Hyperparathyroidism is an increase in parathyroid hormone (PTH) levels in the blood. This occurs from a disorder either within the parathyroid glands (primary hyperparathyroidism) or as response to external stimuli (secondary hyperparathyroidism). Symptoms of hyperparathyroidism are caused by inappropriately elevated blood calcium excreted from the bones into the blood stream in response to increased production of parathyroid hormone. In healthy people, when blood calcium levels are high, parathyroid hormone levels should be low. With long-standing hyperparathyroidism, the most common symptom is kidney stones. Other symptoms may include bone pain, weakness, depression, confusion, and increased urination. Both primary and secondary may result in osteoporosis (weakening of the bones).
In 80% of cases, primary hyperparathyroidism is due to a single benign tumor known as a parathyroid adenoma. Most of the remainder are due to several of these adenomas. Very rarely it may be due to parathyroid cancer. Secondary hyperparathyroidism typically occurs due to vitamin D deficiency, chronic kidney disease, or other causes of low blood calcium. The diagnosis of primary hyperparathyroidism is made by finding elevated calcium and PTH in the blood.
Primary hyperparathyroidism may only be cured by removing the adenoma or overactive parathyroid glands, known as parathyroidectoy. In asymptomatic patients who present with mildly elevated blood calcium levels, with otherwise normal kidneys, and with normal bone density, monitoring may be all that is required. The medication cinacalcet may also be used to decrease PTH levels in those unable to have surgery although it is not a cure. In patients with very high blood calcium levels, treatment may include large amounts of intravenous normal saline. Low vitamin D should be corrected in those with secondary hyperparathyroidism but low Vitamin D pre-surgery is controversial for those with primary hyperparathyroidism. Low vitamin D levels should be corrected post-parathyroidectomy.
Signs and symptoms In primary hyperparathyroidism, about 75% of people are "asymptomatic". 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. These "asymptomatic" patients may have other symptoms such as depression, anxiety, gastrointestinal distress, and neuromuscular problems that are not counted as symptoms. The problem is often picked up incidentally during blood work for other reasons, and the test results show a higher amount of calcium in the blood than normal. Many people only have non-specific symptoms.
Common manifestations of hypercalcemia include constipation, vomiting, weakness, lethargy, fatigue, depression, bone pain, muscle soreness (myalgias), joint pain, decreased appetite, feelings of nausea, abdominal pain, pancreatitis, polyuria, polydipsia, cognitive impairment, kidney stones (), vertigo and osteopenia or osteoporosis.Hyperparathyroidism . National Endocrine and Metabolic Diseases Information Service. May 2006. A history of acquired racquet nails (brachyonychia) may be indicative of bone resorption. Radiographically, hyperparathyroidism has a pathognomic finding of rugger jersey spine. Parathyroid adenomas are very rarely detectable on clinical examination. Surgical removal of a parathyroid tumor eliminates the symptoms in most patients.
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 as rickets, osteomalacia, and renal osteodystrophy.
Causes 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). Primary hyperparathyroidism occurs sporadically and most patients do not have a family history. Radiation exposure increases the risk of primary hyperparathyroidism. Additional risk factors include lithium and thiazide diuretics exposure. A number of genetic conditions including multiple endocrine neoplasia syndromes, hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism also increase the risk. Parathyroid adenomas have been linked with DDT although a causal link has not yet been established. The most common causes for secondary hyperparathyroidism include vitamin D deficiency, chronic kidney disease, inadequate calcium intake, malabsorption. Tertiary hyperparathyroidism most commonly occurs from prolonged secondary hyperparathyroidism.
Development The parathyroid is composed of 4 glands with 2 located superiorly and 2 located inferiorly. The parathyroid glands are located on the posterior thyroid and are derived from the endoderm of the 3rd and 4th pharyngeal pouches. Specifically, the inferior parathyroid glands are derived from the 3rd pharyngeal pouch and the superior parathyroid glands are derived from the 4th pharyngeal pouch dorsal wing. The ultimopharyngeal body is derived from the 4th pharyngeal pouch ventral wing and the parafollicular cells ( C-cells) are derived when the ultimopharyngeal bodies fuse with the posterolateral thyroid. The parathyroid glands separates from the pharyngeal wall and attaches to the posterior thyroid during the 7th week of human embryonic development.
Mechanism 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.
Regulation of PTH Rapid PTH regulation is controlled by the parathyroid G-protein coupled, calcium sensing receptors which responds to fluctuations in serum calcium levels. Alternatively, prolonged changes in serum calcium influences mRNA-binding proteins altering the encoding of PTH mRNA. There are also calcium independent mechanisms which include repression of PTH transcription through 1α,25-dihydroxyvitamin D binding with the vitamin D receptor. Furthermore, 1α,25-dihydroxyvitamin D also has an impact on the expression of calcium-sensing receptors, indirectly affecting PTH secretion.
Effects of PTH on the Bones
PTH stimulates the bones to release calcium through multiple mechanisms. 1) PTH stimulates osteoblasts which increase expression of RANKL which causes differentiation of the osteoblasts into osteocytes. 2) PTH inhibits secretion of osteoprotegerina to allow for osteoclast differentiation. 3) PTH will also directly activate osteoclasts to cause bone resorption through degradation of hydroxyapatite and organic material. This then causes bone to release calcium into the blood.
Effects of PTH on the Kidneys
Calcium reabsorption in the nephron occurs in proximal convoluted tubule and at the ascending Loop of Henle. PTH acts on the distal convoluted tubule and collecting duct to increase calcium reabsorption in the nephron. PTH also acts on the proximal convoluted tubule to decrease phosphate reabsorption to lower the serum phosphate. 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 of 1-alpha-hydroxylase in the proximal convoluted tubule. This enzyme activation hydroxylates inactive 25-hydroxycholecalciferol to active vitamin D (1, 25 dihydroxycholecalciferol). Active vitamin D allows for calcium absorption through transcellular and paracellular pathways.
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 hypocalcemia is present. 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. 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, and it is converted into the active hormone, 1,25 dihydroxyvitamin D3. 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
The gold standard of diagnosis is the PTH immunoassay. 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 serum calcium, phosphate, and PTH levels.
Serum calcium Phosphate Vitamin D Level PTH Likely type ↑ ↓ ↑ ↑/↔ Primary hyperparathyroidism ↓/↔ ↑ ↓ ↑ Secondary hyperparathyroidism↑↑↓↑Tertiary hyperparathyroidism
Primary hyperparathyroidism has high calcium, vitamin D, and PTH levels and a low phosphate level. Secondary hyperparathyroidism has low serum calcium and vitamin D levels, and high phosphate and PTH levels. Tertiary hyperparathyroidism has high serum calcium, phosphate, and PTH and low vitamin D levels. Tertiary hyperparathyroidism is differentiated from primary hyperparathyroidism by a history of chronic kidney failure and secondary hyperparathyroidism.
Hyperparathyroidism can cause hyperchloremia and increase renal bicarbonate loss, which may result in a normal anion gap metabolic acidosis. 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 a 24-hour urinary calcium for familial hypocalciuric hypercalcemia, DEXA scan to evaluate for osteoporosis, osteopenia, or fragility fractures, and genetic testing. Additionally a CT scan without contrast or renal ultrasound can be done to assess for nephrolithiasis and/or nephrocalcinosis if there is concern for it.
Differential diagnosis Differential diagnoses of hypercalcemia include humoral hypercalcemia of malignancy, renal failure, malignant bone destruction (such as multiple myeloma, metastatic breast cancer, lymphoma), thiazide diuretics, lithium, immobilization, hyperthyroidism, milk alkali syndrome, multiple endocrine adenomatosis syndromes, and granulomatous diseases. Additionally, familial benign hypocalciuric hypercalcamia can present with similar lab changes. In this condition, the calcium creatinine clearance ratio, however, is typically under 0.01 due to the low levels urine calcium.
Blood tests Intact PTH 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 kidney dysfunction. Intact PTH blood tests may be falsely low if biotin has been ingested in the previous few days prior to the blood test.
Calcium levels In cases of primary hyperparathyroidism or tertiary hyperparathyroidism, heightened PTH leads to increased serum calcium (hypercalcemia) due to: increased bone resorption, allowing the flow of calcium from bone to blood reduced kidney clearance of calcium increased intestinal calcium absorption
Serum phosphate