The classic bone disease in hyperparathyroidism is osteitis fibrosa cysticaOsteitis fibrosa cysticaOsteitis fibrosa cystica , abbreviated OFC, and also known as osteitis fibrosa, osteodystrophia fibrosa, not to be confused with Von Recklinghausen's disease of bone . Osteitis Fbrosa Cystica is a skeletal disorder caused by a surplus of parathyroid hormone from over-active parathyroid glands...
, which results in pain and sometimes pathological fractures. Other bone diseases associated with hyperparathyroidism are osteoporosisOsteoporosisOsteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, osteomalaciaOsteomalaciaOsteomalacia is the softening of the bones caused by defective bone mineralization secondary to inadequate amounts of available phosphorus and calcium, or because of overactive resorption of calcium from the bone as a result of hyperparathyroidism...
, and arthritisArthritisArthritis is a form of joint disorder that involves inflammation of one or more joints....
. - "Abdominal groans" refers to gastrointestinal symptoms of constipationConstipationConstipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, indigestion, nauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomitingVomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
. Hypercalcemia can lead to peptic ulcers and acute pancreatitisAcute pancreatitisAcute pancreatitis or acute pancreatic necrosis is a sudden inflammation of the pancreas. It can have severe complications and high mortality despite treatment...
. The peptic ulcers can be an effect of increased gastric acidGastric acidGastric acid is a digestive fluid, formed in the stomach. It has a pH of 1 to 2 and is composed of hydrochloric acid , and large quantities of potassium chloride and sodium chloride...
secretion by hypercalcemia, but may also be part of a multiple endocrine neoplasia type 1Multiple endocrine neoplasia type 1Multiple endocrine neoplasia type 1 or Wermer's syndrome is part of a group of disorders that affect the endocrine system.-Explanation:...
syndrome of both hyperparathyroid neoplasia and a gastrinomaGastrinomaA gastrinoma is a tumor in the pancreas or duodenum that secretes excess of gastrin leading to ulceration in the duodenum, stomach and the small intestine. There is hypersecretion of the HCl in the duodenum which causes the ulcers...
. - "Psychiatric moans" refers to effects on the central nervous systemCentral nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. Symptoms include lethargy, fatigue, depression, memory loss, psychosis, ataxia, delirium, and coma. - Left ventricular hypertrophyLeft ventricular hypertrophyLeft ventricular hypertrophy is the thickening of the myocardium of the left ventricle of the heart.-Causes:While ventricular hypertrophy occurs naturally as a reaction to aerobic exercise and strength training, it is most frequently referred to as a pathological reaction to cardiovascular...
. - Increased all-cause mortality
The German description of the same symptoms is "", literally "stone, bone, and stomach-pain".
Other signs include proximal muscle weakness, itching, and band keratopathy
Band keratopathy
Band keratopathy is a corneal disease derived from the appearance of calcium on the central cornea. This is an example of metastatic calcification, which by definition, occurs in the presence of hypercalcemia...
of the eyes.
However, when subjected to formal research, nonspecific symptoms, fatigue, musculoskeletal pain, constipation, depression, do not correlate with hypercalcemia.
Diagnosis
The diagnosis of primary hyperparathyroidism is made by blood tests.Serum calcium levels are elevated, and the parathyroid hormone level is abnormally high compared with an expected low level in response to the high calcium. A relatively elevated parathyroid hormone has been estimated to have a sensitivity
Sensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...
of 60%-80% and a specificity
Sensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...
of approximately 90% for primary hyperparathyroidism.
A more powerful variant of comparing the balance between calcium and parathyroid hormone is to perform a 3 hour calcium infusion. After infusion, a parathyroid hormone level above a cutoff of 14 ng/l has a sensitivity
Sensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...
of 100% and a specificity
Sensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...
of 93% in detecting primary hyperparathyroidism, with a confidence interval
Confidence interval
In statistics, a confidence interval is a particular kind of interval estimate of a population parameter and is used to indicate the reliability of an estimate. It is an observed interval , in principle different from sample to sample, that frequently includes the parameter of interest, if the...
of 80% to 100%.
The serum chloride/phosphate ratio is 33 or more in most patients with primary hyperparathyroidism. However, usage of thiazide
Thiazide
Thiazide is a term used to describe a type of molecule and a class of diuretics often used to treat hypertension and edema ....
medications have been reported to causes ratios above 33. Studies without any usage of thiazide diuretics have estimated a serum chloride/phosphate ratio to have a sensitivity of 94% or 95% and a specificity of 96% or 100%.
Urinary cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
is occasionally measured; this is generally elevated..
Causes
The most common cause of primary hyperparathyroidism is a sporadic, single parathyroid adenomaParathyroid adenoma
A parathyroid adenoma is a benign tumor of the parathyroid gland. It can cause hyperparathyroidism.CT scans or sestamibi parathyroid scintigraphy can be used in detection.It can be associated with Cyclin D1 expression....
resulting from a clonal mutation (~97%). Less common are parathyroid hyperplasia (~2.5%), parathyroid carcinoma
Parathyroid carcinoma
Parathyroid carcinoma is a rare cause of hypercalcemia. It forms in tissues of one or more of the parathyroid glands ....
(malignant tumor), and adenomas in more than one gland (together ~0.5%).
Primary hyperparathyroidism is also a feature of several familial endocrine disorders: Multiple endocrine neoplasia
Multiple endocrine neoplasia
The term multiple endocrine neoplasia encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign...
type 1 and type 2A (MEN type 1
Multiple endocrine neoplasia type 1
Multiple endocrine neoplasia type 1 or Wermer's syndrome is part of a group of disorders that affect the endocrine system.-Explanation:...
and MEN type 2A
Multiple endocrine neoplasia type 2
Multiple endocrine neoplasia type 2 is a group of medical disorders associated with tumors of the endocrine system. The tumors may be benign or malignant . They generally occur in endocrine organs Multiple endocrine neoplasia type 2 (also known as "Pheochromocytoma and amyloid producing medullary...
), and familial hyperparathyroidism.
Genetic associations include:
| OMIM | Name | Gene |
|---|---|---|
| HRPT1 | MEN1 MEN1 Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1.... , HRPT2 |
|
| HRPT2 | HRPT2 | |
| HRPT3 | unknown at 2p13.3-14 |
In all cases, the disease is idiopathic
Idiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...
, but is thought to involve inactivation of tumor suppressor gene
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
s (Menin
Menin
Menin may refer to:*Menin , office in Ancien Régime France*Umberto Menin, Italian artist*The French name for the Belgian town of Menen *Menin, a tumor suppressor associated with multiple endocrine neoplasia type 1....
gene in MEN1), or involve gain of function mutations (RET proto-oncogene
RET proto-oncogene
The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules....
MEN 2a).
Recently, it was demonstrated that liquidator
Liquidator (Chernobyl)
Liquidators , or "clean-up workers", is the name given in the former USSR to people who were called upon to work in efforts to deal with consequences of the April 26, 1986, Chernobyl disaster on the site of the event...
s of the Chernobyl
Chernobyl disaster
The Chernobyl disaster was a nuclear accident that occurred on 26 April 1986 at the Chernobyl Nuclear Power Plant in Ukraine , which was under the direct jurisdiction of the central authorities in Moscow...
power plant are faced with a substantial risk of primary hyperparathyroidism, possibly caused by radioactive strontium
Strontium
Strontium is a chemical element with the symbol Sr and the atomic number 38. An alkaline earth metal, strontium is a soft silver-white or yellowish metallic element that is highly reactive chemically. The metal turns yellow when exposed to air. It occurs naturally in the minerals celestine and...
isotope
Isotope
Isotopes are variants of atoms of a particular chemical element, which have differing numbers of neutrons. Atoms of a particular element by definition must contain the same number of protons but may have a distinct number of neutrons which differs from atom to atom, without changing the designation...
s.
Primary hyperparathyroidism can also result from pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
. It is apparently very rare, with only about 110 cases have so far been reported in world literature, but this is probably a considerable underestimate of its actual prevalence in pregnant women.
Complications
The classic bone disease in hyperparathyroidism is osteitis fibrosa cysticaOsteitis fibrosa cystica
Osteitis fibrosa cystica , abbreviated OFC, and also known as osteitis fibrosa, osteodystrophia fibrosa, not to be confused with Von Recklinghausen's disease of bone . Osteitis Fbrosa Cystica is a skeletal disorder caused by a surplus of parathyroid hormone from over-active parathyroid glands...
, which results in pain and sometimes pathological fractures. Other bone diseases associated with hyperparathyroidism are osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, osteomalacia
Osteomalacia
Osteomalacia is the softening of the bones caused by defective bone mineralization secondary to inadequate amounts of available phosphorus and calcium, or because of overactive resorption of calcium from the bone as a result of hyperparathyroidism...
, and arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
.
Medications
Medications include estrogen replacement therapy in postmenopausal women and bisphosphonateBisphosphonate
Bisphosphonates are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases...
s. Bisphosphonate
Bisphosphonate
Bisphosphonates are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases...
s may improve bone turnover.
Newer medications termed "calcimimetics" used in secondary hyperparathyroidism are now being used in Primary hyperparathyroidism. Calcimimetics reduce the amount of parathyroid hormone released by the parathyroid glands. They are recommended in patients in whom surgery is inappropriate.
Surgery
The symptoms of the disease, listed above, are indications for surgery. Surgery reduces all cause mortality as well as resolving symptoms. However, cardiovascular mortality is not significantly reduced.A consensus statement in 2002 recommended the following indications for surgery in asymptomatic hyperparathyroidism:
- Serum calcium: 1.0 mg/dl above upper limit of normal
- 24-h urinary calcium >400 mg
- Creatinine clearance reduced by 30% compared with age-matched subjects.
- Bone mineral density t-score <−2.5 at any site
- Age <50
More recently, three randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
s have studied the role of surgery in patients with asymptomatic hyperparathyroidism. The largest study reported that surgery showed increase in bone mass, but no improvement in quality of life after one to two years among patients with:
- Untreated, asymptomatic primary hyperparathyroidism
- Serum calcium between 2.60–2.85 mmol/liter (10.4–11.4 mg/dl)
- Age between 50 and 80 yr
- No medications interfering with Ca metabolism
- No hyperparathyroid bone disease
- No previous operation in the neck
- Creatinine level < 130 µmol/liter (<1.47 mg/dl)
Two other trials
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
reported improvements in bone density and some improvement in quality of life with surgery.
Non-invasive treatment
The French company Theraclion developed a new device named “TH-One” for the non-invasive treatment (no scars) of fine endocrine targets such as thyroid nodules and parathyroids.TH-One uses High Intensity Focused Ultrasound (HIFU), which is a process that allows the delivery of a large amount of acoustic energy to a confined space resulting in localized tissue necrosis.
The TH-One enables to treat primary hyperparathyroidism by ablating the adenoma. It also allows to lower in a control manner the PTH level for secondary hyperparathyroidism
Secondary hyperparathyroidism
Secondary hyperparathyroidism refers to the excessive secretion of parathyroid hormone by the parathyroid glands in response to hypocalcemia and associated hypertrophy of the glands. This disorder is especially seen in patients with chronic renal failure...
patients. It is scar-less, totally non invasive.
Future therapies
Future developments such as calcimemetic agents (e.g. cinacalcetCinacalcet
Cinacalcet is a drug that acts as a calcimimetic by allosteric activation of the calcium-sensing receptor that is expressed in various human organ tissues. It is sold by Amgen under the trade name Sensipar in North America and Australia and as Mimpara in Europe...
) which activate the parathyroid calcium-sensing receptor
Calcium-sensing receptor
The calcium-sensing receptor is a Class C G-protein coupled receptor which senses extracellular levels of calcium ion. In the parathyroid gland, the calcium-sensing receptor controls calcium homeostasis by regulating the release of parathyroid hormone .-Signal transduction:The release of PTH is...
may offer a good alternative to surgery.
External links
- Non-Invasive Parathyroid Surgery at Theraclion