Carotid body tumors (CBTs) are more common at higher altitudes. It also has been proposed that altitude can play a role in the genetic mutations that cause CBTs to form in the inherited types of CBTs. How might altitude affect the genetics of CBT formation?
The carotid body is a peripheral nervous system sense organ. It is located bilaterally at the bifurcation of the common carotid artery, between the internal and external carotid arteries. The carotid body helps maintain physiologic homeostasis with the help of its sensory chemoreceptors. These sensory chemoreceptors “detect changes in the quality in the composition of arterial blood flow, such as pH, CO2, temperature, and partial pressure of arterial oxygen” (Forbes & Menezes, 2021). The carotid body therefore responds to states of hypoxia, hypercapnia and acidosis.
Carotid body tumors (CBTs) are rare paragangliomas of the head and neck. Sporadic, familial and hyperplastic are the 3 different forms of CBTs. The hyperplastic form is most prevalent in patients who are in chronic hypoxic states. Chronic hypoxic states are seen in patients with COPD or cyanotic heart disease. However, chronic hypoxic states are also seen in people who live at high altitude. The only known risk factors for developing a carotid body tumor include chronic hypoxia and genetic predisposition. The only treatment for CBTs is surgery, which is a very challenging surgery due to the complex location of CBTs by a main vessel, the carotid artery.
Risk for CBT’s are related to different altitudes. Prasad et al. (2019) stated the prevalence of CBTs were increased at altitudes exceeding 2000 feet of above sea level where as Chaaban (2021) states CBTs are more common in people living at altitudes exceeding 5000 feet above sea level. The big question becomes why are CBTs more prevalent at altitude? Forbes & Menezes (2021) found that the Carotid body plays a role in the acclimation to high altitude in regards to ventilation, respiratory rate and oxygen levels. At increasing altitudes, there is less oxygen in the air. This leads to a hypoxic state and causes the respiratory rate to increase. The Carotid body itself is responsible for detecting the low oxygen level at high altitude and then increasing the respiratory rate. There may be a chronic hypoxic state as acclimation to high altitude occurs. There also may be a defect in oxygen sensing by the carotid body, which worsened by moderately high altitudes (Astrom et al., 2003). Hyperplasia of the glomus cells of the Carotid body occurs due to the chronic hypoxia and cellular proliferation can occur due to the defect in oxygen sensing. Hyperplasia and cellular proliferation can then lead to tumor formation. It is even found that patients with multiple tumors, like having bilateral CBT’s (as pictured on the MRI imaging) at first time of diagnosis live at higher altitudes, with longer duration of high altitude residence. (Astrom et al., 2003).
CBTs are rare and some surgeons may only see a few CBTs in their career. According to two ENT surgeons in Lakewood, Colorado at a Level I Trauma center, they have encountered many more CBTs in Colorado in their career than in other places at lower altitude. Peter McGuire, MD has been practicing in Colorado for over 5 years as an ENT surgeon. He has encountered about 5-10 CBTs since being in Colorado (P. McGuire, MD, personal communication, November 9, 2021). He states he has only encountered two at lower altitude. When talking to Erin Roark, FNP, who practices alongside ENT surgeon Christopher Mawn, MD, in the 10 years they have been working together in Colorado they have encountered about 15-20 CBTs. (E. Roark, FNP, personal communication, November 10, 2021).
There is evidence that altitude can affect gene mutations. “It has been proposed that environmental hypoxia modulates genetic predisposition to CBP” (Praasad et al., 2019). It has been found that CBTs that develop at high altitudes have been associated with the penetrance, expressivity, and population genetics of what are considered inherited CBTs. Again, cellular proliferation can occur when there is a defect in oxygen sensing by the carotid body and this defect in oxygen sensing can be worsened by moderately high altitudes. This causes cellular proliferation, increased number of actively dividing cells and increased likelihood of an alteration of the DNA sequence (Astrom et al., 2003). An alteration of the DNA sequence is also called a second-hit somatic mutation. “Therefore, living at higher altitudes is expected to facilitate the development of independent tumor foci that develop clonally following the second-hit mutation” (Astrom et al., 2003).
Many questions remain regarding the increased prevalence of CBT’s at altitude. Research is needed to determine if an existent CBT grows when the patient moves from an area of low altitude to an area of high altitude. Genetic studies looking for underlying predispositions to these tumors and other conditions related to altitude will continue to be fundamental.
For more another article related to genetics and altitude see blog entry from December 2019 on aural atresia.
Astrom, K., Cohen, J. E., Willett-Brozick, J. E., Aston, C. E., & Baysal, B. E. (2003). Altitude is a phenotypic modifier in hereditary paraganglioma type 1: Evidence for an oxygen-sensing defect. Human Genetics, 113(3), pp. 228-237. https://doi.org/10.1007/s00439-003-0969-6.
Burgess, A., Calderon, M., Jafif-Cojab, M., Jorge, D., & Balanza, R. (2017). Bilateral carotid body tumor resection in a female patient. International Journal of Surgery Case Reports, 41, 387-391. https://doi.org/10.1016/j.ijscr.2017.11.019
Chaaban, M.R. (2021). Carotid body tumors. Medscape. Retrieved November 7, 2021 from https://emedicine.medscape.com/article/1575155-overview#a8.
Forbes, J. & Menezes, R. (2021). Anatomy, head and neck, carotid bodies. StatPearls Publishing. Retrieved November 7, 2021 from https://www.ncbi.nlm.nih.gov/books/NBK562237/.
Pacheco-Ojeda, L. A., MD. (2017). Carotid body tumors: Surgical experience in 215 cases. Journal of Cranio-Maxillo-Facial Surgery, 45(9), pp. 1472-1477. https://doi.org/10.1016/j.jcms.2017.06.007.
Prasad S., Paties C., Pantalone M., et al. (2019). Carotid body and vagal paragangliomas: Epidemiology, genetics, clinicopathological features, imaging, and surgical management. In: Mariani-Costantini R. (Ed.), Paraganglioma: A Multidisciplinary Approach (ch. 5). Brisbane (AU): Codon Publications. doi: 10.15586/paraganglioma.2019.ch5. Retrieved November 7th, 2021 from https://www.ncbi.nlm.nih.gov/books/NBK543230/.
Katelyn Guagenti is a FNP student at the University of Cincinnati. She graduates December 10, 2021. She lives in Lakewood, CO and she plans to work with Dr. Christopher Mawn and Dr. Peter McGuire at Aspen Ridge ENT clinic after graduation. In her free time she likes to do CrossFit, hike, ski, snowmobile, and any other activity that involves hanging out with her Husband, Vincent, and dog, Judd. Most of all she loves to go to Grand Lake, CO, her favorite place here in beautiful CO.