Tuesday, September 3, 2013

Why Would My Intracellular Calcium Be Elevated?

I recently received a question from someone reading this blog asking me why his/her intracellular calcium would be elevated. Intracellular Calcium is not something that is typically measured, but I would suspect that it is elevated in most ME patients. Why? Because it takes energy (ATP) to pump Calcium out of cells. Energy (ATP) is not something we have a whole lot of, or at least are able to utilize normally. On most cells there are a couple different ways to keep Calcium ions on the outside of the cell so that a gradient is present and the Ca++ ions can rush back into the cell to cause some sort of event - this is important for cell signaling, nerve action potentials, muscle contraction, and a host of other physiologic events.

Check out these graphics that show what happens to nerve cells in the brain during/after a stroke. I believe this is very much analogous to what is happening all the time to all cells in ME patients, just not to the same extreme, or lethal, degree. ME patients show signs of being functionally hypoxic, meaning they are not actually hypoxic (have normal O2 levels), but look very similar to people who are hypoxic - see previous post and look at how normal people in the Everest III study (simulated high altitude) look exactly the same as ME patients on ECHO. Getting into why we look functionally hypoxic is a big topic that I am too weak to write about now, but hopefully sometime soon.

While we are discussing Calcium it would be a shame not to mention vitamin D. Vitamin D, its regulation, and its many effects are often misunderstood or at least over-simplified by physicians into, high vitamin D = good, low vitamin D = bad. The whole vitamin D axis is extremely complex and even those who know it the best, I am sure do not know everything as it is highly unlikely that we have discovered all of its effects at this time.

That being said, it is important to note that ME patients often have strange, often widely varying levels of the "regular" form of vitamin D that is typically tested: 25-hydroxyvitamin D (25-D).  It is also important to know that 25-D has little to no correlation to the bioactive form that our bodies primarily use: 1,25-dihydroxyvitamin D, also named Calcitriol.  If you are a ME patient and your doctor is suggesting you take vitamin D based off the "regular" 25-D vitamin D test, I would look into getting the bioactive form tested before taking any action.

Why?  Because 1,25-dihydroxyvitamin D, (aka Calcitriol or 1,25-D) is the bio-active form of vitamin D. It is the form of vitamin D that actually causes the important physiological changes of calcium metabolism and immune system regulation.

In healthy people, or those without chronic inflammatory diseases, 25-hydroxyvitamin D (25-D) is an excellent test because it indicates the vitamin D stored in a patient's body and consequently is the typical vitamin D lab ordered.

Calcitriol in healthy people is rarely abnormal as it is normally very tightly regulated. However, in patients with ME and similar chronic inflammatory diseases, the vitamin D axis can become dysregulated and any correlation between 25-D and Calcitriol no longer exists and cannot be assumed. For example, in patients with ME, Calcitriol levels may be extremely high, while 25-D remains normal or even low.


Saturday, April 27, 2013

Dr. Paul Cheney's Latest Observations, Research, Treatments, and Thoughts on ME/CFS

Dr. Paul Cheney is one of the major players in the ME world. He was an internal medicine doctor in Incline Village when the CFS outbreak occurred there nearly 30 years ago and has been studying the complicated and perplexing disease ever since. Recently (April 2013) Dr. Cheney presented at a conference and his power point slides and audio were recorded and uploaded to youtube. You can see his entire presentation including a question and answer session at the bottom of this post.

The presentation itself is quite lengthy - nearly 2 hours, and the Q&A is about 30 minutes. A summary of the key points (as I see them) is posted below if you do not have the energy or time to listen to the entire recording.

If you have questions like, "what do you think he meant when he said...?" ask in the comments section and I will see if I can figure it out.

A summary will follow each video. Major important points for all 3 videos in my opinion are here:
  • ME patients have a cellular energy deficit. This is a compensatory response caused by an inability to deal with the by-products of normal metabolism (energy production). The body decreases energy production so that we do not die from killing off all of our mitochondria with oxidative stress.
  • This decreased energy production causes cardiac issues, namely, diastolic dysfunction, which in turn causes significantly decreased cardiac output. Decreased cardiac output manifests itself in multiple ways:
    • Compensatory increased systolic squeeze = higher ejection fraction.
    • Difficulty perfusing multiple organs especially when standing. POTS and NMH are not purely autonomic problems (as many think), but due to low cardiac output.
    • The increased systolic squeeze causes higher than normal pressures in the right ventricle that the tricuspid valve is not really designed to handle - this causes blood to go back the wrong way (tricuspid regurgitation and flow reversal) into the brain (CCSVI) and the liver (CHVI), destroying normal capillary throughput in those organs at least. 
      • This could explain some of the cognitive, liver (problems with detoxification), and gut issues in ME.
    • Physiology of cardiac abnormalities, CCSVI and CHVI:
      • Poor redox control → low free energy levels → diastolic dysfunction → low cardiac output → low venous return to the heart → compensatory high ejection fraction → tricuspid regurgitation → flow reversal in inferior and superior vena cava → flow reversal in veins draining brain and liver. 
      • What causes impaired redox control in the first place? No one knows.
    • Very preliminary results using VIP show that it can at least transiently decrease the tricuspid regurgitation and thus flow reversal in the brain and liver, likely by decreasing the pulmonary artery pressure, making it easier for blood to flow in the correct direction.
    • A small study in a similar patient population (CIRS-WDB) with VIP had promising results with all patients having increased quality of life and normalization of many inflammatory markers.

  • History of Lake Tahoe outbreak in 1984 (0:00-5:30), CDC Fuduka case definition (5:30-7:00)
  • Dr. Cheney's view of ME. Note that he typically calls this disease CFS, but uses his own "definition" (also note that the people he describes as a "CFS patients" per his definition will almost always meet the ICC for ME as well). 
  • He simplifies the symptoms down to 3 major categories:
    • Energy impairment, brain dysfunction, and pain.
      • Energy impairment is a dynamic loss of function with push-crash phenomenon.
      • Brain dysfunction is subcortical with issues processing information.
      • Pain is present in almost all cases in one form or another
    • Natural history of disease is a high misery component at first but then the patient becomes less miserable but more limited (disabled) as time goes on.
  • Evidence of cellular energy deficits:
    • Exercise ergometry - VO2 max is much lower in ME patients compared to controls. These levels are not due to de-conditioning, they are too low (an organic disease).
    • MRSI shows elevated ventricular lactate peaks in ME vs controls (Shungu @ Cornell Weill). Ventricular lactate and glutathione are inversely correlated and both are predictors of disability. 
    • Loss of fingerprints: when biopsied, these demonstrate perivascular lymphoid infiltrates (just means non-specific immune activation) and punched out lesions in fibroblasts (oxidative stress). 
    • Dr. Cheney's biochemical model of ME (starting @ 23:15)
      • Essentially, the problem is with the enzymes that deal with the oxidative stress that results from normal energy production - the redox system isn't working correctly so in order to save itself, the body lowers energy production. So, lower energy production is not the problem, but an appropriate compensatory mechanism (feedback loop) to prevent further damage the mitochondria, and ultimately, the person with ME. 
    • Mitochondrial dysfunction evidence - multiple studies show low energy levels and increased damage to mitochondrial membranes compared to controls.
  • Is there a ME associated cardiomyopathy?
    • Although this is not intuitive, during the cardiac cycle, energy is consumed when the heart relaxes (diastole) NOT when the heart squeezes (systole).
      • ATP (energy) is required to pump all the calcium out of the cardiac cells which then allows the individual cardiac muscle cells to relax, then allowing the heart to fill with blood.
      • During systole the cardiac muscle cells ion channels open and allow a huge influx of calcium - this causes the cardiac cells to contract, but does not consume any energy - it just releases the energy built up during the diastole.
      • Hollingsworth et al used MRSI to look at the heart - 1/3 of the ME patients were in the cardiomyopathic range (that would be lethal in "normal" heart disease).
      • Peckerman et al showed that cardiac output (how much blood the heart pumps in liters per minute) was much lower in ME, especially during standing, and was correlated with disability.
      • This is all due to diastolic dysfunction from lower cellular energy levels. In an attempt to compensate for this, people with ME, squeeze very hard during systole to try to boost cardiac output. This manifests itself in higher than normal ejection fraction, POTS, and NMH.
      • Dr. Cheney began looking at cardiac output and has found that the average person in his practice had a cardiac index of about 2.3 (normal is about 3-3.5), 1/3 of his patients are below the cardiogenic shock range (1.8).
      • Stroke volume is much lower in ME vs controls.
      • E/A, e'/a', and D/S ratios are abnormal in ME - these are just ways of measuring diastolic dysfunction.
      • ME patients have atrial cavitation on standing (not normal) - this causes low pressure in the left atrium and blows up the foramen ovale (patent foramen ovale). 
      • To compensate for diastolic dysfunction, during systole, the ventricles squeeze much harder than in normal people. Unfortunately the contraction is asynchronous (different parts of the ventricle does not contract in synchrony) which further decreases efficiency and cardiac output.
      • Also ME patients have positive strain patterns on tissue doppler.

  • Regarding Fibromyalgia vs. ME
    • Essentially patients who have fibromyalgia (FM) benefit from exercise while patients with CFS/ME the opposite occurs with exercise - they get significantly worse.
    • Significant cognitive impairments and abnormal neurological exams occur in almost all ME patients while they rarely occur in FM.
    • Note that a patient can have both ME/CFS and FM at the same time.
  • Everest III Studies
    • Normal healthy young men were put into hypobaric chamber and the pressure was decreased so that it simulated climbs up to 8000m.
    • These people were ECHO'd as the pressure decreased and abnormal cardiac changes occurred that are exactly the same as those in ME (4:25):
      • Progressive increase in IVRT
      • Progressive left atrial cavitation
      • Progressive mitral E/A ratio decline
      • Progressive pulmonary vein D/S ratio decline
      • Progressive increase in pulmonary artery pressure
      • Progressive decline in stroke volume
      • Increased hyperadrenergic tone (increased heart rate and left ventricle cavitation)
      • Preserved left ventricular function and LVEDP
    • When the healthy people in the study were given oxygen at simulated high altitude all those ECHO changes totally normalized.
    • When ME patients are given O2 all those same abnormal ECHO parameters get even worse.
      • So what does this mean? That ME patients cannot deal with increased O2 throughput (required to make energy via aerobic metabolism) and therefore their bodies restrict it to prevent oxidative damage.
  • Isovolumetric Relaxation Time (IVRT)
    • This is the time between between the Aortic valve closing and the Mitral valve opening.
    • It essentially is the time required for the cardiac cells to pump out all the calcium in them into the extracellular space.
      • This requires free energy to pump the calcium out of the cells - so the longer it takes, the less free energy is available in the system. 
      • IVRT is inversely proportional to the available energy in the cardiac cells.
    • IVRT is elevated in ME and when given oxygen it gets worse transiently and then goes back to baseline. This suggests that whatever causes the changes in IVRT is buffered and that people with ME have a difficult time buffering it compared to controls. 
    • This suggests oxygen toxicity and has been present in 100% of Dr. Cheney's untreated ME patients so far (N>500)
    • What is it that is being buffered? The only thing that really makes sense (given that 1/IVRT ~ Free Energy (G) and the Gibb's free energy equation) is the entropy or oxidative stress of the system. This biochemical process of buffered oxydation/reduction can be called "the redox state" (see 13:45 if interested).
  • Other cardiovascular complications associated with low cardiac output in ME
    • Patent foraman ovale (PFO) - in 89% of cases (N=60)
      • Collapse of left atrium causes pressure differential which can blow open the formerly closed foramen ovale.
    • Chronic cerebrospinal venous insufficiency (CCSVI) - 100% of cases so far (N=20)
    • Chronic hepatic venous insufficiency (CHVI) - 100% of cases so far (N=20)
      • These are all due to increased ventricular squeeze to compensate for low cardiac output.  
        • CCSVI and CHVI destroys normal capilary flow which causes decreased nutrient and oxygen delivery to the central nervous system and liver and inability to effectively remove toxins from both.
        • Worst of all is that the primary redox control center is impaired, particularly NADPH production, which occurs in the liver.
  • Chronic cerebrospinal venous insufficiency (CCSVI)
    • First discovered in MS patients. Also found in Autism and Chronic Lyme disease.
    • Likely causes many of the cognitive abnormalities found in ME.
  • Chronic hepatic venous insufficiency (CHVI)
    • Can impact the detoxification, immunologic, and nutrient processing functions of the liver.
    • Linked to pure diastolic dysfunction
    • Because of large right ventricular squeeze and low pressure of the blood coming back into the heart, tricuspid regurgitation occurs which transiently reverses blood flow of the veins draining into the right side of the heart (inferior and superior vena cava).
  • Nasal Vasoactive Intestinal Peptide (VIP) treatment:
    • Tested on a few cases so far. It has decreased the Tricuspid reflux response by 8-38% after 5 minutes.
      • It does this because VIP is a potent vasodilator of the pulmonary vascular bed - it simply decreases the blood pressure in the lungs so that it is easier for the right side of the heart to push the blood through the lungs (the correct direction).
    • It has either significantly reduced or completely abolished flow reversal in the hepatic veins (liver)
    • What is VIP?
      • 28 Amino Acid Peptide
      • Member of the Glucagon/Secretin superfamily
      • Similar to Growth Hormone Releasing Hormone
      • Produced in the gut, pancreas and hypothalmus
      • VIP receptors (G-protein coupled receptors) are found in the central nervous system, liver, lung, intestine, T-lymphocyte, heart, adipose tissue, kidney, skeletal muscle, testis, and stomach.
      • Responsible for circadian rhythm
      • Increases intestinal motility, pancreatic secretion, biliary secretion (note ME patients almost always have reduced biliary secretion), stomach pepsin secretion, inhibits stomach acid, increases chronotropism and inotropism in the heart.
      • Most importantly it is a FDA approved pulmonary vasodilatory for pulmonary arterial hypertension. This makes it easier for the right ventricle to push blood through the lungs so that it does not reflux into the liver and brain as much.
    • Paper by Shoemaker RC, et al. for treatment of 20 patients with chronic inflammatory response syndrome due to water damaged buildings (CIRS-WDB).
      • These patients are clinically very similar to ME patients and treatment with VIP worked very well (See 25:30)
        • Corrected numerous inflammatory biomarkers and hormones.
        • Reduced pulmonary artery pressure and increased T-reg cells (CD4+ CD25+).
        • Enhanced quality of life in all 20 patients.
  • Physiology of CCSVI and CHVI (overview, previously talked about)
    • Poor redox control → low free energy levels → diastolic dysfunction → low cardiac output → low venous return to the heart → compensatory high ejection fraction → tricuspid regurgitation → flow reversal in inferior and superior vena cava → flow reversal in veins draining brain and liver. 
      • What causes impaired redox control? No one knows.
  • Are viruses linked to ME? 
    • Natural immunity pathway (see 29:00 for full pathway)
      • Essentially the point is that in CFS patients in the Lake Tahoe region (at least in the beginning of their illness) had highly up-regulated this anti-viral pathway suggesting some sort of viral insult.
    • HHV-6 
      • Is found in the general population, the cause of Roseola (B-strain). 
      • There are 2 major strains: the B-strain is what causes Roseola, and the A-strain which is associated with neuroinflammatory diseases including AIDS, MS, and ME.
      • It can persist in various tissues and integrate itself into your DNA.
    • Epstein Barr Virus
      • Causes mononucleosis, persists in tissues, can alter human genomic expression, and is cable of activated human endogenous retroviruses (HERVs).
    • Retroviruses (See 31:52 for more info)
      • Essentially nothing has panned out so far for a specific exogenous retrovirus.
      • Small study by De Meirleir showed some immunoreactivity against HERV proteins - this may suggest that HERVs are activated in this disease.
        • One of the proteins found - HERV envelope (env) protein produces nagalase activity. 
  • GcMAF Treatment
    • Elevated Nagalase 
      • Nagalase is an enzyme that destroys the precursor to GcMAF. GcMAF is important for immunocompetence (it activates macrophages).
      • Diseases with the highest Nagalase activity include AIDS, cancer, and ME/CFS. Nagalase levels in cancer and ME are very similar.
      • Nagalase activity is highly correlated to disease severity or disability measured by KPS (see 36:35 for graph and explanation).
    • GcMAF is part of the functional vitamin D axis (see 37:45 for further explanation of GcMAF)
      • Essentially GcMAF regulates and is a crucial part of the immune system.
    • Study with 19 CFS patients taking chemical GcMAF under the tongue.
      • 37% had significant clinical improvement
      • 21% did not respond or got worse
      • The rest had a mild to moderate positive response
      • Calcitriol normalization predicted positive responses to GcMAF
    • Study with Probiotic form of GcMAF - 21 patients.
      • Nagalase dropped in all cases, but patients only responded clinically if the calcitriol normalized, similar to the other study.
      • Decreased urinary thiosulfates (measure of gut toxicity)
      • 47.6% had a significant response positive response
      • 23.8% failed to respond
      • 28.6% had mild to moderate improvement
    • When treating with GcMAF the response curve is an inverted U shape (see 49:30 for graphic). 
      • If you decrease Nagalase to a moderate level when it is really high patients tend to get better, but if you decrease it too much the patients get worse.

Sunday, April 7, 2013

How I Presented With Myalgic Encephalomyelitis (ME)

I won't go into too much detail, but I am doctor and was in the middle of my residency training (specialty training after medical school) and everything was going really well: I was very healthy and physically active, was learning a lot and doing well in a residency that I loved.

Then one day I woke up and felt like I was getting a viral infection. I had a sore throat, fatigue, myalgias, headaches, and malaise. I went to work anyway because I usually just push through such things but throughout the day my symptoms became worse and worse so that by the time the day was over, I was barely able to walk and had to take multiple little breaks to make it back to my car.

I was not too concerned at first - I thought it was probably a relatively harmless virus, or at worst, the flu, and that it would go away quickly. Unfortunately I was wrong and it got worse until I was bedridden and had to be cared for completely by my spouse within about a week. By this time I knew this was not the flu or anything remotely similar to any infection I ever had before - it was nothing like the flu or mono that I had personally experienced, or anything I had ever learned about in my extensive training. I went to a local doctor who, even though I was also a MD, didn't really listen to me when I tried to explain this this was no simple virus, and told me I would be fine in a couple more days. He ran some standard blood work that appeared relatively normal. After a couple days I decided to try to go back to work and will myself into feeling better - that lasted a couple hours before I literally could not stand or sit upright anymore. That was the first time that I noticed how slow my cognition had become and how my brain wouldn't correctly filter out ambient stimuli any more.

One of the reasons I decided to become a physician and went to medical school in the first place was that I am close to some individuals who have ME (they were diagnosed with chronic fatigue syndrome at the time) and saw how much they suffered from the illness itself and at the hands of those who swore to "first do no harm...."  Consequently, I kept up with the developments in the ME/CFS world throughout medical school and ever since. Because of that knowledge, it did not take me very long to figure out I had a classic moderate to severe case of Myalgic Encephalomyelitis per the international consensus criteria paper. I hoped and prayed that I was wrong. I even hoped something that, before that point in my life, I never thought possible - that it would turn out to be something else, anything else, even terrible diseases like HIV, lupus, a number of different cancers, etc. rather than the untreatable, severely disabling, and poorly understood disease I knew was wreaking havoc on my body.

I went to a few more local doctors who could not figure out what was wrong with me even though they had to admit something was wrong since normal people don't have a 60 beat per minute increase in their heart rate from lying down to standing, but they were downright unwilling to listen to anything I had to say regarding ME or even postural orthostatic tachycardia syndrome (POTS), which was blatantly obvious! Those doctors had never heard the term ME and clearly thought people with CFS were in some sort of gray area that they didn't really know what to do with, even though when questioned, actually had no idea what CFS really was other than that it involved "fatigue" in some way :-)

Eventually I went to one of the "ME specialists" in the USA and was officially diagnosed with ME based on my history, physical exam, and a number of diagnostic studies. Unfortunately, since then I have not significantly improved - I remain bedridden on bad days and essentially housebound on good days. So, at this point, this is not a story about how I beat ME, or an encouraging story about recovery, but just an honest one that I hope will help others with this same debilitating disease.

In the next few posts I will write about some things that I hope will help others including how to interact with doctors, what diagnostic studies may be helpful, and my own personal theories regarding the pathophysiology of ME. In the future, I hope to write summaries and critiques of ME research articles and whatever I feel might be beneficial for people reading my blog.

Soon, I will create a section where you can send me requests for things that you would like me to write about, but you can also use the comments feature on any of my posts.

At this point I wish to remain anonymous for a number of reasons but that could change in the future depending how things work out. Due to the fact that I am a physician I also have to include a disclaimer: anything I say in this blog is my own personal opinion and will undoubtedly change over time; this blog does not establish a doctor-patient relationship; nothing written here is specific medical advice for anyone; any changes to your treatment should always be handled by you and your personal physician.