Category Archives: Genetics

Doc Talk: Nutrition & Oxygen as Preventative Medicine

Dr. C. Louis Perrinjaquet has been practicing in Summit County, Colorado’s mountain communities since the 80’s, when he first arrived as a medical student. He currently practices at High Country Health Care, bringing with him a wealth of experience in holistic and homeopathic philosophy, such as transcendental meditation and Ayurvedic medicine, as well.

This past week, Dr. Chris managed to sit him down over a cup of coffee in Breckenridge to talk Altitude Medicine. And not a moment too soon, as PJ is already on his way back to Sudan for his 11th trip, one of many countries where he has continued to provide medical resources for weeks at a time. He’s also done similar work in the Honduras, Uganda, Gambia, Nepal, and even found himself out in the remote Pacific, on Vanuatu, an experience overlapping Dr. Chris’s own experience spending decades as a physician in the Commonwealth of the Northern Mariana Islands.

Experience is everything when it comes to High Altitude Health. I asked PJ if there was any such thing as a “dream team” of specialists he would consult when it came to practicing in the high country: more than any particular field, he would prefer physicians with the long-served, active experience that Dr. Chris has in the mountain communities.

Complications at altitude aren’t always so straight-forward. Doc PJ sometimes refers to the more complex cases he’s seen as “bad luck”, “Not in a superstitious way,” he explains, but in “a combination of factors that are more complex than we understand,” not least of all genetics and hormones.

At this elevation (the town of Breckenridge is at 9600’/2926 m), he’s seen all cases of High Altitude Pulmonary Edema (HAPE): chronic, recurring and re-entry. The re-entry HAPE he sees is mostly in children, or after surgery or trauma, which Dr. Chris speculates may be a form of re-entry HAPE.

He’s seen one case of High Altitude Cerebral Edema (HACE), a condition more commonly seen in expeditions to even more extreme elevations (see our previous article, Altitude and the Brain). In this case, “a lady from Japan came in with an awful headache, to Urgent Care at the base of Peak 9 … she lapsed into a coma, we intubated her, then flew her out.”

How common are these issues in residents?

It’s probably a genetic susceptibility. More men come down with HAPE at altitude, or estrogen-deficient women. Estrogen may protect against this. When I first moved up here, we used to have a couple people die of HAPE every year! The classic story is male visitors up here drink on the town after a day of skiing, don’t feel well, think it’s a cold, and wake up dead. A relatively small number of the population up here has been here for decades. Most move here for only 5 – 10 years; even kids [from Summit County] go to college elsewhere, then move away.

In addition to hypoxia, severe weather and climate are also associated with extreme elevation. Do you observe any adverse physiological responses to the cold or dryness, etc. at this elevation?

Chronic cold injury probably takes off a few capillaries every time you’re a little too cold.

At this, Dr. Chris chimes in, “People who have lived here a long time may have more trouble keeping their hands and feet warm.”

Do you have any advice for athletes, or regarding recreation at altitude?

Don’t be an athlete up here very long. Don’t get injured. You can train yourself to perform a certain task, but that might not be healthy for you [in the long term]. Really long endurance athletes – that might not be good for your health, long-term. I see chronic fatigue often, they kinda hit a wall after years: joint issues, joint replacement, …

We’re observing a relatively recent trend with many high altitude and endurance athletes subscribing to a sustainable, plant-based diet. We’ve also encountered a lot of athletes consuming vegetables and supplements rich in nitrates to assist with their acclimatization. Do you have any experience with or thoughts on these techniques?

Eat a lot of fruits and vegetables, not a lot of simple carbohydrates, not a lot of refined grains. Eat whole grains. I’ve been vegan for a while; it’s been an evolving alternative diet.

Do you ever recommend any other holistic or homeopathic approaches to altitude-associated conditions, healing or nutrition?

Why don’t you get some sleep? Eat better? Don’t drink? Pay attention to your oxygen? Sleep with air? … If you’re over 50 and plan to be here a while, you might sleep on oxygen. I can’t imagine chronic hypoxia would benefit anyone moving here over 50. It may stimulate formation of collateral circulation in the heart, but we’re probably hypoxic enough during the day. It might benefit athletes that want to stimulate those enzymes in their bodies, but even that would be at a moderated level, not at 10,000 ft.

We’re onto something here: Dr. Chris has seen a lot of benefits in some of her patients sleeping on oxygen. If you haven’t already heard, Ebert Family Clinic is currently deep in the middle of a nocturnal pulse oximeter study, where subjects spend one night with a pulse oximeter on their finger to track oxygen levels as they sleep. This will provide more data on whether certain individuals or demographics may benefit from sleeping on oxygen.

In the case of pulmonary hypertension, probably 50% of people who get an electrocardiogram may experience relief from being on air at night. Decreased exercise tolerance when you’re over 50 might be a good case for a recommendation. I don’t think we ever have ‘too much oxygen’ up here; ‘great levels of oxygen at night’ are about 94%. Humans evolved maintaining oxygen day and night [in the 90s], same with sodium, potassium, etc., at a fairly narrow tolerance.

Are there any myths about altitude you find you frequently have to clarify or dispel?

Little cans of oxygen! it’s predatory marketing! It’s so annoying! We’re littering the earth and taking people’s money for ‘air’! Just take some deep breaths, do some yoga for a few minutes … sitting for 30 minutes at an oxygen bar might help. There’s no way to store oxygen in your body, so within 15 minutes, it’s out, but the effects might last, but it gives a false sense of security. 

Also,

IV fluids! DRINK WATER! Or go to a place where you can get real medical care. Most vitamin mixtures, or ‘mineral mojo’, is not real. First of all, don’t get drunk! Drink way less. Dr. Rosen, a geriatric psychiatrist, sees a lot of older guys with MCI (mild cognitive impairment), they’ve had a few concussions, have a drink a day and have lived at altitude for a while. He sees more of these guys here than at low altitude. It’s part of my pitch for guys to sleep on oxygen and minimize alcohol. We don’t have the science to take one or two drinks a week away, but just add oxygen.

Do you have to change the way you prescribe medications due to altitude? Has anything else changed about your practice after moving to altitude?

I don’t [prescribe] steroids as much. Even if it’s rare, I don’t think [steroids] are as benign as other doctors. I avoid antibiotics if possible.

Do you yourself engage in any form of recreation at altitude? How has the altitude played a role in your own experience of this?

I didn’t exercise much until I was 40. [Now] I trail run in the summer, which I think is better than road running (‘cave man’ didn’t have completely flat pavement to run on for miles and miles). In the winter, I skin up the mountain almost every morning; [also] mountain biking. 

Ease in to exercise gradually. Exercise half an hour to an hour a day, but do something every day, even if it’s 10 minutes. And don’t get injured.

Doc PJ also has a handout he most often refers his patients and visitors at High Country Health to, here.

robert-ebert-santos

Roberto Santos is from the remote island of Saipan, in the Commonwealth of the Northern Mariana Islands. He has since lived in Japan and the Hawaiian Islands, and has made Colorado his current home, where he is a web developer, musician, avid outdoorsman and prolific reader. When he is not developing applications and graphics, you can find him performing with the Denver Philharmonic Orchestra, snowboarding Vail or Keystone, soaking in hot springs, or reading non-fiction at a brewery.

Sickle Cell Anemia at Altitude: a Case Report

Martin, a 27-year-old African American male, presents to a rural mountain hospital with complaints of left upper quadrant abdominal pain. Martin arrived at altitude (9,400 feet) two days ago from Oklahoma City after a 12-hour drive. Shortly after arriving to his condo in the mountains, Martin developed a dull aching pain to his left upper quadrant. The pain is constant but radiates to his L flank intermittently. Martin tried snowboarding today but had to end his day early because the pain became too severe. Martin cannot identify any aggravating or relieving factors and states that ibuprofen “didn’t even touch the pain.” Martin denies associated nausea, vomiting, diarrhea, constipation, urinary symptoms, fevers, chills, enlarged lymph nodes, or fatigue. His medical history is significant sickle cell trait without active disease. He has a negative surgical history, takes no daily medications, and has no known allergies. *

Differential diagnoses considered include kidney stones, pancreatitis, gastritis, diverticulitis, splenic enlargement, an infarcted spleen, or mononucleosis. Laboratory tests ordered include a complete blood count, reticulocyte count (indicator of immature red blood cells production), lactate dehydrogenase (an indicator of red blood cell destruction), haptoglobin (a binding protein that binds free hemoglobin after red blood cell destruction), a complete metabolic panel, and a urine analysis. A CT scan of the abdomen with contrast was also ordered and performed. 

Martin’s results showed an elevated white blood cell count, sickled cells on his blood smear, mildly elevated reticulocyte count and lactate dehydrogenase, low haptoglobin, and an elevated bilirubin. The remainder of his blood work was unremarkable. The CT scan showed a 40% infarction of his spleen. Martin was treated with oxygen, fluids, and IV pain medication and was promptly transferred to a larger hospital at lower elevation. 

What caused all of this to happen? 

Sickle cell anemia (SCA) is a mutation of the HBB gene that affects the development of normal hemoglobin, the major oxygen transporting protein in the body. SCA is an autosomal recessive genetic disorder which means that two copies of the abnormal gene have to be passed on from both parents in order for the disease to be active in the offspring. So, in other words, if both parents are carriers of the abnormal gene, their offspring have a 25% chance of developing the active disease and a 50% chance of becoming carriers themselves. 

http://www.healthnucleus

The hemoglobin protein is made up of four subunits, 2 alpha-globin and 2 beta-globin. Sickle cell carriers will have a mutation of one of the beta-globin units, resulting in no clinical manifestations of the disease. These individuals live normal lives and are virtually unaffected by the mutation, as seen in Martin’s case. Individuals with active disease will have a mutation in both of the beta-globin subunits, creating sickling of their red blood cells. Sickling of red blood cells makes them less flexible in maneuvering through the vasculature, ultimately resulting in a blockage of blood flow to various tissues in the body. This is cause of severe pain that many individuals experience when in crisis. Sickled cells are also more prone to destruction leading to an anemic state and are inefficient oxygen transporters. 

https://www.flickr.com/photos/nihgov/27669979993

The sickle cell mutation is typically found in certain ethnic groups which is thought to be related to the protective quality of sickled cells from the development of Malaria. The ethnic groups most likely to be affected include African Americans, Sub-Saharan Africans, Latinos, Indians, Individuals from Mediterranean descent, and those from the Caribbean. 

But if Martin was a carrier without active disease, why did he develop sickle cell anemia?

Individuals with the sickle cell trait can cause their cells to sickle under extreme stress including during strenuous exercise, severe dehydration, and when at high altitude. The resulting consequence is the manifestation of all of the symptoms of active disease. Although Martin had never had any symptoms related to his sickle cell trait, he was now in full sickle cell crisis that required immediate intervention. 

What are the implications? 

Individuals from any of the ethnic groups listed above should be tested for the sickle cell trait to ensure they are not carriers. A carrier must exercise extreme caution in ascending to high altitude, should stay well hydrated, and avoid strenuous exercise to prevent the development of a sickle cell crisis. 

*Case scenario is not based on any individual patient rather a compilation of varying presentations seen in the emergency department. 

Liya is 3rd year Doctor of Nursing Practice Student attending North Dakota State University. She lives in Breckenridge, Colorado and works as a registered nurse in the Emergency department. Liya was born in Latvia and moved to the United States in 1991 with her family. She grew up in the Washington, DC area until she moved to Colorado in 2012.  She is passionate about helping immigrant families and other underserved individuals gain access to basic healthcare services. She hopes to work in Family Medicine in a federally qualified health center in the Denver metro or surrounding areas. In her spare time, Liya enjoys hiking, snowboarding, biking, and camping. 

References

Adewoyin A. S. (2015). Management of sickle cell disease: A review for physician education in Nigeria (sub-Saharan Africa). Anemia, 2015. doi:10.1155/2015/791498

American Society of Hematology. (n.d). Sickle cell trait. Retrieved from https://www.hematology.org/Patients/Anemia/Sickle-Cell-Trait.aspx

Mayo Clinic. (2018). Sickle cell anemia. Retrieved from https://www.mayoclinic.org/diseases-conditions/sickle-cellanemia/symptoms causes/syc-20355876

U.S National Library of Medicine. (2019). Sickle cell disease. Retrieved from https://ghr.nlm.nih.gov/condition/sickle-celldisease#inheritance

Yale, S.H,, Nagib, N., & Guthrie, T. (2000). Approach to the vasoocclusive crisis in adults with sickle cell disease. American Family Physicians, 61(5), 1349-1356. Retrieved from https://www.aafp.org/afp/2000/0301/p1349.html

Tatum Simonson and Altitude Adaption: Physiologic and Genetic

Tatum Simonson is a researcher at the University of California, San Diego who is interested in high altitude medicine: specifically, how high altitude adaptations can, over hundreds of generations, become part of our genes. I read one of her publications called Altitude Adaptation: A Glimpse Through Various Lenses. It delves into the research that has been done on physiologic and genomic changes of high altitude inhabitants and how these two factors coincide.

When looking at this information, it is important to remember that the reason high altitude is so much different from sea level or lower altitude is the oxygen in the air. It is not necessarily the percentage of the oxygen in the air, because the air is 20.9% oxygen at all altitudes. It is actually the lower air pressure that makes it feel like there is less oxygen. The air pressure comes from the weight of the air above us in the atmosphere. The further you go up, the less atmosphere there is above you to press down, and therefore less air pressure. Boyle’s law (whoa physics!) basically says that because of the lower pressure, in a given volume of air there are fewer molecules. Because there are fewer molecules of everything, the percentage of oxygen remains 20.9% but it feels like there is less oxygen in the air.

This is all to say that organisms have to adapt to this lower air pressure and less molecules in a given volume. Things that we know are affected include the saturation of oxygen of our blood. With less air pressure to drive the saturation of our blood with oxygen, sometimes it leads to low oxygen levels, or hypoxia. Hypoxia is detrimental because our body needs oxygen for our cells to function.

Simonson looks at 3 populations that have lived at high altitudes (3500m-4500m or 11,483ft-14,764ft) for hundreds of generations: Qinghai-Tibetan Plateau, Andean Altiplano, and Semien Plateau of Ethiopia (see map below). In her paper she goes further into the history of these populations and the uncertainty that exists with their timeline, but for our purposes just know that these populations have inhabited these high altitude areas for anywhere from 5,000-70,000 years.

Figure 1. Map with three locations where high-altitude adapted populations have lived for hundreds of generations. (Image modified from http://www.nasa.gov/topics/earth/features/20090629.html; low elevations are purple, medium elevations are greens and yellows, and high elevations are orangered and white.) Tatum S. Simonson. High Alt Med Biol. 2015 Jun 1;16(2):125-137.

The first lens she looks through is physiologic, or how the body functions. There has been extensive research in this lens, summarized below.

  • Increased common iliac blood flow into uterine arteries in Tibetan and Andeans leads to increased utero-placental oxygen delivery at altitude, allowing less growth restriction. In other words, Tibetan and Andean populations have increased the blood flow to the growing fetus to help it grow more like someone living at lower altitudes. Furthermore, some studies show that their babies are actually bigger.
  • Tibetan and Amhara Ethiopian populations show the characteristic increase in hemoglobin levels that has long been associated with travelers to high altitude, but to a much lower extent than someone who has just traveled to altitude (i.e. native lowlander). This is in contrast even with Andean populations, who have higher hemoglobin levels than Tibetans. The Tibetan and Amhara Ethiopian populations don’t necessarily need a higher level of hemoglobin (molecule that carries oxygen) to get the oxygen that they need to their tissues.
  • Differences in the control of breathing: the hypoxic ventilation response is an increase in ventilation that is induced by low oxygen levels. The research shows that Tibetans exhibit an elevated hypoxic ventilation response while Andeans exhibit a blunted response.
  • Tibetan and Sherpa have been shown to have higher heart rates than lowlanders at altitude, as well as increased cardiac output, or blood that they are able to pump out of their hearts. There are also differences in the energy sources that some high altitude populations use for their heart to pump.
  • There are certain adaptive changes in skeletal muscle that Sherpa populations have made as well. Specifically, increased small blood vessels and increased maximal oxygen consumption.

The second lens is genomic, or the evidence for different genes in highlanders that have allowed them to survive and thrive at higher altitudes. One theory is that the ancestors of modern day highlanders had specific genes that gave them traits that were favorable for surviving at high altitudes. By matter of Darwinian selection, these genetic variants were passed down favorably over generations.

  • Many genes studies are involved in the hypoxia-inducible factor (HIF) pathway, which is involved in regulating various responses to hypoxia including making new blood vessels, making new red blood cells, iron regulation, and metabolism.
  • Specific genes studied include EPAS1has been associated with low (within sea level range rather than elevated) hemoglobin in Tibetans at altitude discussed above. EGLN1 and PPARA have also been associated with hemoglobin concentration changes.
  • There are many other specific genes that have been associated with specific adaptive changes for these high altitude populations.

It is important to realize the physiologic and genetic components of adaptation to high altitude environment. Simonson sums it up best herself:

“Understanding the associations between genetic and physiological variation in highlanders has additional application for understanding maladaptive and general responses to hypoxia, which remain an important biomedical component of hypoxia research. This is also of clinical value when considering distinct and shared hypoxia-associated genetic variants and combinations thereof may contribute to physiological responses in residents and visitors to the environmental hypoxia at altitude as well as chronic…or intermittent…states of hypoxia.

I was happy to read this article and see how high altitude medicine may be affected by genomics in the not-so-distant future. Hopefully you learned something about hypoxia, physiologic and genetic adaptations!

Hannah Evans-Hamer, MD

 

Resources:

Simonson T. Altitude Adaptation: A Glimpse Through Various Lenses. High Alt Med Biol. 2015 Jun; 16(2):125-37. PMID: 26070057; PMCID: PMC4490743.