Carotid Body Tumors at High Altitude

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.

This is an image of an MRI showing carotid body tumors (Burgess et al., 2017)

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.

References

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. 

Wound Healing at High Altitude: Hyperbaric Therapy, A Patient’s firsthand experience with post-surgical wound healing in Summit County

The nuances of wound healing at high altitude is a topic that has already been explored on this platform (see Eric Meiklejohn’s “Wound Care at Altitude”). Identifying the impact that impaired oxygen delivery can have on healing time, tissue regeneration, and infection rates offers great insight into the roles health care providers can assume to support our high-altitude patients. For this interview, I was able to speak directly with  a Summit County resident who had firsthand experience with these processes.

I’ve heard a bit about your experiences with wound healing at high altitudes I will ask some preliminary questions,. This entire experience was more of a marathon than a sprint. How long have you been living at this altitude, and how old were you at the time of your procedure? I’d lived at high altitude for over twenty-six years before I was diagnosed with breast cancer. I was Fifty-three when I had my surgery. I was in great shape, exercising regularly, and eating really well.

Tell me about your procedure: Well, the initial procedure was in January 2018 down in Denver. I had a bilateral mastectomy done to remove the cancerous tissue, and bilateral expanders were inserted during that surgery so that down the line I could have implants placed. Within the first week we started noticing some necrotic changes to my incisions, and that they were not healing well. The expanders were inflated with air, and it was thought that my traveling back to high altitude from Denver could have increased the pressure inside them.  By the end of week one I went back in to see my doctor, who deflated my expanders pretty significantly.

Have you ever been diagnosed with a medical condition that could affect wound healing, such as Diabetes or Hypertension? No. Breast Cancer was my first real medical diagnosis.

Had you ever had surgery while living at this altitude before? And if so, what was the outcome? Yes, I’d had surgery for an umbilical hernia and that went very well. No complications at all, everything healed just fine. I’d also had tendon damage in my right hand after a fall, and I recovered really well after that surgery at this same altitude.

Regarding healing after your mastectomies, describe the anticipated wound healing time and wound care directions. The time estimate for  recovery was four weeks. I was to rest for two weeks, increase activity slightly for the second two weeks with minimal physical therapy, then by the end of that fourth week the projection was that I would be mostly recovered. I was given strict precautions against heavy lifting, restricting arm movements, and not driving. For wound care I was doing daily dressing changes, not submerging the area in water, and applying Silvadene cream twice daily.

Following the removal of the expanders, what was the rest of the healing process like? Over the next two months I cared for my wounds at home. They were open and oozing, and over time the daily dressing changes and medication applications became quite taxing, both physically and emotionally. It took a lot out of me, and really interfered with my day-to-day life…not to mention the pain. On March 9th, 2018 I underwent an incision revision and resection procedure for the necrotic tissue. At that point my breast tissue had manifested itself as far as which parts were healthy and which would die, so they went in and resected the areas that were not viable. On the left side I lost most of the top surface of the breast, including the entire nipple area. Two weeks after that, I had a [chemo therapy] port placed in my arm  so I could begin treatments, but that incision also had a difficult time healing. That eventually led to a one month delay in my chemo therapy.

In March and April the incisions on the right breast eventually healed, but because of all the tissue loss and necrosis on the left side those wounds did not heal. There was still a lot of drainage from that breast and it was mostly still open so I had to keep the bandage on. By early May (after this wound had been open for 5 straight months) my doctor and I started seeing more signs of infection to that breast, so around May 12th of 2018 he called me in for an emergency procedure and I had the expander completely removed from my left breast. I continued chemo and eventually that left side began to heal in the absence of the expander.

During this time, from March until I finished chemo in August, the port site never healed. The whole reason behind having the port placed was so it could heal over and I could go back to a normal life between chemo sessions. But instead I walked around with a bandage for those six months because my port site remained open. I had Her2 positive cancer, so after my six months of chemo I needed to continue taking Herceptin for one additional year. I opted to have the port removed after six months and had an IV placed every three weeks for my treatments. It was very hard on my veins, but I felt I had no choice.

In late August, with the port out and the left expander out, the last of my open wounds really started healing. I started looking at what I could do to help my tissue heal even better- my thought was that when this is all done and I am all well healed I would like to have my expanders placed and inflated again, but I don’t want to have to go backwards through this process. I did all this research, and that’s where I learned about hyperbaric therapy. That changed everything for me.

What did you learn about Hyperbaric therapy, and what was your experience with it? I did a lot of independent research online and came up with two options that I wanted to discuss with my doctor. The first was a topical option for applying oxygen directly to the wound, which was a very complicated and involved process -and the second was hyperbaric therapy.

I discussed this with my oncologist who was very familiar with hyperbaric chamber treatment centers in Denver, and who wrote me a referral to be evaluated at the one in Presbyterian St. Luke’s Medical Center. I was evaluated by their team, showed them all the photos I had been taking throughout this entire ordeal, and they seemed hopeful that they would be able to help me. I really wish I’d gone there sooner.

My plan was to use this to help me recuperate a little bit so I could give the expander one more shot on the left side. After having the left expander placed, the second phase of my plan was to get another course of hyperbaric therapy to aid in recovering from that procedure. It was eventually prescribed and accepted by insurance, who approved 27 hyperbaric sessions following my surgery.

I underwent the left expander placement in February of 2019, observed the same restrictions, and had identical at-home wound care as my initial surgery in January 2018, but with the addition of hyperbaric therapy my results were night and day. The day after surgery I started hyperbaric, and in so much less pain. I was off all pain medications within 48hours. I was able to get out, walk, function in my daily life, and the tissue healed really well. It was amazing! I felt great, had tons of energy, and it was just a completely different experience. It was nothing short of miraculous.

What was your hyperbaric chamber treatment like? It was five days a week in Denver. Being there was for me a huge learning experience. There were people there being treated for diabetic wounds, hearing loss, adjunct therapy for various types of cancer, joint and tendon disease, tissue necrosis, concussions, head trauma, and so many other things. I hadn’t known that this therapy could be utilized in all these different areas.

After your successful left expander placement, how was your transition to breast implants? Months after the left expander was reinserted, I did transition to breast implants (summer 2019) but even then, I insisted on post operative hyperbaric therapy. I was only approved for ten sessions that time, but the results were the same. Rapid healing time, noticeable decrease in pain after starting therapy, and the ability to function throughout the day. Of all the factors that played a role in this process for you, what variable would you most want to adjust? Honestly, I just wish I’d started hyperbaric therapy sooner. If there was a way to get providers who work with high altitude dwellers to recommend hyperbaric treatment as a part of their primary or secondary treatment course, that’s the one thing I would change.Well, I am very happy to know that despite the difficulty you experienced in this process, you are now three years post op, well healed, and satisfied with your results. Thank you again for sharing your story. My pleasure. If my sharing can help someone else find hyperbaric therapy or open them up to alternative methods of treatment sooner so as not to have to experience what I went through in those first few months, then it was all worth it.

Janell Malcolm is a second year Physician Assistant student in the Red Rocks PA Program in Arvada, Co. A Jamaica native, she loves the ocean, tropical fruit, and 100 degree weather. You will likely find her spending her free time with family or reading/re-reading Jane Eyre. Her personal and career goals are geared towards providing adequate medical care to underserved communities. Special interests post graduation: Labor & Delivery, General Surgery.

Effects of High Altitude on Brain Metabolism & Concussion Information

Changes in altitude have many effects on the physiology of the human body and even metabolism. Some people exposed to high altitude develop acute or chronic mountain sickness due to hypoxia with a spectrum of symptoms including neurocognitive decline of performance and impacting brain function. Head truma at altitude is more likely to lead to brain injury or concussion than those at low altitude.

Imaging with PET/CT using FDG-18 has been used to measure brain metabolism in both human and mice subjects. This type of imaging scans the accumulation of a glucose analog in tissue, specifically the brain in this case. This allows determination of which regions have high or low uptake in metabolism in comparison to a brain at baseline at sea level.

In 2017, mice were studied by being placed in a hypobaric chamber to stimulate hypoxic conditions similar at 5000 meters. Conditions were placed to minimize brown adipose tissue uptake and imaging was performed 45 minutes after an estimated 0.5 mCi FDG injection. After appropriate processing, the results showed an increase in glucose metabolism in the cerebellum and medulla of the mice exposed to high altitude conditions compared to those at baseline. Additionally, certain cortical regions had lower metabolism than baseline mice, and lower cardiac uptake as well. It is thought that the brain’s acclimation response to high altitude.

Another study using mice as subjects compared brain metabolism at high altitude after a traumatic brain injury (TBI) to determine if hypoxia alters glucose uptake. A total of 32 mice were imaged at sea level (baseline) and again after 12 weeks exposure at 5000m (hypobaric stimulation), and again after a repetitive closed injury. An SUV (standard uptake value) was compared in each set of images to determine a change in glucose metabolism. 

This study showed a significant increase in FDG uptake in the medulla, cerebellum, and pons, and a decreased uptake in the corpus callosum, cortex, midbrain, and thalamus. A TBI affects glucose metabolism in the brain by decreasing cortical uptake in both high altitude and sea level. This study showed that high altitude affects the brain by making it more susceptible to repeated concussions than mice at sea level.

A third study employed PET/CT imaging to assess regional cerebral glucose metabolism rates in six US Marines before and after a rigorous training period from sea level to high altitude conditions ranging from 10,000-20,000 ft. It was thought that other conditions would be relatively stable as the military has similar regimens for their members. After comparing imaging performed at baseline sea level and after two months of high-altitude exposure, it was clear that brain metabolism changed. There was a decrease in glucose metabolism in three frontal regions, left occipital, and right thalamus. Right and left cerebellum showed an increase in glucose uptake and metabolism.

Red and orange coloring signifies greater FDG-18 uptake which correlates to increased glucose metabolism. The post imaging signifies decreased uptake and hypometabolism of certain brain regions as mentioned previously.

The data from these three studies clearly show high altitude exposure with hypoxia changes the way our brain tissue metabolism functions. Studies show Sherpas, native to the Himalayas are the most well adapted high-altitude humans.  Their brain metabolism is the same of that of “low-landers”. Conversely, the Quechuas who are native to the Andes of South America still show small amounts of hypometabolism in their brain. As mentioned previously, it is unknown how long it takes for humans to fully acclimate regarding brain metabolism.

These studies indicate the need for more research regarding brain metabolism and function.  Glucose metabolism is crucial for proper functioning of the brain, its neurons, and other regulatory functions. This brings into question what type of impact high altitude may have on the cognitive functions of the brain in people who move or even live at high altitude. Additionally, the fact that the human brain is more prone to injury or developing a concussion, safety should be a consideration for those involved in high impact sports at high altitude.

Reference

  1. Hochachka PW, Clark CM, Matheson GO, et al. Effects on regional brain metabolism of high-altitude hypoxia: a study of six US marines. Am J Physiol. 1999;277(1):R314-R319. doi:10.1152/ajpregu.1999.277.1.R314
  2. Jaiswal, Shalini & Knutsen, Andrew & Pan, Hongna & Cramer, Nathan & Whiting, Kathleen & Xu, Xiufen & Haight, Thaddeus & Allison, Nathanael & Galdzicki, Zygmunt & Dardzinski, Bernard. (2019). FDG PET Study Showing the Effect of High Altitude and Traumatic Brain Injury on Regional Glucose Uptake In Mice.
  3. Jaiswal, S., Cramer, N., Scott, J., Meyer, C., Xu, X., Whiting, K., Hoy, A., Galdzicki, Z. and Dardzinski, B., 2021. [18F] FDG PET to study the effect of simulated high altitude on regional brain activity in mice. [online] Journal of Nuclear Medicine.

Roberta Grabocka is a second-year physician assistant student at Red Rocks Community College’s PA Program in Arvada, Colorado. Roberta attended Stony Brook University in Long Island, NY for her degree in Health Science and received a post-baccalaureate degree in Nuclear Medicine Technology. She practiced for 3 years as a Nuclear Medicine Technologist in multiple hospitals. This included working in oncological, cardiac, and general nuclear settings performing a variety of studies from PET/CTs, myocardial perfusion imaging, HIDAs, V/Qs, etc. Roberta decided to pursue a career as a Physician Assistant to expand her scope of practice and further her medical knowledge. In her free time, she likes to explore local culture and travel.