Category Archives: Genetics

High Altitude and Pre-Eclampsia

Human adaptation to hypoxia is an evolutionary change, evidenced by genetic modifications seen in certain populations such as Tibet in Asia, the Andes of the Americas, and Ethiopia in Africa, who thrive at extremely high altitudes. This is done by a process of natural selection, in which those who possess a higher degree of genetic variability are at an advantage over those with limited variability. There was a study that showed statistically similar genotypic and allelic frequencies in sea-level sojourners who undergo acclimatization on the ascent to high altitude and the adapted high altitude natives, particularly in the variants of the genes EDN1 (endothelin 1), ADRB2 (beta-2 adrenergic receptor, surface), ADRB3 (beta-3 adrenergic receptor), eNOS (nitric oxide synthase, endothelial), SCNN1B (sodium channel, non-voltage gated 1 beta subunit), TH (tyrosine hydroxylase) and VEGF (vascular endothelial growth factor) (Tomar et al. 2015).

Pre-eclampsia is the leading worldwide cause of maternal and fetal morbidity and mortality. However, in spite of extensive research, an exact etiology of pre-eclampsia is unknown. The thought is that there may be insufficient adaptation of spiral arterioles or shallow trophoblastic invasion, resulting in reduced uteroplacental blood flow leading to placental hypoxia. In other words, hypoxia may be a contributing factor to pre-eclampsia. This is shown by higher incidences of pre-eclampsia happening in areas of high altitude, along with higher risks of reproductive loss, intrauterine growth restriction, and other pregnancy complications (Zamudio 2007). Therefore, the main question to ask is, can a hypoxia-induced disorder like pre-eclampsia overcome the scarce microenvironment of oxygen deprivation by “acclimatization,” as a rapid form of adaptation?

A study conducted in 2017 evaluated more than 40 genes that are known to be associated with hypoxia for their genetic variability. A total of 36 RNA-seq samples from the amniotic fluid were retrieved from the NCBI. It involved samples of 19 pre-eclamptic preterm births while the controls were from 17 full-term births. The study revealed that the genes that are well-known to be associated with adaptation to high altitude had almost three times higher genetic variability in cases compared to control. In particular, EPAS1 gene showed the highest number of variants, followed by ADAM9 and EGLN1. This suggests there is higher selective pressure on the deprived cells of preeclampsia that leads to a high degree of genetic variability, which reflects their potency to survive the hypoxic microenvironment (Figure 1 and Figure 2).

Furthermore, while cases of preeclampsia were more hypoxic and had the highest number of hypoxic variants, they still had a lower number of adaptive variants (Table 2). This suggests the role of adaptive variants in relieving hypoxic pressure. Interestingly, there was a kind of reciprocal relation between the number of acclimatized variants and the number of hypoxic variants. In the controls, a higher number of acclimatized variants relieved the high pressure and thus resulted in a lower number of hypoxic variants, whereas in preeclamptic cases, the high number of hypoxic variants existed indicating for persistent signal of high selective pressure.

In summary, our human bodies have an incredible ability to shuffle their genes to win newer and better physiological characteristics in extreme conditions such as high altitude and pre-eclampsia. Samples indicate that those who were pre-eclamptic and therefore in hypoxic states, had higher genetic variability than those with normal pregnancies. This shows that the genes strive to alter and change to better fit their environmental conditions driven by the high selective pressure. Although more studies are required to fully understand the mechanisms of genetic variants in high altitude and preeclampsia, identifying these variants can pave the way to new treatment strategies that can help the body to better overcome challenging situations.

References

Ahmed, S. I., Ibrahim, M. E., & Khalil, E. A. (2017). High altitude and pre-eclampsia: Adaptation or protection. Medical Hypotheses, 104, 128-132. doi:10.1016/j.mehy.2017.05.007

Tomar, A., Malhotra, S., & Sarkar, S. (2015). Polymorphism profiling of nine high altitude relevant candidate gene loci in acclimatized sojourners and adapted natives. BMC Genetics, 16(1). doi:10.1186/s12863-015-0268-y

Zamudio, S. (2007). High-altitude hypoxia and preeclampsia. Frontiers in Bioscience, 12(8-12), 2967. doi:10.2741/2286

Esther Kwag is a second-year Physician Assistant student at the Red Rocks Community College, Colorado. Esther was born in Seoul, South Korea and spent her elementary years there until she moved to Colorado and has been living here since. She graduated from the University of Colorado with B.S. Biology with Cum Laude in 2017. Prior to PA school, she worked as a CNA at a physical rehabilitation facility working primarily with post-operative patients who underwent orthopedic surgeries. Interacting with patients and advocating for healthier lifestyle motivated Esther to further pursue her education in medicine. In her free time, she enjoys spending time with family and friends, reading books, and travelling.

Maternal Intermittent Hypoxia and the Effect on Adult Respiratory Control and the Gut Microbiome in Male Offspring

On Friday, June 4th, I had the pleasure of attending the, online, Fifth Annual Center for Physiological Genomics of Low Oxygen (CPLGO) Summit. There were many great presentations that I had the opportunity to watch, including the presentation of Dr. Christine Ebert-Santos’ study looking at nighttime pulse oximetry in participants living at high altitude for longer than one year. The presentation this post will discuss is about research conducted at the University of Florida by Dr. Tracy Baker, PhD. This presentation was particularly of interest because it looks at hypoxia in relationship to Obstructive Sleep Apnea (OSA). OSA occurs when patency of the upper airway is compromised and air is inhibited from passing, leading to hypopnea and obstructive apneas1. Hypopnea are episodes of greater than 30% decrease in air flow that lasts ≥ 10 seconds with continued respiratory effort1. Obstructive apnea is a total stop in airflow that lasts ≥ 10 seconds with chest and abdominal efforts to continue breathing1. Patients with OSA have a higher apnea-hypopnea index (AHI) at altitude than at sea level, meaning that their time with decreased oxygenation while sleeping is increased at higher altitude2. Additionally, patients living at altitude with mild or moderate sleep apnea may have a false negative sleep apnea result when having a sleep study performed at sea level, which means that patients who have OSA at altitude will not show signs of sleep apnea at sea level, therefore missing the diagnosis on sleep study2.

Currently, it is understood that the effects of hypoxia secondary to sleep apnea takes a toll on the body over time. Patients often experience snoring and daytime sleepiness in addition to other symptoms or changes to the body that may not be as easily recognizable, such as living in an increased inflammatory state1,3. Further, it is well known that an adverse maternal environment during pregnancy can lead to long term fetal complications3. Combining these two concepts, Dr. Baker wanted to further investigate the adverse effects of hypoxia due to maternal sleep apnea to get a better understanding of the subsequent consequences this deprived oxygen state has on mothers and their offspring. The hypothesis of this study was: Intermittent hypoxia during pregnancy has detrimental and long-lasting consequences on offspring neural function.

To test this hypothesis, Dr. Baker and her team exposed pregnant rats to intermittent hypoxia during days 10-21 of gestation. OSA was modeled from hypoxia episodes, but not the sleep fragmentation that accompanies the disease. It is understood that both components of sleep apnea, hypoxia and sleep fragmentation, would have their own influence on the offspring. The rats were put into a chamber and delivered 15 episodes of hypoxia per hour, as people can experience up to 10-20 episodes of apnea per hour during pregnancy, in increments of 90 seconds with 90 seconds of normoxia in between. During hypoxic episodes, oxygen levels were brought down to 10% and oxygen saturation was reliably reduced to 85% with adequate re-saturation during episodes of normoxia. Control rats were exposed to normoxia, 21% oxygen “on and off”, to control for and take into consideration confounding factors such as air flow within the chamber. While in labor, the rats were then removed from the chamber to give birth in a normal environment. The baby rats, or pups, were never exposed to hypoxia after they were born. Lastly, the pups were followed into adulthood to monitor for long term effects.3

Next, data from the gestational induced hypoxia (GIH) offspring and the control rat offspring (GNX) was compared. The GIH offspring showed no evidence for obesity and no difference in the volume of fat pads from shortly after birth to 12 weeks, as they had the same trajectory as the GNX offspring. There was also no difference between gestational length, number of pups, pup retrieval time, or pup survival between the two groups. To evaluate effects of gestational hypoxia on breathing, the adult offspring were placed in a plethysmography chamber. A plethysmography chamber measures changes in volume in the body to assess how much air is in the lungs when breathing. The rats were given one-hour to acclimate in the chamber and ventilation was then measured over the following three hours. Of the two groups, male GIH offspring had a significantly increased number of spontaneous apneas per hour compared to male and female GNX offspring and female GIH offspring, who had no change in the number of apneic episodes. Apneic episodes are defined as a pause in breathing that lasts longer than the duration of two breaths. Spontaneous apneic episodes are episodes of apnea with no apparent trigger on plethysmography signal. Approximately 60% of GIH male offspring had spontaneous apnea out of the 95% confidence interval, suggesting gestational intermittent hypoxia altered the phenotype in the male offspring. Again, this was not a congruent finding in GIH females.3

An additional factor to be considered in this scenario is respiratory plasticity, which is the body’s ability to help animals adapt to life changing circumstances, such as hypoxia and sleep apnea. A body’s ability to have respiratory plasticity is suggestive of a healthy neural system because breathing is an automatic and rhythmic function of the brain stem. Ultimately, the respiratory system you are born with is not the one you will die with. Recurrent central apnea can promote respiratory plasticity. Dr. Baker’s team further investigated whether the GIH rats had an altered adaptive response to conditions that alter the body’s natural response to breathing, which in this case is recurrent central apnea. Her team mechanically ventilated adult offspring that were vagalized, paralyzed, and urethane anesthetized to study neural control of breathing independent from the process of ventilation, and data was recorded via phrenic neurograms. A neural apnea was caused by lowering PaCO2 levels lower than the level for breathing and was then stopped by raising PaCO2 back to baseline levels. Recurrent neural apneas triggered plasticity mechanisms to make it harder to elicit the next apnea. Data showed adult male GIH offspring have impaired responses to recurrent reductions in respiratory neural activity and did not express plasticity following a triggered central apnea episode. Like prior results, female GIH offspring did not have this same neural plasticity impairment as the males, showing no elevations in spontaneous apnea and intact compensatory plasticity triggered by central apneas.3

Further, adult offspring were assessed for increased inflammation. To no surprise, GIH males had increased basal neuroinflammation. Although both male and female GIH offspring had increased inflammatory markers, the females were able to suppress the inflammation by an unknown mechanism that the male GIH offspring could not. Adult offspring of GIH and GNX groups were exposed to bacterial lipopolysaccharide (LPS), which confirmed that the GIH males mounted a greater inflammatory response compared to the other offspring, suggesting these males have an altered inflammation response. In the central nervous system (CNS), microglia are innate immune cells that can produce inflammatory cytokines and comprise 5-10% of CNS cells. Dr. Baker’s team pharmacologically depleted these cells in the adult offspring by administering the drug PLX3397 for seven days. This resulted in a stark reduction of microglia by 86%. The GIH male offspring with depleted microglia were able to regain compensatory plasticity triggered by recurrent central apneas. Three days after stopping PX3397, the microglia came back and expanded. When the microglia repopulated, there was restoration of the impaired plasticity phenotype in GIH males.3

To get a better understanding of what could be driving the persistent microglial inflammation in the GIH males, the gut-brain-axis was assessed. In human literature, it is suggested that sleep apnea is associated with gut dysbiosis. Investigating this link, feces was collected from the rats which showed diversity in the bacterial species present in GIH males compared to GIH females and both sexes of the GNX group. Dr. Mangalam looked at the GI bacteria shift and determined the gut microbiomes were comprised of two main phyla of bacteria, Bacteroidetes and Firmicutes. GIH males had increased Bacteroidetes and decreased Firmicutes compared to the other offspring. Initially unsure of this significance, Dr. Mangalam deduced that the decreased bacteria in the GIH male microbiome produce a short string fatty acid called butyrate. Once produced, this fatty acid stimulates the release of neuropeptides and serotonin, which are up taken by the portal vein. From there, butyrate enters the blood circulation and crosses the blood brain barrier (BBB), stimulating active receptors on the vagus nerve. Butyrate supports plasticity in the brain and reduces inflammation.3

This leads to the final question: can the neural plasticity deficit be rescued by decreasing neuroinflammation by supplementing male GIH offspring with butyrate? GIH male rats were supplemented with eight doses of 2mg/kg of Tributyrin over 22 days, which is converted into butyrate3. Upon creating central apnea in the GIH males treated with Tributyrin, it was found that their respiratory plasticity was fully rescued3. So, what does this mean?

Simply, this means gestational intermittent hypoxia has sex-specific, long-lasting effects on adult offspring physiology. This is shown by: 1) gut dysbiosis in male offspring, 2) increased central apneas during sleep with impaired respiratory plasticity, 3) enhanced basal inflammation of microglia in male offspring with increased inflammatory response upon provocation, and 4) microglial depletion or butyrate supplementation repaired deficits in respiratory plasticity.3

The research conducted by Dr. Baker’s team opens additional research opportunities regarding effects of hypoxia on vulnerable populations, such as pregnant mothers and their offspring. The findings from this study can be retested and built upon as research continues to be done. Although this research was not conducted at altitude, it is still interesting and pertinent to the altitude community, as hypoxia and OSA are common problems at altitude. This study contributes important knowledge to the science and medical community; however, more research will need to be done to confirm and fully understand the adverse effects of hypoxia during pregnancy. Further, more information is needed to understand how effects of gestational hypoxia can be applied to populations experiencing hypoxia secondary to living at altitude in a low oxygen environment.

References:

  1. Guilleminault C, Zupancic M. Sleep Disorders Medicine. Third Edition. Philadelphia, PA. Saunders. 2017. pp: 319-339.
  2. Patz D, Spoon M, Corbin R, et al. The effect of altitude descent on obstructive sleep apnea. CHEST. 2006; 130(6): 1744-1750. Doi: https://doi.org/10.1378/chest.130.6.1744
  3. Baker T. CoBAD: Maternal Intermittent Hypoxia and the Effect on Adult Respiratory Control and the Gut Microbiome in Male Offspring. Oral presentation at: the Fifth Annual Center for Physiological Genomics of Low Oxygen (CPLGO) Summit; June 4th, 2021; online.

Amanda Smith is a second year PA student at Drexel University in Philadelphia, Pennsylvania. Amanda was raised in the “sweetest place on Earth”, Hershey, Pennsylvania. She obtained her B.S. in Health Science with a double minor in Creative Writing and Community Health at Hofstra University on Long Island. Between obtaining her undergraduate and graduate degrees, Amanda worked as an Emergency Department scribe, pediatric nurse aide, and as a lead research coordinator in Neurosurgery/Neuro-Oncology at the Penn State Hershey Neuroscience Institute. Amanda loves to travel and was able to incorporate her love for traveling and medicine by traveling across the country for clinical rotations, rotating at sites in New York, California, Pennsylvania, and Colorado, with her next destination in Alaska!

Doc Talk with Cardiologist Dr. Pete Lemis

Dr. Peter Lemis is a cardiologist in Summit County, CO. He sat down with us in December to share his experience treating heart patients in the mountains.

Summit County cardiologist Dr. Pete Lemis

I graduated medical school in ‘77, practiced internal medicine in New Rochelle, New York, the first county just north of the Bronx. Then I went to New Hampshire for three years. I was reading the New England Journal and saw an unexpected cardiology opening at Henry Ford Hospital in Detroit. Next I was in Pittsburg for 26 years practicing cardiology. Decided I wanted to retire to Colorado, so I built a vacation home here only to discover I didn’t have to wait to retire to move here, so I came five years ago. 

What is it about high altitude and the heart that makes it healthy for heart patients?

Summit is the fifth highest county in the US with the highest population of those counties. The 21 highest are all in Colorado. Lower air pressure means that although there is 21% oxygen in the atmosphere, there are fewer oxygen molecules. So every breath we take is giving us less oxygen, unless we breathe faster and deeper to make up for it, a natural tendency for people. They don’t even think about it. Some people have hypoxia without shortness of breath. Every once in a while, I’ll see a patient who moved to altitude for work or something, and they’re hypoxic. It is probably genetic that some people have a decreased central respiratory drive. 

These patients with low oxygen often are ordered to have an echocardiogram. When they first come up here, they usually won’t have pulmonary hypertension. For some, the decreased central respiratory drive develops not when they first move here, but years after they move here. They become more and more hypoxic without having the feeling of shortness of breath. They have the same physiological response that people with hypoxia get. Their pulmonary vessels are still being constricted, which is reversible if diagnosed and treated with oxygen supplementation during the first few years of high altitude living. If not treated they are likely to get scarring of their pulmonary vessels. The length of time for this to develop is different for different people, and is unpredictable.

For example, I had somebody just this week who’s been here about 2 years who has a resting oxygen saturation of about 82% at 60 years old. 

We can’t tell who is susceptible to this problem. There are likely some genetic factors involved. Dr. Johnson, who recruited me for my job in Summit County, has been here since 2008. He warned me about the issue of high altitude and hypoxia. Most doctors who are unfamiliar with life at high altitude think you adapt and that’s it. Dr. Johnson said to me, “wait three months and test yourself and your wife with an overnight oximetry to see if there’s hypoxia.” Based on that test I started using nocturnal oxygen and I sleep better when I use it. My wife doesn’t need it. Neither does her mother, who is 90 years old. Neither do my sons.

Awake, we’re able to maintain our oxygen levels, but at night when asleep most people who are here in Summit County have low oxygen. Hence my advice is to get a nocturnal pulse oximetry test. Low oxygen for several hours every night over the years can lead to pulmonary hypertension due to the narrowing of the pulmonary arteries. Then there is the question of what is normal: most high altitude studies were done in La Paz with indigenous, adapted populations as opposed to people living in the mountains of Colorado who have been here years or decades. (See what Dr. Chris has written on her collaboration with physicians and scientists in La Paz, Bolivia.)

We asked Dr. Lemis about arrhythmias at altitude. There are two categories-atrial (from the top chamber) and ventricular (from the bottom chamber).

Studies have shown that cardiac arrhythmias are increased initially, but people become acclimated after about 3 – 5 days and the risk returns to baseline. I don’t think these studies have been conducted over enough time. Hypoxia leads to an increase in arrhythmias. I see a lot of atrial fibrillation  and atrial flutter up here; plus, I send three to four patients a month for an electrical procedure to ablate some of the cardiac conduction pathways to get rid of their arrhythmias. Many patients experience relief from atrial arrhythmias when put on nocturnal oxygen.

JB is a 70 year old who has lived at high altitude for 14 years. He experienced atrial fibrillation several times after returning to Summit County from a trip to sea level. He wore a heart monitor for over a month to see how his heart was beating. He felt the atrial fibrillation was related to dehydration and has prevented further episodes, never needing a pacemaker or other treatment. Jim uses a device that monitors his oxygen and heart rate continually while he sleeps, downloading a written report in the morning.

Why do so many people who live up here have bradycardia?

I think because many are athletes. Athletes often have an efficient heart; I see just as many people who have tachycardia because they have low oxygen. Low oxygen causes higher levels of epinephrine. This stimulates their adrenal gland, which can increase their blood pressure. Many people have high blood pressure at high altitude because they have low oxygen. One of my criteria for testing someone for low oxygen at night is if they have high blood pressure.

Many people have central apnea during sleep at altitude caused by the brain’s blunted response to high CO2 and low O2. Similar to obstructive sleep apnea, this central sleep apnea can increase the risk of heart problems. Many people with obstructive sleep apnea here at high altitude need to have oxygen put into their CPAP machine so they get oxygen, rather than just air with continuous positive airway pressure.

There is less fatal ischemic heart disease up here. People tend to be healthier, more athletic. They’ve moved here for an active lifestyle. There’s less cigarette smoking, more exercise, generally better diet (not always), but people up here still have heart attacks. My impression is more of them survive their heart attacks because of their increased physical activity and healthy lifestyle. They have better collateral flow with more capillaries in the heart. They’re protected to some degree. The corollary to this is the fact that when visitors come here and have heart disease, I don’t think that their cardiologist back at low altitude understands high altitude risks and therefore are unable to provide appropriate medical advice. The same amount of exertion here is much harder on the heart, much more stressful to the heart, than it would be at low altitude. There’s something called a double product when you do an exercise test, related to blood pressure and heart rates. You get the same double product causing the same stress on the heart here as at low altitude, but it takes much less exertion to get to a specific double product. 

People who are accustomed to a certain work load at home come up here and try to do the same amount of exertion. If they have coronary artery disease, suddenly there is a middle aged guy with coronary disease having a cardiac ischemic event, perhaps even sudden cardiac death. 

Another important point is that people with known heart disease who live at low altitude, if they’re unstable at all, they shouldn’t be up here within three to six weeks of a heart attack. They should be able to pass a stress test at low altitude before coming to high altitude to visit.

Valvular heart disease patients who have not been treated with surgery, who don’t already live up here, shouldn’t come up here from lower altitude. People with heart failure can come up here if the failure is compensated.

For people who have trouble acclimating to high altitude in the short term, Diamox is quite useful. Using oxygen at night helps you acclimate as well. Diamox makes your blood a little acidotic which increases your respiratory drive.

Avoid alcohol when you first come to high altitude. Unfortunately people on vacation don’t do that. Alcohol is a respiratory suppressant. At high altitude the hypoxia and cold promotes diuresis, so people tend to get dehydrated. Anti-inflammatory drugs are useful in treating the acute altitude sickness for some people. During the first two or three days, try not to push your physical activity to the limits. Try to get a good amount of sleep.

I would say that I have way fewer heart failure patients [up here]. Because patients who develop advanced heart failure really do not do well here, so they tend to move away to lower altitude before that happens. I have younger patients as compared with my former Pittsburgh practice. I also have way fewer patients with COPD. Anything that causes chronic respiratory difficulties you will find a lot less of that up here. Plus, I’m working in an environment where there are less consultants. 

Back in Pittsburg, two thirds of my practice was taking care of patients in the hospital, so I would deal with patients who would come in with a heart attack, with a heart failure exacerbation, or other acute cardiac problem. Here in Summit County, those severely ill patients get transferred down to Denver, so I provide more in-office preventive or post-illness follow-up than I do care in the hospital. My patients who need advanced procedures (e.g. heart catheters, ablation for arrhythmias), I generally send them down to our sister hospital (St. Anthony in Lakewood). 

The cardiac surgeon who will do the bypass surgery usually knows that the patient returning to the mountains will have to be on oxygen for two weeks after surgery.


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.

 

 

 

Adaptation v.s. Aclimatization

Why don’t babies in Nepal and La Paz need oxygen? 

IMG_2996
Dr. Chris in La Paz with 20 year old Maria and her mother

Research comparing ethnic groups that have lived at high altitude for centuries, such as native Tibetans, and more recent immigrants such as the Han Chinese in Tibet, showed changes in adaptation. People living in the Andes, Himalayas and mountains of Ethiopia have higher lung volumes, more nitric oxide in the blood, high oxygen-carrying hemoglobin levels and increased respiratory rates which are genetic.

Those of us living in the mountains of Colorado have been here at the most 150 years, not long enough to establish gene-based adaptation. We do acclimatize over weeks and months with changes in hemoglobin levels, respiratory rates and lung volumes but not to the extent of the above populations.

During my travels to La Paz Bolivia and Cuzco, Peru I noticed the people were smaller. At Ebert Family Clinic we analyzed over 10,000 pieces of growth data on children up to four years old from our electronic medical record. A high percent are below the standard growth chart: seven percent compared to three percent. Most catch up by age two years.