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Physiology, Parathyroid Hormone (PTH)

Maqsood Khan; Sandeep Sharma.
Author Information

Last Update: October 27, 2018.

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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, calcitriol (1,25-dihydroxyvitamin D) 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, 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.
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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.
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Organ Systems Involved

Parathyroid hormone is directly involved in the bones, kidneys, and the small
intestine.
Effects of PTH in the Bones
In the bones, PTH stimulates the release of calcium in an indirect
process through osteoclasts which ultimately lead to 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 osteoclasts. 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
At the kidneys, 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 a 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.
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Related Testing
Parathyroid gland dysfunctions will be characterized as underactivity 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.
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 that is utilized due to the 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 as well.
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.
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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.
Hyperparathyroidism
Hyperparathyroidism is further characterized as primary, secondary, and
tertiary dysfunction. Primary hyperparathyroidism refers to an abnormality to
the parathyroid gland itself such as an adenoma or hyperplasia causing the
gland to oversecrete. 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. Tertiary
hyperparathyroidism is exceedingly rare but is seen in the context of
continuous PTH secretion even after a secondary hyperparathyroidism
precipitating condition is resolved. 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. Both of these are rare conditions 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.
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 during a thyroid resection procedure due to the close anatomical
proximity. The next most common cause of underproduction of PTH is
associated with autoimmune disorders causing the destruction or damaging
the glands individually or collectively. Hypoparathyroidism is similarly
correlated with hypocalcemia which can cause abdominal pains, muscle
cramping and numbness and tingling. The 2 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 the
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 the nerve excitability.
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Clinical Significance
Calcium's Role 
Calcium is a divalent cation essential to heart, kidney, bone, and nervous
system functioning, making PTH's functioning very 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. 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 for bone
degradation systemically releasing dangerous amounts of calcium into the
blood. This can facilitate the premature transition into osteoporosis and
increase the susceptibility for fractures.
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, causes nerve
hyperexcitability at every level of neurons throughout the nervous system.
The mechanism behind this is associated with the 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 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
increasing serum calcium levels. In certain cancers like breast and prostate,
tumors may release 1alpha-hydroxylase increasing the synthesis of calcitriol
allowing for excessive reabsorption of calcium. A physiological phenomenon
is seen in 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.
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 quantity.
Some of the functions that PTHrP serves is 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
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 isn't conclusive for identifying the presence of cancer. Some
physiological conditions can produce PTHrP in large quantities such as
pregnancy.
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Questions
To access free multiple choice questions on this topic, click here.
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References
1.
Johnson JA, Kumar R. Vitamin D and renal calcium transport. Curr.
Opin. Nephrol. Hypertens. 1994 Jul;3(4):424-9. [PubMed]
2.
Christakos S, Dhawan P, Porta A, Mady LJ, Seth T. Vitamin D and
intestinal calcium absorption. Mol. Cell. Endocrinol. 2011 Dec
05;347(1-2):25-9. [PMC free article] [PubMed]
3.
Lofrese JJ, Lappin SL. StatPearls [Internet]. StatPearls Publishing;
Treasure Island (FL): Oct 27, 2018. Physiology, Parathyroid.
[PubMed]
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Babwah F, Buch HN. Normocalcaemic primary
hyperparathyroidism: a pragmatic approach. J. Clin. Pathol. 2018
Apr;71(4):291-297. [PubMed]
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Cianferotti L, Brandi ML. Pseudohypoparathyroidism. Minerva
Endocrinol. 2018 Jun;43(2):156-167. [PubMed]
6.
Frank E, Ale-Salvo D, Park J, Liu Y, Simental A, Inman JC.
Preoperative imaging for parathyroid localization in patients with
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Jul;40(7):1577-1587. [PubMed]
Copyright © 2018, StatPearls Publishing LLC.
This book is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution, and
reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the
source, a link is provided to the Creative Commons license, and any changes made are indicated.

Bookshelf ID: NBK499940PMID: 29763115

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In this Page
 Introduction
 Development
 Organ Systems Involved
 Related Testing
 Pathophysiology
 Clinical Significance
 Questions
 References

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