This unusual paper “Investigating Fatigue and Exercise Intolerance in a University Immunology Clinic” is the outcome of 20 years’ work (1998-2019) at the SUNY University immunology clinic in Buffalo, New York by the primary care doctors, rheumatologists, and others trying to figure out what was causing the “life-altering fatigue and exercise intolerance” they’d found in some of their patients.
After normal laboratory tests failed to provide an explanation for the mysterious exercise intolerance, they turned – noting that the most common symptoms of a metabolic disorder are fatigue and exercise intolerance – to tests for metabolic disorders. (They also noted that other symptoms commonly found in their patients (heat intolerance, difficulty with some medications, recurrent infections, gut motility problems, and accelerated osteoarthritis) also frequently show up in metabolic disorders.) They focused on metabolism because metabolic processes produce the adenosine triphosphate (ATP) used to power our cells.
- Immunologists at SUNY University at Buffalo have been digging into metabolic abnormalities in over 300 patients with mysterious problems with exercise intolerance and fatigue for over 20 years.
- Over eighty percent of the patients in the study were diagnosed with fibromyalgia.
- The study “Investigating Fatigue and Exercise Intolerance in a University Immunology Clinic” used lactic acid blood tests, ischemic forearm tests, muscle biopsy, biochemical tests, and genetic tests to determine if metabolic dysfunctions were present.
- The study reported that the testing provided a ‘treatable diagnosis” for 95% of those in the study.
- High lactate and/or CPK levels, muscle atrophy, abnormalities mitochondrial respiratory chain function, low carnitine palmitoyl transferase activity, and abnormalities in an enzyme in the glycogen storage pathway were common.
- The authors matched the metabolic dysfunctions found with rather simple treatment protocols involving mitochondrial enhancers and/or different diets. Dosing was not provided. They reported that many patients received “life-altering” responses. Those responses, however, were not quantified.
- The treatment response was not the big news from the study. Aside from the fact that dosing and treatment responses were not quantified, more and better treatment options now exist.
- The big news from the study concerned the widespread metabolic dysfunctions found which could conceivably be contributing to or causing the mysterious exercise intolerance and fatigue found.
- The authors pointed out that metabolic dysfunctions can be hidden until other stressors arise, that they can arise in middle age and they’re being investigated in more and more diseases.
Many of the 372 patients included in this overview, they noted, had been sent to psychiatrists prior to seeing them.
Strangely enough, chronic fatigue syndrome (ME/CFS) is mentioned only once in this paper (to point out it may be a metabolic disorder) and is not included in the diagnostic section. This is probably not unusual and probably just reflects the diagnostic thrust the doctors at this University have taken. When confronted with a patient with fatigue, pain, and exercise intolerance they usually diagnose her/him with fibromyalgia (FM). (Over 80% of the patients in this overview had been diagnosed with FM.) With their high rates of gut problems and migraine they looked very much like ME/CFS/FM. That no instances of orthostatic intolerance were noted probably reflects the doctor’s focus on FM; orthostatic has only recently begun to be assessed in FM.
The patients in the study had been diagnosed with a variety of conditions:
- Fibromyalgia – 81%
- Gut motility and IBS problems (gastroesophageal reflux, gastroparesis, nausea, vomiting, constipation, diarrhea, pseudo-obstruction) – 73%
- Migraine – 54% (as of the patients with migraines responded to centrally acting vasodilators, the authors believed they probably had reversible central nervous system vasospasm, or Raynaud’s of the brain
- Food hypersensitivities – 45%
- Recurrent infections – 44%
- Raynaud’s Disease – 37%
- Asthma – 17%
- Accelerated osteoarthritis (possibly due to poor muscle function supporting the joints)- 15%
- Anti-phospholipid antibodies – 15%
- Sjogren’s syndrome – 14%
- Depression – 11%
- Inflammatory arthritis – 10%
- Peripheral neuropathy – 6%
- Dyspnea – 5%
All the patients were given complete blood counts, comprehensive metabolic profiles, urinalysis, carnitine, TSH, free T4, CPK, ammonia, lactic acid blood test, and, in most cases, an ischemic forearm test.
Ischemic Forearm Test
They used an ischemic forearm test to assess changes in lactic acid and ammonia during exercise. (The test stresses one’s ability to produce energy using anaerobic metabolism).
Lactic Acid Blood Test Interpretation
- Normal lactic acid levels – lactic acid and ammonia rise 3-4 times the baseline levels.
- Failure of lactic acid to rise – glycogen storage disease
- Failure of ammonia to rise appropriately – a myoadenylate deaminase deficiency or a disorder of the urea acid cycle
- Elevated lactic acid test at rest on more than one occasion – increased reliance on glycolytic metabolism, suggestive of a mitochondrial disorder .
Muscle biopsies were done in patients with normal or confusing lab findings, patients who failed to respond to treatments, and/ or patients who just wanted to search further.
The muscle biopsies assessed the levels of a wide variety of compounds (carnitine palmitoyl transferase, myoadenylate deaminase, phosphorylase, phosphorylase b kinase, phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, acid and neural maltase, NADH dehydrogenase, NADH cytochrome c reductase, succinate dehydrogenase, succinate cytochrome c reductase, cytochrome c oxidase and citrate synthase.)
Biochemical studies were done in most patients. They included: carnitine palmitoyl transferase, myoadenylate deaminase, phosphorylase, phosphorylase b kinase, phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, acid and neural maltase, NADH dehydrogenase, NADH cytochrome c reductase, succinate dehydrogenase, succinate cytochrome c reductase, cytochrome c oxidase and citrate synthase from freshly obtained muscle biopsies. In some patients CoQ10 levels were also assessed.
Whole-exome/mitochondrial DNA sequencing
Genetic studies (whole exome/mitochondrial DNA sequencing) were done in 83 patients.
Ischemic Forearm and blood lactic acid tests:
- Forty-six percent of the participants had an elevated lactic acid at rest. Forty-seven percent had an elevated CPK at rest.
- Ischemic Forearm Tests about half (48%) of the participants had an abnormal result during the ischemic forearm test.
- Ninety of the 123 patients with abnormal ischemic forearm tests had findings that allowed a treatment strategy to be initiated.
- Serum carnitine was low in only 17 patients (5%).
Muscle Biopsy Findings
Few people had normal biopsy findings (11%) with muscle fiber atrophy commonly found (67%). Besides inflammatory myositis found in 11%, other abnormalities were rare (ragged red fibers or abnormal mitochondria on EM (4%), inclusion body myositis (3 patients), abnormal lipid deposition (1 patient), abnormal glycogen deposition (1 patient), and vasculitis (2 patients).
Mitochondrial Respiratory Chain Activity
The complexes refer to the different parts of the mitochondrial respiratory chain where aerobic energy is produced. Complex 1 and complex 3 activity was dramatically reduced in 33% and 22% of patients respectively.
- Complex 1 activity <70% – 71/216 (33%)
- Complex 1 activity <50% – 10/216 (5%)
- Complex 2 activity <70% – 15/216 (7%)
- Complex 2 activity <50% – 1/216 (0.5%)
- Complex 3 activity <70% – 48/216 (22%)
- Complex 3 activity <50% – 13/216 (6%)
- Complex 4 activity <70% – 16/216 (7%)
- Complex 4 activity <50% – 5/216 (2%)
Biochemical Study Results
CoQ10 activity was reduced in 22% of patients. Carnitine palmitoyl transferase activity was down <65% in 32% and LDH activity was <20% in 27% of the 216 patients tested.
Of the 83 patients given genetic tests, 17% had a glycogen storage disease of some type (Pompe, McArdle’s and Tarui disease, types IX, XIII).
Deep Dive into Metabolics Provides “Treatable Diagnosis” for Many
No studies have dug as deeply into mitochondrial and energy production issues as this study. The authors reported that the deep dive worked provided 95% of patients with a “treatable diagnosis”. Providing 58% of the treatable diagnoses, the biochemical studies were the most revealing followed by the genetic (21%) and laboratory (20%) studies.
The treatable diagnoses included
- abnormalities of a mitochondrial respiratory chain function (168 patients)
- abnormalities of an enzyme in the glycogen storage pathway (78 patients)
- low carnitine palmitoyl transferase activity (70 patients)
- defects in other mitochondrial proteins (12 patients)
- mutations in proteins associated with congenital myopathies (11 patients)
- mitochondrial depletion syndromes (8 patients)
- abnormal myoadenylate deaminase (7 patients)
It should be noted that because other treatments to address things like sleep apnea, food hypersensitivities, and Raynaud’s were provided, all the improvements may not have been the result of the metabolic treatments. (The doctor clearly believed they were essential).
One of the great questions regarding enhancing mitochondrial activity involves targeting the specific energy production problems found with the right treatments. Different treatments were employed depending on which abnormalities were found. Doses, unfortunately, were not given.
Treatments For The Metabolic Conditions Found
Mitochondrial dysfunction or mitochondrial respiratory chain disorders – people with these issues were treated using a fairly standard mix of energy enhancing and antioxidant boosting supplements
- CoQ10 – transports electrons between complex 1 and III
- Carnitine – imports fatty acids into the mitochondria
- Alpha-lipoic acid (ALA) – strong antioxidant
- Creatine – generates ATP via the creatine phosphate shuttle
Low carnitine palmitoyl transferase activity – diets minimizing long-chain fatty acids. (Long-chain fatty acids are found in most fats and oils, including olive oil, soybean oil, fish, nuts, avocado, and meat.
Glycogen storage problems – diets that restricting complex carbohydrates with larger amounts of simple sugars
Low lactate dehydrogenase activity – provided treatments for mitochondrial dysfunction (because of the influence of lactic acid on mitochondrial functions)
Myoadenylate deaminase deficiency – D-ribose plus the mitochondrial supplement treatments
The authors reported that while improvements in treatments for metabolic disorders are clearly needed that the treatments were “life-altering for many of these patients”. That, unfortunately, was the end of the story.
We don’t know what “life-altering” means (10%, 20% more functionality? 50%???) nor were any statistical analyses done. We simply know that the doctors considered the treatments “life-altering for many of (their) patients.”
This rather astonishing paper contains thirty years of work documenting the metabolic results in around 300 patients with a fibromyalgia/chronic fatigue syndrome-like diagnosis. We’ve never seen anything like it. Unbeknownst to us, doctors at a University Immunology center in New York have been working away for decades on a topic – metabolic disorders – that’s only now getting much attention in the fibromyalgia / ME/CFS world.
With their forearm test, their muscle biopsies, and their biochemical and genetic analyses this University group tried harder than any medical group I’ve seen to try to metabolically explain the strange exercise intolerance found. In fact, given that exercise intolerance implies problems producing energy exist it seems strange that we haven’t seen these kinds of analyses more often.
Many abnormalities were found with particularly high rates of increased lactic acid levels at rest or after the ischemic forearm test (%50), CPK levels at rest (47%), and muscle atrophy (67%).
Other common diagnoses included: reduced Complex 1 activity (33%), reduced carnitine palmitoyl transferase activity (32%), reduced LDH activity (27%). reduced complex 3 activity (22% ), reduced CoQ10 level (22%), glycogen storage problem (17%).
The treatments were simple, dosing was not provided, no control groups were present and treatment effects weren’t quantified.; i.e. the treatment news wasn’t the highlight of this study. Better treatments are available. Health Rising’s Mitochondrial Enhancing Series, for instance, is not nearly done and it’s already covered some potential mitochondrial enhancers they didn’t use.
The Mitochondrial Enhancers for Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia Series
- Pt I: D-Ribose, CoQ10 and PQQ
- Pt II: L-carnitine and Acetylcarnitine
- Pt. III: Magnesium
- Pt IV: N-acetyl cysteine (NAC)
- Pt V: Oxaloacetate
Plus, new and better forms of CoQ10, as well as “new” supplements like oxaloacetate, are showing up. Since defective mitochondria are often inflammatory mitochondria that further impair mitochondrial production, more effective antioxidants (new forms of NAC, glutathione, cysteamine, hydrogen sulfide donors, and intranasal preparation for the brain) and antioxidant protocols promise more help for these problems.
The big news from this study was the high degree of metabolic dysfunction found. The authors noted that metabolic disorders are greatly underdiagnosed and that many people who unknowingly have them have found their way around by altering their activities. People with inherited metabolic disorders typically avoid competitive sports; people with glycogen storage diseases often learned to avoid complex carbohydrates. It’s only when other stressors such as infections (which cause post-infectious illnesses) is it clear that something has gone really wrong.
These metabolic disorders can have surprising downstream effects. Metabolic problems with immune cells, they report, can result in recurrent and long-lived infections which then further impair gut functioning, causing food hypersensitivities and increasing the risk of autoimmunity. Metabolic disorders can affect blood vessel functioning – possibly a very big deal in ME/CFS/FM and long COVID – by reducing the production of such important vasodilators like nitric oxide. Mitochondrial problems are being investigated in many neurological diseases including Parkinson’s Disease, multiple sclerosis, and migraine.
Plus, in a statement that has potentially important implications for ME/CFS, FM, and long COVID, the authors report that it’s become clearer over time that many metabolic disorders can pop up as a result of another disease or stressor. People with hypoxia-producing diseases, for instance, can develop secondary mitochondrial dysfunction as a result of oxygen deprivation. People with sepsis can develop “multiple secondary metabolic disorders”. Chronic inflammation can damage the mitochondria where the inflammation is occurring.
The fact that the paper didn’t come close to meeting rigorous standards of academic scholarship shouldn’t be a surprise. This was an apparently unfunded effort by a group of researchers and doctors to get the word out and inspire others to investigate these diagnoses, treat them, and inspire more rigorous studies. While this study is clearly not the answer to the question of how important metabolic disorders are in ME/CFS/FM – we need studies with better methodologies – it’s hopefully a stepping stone to those studies.
One such study is underway. Dr. Camille Birch found rare mutations that could be affecting the energy metabolism in five out of ten ME/CFS patients. Among other things, several of those mutations could be producing glycogen storage issues similar to those reported in this study. Aided by a Ramsay Award from Solve ME Birch is taking a deep dive into genetically produced metabolic dysfunctions in ME/CFS – some of which might not be manifested until middle age or until other stressors appear.