| Hyperparathyroidism | |
|---|---|
 | |
| 3D diagram of hyperparathyroidism | |
| Specialty | Endocrinology |
| Symptoms | None,kidney stones, weakness, depression, bone pains, confusion, increased urination[1][2][3] |
| Complications | Osteoporosis[2][3] |
| Usual onset | 50 to 60[2] |
| Types | Primary, secondary |
| Causes | Primary:parathyroid adenoma, multiple benign tumors,parathyroid cancer[1][2] Secondary:vitamin D deficiency,chronic kidney disease,low blood calcium[1] |
| Diagnostic method | High blood calcium and high PTH levels[2] |
| Treatment | Monitoring, surgery,intravenous normal saline,cinacalcet[1][2] |
| Frequency | ~2 per 1,000[3] |
Hyperparathyroidism is an increase inparathyroid hormone (PTH) levels in theblood.[1][4] This occurs from a disorder either within theparathyroid glands (primary hyperparathyroidism) or as response to external stimuli (secondary hyperparathyroidism).[1] Symptoms of hyperparathyroidism are caused by inappropriatelyelevated blood calcium excreted from the bones into the blood stream in response to increased production of parathyroid hormone.[1] In healthy people, when blood calcium levels are high, parathyroid hormone levels should be low. With long-standing hyperparathyroidism, the most common symptom iskidney stones.[1] Other symptoms may include bone pain, weakness, depression, confusion, and increased urination.[1][2] Both primary and secondary may result inosteoporosis (weakening of the bones).[2][3]
In 80% of cases, primary hyperparathyroidism is due to a singlebenign tumor known as aparathyroid adenoma.[1][2] Most of the remainder are due to several of these adenomas.[1][2] Very rarely it may be due toparathyroid cancer.[2] Secondary hyperparathyroidism typically occurs due tovitamin D deficiency,chronic kidney disease, or other causes oflow blood calcium.[1] The diagnosis of primary hyperparathyroidism is made by finding elevated calcium and PTH in the blood.[2]
Primary hyperparathyroidism may only be cured by removing the adenoma or overactive parathyroid glands.[5][1][2] In asymptomatic patients who present with mildly elevated blood calcium levels, with otherwise normal kidneys, and with normalbone density, monitoring may be all that is required.[2] The medicationcinacalcet may also be used to decrease PTH levels in those unable to have surgery although it is not a cure.[2] In patients with very high blood calcium levels, treatment may include large amounts ofintravenous normal saline.[1] Low vitamin D should be corrected in those with secondary hyperparathyroidism but low Vitamin D pre-surgery is controversial for those with primary hyperparathyroidism.[6] Low vitamin D levels should be corrected post-parathyroidectomy.[2]
In primary hyperparathyroidism, about 75% of people are "asymptomatic".[1] While most primary patients are asymptomatic at the time of diagnosis, 'asymptomatic' is poorly defined and represents only those without "obvious clinical sequelae" such as kidney stones, bone disease, or hypercalcemic crisis.[5] These "asymptomatic" patients may have other symptoms such as depression, anxiety, gastrointestinal distress, and neuromuscular problems that are not counted as symptoms.[5] The problem is often picked up incidentally duringblood work for other reasons, and the test results show a higher amount of calcium in the blood than normal.[3] Many people only havenon-specific symptoms.[7]
Common manifestations of hypercalcemia includeconstipation,vomiting, weakness, lethargy, fatigue, depression, bone pain, muscle soreness (myalgias), joint pain, decreased appetite, feelings ofnausea, abdominal pain,pancreatitis,polyuria,polydipsia, cognitive impairment,kidney stones ([nb 1]), vertigo andosteopenia orosteoporosis.[10][11] A history of acquiredracquet nails (brachyonychia) may be indicative of bone resorption.[12] Radiographically, hyperparathyroidism has a pathognomic finding of rugger jersey spine.[13] Parathyroid adenomas are very rarely detectable on clinical examination. Surgical removal of a parathyroid tumor eliminates the symptoms in most patients.[citation needed]
In secondary hyperparathyroidism due to lack of vitamin D absorption, the parathyroid gland is behaving normally; clinical problems are due to bone resorption and manifest as bone syndromes such asrickets,osteomalacia, andrenal osteodystrophy.[14]
Causes of primary hyperparathyroidism include parathyroid adenoma (80% of patients), multiglandular disease usually seen as hyperplasia of the 4 parathyroid glands (15–20% of patients), parathyroid carcinoma (less than 1% of patients).[15] Primary hyperparathyroidism occurs sporadically and most patients do not have afamily history.[15] Radiation exposure increases the risk of primary hyperparathyroidism.[1] Additional risk factors includelithium[16] andthiazide diuretics[17] exposure. A number of genetic conditions includingmultiple endocrine neoplasia syndromes, hyperparathyroidism-jaw tumor syndrome,[18]familial hypocalciuric hypercalcemia,[19] neonatal severe hyperparathyroidism also increase the risk.[1]Parathyroid adenomas have been linked withDDT although a causal link has not yet been established.[20] The most common causes for secondary hyperparathyroidism include vitamin D deficiency, chronic kidney disease, inadequate calcium intake,malabsorption.[21] Tertiary hyperparathyroidism most commonly occurs from prolonged secondary hyperparathyroidism.[22]
The parathyroid is composed of 4 glands with 2 located superiorly and 2 located inferiorly.[23] The parathyroid glands are located on the posteriorthyroid and are derived from theendoderm of the 3rd and 4thpharyngeal pouches.[23] Specifically, theinferior parathyroid glands are derived from the 3rd pharyngeal pouch and thesuperior parathyroid glands are derived from the 4th pharyngeal pouch dorsal wing.[24] Theultimopharyngeal body is derived from the 4th pharyngeal pouch ventral wing and theparafollicular cells ( C-cells) are derived when the ultimopharyngeal bodies fuse with the posterolateral thyroid.[24] The parathyroid glands separates from the pharyngeal wall and attaches to the posterior thyroid during the 7th week ofhuman embryonic development.[23]
Normal parathyroid glands measure theionized 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.[8]
Rapid PTH regulation is controlled by the parathyroidG-protein coupled,calcium sensing receptors which responds to fluctuations in serum calcium levels.[25] Alternatively, prolonged changes in serum calcium influences mRNA-binding proteins altering the encoding of PTH mRNA.[26] There are also calcium independent mechanisms which include repression of PTH transcription through1α,25-dihydroxyvitamin D binding with thevitamin D receptor.[26] Furthermore, 1α,25-dihydroxyvitamin D also has an impact on the expression of calcium-sensing receptors, indirectly affecting PTH secretion.[26]
Effects of PTH on the Bones
PTH stimulates the bones to release calcium through multiple mechanisms. 1) PTH stimulatesosteoblasts which increase expression ofRANKL which causes differentiation of the osteoblasts intoosteocytes.[27] 2) PTH inhibits secretion ofosteoprotegerina to allow forosteoclast differentiation.[27] 3) PTH will also directly activate osteoclasts to cause bone resorption through degradation ofhydroxyapatite and organic material.[27] This then causes bone to release calcium into the blood.
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Effects of PTH on the Kidneys
Calcium reabsorption in the nephron occurs inproximal convoluted tubule and at theascending Loop of Henle.[28] PTH acts on thedistal convoluted tubule andcollecting duct to increase calcium reabsorption in thenephron.[28] PTH also acts on the proximal convoluted tubule to decreasephosphate reabsorption to lower the serum phosphate.[28] This decreases formation of insoluble calcium phosphate salts leading to an increase in serum ionized calcium.
Effects of PTH on the Small Intestines
PTH stimulates the production of1-alpha-hydroxylase in the proximal convoluted tubule.[28] This enzyme activation hydroxylates inactive25-hydroxycholecalciferol to active vitamin D(1, 25 dihydroxycholecalciferol).[28] Active vitamin D allows for calcium absorption throughtranscellular andparacellular pathways.[28]
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 the1,25 dihydroxyvitamin D3 levels in the blood are low andhypocalcemia is present. A lack of 1,25 dihydroxyvitamin D3 can result from a deficient dietary intake ofvitamin D, or from a lack of exposure of the skin to sunlight, so the body cannot make its own vitamin D from cholesterol.[29] The resultinghypovitaminosis D is usually due to a partial combination of both factors. Vitamin D3 (orcholecalciferol) is converted to 25-hydroxyvitamin D (orcalcidiol) by the liver, from where it is transported via the circulation to the kidneys, and it is converted into the active hormone, 1,25 dihydroxyvitamin D3.[8][29] Thus, a third cause of secondary hyperparathyroidism ischronic kidney disease. Here the ability to manufacture 1,25 dihydroxyvitamin D3 is compromised, resulting in hypocalcemia.[citation needed]
The gold standard of diagnosis is the PTHimmunoassay. Once an elevated PTH has been confirmed, the goal of diagnosis is to determine the type of hyperparathyroidism (primary, secondary, or tertiary hyperparathyroidism) by obtaining a serumcalcium, phosphate, and PTH levels.
| Serum calcium | Phosphate | Vitamin D Level | PTH | Likely type |
|---|---|---|---|---|
| ↑ | ↓ | ↑ | ↑/↔ | Primary hyperparathyroidism[30] |
| ↓/↔ | ↑ | ↓ | ↑ | Secondary hyperparathyroidism[30] |
| ↑ | ↑ | ↓ | ↑ | Tertiary hyperparathyroidism[31] |
Primary hyperparathyroidism has highcalcium,vitamin D, andPTH levels and a lowphosphate level.[30][31] Secondary hyperparathyroidism has low serum calcium and vitamin D levels, and high phosphate and PTH levels.[30][31] Tertiary hyperparathyroidism has high serum calcium, phosphate, and PTH and low vitamin D levels.[30][31] Tertiary hyperparathyroidism is differentiated from primary hyperparathyroidism by a history ofchronic kidney failure and secondary hyperparathyroidism.[citation needed]
Hyperparathyroidism can causehyperchloremia and increase renalbicarbonate loss, which may result in a normal anion gap metabolic acidosis.[32] ALP level can be elevated due to bone turnover. Additionally further tests can be completed to rule out other causes and complications of hyperparathyroidism including a24-hour urinary calcium for familial hypocalciuric hypercalcemia,DEXA scan to evaluate forosteoporosis,osteopenia, orfragility fractures, and genetic testing.[33][34][35][36] Additionally aCT scan without contrast orrenal ultrasound can be done to assess fornephrolithiasis and/ornephrocalcinosis if there is concern for it.[36]
Differential diagnoses of hypercalcemia include humoral hypercalcemia of malignancy, renal failure, malignant bone destruction (such asmultiple myeloma, metastaticbreast cancer,lymphoma), thiazide diuretics, lithium, immobilization,hyperthyroidism,milk alkali syndrome, multiple endocrine adenomatosis syndromes, andgranulomatous diseases.[37] Additionally,familial benign hypocalciuric hypercalcamia can present with similar lab changes.[1] In this condition, the calcium creatinine clearance ratio, however, is typically under 0.01 due to the low levels urine calcium.[1]
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 isintact 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 kidney dysfunction.[citation needed] Intact PTH blood tests may be falsely low if biotin has been ingested in the previous few days prior to the blood test.[38]
In cases of primary hyperparathyroidism or tertiary hyperparathyroidism, heightened PTH leads to increased serum calcium (hypercalcemia) due to:[citation needed]
In primary hyperparathyroidism, serum phosphate levels are abnormally low as a result of decreased reabsorption of phosphate in the kidney tubules. However, this is only present in about 50% of cases. This contrasts withsecondary hyperparathyroidism and tertiary hyperparathyroidism, in which serum phosphate levels are generally elevated because of kidney disease.[citation needed]
Alkaline phosphatase levels are usually high in hyperparathyroidism due to high bone turn over. In primary hyperparathyroidism, levels may remain within the normal range, but this is inappropriately normal given the increased levels of plasma calcium.[citation needed]
Nuclear medicine imaging methods are used by surgeons to locate which parathyroid gland is responsible for hyperparathyroidism or to findectopic parathyroid adenomas, most commonly found in the anteriormediastinum.[citation needed] Historically,technetium sestamibi scintigraphy was the main method used or this indication.[39] Recently 18F-fluorocholinePET/CT tend to be more and more performed due to excellent diagnostic performance.[40][41]
Primary hyperparathyroidism results from ahyperfunction of theparathyroid glands themselves. The oversecretion of PTH is due to aparathyroid adenoma,parathyroid hyperplasia, or rarely, aparathyroid carcinoma. This disease is often characterized by the quartetstones, bones, groans, and psychiatric overtones referring to the presence ofkidney stones, hypercalcemia, constipation, andpeptic ulcers, as well asdepression, respectively.[42][43]
In a minority of cases, this occurs as part of amultiple endocrine neoplasia (MEN) syndrome, eithertype 1 (caused by a mutation in the geneMEN1) ortype 2a (caused by a mutation in the geneRET), which is also associated with the adrenal tumorpheochromocytoma. Other mutations that have been linked to parathyroid neoplasia include mutations in the genesHRPT2 andCASR.[44][45]
Patients withbipolar disorder who are receiving long-termlithium treatment are at increased risk for hyperparathyroidism.[46] 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 leads tohypercalcemia in about 4% of lithium-treated patients.[47]Calcium levels should be checked for patients undergoing long-term lithium treatment.[47] Lithium-associated hyperparathyroidism is usually caused by a single parathyroid adenoma.[46]
Secondary hyperparathyroidism is due to physiological (i.e. appropriate) secretion ofparathyroid hormone (PTH) by theparathyroid glands in response tohypocalcemia (lowbloodcalcium levels). The most common causes arevitamin D deficiency[48] (caused by lack of sunlight, diet or malabsorption) andchronic kidney failure.[citation needed] Vitamin D deficiency can result from malabsorption or decreased vitamin D intake such as withgastric bypass, small bowel disease,pancreatic disease, anddietary causes.[49] Other causes include decreased skin synthesis of vitamin D such as decreased exposure to sunlight and skin disorders. Insufficient vitamin D synthesis such as defective 25-hydroxylation,1-alpha hydroxylase, and 1-alpha 25-hydroxylation can also contribute to vitamin D deficiency.
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 kidney failure is termedrenal osteodystrophy.[50]
Tertiary hyperparathyroidism is seen in those 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 end-stage kidney disease and is an autonomous activity.[51] Patients with late-stage kidney disease have an increased likelihood of developing tertiary hyperparathyroidism if not promptly corrected.[52] In patients with late-stage kidney disease phosphate levels are elevated which directly affects the parathyroid glands and increases PTH production. Additionally, studies have shown that even in the absence of secondary hyperparathyroidism, those with X-Linked hypophosphatemia rickets who are on phosphate treatment are more susceptible to developing tertiary hyperparathyroidism.[53]
Treatment depends on the type of hyperparathyroidism encountered.
Parathyroidectomy is a curative therapy for symptomatic hyperparathyroidism. Additionally, it decreases the risk ofnephrolithiasis,osteoporosis,fragility fractures, and improvesbone mineral density. Studies have also found that parathyroidectomy for hyperparathyroidism improvesfatigue,weakness,depression, and memory. While parathyroidectomy is recommended for all patients with hyperparathyroidism who are symptomatic, indications ofsurgery for those who are asymptomatic include the following:[54]
A 2020Cochranesystematic review compared the surgical procedures of minimally invasiveparathyroidectomy and classically used bilateral neck exploration, however it did not find one approach to be superior to the other in either benefits or risks.[55]
Surgery can rarely result inhypoparathyroidism.[citation needed]
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 (usuallyvitamin D deficiency orchronic kidney failure). If this is successful, PTH levels return to normal levels, unless PTH secretion has becomeautonomous (tertiary hyperparathyroidism).[51]Hyperphosphatemia may be treated by decreasing dietary intake of phosphate. If phosphate remains persistently elevated above 5.5 mg/dL with dietary restriction, thenphosphate binders may be used.[56] Vitamin D deficiency may be treated with vitamin D supplementation. However in patients with chronic kidney disease, patients should not receive vitamin D supplementation if they are elevated serum phosphate levels or have hypercalcemia.[57]
Parathyroidectomy is indicated in tertiary hyperparathyroidism for patients who have severeosteopenia, severe persistenthypercalcemia (>11.0 mg/ dL),calciphylaxis, bone pain, or pathological fracture.[58] A systematic review found surgical treatment to be superior regarding cure rates than medical therapy withcinacalcet with lower risk of complications.[59]
Acalcimimetic (such ascinacalcet) 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.[60][61] Treatment of secondary hyperparathyroidism with a calcimimetic in those on dialysis for CKD does not alter the risk of early death; however, it does decrease the likelihood of needing a parathyroidectomy.[62] Treatment carries the risk of low blood calcium levels andvomiting.[62]
In thedeveloped world, between one and four per thousand people are affected.[3] Primary hyperparathyroidism is the most common type.[1] Certain exposures increase the risk of developing primary hyperparathyroidism such as sex and age. It occurs three times more often in women than men and is often diagnosed between the ages of 50 and 60 but is not uncommon before then.[2] The disease was first described in the 1700s.[32] In the late 1800s, it was determined to be related to the parathyroid.[32] Surgery as a treatment was first carried out in 1925.[32] The United States prevalence of primary hyperparathyroidism from 2010 was 233 per 100,000 women and 85 per 100,000 men. Black and white women aged 70–79 have the highest overall prevalence.[63] Secondary hyperparathyroidism is most commonly caused bychronic kidney disease andvitamin D deficiency.[64] The prevalence of vitamin D deficiency is about 50% of the world population and chronic kidney disease prevalence is 15% of the United States population.[52]
The oldest known case was found in a cadaver from an EarlyNeolithic cemetery in southwest Germany.[65]
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.
"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.
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