Introduction

In the blood, the sensitive process of calcium and phosphate homeostasis is maintained primarily by an appropriately functioning parathyroid gland. The parathyroid gland is comprised of 4 small glands located posteriorly to the thyroid in the middle aspect of the anterior neck. The parathyroid gland secretes parathyroid hormone (PTH), a polypeptide, in response to low calcium levels detected in the blood. PTH facilitates the synthesis of active vitamin D and calcitriol (1,25-dihydroxycholecalciferol) in the kidneys. In conjunction with calcitriol, PTH regulates calcium and phosphate. PTH effects are present in the bones, kidneys, and small intestines. As serum calcium levels drop, the secretion of PTH by the parathyroid gland increases. Increased calcium levels in the serum serve as a negative-feedback loop signaling the parathyroid glands to stop the release of PTH. The mechanism of PTH in the body is intricate, and the clinical ramifications of irregularities are significant. The understanding of PTH is of paramount relevance and importance.[1][2][3][4]

Development

Parathyroid hormone is a polypeptide that is synthesized and cleaved into an active form within the parathyroid gland. The initial structure formed is a pre-pro-PTH, a 115 amino acid polypeptide that is cleaved to form pro-PTH comprised of 90 amino acids. It is then cleaved a second time, again at the amino-terminal portion, to form active parathyroid hormone comprised of 84 amino acids. This is the primary hormone that is stored, secreted, and functions in the body. The process of synthesis, cleavage, and storage is estimated to take less than an hour. Active PTH secretion can occur as quickly as a few seconds when low serum calcium is detected. The mechanism of secretion is via exocytosis, a process where the hormone is released through a membrane vesicle carried to the cell membrane, releasing the hormone after the vesicle fuses with the outer membrane. The serum half-life of activated PTH is a few minutes, and is removed from the serum quickly by the kidney and liver.[5][6]

Organ Systems Involved

Parathyroid hormone is directly involved in the bones, kidneys, and small intestine.

Effects of PTH on the Bones

In the bones, PTH stimulates the release of calcium in an indirect process through osteoclasts which ultimately leads to the resorption of the bones. However, before osteoclast activity, PTH directly stimulates osteoblasts which increases their expression of RANKL, a receptor activator for nuclear factor kappa-B ligand, allowing for the differentiation of osteoblasts into osteocytes. PTH also inhibits the secretion of osteoprotegerin, allowing for preferential differentiation into osteoclasts. Osteoprotegerin normally competitively binds with RANKL diminishing the ability to form osteoclasts. Osteoclasts possess the ability to remodel the bones (resorption) by dissolution and degradation of hydroxyapatite and other organic material, releasing calcium into the blood.

Effects of PTH on the Kidneys

In the kidneys, the parathyroid hormone has 3 functions in increasing serum calcium levels. Most of the physiologic calcium reabsorption in the nephron takes place in the proximal convoluted tubule and additionally at the ascending loop of Henle. Circulating parathyroid hormone targets the distal convoluted tubule and collecting duct, directly increasing calcium reabsorption. Parathyroid hormone decreases phosphate reabsorption at the proximal convoluted tubule. Phosphate ions in the serum form salts with calcium that are insoluble, resulting in decreased plasma calcium. The reduction of phosphate ions, therefore, results in more ionized calcium in the blood. 

PTH Indirect Effects on the Small Intestines and Reabsorption of Calcium 

Starting at the kidneys, PTH stimulates the production of 1alpha-hydroxylase in the proximal convoluted tubule. This enzyme, 1alpha-hydroxylase, is required to catalyze the synthesis of active vitamin D - 1,25-dihydroxycholecalciferol from the inactive form 25-hydroxycholecalciferol. Active vitamin D plays a role in calcium reabsorption in the distal convoluted tubule via calbindin-D, a cytosolic vitamin D-dependent calcium-binding protein. In the small intestine, vitamin D allows the absorption of calcium through an active transcellular pathway and a passive paracellular pathway. The transcellular pathway requires energy, while the paracellular pathway allows for the passage of calcium through tight junctions.

Related Testing

Parathyroid gland dysfunctions will be characterized as under-activity or overactivity of the gland and will be evaluated in the context of serum calcium. Whenever there is a calcium imbalance suspected or found, the following pertinent labs are initially obtained: PTH, calcium, phosphate, albumin, vitamin D, and magnesium.[7]

PTH in the Context of Hypercalcemia

If your blood is found to have high levels of calcium, you would expect to find suppressed levels of PTH in circulation, lower than the normal range of 10 to 65 ng/L. If serum PTH is found to be elevated in the context of hypercalcemia, further investigation of the parathyroid gland is warranted and will be initiated with imaging.

Parathyroid Pathology and Ultrasound 

For suspected parathyroid gland pathology, ultrasound is the first imaging modality utilized due to its efficiency and cost-effectiveness. Ultrasound will usually be able to identify the presence of an adenoma as a hypoechoic mass- a darker area representing a structure that isn't bouncing back sound waves very well. The ultrasound can also be useful for anatomy orientation in a preoperative setting once surgery has been determined.

Parathyroid Pathology and Scintigraphy

Scintigraphy is another effective imaging modality that is gaining more favor in identifying parathyroid abnormalities. Scintigraphy utilizes a radioisotope tracer that gets taken up by local structures and allows for visualization of specific anatomy. The specific tracer utilized in this setting is sestamibi combined with 99mTC. In practice, it is found that adenomatous and hyperplastic parathyroid glands will take up a greater amount of tracer and will retain it longer than other adjacent benign structures.

Other Imaging Modalities

Other imaging, such as enhanced contrast CT and MRI, have their place in the clinical investigation of hyperparathyroidism.

PTH in the Context of Hypocalcemia 

If hypocalcemia and low levels of PTH characterize the clinical scenario, then the concern is that the parathyroid glands are not producing enough PTH. Hypoparathyroidism can be caused by a variety of different conditions and can manifest in various ways. The underproduction of PTH can be chronic or transient, depending on the etiology. More common causes of hypoparathyroidism are the autoimmune destruction of the gland, damage during thyroid resections, or severe illnesses. Each of those conditions would need to be investigated further.

Pathophysiology

The 2 umbrella categorizations of parathyroid dysfunctions are hyperparathyroidism and hypoparathyroidism. The inappropriately high secretion of PTH is classified as hyperparathyroidism, while the inappropriately low secretion of PTH is designated as hypoparathyroidism. [8][9]

Hyperparathyroidism

Hyperparathyroidism is further characterized as primary, secondary, and tertiary dysfunction.

Primary hyperparathyroidism refers to an abnormality in the parathyroid gland itself, such as an adenoma or hyperplasia, causing the gland to oversecrete. This is characterized by lab values that show elevated PTH levels, hypercalcemia, and hypophosphatemia. Primary hyperparathyroidism is customarily due to an adenoma, hyperplasia, or, even more rare, a carcinoma. Adenomas are very sporadic and can be surgically resected. Hyperplasia can be found in cases of multiple endocrine neoplasia (MEN) types I and IIa and in an autosomal dominant condition called familial hypocalciuric hypercalcemia. In MEN type I, patients are often characterized by having tumors in the pituitary gland, parathyroid gland, and pancreas. MEN type IIa is characterized by the presence of medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia. In familial hypocalciuric hypercalcemia, there is a mutation of the calcium-sensing receptor in the parathyroid gland and kidney, resulting in a higher-than-normal setpoint. This causes a lack of inhibition of PTH secretion until a higher level of serum calcium, thus resulting in increased bone resorption and hypercalcemia. Hypercalcemia is further exacerbated with increased renal absorption of calcium, resulting in hypocalciuria. These conditions are rare and are not always favored for surgical resection. Patients with hyperparathyroidism will have correlated hypercalcemia which can cause symptoms of excessive thirst and urination, constipation, bone pain, fatigue, depression, and possibly kidney stones. This is commonly memorized as "stones, bones, groans, thrones, and psychiatric overtone."[10]

Secondary hyperparathyroidism refers to the compensatory oversecretion of PTH in response to abnormally low calcium in the blood due to other pathological processes such as renal failure, gastrointestinal malabsorption, or simply a vitamin D deficiency. Lab values differ according to the underlying pathology. In chronic renal failure, there will be elevated PTH but with decreased calcium and elevated phosphate. In the setting of malabsorption and vitamin D deficiency, there will be elevated PTH but decreased calcium and phosphate.[11]

Tertiary hyperparathyroidism is exceedingly rare but is seen in the context of continuous PTH secretion even after a secondary hyperparathyroidism precipitating condition is resolved. Lab values will show moderately elevated PTH, normal or elevated calcium, and decreased phosphate.[11]

Hypoparathyroidism

Hypoparathyroidism doesn't occur with the same frequency as an overactive gland and can also vary in duration. Hypoparathyroidism can be chronic, or it can resolve transiently. Most commonly, a person becomes hypo-parathyroid when their parathyroid gland is removed with elective surgery or it is damaged iatrogenically during a thyroid resection procedure due to the close anatomical proximity. The next most common cause of the underproduction of PTH is associated with autoimmune disorders causing the destruction or damage of the glands individually or collectively. This can be found in Autoimmune polyendocrine syndrome type I. Autoimmune polyendocrine syndrome type I is due to mutation of the autoimmune regulatory (AIRE) gene and is characterized by the triad of chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison disease. Another cause of hypoparathyroidism is due to failure of embryological formation of the parathyroid glands. DiGeorge syndrome is a condition due to chromosomal 22q11 deletion and is characterized by the failure of the formation of the 3rd and 4th pharyngeal pouches, which are responsible for the embryological formation of the thymus and parathyroid gland. Manifestations of DiGeorge syndrome are chronic infections (due to lack of mature T lymphocyte proliferation in an absent thymus), hypoparathyroidism, cleft lip/palate, congenital cardiac defects (i.e., persistent truncus arteriosus, tetralogy of Fallot, or ventricular septal defect), and craniofacial abnormalities.[12][13]

Hypoparathyroidism is similarly correlated with hypocalcemia which can cause abdominal pains, muscle cramping, and paresthesias. The 2 clinical tests commonly done to evaluate for hypocalcemia are Chvostek and Trousseau signs. Chvostek sign is positive when the cheek is tapped lightly and the face contracts on the same side. This indicates that the facial nerve is hyperexcitable due to hypocalcemia. Trousseau sign is positive when a blood pressure cuff is placed on an arm and inflated greater than the systolic blood pressure and maintained for three minutes, eliciting muscle spasms of the ipsilateral hand and forearm. This occurs after the brachial artery is occluded, allowing the hypocalcemia to induce nerve excitability.

Clinical Significance

Calcium's Role 

Calcium is a divalent cation essential to heart, kidney, bone, and nervous system functioning, making PTH's functioning crucial. Calcium plays an integral part in cardiac contractions. The contractility of the heart is predicated on the availability and role of calcium inside myocardial cells. When there is an excess amount of calcium within cardiac cells, contractility will increase, and similarly, when there is a lesser concentration of calcium within the cardiac cells, contraction will decrease. This can potentially lead to prolonged QT intervals seen on ECG. Extreme hypercalcemia's effect on the myocardium can be manifested in ECG changes, causing very short QT intervals. This could potentially precipitate the onset of fatal arrhythmias such as ventricular tachycardia or even ventricular fibrillation if gone unattended. Abnormal oversecretion of PTH is also the source of bone degradation, systemically releasing dangerous amounts of calcium into the blood. This can facilitate the premature transition into osteoporosis and increase the susceptibility to fractures.[14]

Calcium Related Pathologies

Electrolyte homeostasis is crucial for appropriate nerve health and function, which is especially true for calcium. Low levels of calcium, which can be caused by an underproductive parathyroid gland, cause nerve hyperexcitability at every level of neurons throughout the nervous system. The mechanism behind this is associated with a decrease in the threshold potential in the presence of low levels of calcium. The sodium channels are opened at a much lower membrane potential requiring smaller amounts of stimulus. In addition to the overfiring of neurons, patients may also feel numbness, tingling, and muscle cramps. High levels of calcium can cause debilitating effects on the kidneys, potentially precipitating renal stones, which can be destructive and excruciating.

PTH and Malignancy

In a clinical scenario where hypercalcemia is found with appropriately suppressed levels of PTH, malignancy needs to be ruled out. In metastasis, bones can be invaded by cancer, stimulating local osteolytic activity and increasing serum calcium levels. In certain cancers like breast and prostate, tumors may release 1-alpha-hydroxylase, increasing the synthesis of calcitriol and allowing for excessive reabsorption of calcium. A physiological phenomenon is seen in the bladder, kidney, ovarian, uterine, head and neck, lung, and breast carcinomas where the primary tumor secretes a parathyroid hormone-related protein (PTHrP). Some neuroendocrine tumors occasionally secrete PTHrP, while some sarcomas and hematological cancers are found to produce the protein sporadically.[15][16]

PTHrP, Malignancy, and Hypercalcemia

PTHrP is a monomeric polypeptide ranging in size from 60 to 173 amino acids that can exist in several different isoforms mimicking the functions of PTH associated with the pathological condition known as humoral hypercalcemia of malignancy (HHM). In normal conditions, this protein is secreted throughout the body in all types of tissues but in small quantities. Some of the functions that PTHrP serves are associated with calcium transport in the mammary gland and kidney. It is also known to serve a role in the relaxation of smooth muscle in the arterial walls, gastrointestinal (GI) tract, uterus, and bladder. Its presence is also associated with fetal development and the progression of successful gestation. Sometimes PTHrP will be greatly elevated in pregnancies. Screening patients for elevated levels of PTHrP in the context of hypercalcemia of unknown etiology is important. If found, it may be indicative of a malignant process producing ectopic PTHrP, which will cause hypercalcemia. It is also important to note that all scenarios with elevated PTHrP are not conclusive for identifying the presence of cancer. Some physiological conditions can produce PTHrP in large quantities, such as pregnancy.[14]

Osteoporosis

Synthetic PTH is used to treat osteoporosis in men and women but has caused osteosarcoma in animals.