Hyperparathyroidism
Encyclopedia
Hyperparathyroidism is overactivity of the parathyroid gland
s resulting in excess production of parathyroid hormone
(PTH). The parathyroid hormone regulates calcium and phosphate levels and helps to maintain these levels. Excessive PTH secretion may be due to problems in the glands themselves, in which case it is referred to as primary hyperparathyroidism and which leads to hypercalcemia (raised calcium levels). It may also occur in response to low calcium levels, as encountered in various situations such as vitamin D deficiency
or chronic kidney disease; this is referred to as secondary hyperparathyroidism. In all cases, the raised PTH levels are harmful to bone
, and treatment is often needed. Recent evidence suggests that Vitamin D
deficiency/insufficiency plays a role in the development of hyperparathyroidism. Lithium is associated with an increased incidence of 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.
is the reaction of the parathyroid glands to a hypocalcemia caused by something other than a parathyroid pathology, e.g. chronic renal failure.
result from 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.
removal of primary hyperparathyroidism, when it has led to renal damage that now again causes a form of secondary (quartary) hyperparathyroidism that may itself result in autonomy (quintary hyperparathyoidism).. Additionally, quartary hyperparathyroidism may ensue from hungry bone syndrome after parathyroidectomy
.
, polydipsia, cognitive impairment, kidney stone
s and osteoporosis
. Surgical removal of a parathyroid tumor will eliminate the symptoms in most patients.
s as they lack a PTH receptor. Instead, PTH stimulates osteoblasts, which in turn increases their expression of RANKL
. RANKL
is then able to bind osteoclasts which stimulates their activation which ultimately leads to the removal of calcium from the bones. Thus, the high calcium in the blood comes partly from the bones as well as from increased renal reabsorption. Removing the offending parathyroid gland will restore normal bone density over several years.
Elevated ionized (Ca++) calcium may be a more reliable indicator of hyperparathyroidism.
By contrast, in secondary hyperparathyroidism effectiveness of PTH is reduced.
levels are usually elevated in hyperparathyroidism. In primary hyperthyroidism, levels may remain within the normal range, however this is 'inappropriately normal' given the increased levels of plasma calcium.
which is performed to identify hyperparathyroidism (or parathyroid adenoma
). It is used by surgeons to locate ectopic parathyroid adenomas, most commonly found in the anterior mediastianum.
is due to excessive secretion of parathyroid hormone
(PTH) by the parathyroid gland
s in response to hypocalcemia (low blood
calcium
levels) and/or hyperphosphatemia
(high blood
phosphate
levels), usually due to chronic renal failure
. The bone disease in secondary parathyroidism along with renal failure is termed renal osteodystrophy
.
Patients with bipolar disorder who are receiving long-term lithium treatment are at increased risk for hyperparathyroidism. 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.
, the hypertrophied parathyroid glands can become autonomously functioning and continue to secrete PTH
independent of whether the original stimuli to secrete PTH are still present.
level:
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.
Testing for hyperparathryroidism:
) is a new type of drug to be considered as a potential therapy for some people with primary and secondary hyperparathyroidism on dialysis. It is recognised by the body as if it is calcium, in other words, it mimics the effect of calcium in your tissues. This tricks your body into thinking there is more calcium in the blood which reduces PTH release from parathyroid glands, leading to lower calcium and phosphorus levels in your blood. Calcimimetics control PTH release from parathyroid glands without increasing calcium and phosphorus levels. The most common side effects of calcimimetics are mild or moderate nausea and vomiting.
, 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.
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 resulting in excess production of parathyroid hormone
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). The parathyroid hormone regulates calcium and phosphate levels and helps to maintain these levels. Excessive PTH secretion may be due to problems in the glands themselves, in which case it is referred to as primary hyperparathyroidism and which leads to hypercalcemia (raised calcium levels). It may also occur in response to low calcium levels, as encountered in various situations such as vitamin D deficiency
Hypovitaminosis D
Hypovitaminosis D is a deficiency of Vitamin D. It can result from: inadequate nutritional intake of vitamin D coupled with inadequate sunlight exposure , disorders that limit vitamin D absorption, and conditions that impair the conversion of vitamin D into active metabolites including certain...
or chronic kidney disease; this is referred to as secondary hyperparathyroidism. In all cases, the raised PTH levels are harmful to bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
, and treatment is often needed. Recent evidence suggests that Vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
deficiency/insufficiency plays a role in the development of hyperparathyroidism. Lithium is associated with an increased incidence of hyperparathyroidism.
Primary
Primary hyperparathyroidismPrimary hyperparathyroidism
Primary hyperparathyroidism causes hypercalcemia through the excessive secretion of parathyroid hormone , usually by an adenoma of the parathyroid glands.-Epidemiology:...
results from a hyperfunction of the parathyroid glands themselves. There is oversecretion of PTH due to 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...
, hyperplasia
Hyperplasia
Hyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
or, rarely, carcinoma
Carcinoma
Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
of the parathyroid glands.
Secondary
Secondary hyperparathyroidismSecondary 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...
is the reaction of the parathyroid glands to a hypocalcemia caused by something other than a parathyroid pathology, e.g. chronic renal failure.
Tertiary
Tertiary hyperparathyroidismTertiary hyperparathyroidism
Tertiary hyperparathyroidism is a state of excessive secretion of parathyroid hormone after a long period of secondary hyperparathyroidism and resulting hypercalcemia...
result from 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.
Quartary and Quintary
Quartary and quintary are rare conditions that may be observed after surgicalSurgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
removal of primary hyperparathyroidism, when it has led to renal damage that now again causes a form of secondary (quartary) hyperparathyroidism that may itself result in autonomy (quintary hyperparathyoidism).. Additionally, quartary hyperparathyroidism may ensue from hungry bone syndrome after parathyroidectomy
Parathyroidectomy
Also known as "Parathyroid gland removal", Parathyroidectomy is the surgical removal of one or more parathyroid glands. This procedure is used to remove primary tumors or hyperplasia of the glands, especially when they produce excessive parathyroid hormone. As drugs such as Fosamax do not treat the...
.
Symptoms and signs
Some may present without symptoms. Of those patients who do present with symptoms, they are commonly associated with the effects of an increased level of calcium. Since calcium is involved in trans-synaptic communication in the nervous system, high blood calcium levels have a direct effect on the nervous system. Thus, most of the symptoms of parathyroid disease are "neurological" in origin. Common manifestations of hyperparathyroidism include weakness and fatigue, depression, bone pain, muscle soreness (myalgias), decreased appetite, feelings of nausea and vomiting, constipation, polyuriaPolyuria
Polyuria is a condition usually defined as excessive or abnormally large production or passage of urine . Frequent urination is sometimes included by definition, but is nonetheless usually an accompanying symptom...
, polydipsia, cognitive impairment, kidney stone
Kidney stone
A kidney stone, also known as a renal calculus is a solid concretion or crystal aggregation formed in the kidneys from dietary minerals in the urine...
s and 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...
. Surgical removal of a parathyroid tumor will eliminate the symptoms in most patients.
Osteomalacia
Osteomalacia associated with hyperparathyroidism is caused by the high parathyroid hormone secreted by overactive parathyroid gland(s). Excess parathyroid hormone (PTH) acts indirectly on osteoclastOsteoclast
An osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption. Osteoclasts were discovered by Kolliker in 1873...
s as they lack a PTH receptor. Instead, PTH stimulates osteoblasts, which in turn increases their expression of RANKL
RANKL
Receptor activator of nuclear factor kappa-B ligand , also known as tumor necrosis factor ligand superfamily member 11 , TNF-related activation-induced cytokine , osteoprotegerin ligand , and osteoclast differentiation factor , is a protein that in humans is encoded by the TNFSF11 gene.RANKL is...
. RANKL
RANKL
Receptor activator of nuclear factor kappa-B ligand , also known as tumor necrosis factor ligand superfamily member 11 , TNF-related activation-induced cytokine , osteoprotegerin ligand , and osteoclast differentiation factor , is a protein that in humans is encoded by the TNFSF11 gene.RANKL is...
is then able to bind osteoclasts which stimulates their activation which ultimately leads to the removal of calcium from the bones. Thus, the high calcium in the blood comes partly from the bones as well as from increased renal reabsorption. Removing the offending parathyroid gland will restore normal bone density over several years.
Intact PTH
In primary hyperparathyroidism, parathyroid hormone (PTH) levels will be 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 is intended to detect 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.Serum calcium or Ionized Calcium (Ca++)
In cases of primary hyperparathyroidism or tertiary hyperparathyroidism heightened PTH leads to increased serum calcium (hypercalcemia) due to:- increased bone resorption, allowing flow of calcium from bone to blood
- reduced renal clearance of calcium
- increased intestinal calcium absorption
Elevated ionized (Ca++) calcium may be a more reliable indicator of hyperparathyroidism.
By contrast, in secondary hyperparathyroidism effectiveness of PTH is reduced.
Serum phosphate
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
Alkaline phosphataseAlkaline phosphatase
Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...
levels are usually elevated in hyperparathyroidism. In primary hyperthyroidism, levels may remain within the normal range, however this is 'inappropriately normal' given the increased levels of plasma calcium.
Technetium sestamibi
A sestamibi scan is a procedure in nuclear medicineNuclear medicine
In nuclear medicine procedures, elemental radionuclides are combined with other elements to form chemical compounds, or else combined with existing pharmaceutical compounds, to form radiopharmaceuticals. These radiopharmaceuticals, once administered to the patient, can localize to specific organs...
which is performed to identify hyperparathyroidism (or parathyroid adenoma
Parathyroid 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....
). It is used by surgeons to locate ectopic parathyroid adenomas, most commonly found in the anterior mediastianum.
Primary
- The most common cause of primary hyperparathyroidismPrimary hyperparathyroidismPrimary hyperparathyroidism causes hypercalcemia through the excessive secretion of parathyroid hormone , usually by an adenoma of the parathyroid glands.-Epidemiology:...
is a benign parathyroid adenomaParathyroid adenomaA 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....
that loses its sensitivity to circulating calcium levels. Usually, only one of the four parathyroid glands is affected. - A less common cause is from multiple endocrine neoplasiaMultiple endocrine neoplasiaThe 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...
(MEN), either 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:...
(caused by a mutation in the gene MEN1MEN1Menin 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....
) or type 2a (caused by a mutation in the gene RETRET proto-oncogeneThe RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules....
). Other mutations that have been linked to parathyroid neoplasia include mutations in the genes HRPT2, and CASRCalcium-sensing receptorThe 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...
.
Secondary
Secondary hyperparathyroidismSecondary 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...
is due to excessive secretion of parathyroid hormone
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) by 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 in response to hypocalcemia (low blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
levels) and/or hyperphosphatemia
Hyperphosphatemia
Hyperphosphatemia is an electrolyte disturbance in which there is an abnormally elevated level of phosphate in the blood. Often, calcium levels are lowered due to precipitation of phosphate with the calcium in tissues.-Signs and symptoms:...
(high blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
levels), usually due to chronic renal failure
Chronic renal failure
Chronic kidney disease , also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite...
. The bone disease in secondary parathyroidism along with renal failure is termed renal osteodystrophy
Renal osteodystrophy
Renal osteodystrophy or chronic kidney disease-mineral and bone disorder is a bone pathology, characterized by bone mineralization deficiency, that is a direct result of the electrolyte and endocrine derangements that accompany chronic kidney disease...
.
Patients with bipolar disorder who are receiving long-term lithium treatment are at increased risk for hyperparathyroidism. 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.
Tertiary
Tertiary hyperparathyroidism, quartary and quintary hyperparathyroidism are rare forms that are caused by long lasting disorders of the calcium feedback control system. In cases of long-standing secondary hyperparathyroidismSecondary 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...
, the hypertrophied parathyroid glands can become autonomously functioning and continue to secrete PTH
Parathyroid hormone
Parathyroid hormone , parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids...
independent of whether the original stimuli to secrete PTH are still present.
Diagnosis
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 calciumCalcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
level:
| PTH | serum calcium | likely type >- | high |
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.
Treatment and monitoring
Endocrinologists diagnose diseases affecting glands and should be consulted for hyperparathyroidism. Treatment for the three different types of hyperparathyroidism vary. Generally treatment is first and foremost directed at hypercalcemia; if symptomatic, patients are sent for surgery to remove the parathyroid tumor (parathyroid adenoma) or parathyroid gland (see hypercalcemia). Most experts now believe that almost all patients with hyperparathyroidism should be evaluated for surgery. If hyperparathyroidism is caused by a tumor, it will almost always progress as the tumor grows.Testing for hyperparathryroidism:
- Calcium level
- Bone density
- Vitamin D
- Phosphorus
Calcimimetics
A calcimimetic (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...
) is a new type of drug to be considered as a potential therapy for some people with primary and secondary hyperparathyroidism on dialysis. It is recognised by the body as if it is calcium, in other words, it mimics the effect of calcium in your tissues. This tricks your body into thinking there is more calcium in the blood which reduces PTH release from parathyroid glands, leading to lower calcium and phosphorus levels in your blood. Calcimimetics control PTH release from parathyroid glands without increasing calcium and phosphorus levels. The most common side effects of calcimimetics are mild or moderate nausea and vomiting.
History
Hyperparathyroidism was first described and treated in the 1930s by Fuller Albright of Massachusetts General HospitalMassachusetts General Hospital
Massachusetts General Hospital is a teaching hospital and biomedical research facility in the West End neighborhood of Boston, Massachusetts...
, working at the Mallinckrodt General Clinical Research Center
Mallinckrodt General Clinical Research Center
The Mallinckrodt MGH General Clinical Research Center is a research center at Massachusetts General Hospital. It is located in Boston, Massachusetts, with satellites in Cambridge, MA and Charlestown, MA. It is supported by a GCRC grant through the National Institutes of Health.-History:The MGH...
. The oldest known case was found in a cadaver from an Early Neolithic
Neolithic
The Neolithic Age, Era, or Period, or New Stone Age, was a period in the development of human technology, beginning about 9500 BC in some parts of the Middle East, and later in other parts of the world. It is traditionally considered as the last part of the Stone Age...
cemetery in southwest Germany.
External links
- Description of parathyroid disease and Minimally Invasive Parathyroid Surgery from the World Experts at www.parathyroid.com
- Non-Invasive Parathyroid Surgery at Theraclion
- Section on parathyroid disease at endocrineweb.com
- www.bucksendocrine.com Minimal access parathyroid surgery by a UK specialist surgeon
- Parathyroid surgery information and resources at www.advancedparathyroid.com
- Overview at Endocrine and Metabolic Diseases Information ServiceEndocrine and Metabolic Diseases Information ServiceThe Endocrine and Metabolic Diseases Information Service is an information dissemination service of the National Institute of Diabetes and Digestive and Kidney Diseases . The NIDDK is part of the National Institutes of Health, which is part of the U.S...