Parathyroid Physiology

Come learn about some physiology with us! Our ninth episode focuses on parathyroid physiology, a high yield topic within otolaryngology!

Show Notes

Intro:
Hey everyone and welcome to The Oto Approach, a podcast created by medical students for medical students, to teach you about all things otolaryngology. I'm your host Aileen, and today we're going to talk about the parathyroid glands and their physiology. Tag along for a discussion about this common otolaryngology topic, and stick around to hear some high yield tips at the end. 

Anatomy 

The parathyroid glands are two pairs of small, flattened, oval shaped glands that usually lie posterior to the thyroid in the middle aspect of the anterior neck (Moore et al, 2018; Khan et al, 2021). Most people have four parathyroid glands, although approximately 5% of people have more than four, and some people have less than four (Moore et al, 2018). Additionally, ectopic parathyroids, meaning parathyroid tissue in atypical locations, can result from aberrant migration during development (Noussios et al, 2012). 

Physiology 

The main function of the parathyroids is to regulate calcium and phosphorus levels within the body (Johns Hopkins Medicine, 2021). The chief cells of the parathyroids do this by producing a polypeptide hormone called parathyroid hormone or PTH, which acts to increase serum calcium levels. This is achieved by stimulating the release of calcium from bones into the bloodstream, absorption of calcium from food in the intestines, and conservation of calcium by the kidneys (Johns Hopkins Medicine, 2021). We will get into the details of this in a bit! 

So basically, it is low calcium levels that lead to an increase in PTH, which subsequently leads to an increase in serum calcium. This is all controlled by a negative feedback system in which calcium and vitamin D bind to receptors on the parathyroid glands, inhibiting the release of PTH (Lofrese et al, 2020). More specifically, the calcium-sensing receptor (CaRC), which is a G-coupled protein receptor on the surface of the parathyroid chief cells will recognize and respond to low serum calcium, which will then cause them to activate PTH translation and secretion (Lofrese et al, 2020). This control of Ca2+ in the body through feedback loops is incredibly important because calcium is essential for the heart, kidneys, bones and nervous system to function properly (Khan et al, 2021). 

So what are the more specific effects of PTH in the body? As mentioned, PTH exerts most of its effects at the level of the bones, the kidneys, and the gastrointestinal system. 

Let’s start out with its effect on the skeleton. It is important to realize that although your bones may seem extremely static, or never changing, they are actually constantly being metabolically broken down and rebuilt! It is also important to know that the two main cells involved in this process are osteoblasts and osteoclasts. Osteoclasts cause the resorption of bones by degradation of hydroxyapatite (which is a calcium phosphate mineral that is a major component of bone and teeth) (Khan et al, 2021). Osteoblasts on the other hand synthesize and secrete bone matrix (Qiu et al, 2019). You can remember the function of these two main cell types by remembering that osteoBlasts, with a B, build bone and osteoClasts, with a C, consume bone. PTH inhibits osteoblasts and stimulates osteoclasts, thereby breaking down the bone and causing the release of calcium (Lofrese et al, 2020). PTH does this by binding to receptors on osteoblasts which stimulates the release of Receptor Activator of Nuclear factor Kappa-B Ligand… but that is a little hard to remember, so most of the time this is referred to as RANKL or RANK ligand (Lofrese et al, 2020), and this allow osteoblasts to differentiate into osteoclasts, again increasing bone resorption if serum Ca2+ levels are low (Khan et al, 2021). 

Next, parathyroid hormone increases the serum calcium levels in multiple different ways at the level of the kidneys (Khan et al, 2021). Firstly, it directly increases calcium resorption at the ascending loop of henle, the distal convoluted tubule and the collecting duct of the kidneys (Khan et al, 2021). It does this by up-regulating calcium transporters (Lofrese et al, 2020). Secondly, PTH also increases phosphate excretion in the urine (Lofrese et al, 2020). This indirectly increases calcium serum levels because phosphate ions in serum will form insoluble salts with calcium, thereby decreasing plasma calcium (Khan et al, 2021). So therefore, less phosphate ions, means less salts form, which means more ionized calcium in the blood. Finally, PTH causes the kidneys to up-regulate the synthesis of alpha-1-hydroxylase, which is an enzyme needed to produce the biologically active form of vitamin D, called 1,25-dihydroxycholecalciferol or calcitriol (Khan et al, 2021). Vitamin D is extremely important for the homeostasis of calcium and phosphorus, and in the kidney, vitamin D increases calcium and phosphorus reabsorption (Lofrese et al, 2020).  

Now finally, how does PTH exert its effects in the gastrointestinal system? PTH does not directly affect the small intestine, however, the downstream effects of PTH on the synthesis of vitamin D are seen here (Lofrese et al, 2020). Vitamin D receptors are present along the entirety of the gut epithelium and when they are stimulated, they increase absorption of calcium through both the transcellular and paracellular pathway (Khan et al, 2021). 

So what are the two main categorizations of parathyroid dysfunction? Hyperparathyroidism, which is an inappropriately high PTH level, and hypoparathyroidism which is an inappropriately low PTH level (Khan et al, 2021). 

Hyperparathyroidism 

Hyperparathyroidism can lead to extremely elevated levels of serum calcium, which should now make sense to you, because you now know that the main function of PTH is to increase serum calcium levels (Lofrese et al, 2020). So, how will your patient present in this case? They may complain of nausea, vomiting, kidney stones, constipation, bone pain, or display some psychosis or altered mental status (Lofrese et al, 2020). A very common way to memorize these symptoms is “stones, bones, groans, and psychiatric overtones” (Khan et al, 2021; Lofrese et al, 2020). 

Usually the etiology of hyperparathyroidism is considered to be either primary, secondary, or tertiary. 

Primary hyperparathyroidism is the most common of the three, and it refers to an abnormality of the gland itself  (Khan et al, 2021). This means that something is causing the gland to overproduce or over secrete PTH. In this case, your patient may be displaying some or all of the symptoms of hypercalcemia, and additionally it is important to note that their blood work will show elevated PTH and calcium, and low phosphorus levels, also known as hypophosphatemia (Khan et al, 2021). Some examples of things that could cause the parathyroids to oversecrete PTH include an adenoma (which is a benign tumor that originates from granular tissue) or hyperplasia of the gland (Khan et al, 2021). A parathyroid adenoma is the most common cause, although rarely the cause is parathyroid carcinoma. Of note, in these instances, the PTH level is usually sky-high. Once you have biochemical confirmation of pHPT, imaging is ordered to facilitate localization of the suspected adenoma (the most common etiology, accounting for 85% of patients with pHPT). While cervical ultrasound is least costly, when combined with a sestamibi scan (usually with technetium Tc 99m radioisotope), this combination is the most cost effective strategy.

Secondary hyperparathyroidism usually occurs in response to chronic hypocalcemia (Lofrese et al, 2020). So basically, if the body is unable to maintain high enough levels of calcium, the parathyroids will be overstimulated to try to produce enough PTH to keep serum calcium levels high enough. Some examples of reasons this may happen include in a patient with chronic kidney disease, who are unable to resorb enough calcium, or in patients with a vitamin D deficiency, which would cause them to be unable to gain enough calcium from their diet (Lofrese et al, 2020). Of those, chronic kidney disease is the most common by far. So what will your patient’s blood work look like if they have secondary hyperparathyroidism? Well it depends on the etiology. In chronic kidney disease, PTH will be elevated because there will be decreased calcium and elevated phosphorus, but in a vitamin D deficiency, there will be elevated PTH and decreased calcium and phosphate (Khan et al, 2021). Remember, this should now make sense to you because you know that vitamin D is needed for the absorption of both calcium and phosphorus. 

Finally, there is tertiary hyperparathyroidism. This form of hyperparathyroidism is the rarest of the three and occurs when long-term secondary hyperparathyroidism has been corrected (Khan et al, 2021). Basically, because of the chronically low levels of calcium, the parathyroids will try to compensate to the point that there is hyperplasia, or enlargement, of the glands (Lofrese et al, 2020). Eventually, the parathyroid glands begin to act autonomously, and overproduce and secrete PTH (Lofrese et al, 2020). Then, even if the underlying condition is treated, and calcium levels are no longer low, the parathyroids will still be producing very high levels of PTH. In this case, your patient will have extremely high PTH levels, and calcium and phosphate will also be high (Lofrese et al, 2020). 

In patients with acute hypercalcemia, you should firstly aim to correct the electrolyte levels, as this can be very life-threatening (Lofrese et al, 2020). Administering fluids is extremely important (Lofrese et al, 2020). Calcium lowering medications such as diuretics or bisphosphonates may also be used (Lofrese et al, 2020). In terms of  long-term management, surgery is the most common treatment for hyperparathyroidism, and can result in a cure in the majority of cases (Mayo Clinic, 2021). Usually, the surgeon will remove the glands which are causing the issue (that may be one or two with hyperplasia or an adenoma) (Mayo Clinic, 2021). If all four of the parathyroid glands are affected, the surgeon will most likely remove 3 of the glands, and a portion of the fourth (Mayo Clinic, 2021). They will not remove all four of the glands in that case because some parathyroid tissue will still be needed for calcium homeostasis for the remainder of the patient’s life.

Hypoparathyroidism 

Since we’ve now discussed overactive parathyroid glands, or hyperparathyroidism, it would make sense to now talk about underactive parathyroid glands, or hypoparathyroidism. Usually, endocrinologists are more heavily involved in the care of patients with hypothyroidism than otolaryngologists. However, for completeness, we will cover it here! Hypoparathyroidism is more rare than hyperparathyroidism, and it can be chronic or can resolve transiently (Khan et al, 2021). Remember that in hypoparathyroidism, PTH levels will be abnormally low, so serum calcium levels will also be low because PTH is needed to increase serum calcium levels. 

Paresthesia, weakness, muscle cramps or tetany, and seizures can occur due to hypocalcemia (Lofrese et al, 2020). Additionally, there are two clinical tests that can be used to identify hypocalcemia. Firstly, a positive Chvostek sign is when the cheek is lightly tapped, just anterior to the tragus of the ear, and the face contracts on the ipsilateral side (Khan et al, 2021). This is a positive test because it means that the facial nerve, or cranial nerve 7, is hyperexcitable due to hypocalcemia (Khan et al, 2021). Trousseau’s sign is when muscle spasms of the hand and forearm are induced by inflating a blood pressure cuff above systolic blood pressure (Lofrese et al, 2020). This occurs following the occlusion of the brachial artery because this allows the hypocalcemia to induce nerve excitability (Khan et al, 2021). 

The most common cause of hypoparathyroidism is iatrogenic, meaning that it happens as a result of medical intervention (Lofrese et al, 2020). In this cause, the specific iatrogenic cause of hypoparathyroidism is damage to, or accidental removal of the parathyroid glands during thyroid, parathyroid, laryngeal, and pharyngeal surgeries (Lofrese et al, 2020). There are also autoimmune disorders which can cause damage or destruction of one or more of the parathyroid glands (Khan et al, 2021). For example, autoimmune polyendocrine syndrome type I is due to a mutation of the autoimmune regulatory gene (Khan et al, 2021). Additionally, DiGeorge syndrome, which is secondary to a chromosome 22q11 deletion, is characterized by a failure in the formation of the thymus and parathyroid gland (Khan et al, 2021). Some of the manifestations of DiGeorge syndrome include chronic infections, cleft lip and/or palate, cardiac defects, craniofacial abnormalities, and of course, hypoparathyroidism (Khan et al, 2021). 

In general, hypoparathyroidism will be treated by endocrinology. But given that the most common cause of  it is iatrogenic, it is very important that Otolaryngologists know how to recognize and treat this issue, especially acutely, for example, post thyroid surgery. In fact, the incidence rate of postoperative temporary hypoparathyroidism ranges between 1% and 30% (Kim et al, 2015). Luckily, the rates of postoperative permanent hypoparathyroidism reportedly ranges from 0.9% to 1.6% (Kim et al, 2015). 

Acute management of hypocalcemia requires replacement of the patients’ calcium. Remember, if the patient has hypoparathyroidism, you will also need to replace their Vitamin D, and this is typically given in the form of D3, which goes by the name of Rocaltriol. If the patient is symptomatic, or has a corrected calcium of less than 1.8mmol/L, generally intravenous calcium needs to be given, usually in the form of calcium gluconate. Oral calcium can be given for less severe hypocalcemia, and when the patient is asymptomatic. This is typically in the form of oral calcium carbonate. 

CLINICAL PEARLS 

1. The embryology of the parathyroid glands has important implications in its expected anatomic location, particularly as it relates to the recurrent laryngeal nerve. The inferior parathyroid glands are derivatives of the third pharyngeal pouch, while the superior parathyroid glands are derivatives of the fourth pharyngeal pouch. The inferior parathyroid glands therefore travel a greater distance to its usual, final location. The associated nerve of the fourth pharyngeal pouch includes the vagus nerve, or CN10. Typically, the inferior parathyroid glands will lie superficial to the recurrent laryngeal nerve (a branch of CN10), while the superior parathyroid glands lie deep to the recurrent laryngeal nerve. 

2. When you have a patient with symptomatic hypercalcemia secondary to primary hyper-parathyroidism (pHPT), surgical treatment, i.e., parathyroidectomy, is indicated and offers a chance for cure. Commonly, clinicians use the The National Institute of Health guidelines for deciding when to operate. These guidelines have been updated multiple times and are available in the show notes.

Thank you so much for listening to our podcast! 

Thank you to Aileen Feschuck for leading authorship of this episode.

We would like to extend our sincerest thanks to the Saint John Regional Hospital Department of Surgery within the Horizon Health Network for their generous support. Please head to our website at www.theotoapproach.com for our show notes, and to sign up for our newsletter to stay up to date with our latest episodes.

References 

Bilezikian, J. P., Brandi, M. L., Eastell, R., Silverberg, S. J., Udelsman R., Marcocci, C., Potts, J. T. 2014. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab 99(10): 3561-9. 

Johns Hopkins Medicine. The parathyroid glands. https://www.hopkinsmedicine.org/health/conditions-and-diseases/the-parathyroid-glands Access date: September, 2021. 

Khan, M., Jose, A., Sharma, S. 2021. Physiology, Parathyroid hormone. StatPearls Publishing. 

Kim, S., Kim, H. K., Kim, K., Chang, H. J., Kim, B., Lee, Y. S., Chang, H., Park, C.S. 2015. Recovery from permanent hypoparathyroidism after total thyroidectomy. Thyroid 25(7): 830-833. 

Lofrese, J. L., Basit, H., Lappin, S.L. 2021. Physiology, Parathyroid. StatPearls Publishing. 

Mayo Clinic. Hyperparathyroidism. https://www.mayoclinic.org/diseases-conditions/hyperparathyroidism/diagnosis-treatment/drc-20356199 Access date: September, 2021. 

Moore, K.L., Dalley, A.F., Agur, A.M.R. Moore’s Clinically Oriented Anatomy, 8th Edition. Wolters Kluwer. 

Noussios, G., Anagnostis, P., Natsis, K. 2012. Ectopic parathyroid glands and their anatomical, clinical and surgical implications. Exp Clin Endocrinol Diabetes 120(10): 604-10. 

Qiu, Z., Cui, Y., Wang, X. 2019. Chapter 1- Natural bone tissue and its biomimetic. Mineralized Collagen Bone Graft Substitutes. Woodhead Publishing Series in Biomaterials. 

Sung, J. Y. 2015. Parathyroid ultrasonography: the evolving role of the radiologist. Ultrasonography 34(4): 268-274.