It took a muscle biopsy to uncover it but there it was – strong evidence, apparently, of a bona fide mitochondrial deficiency in some people with fibromyalgia (FM).
Julian Ambrus, the senior author of this paper has published widely in and developed an animal model for Sjogren’s Syndrome, helped produce better diagnostic tests for the disease, is establishing a Sjogren’s Syndrome Center, and is working with drug companies to create better treatments.
Ambrus also hopes to create a center devoted to the study and treatment of metabolic diseases. Ambrus believes metabolic disorders lie at the heart of common symptoms like fatigue, exercise intolerance, gastrointestinal dysmotility, recurrent infections, and accelerated osteoarthritis.
In 2012, he published a case report of a woman with fibromyalgia for whom the standard treatments weren’t working. She was very weak, was unable to get out of bed by herself or hold dishes in her hands to wash them.
First, a muscle biopsy demonstrated decreased levels of citric acid synthase (49% of normal), cytochrome c oxidase (53% of normal), succinate dehydrogenase (72% of normal), and nicotinamide adenine dinucleotide (NADH) dehydrogenase (73% of normal) – all signs of a defect in the mitochondrial respiratory chain.
Genome sequencing next revealed multiple polymorphisms (small changes in the DNA) (POLG1 polymorphisms (C-T polymorphism at 2254, and G-T polymorphism at 3708)) and several mitochondrial genome polymorphisms (1438 A-G, 3992 C-T, 14365 C-T, 14582 A-G, and 4042 A-G) which further cemented a mitochondrial diagnosis.
She improved significantly on a simple formula of coenzyme Q10 (ubiquinone) 200 mg, creatine 1,000 mg, carnitine 200 mg, and folic acid 1 mg taken four times a day. Each was designed to enhance a different part of the mitochondria:
- Co-Q10 transports electrons between complex I and complex III of the mitochondrial respiratory chain
- Creatine generates additional ATP through the creatine phosphate shuttle
- Carnitine enhances the transport of fatty acids – a vital substrate – into the mitochondria.
- Folic acid is necessary for several mitochondrial enzymes to work
- A-lipoic acid is a strong antioxidant.
It took several months, but the woman responded well and reported that she is able to “enjoy normal activities and more”.
Eight years later, the Ambrus group published a follow-up, “Carnitine Palmitoyl Transferase Deficiency in a University Immunology Practice“, which described the results of metabolic workups and treatment plans for 35 patients reporting exercise intolerance and fatigue over time at a university clinic. Many of those patients had been diagnosed with fibromyalgia, most were women, and most had become ill in their 20s and 30s. Quite a few were also diagnosed with Raynaud’s Syndrome, migraine, and gut issues.
Besides fatigue and exercise intolerance, these patients commonly experienced gut problems (diarrhea, constipation, acid reflux), arthritis, headaches, frequent infections, shortness of breath, and others.
The muscle biopsies of these mostly fibromyalgia patients revealed they all had low carnitine palmitoyltransferase activity (at least a third below normal) and about a third of them had another biochemical abnormality. Note that only one patient had low plasma carnitine levels.
All Ambrus’s patients were put on a diet low in long-chain fatty acids, which emphasized the use of medium-chain triglyceride (MCT) oil.
Patients were also given supplements known to enhance ATP generation within the mitochondria (CoQ10, carnitine, folic acid) and outside the mitochondrial (creatine) along with antioxidants (alpha-lipoic acid, and in some cases, vitamin C and/or vitamin E.
The improvements were not quantified. Instead, the paper stated that all the patients showed some symptomatic improvement in fatigue and exercise intolerance.
Long-Chain Fatty Acid Disorders
Fats are categorized by the length of the carbon chains they contain.
Short-chain fats have fewer than six carbons, medium-chain fats have between six to 12 carbons and long-chain fats have between 13–21. The shorter the carbon chain, the easier it is to break down the fat and turn it into energy. On the other hand, longer carbon chain fatty acids (such as Omega 3s) can play important roles in reducing inflammation.
While short and medium-chain fatty acids can get directly absorbed into the mitochondria, the process of preparing longer chain fatty acids for use is more complicated and takes much more work. They need to be broken down and then transported via carnitine into the mitochondria, where they need to get unloaded from carnitine. Several enzymatic reactions are required to carry out this process.
A good deal of the focus on long-chain fatty acid disorders appears to be in inborn errors of metabolism that quickly and dramatically assert themselves early in life and often result in death. These disorders affect either fatty acid transport via the carnitine pathway or mitochondrial b-oxidation (fatty acid metabolism that takes place inside the mitochondria).
They may also, though, crop up later in life and manifest themselves as rhabdomyolysis, sudden weakness, muscle pain, and kidney problems.
People with mild or moderate forms of a long-chain fatty oxidation disorder may only experience symptoms when increased β-oxidation is needed, such as during exercise or fasting, or if Ambrus is right, symptoms may be present most of the time in fatigue and exercise intolerant diseases like fibromyalgia and ME/CFS.
Long-Chain Fatty Acid-Restricted Diets
This diet was an eye-opener for me as it’s almost opposite to my current diet, which is heavy on long-chain fatty acids (nuts and nut butter, olive oil, avocados, oily fish).
According to a 2018 paper, “Fatty acid oxidation disorders,” the treatment of long-chain fatty oxidation disorders (FAODs) – the kind found in this study – involves a long chain fat-restricted diet, supplementing with medium-chain triglyceride (MCT) oil (to support b-oxidation) and an essential fatty acid called docosahexaenoic acid (DHA – 60 mg/day for infants <20 kg; 100 mg/day for children >20 kg; and 100–200 mg/day for adults).
In severe forms of the condition, long-chain fatty acids may need to be restricted to 10% of energy and MCTs may need to make up as much as 20–30% of energy, 12% from protein, and 60-70% from carbohydrates. (A higher protein diet is now being assessed.) People with mild or moderate forms of the condition may require long-chain fatty acids to be restricted to 15–20% of energy intake. Metabolic centers will prescribe a daily limit in the number of grams of long-chain fat allowed and patients are educated about how to count grams of fat in food.
It was surprisingly hard to find much information on long-chain fatty acid levels in foods. According to one article, long or very-long-chain fats are saturated fats (mono or polyunsaturated) and are found in the following foods:
- Saturated long-chain fats – dairy fat, coconut oil, palm kernel oil, peanut oil, and other vegetable oils
- Monounsaturated long-chain fats are found in most animal and vegetable oils, but particularly macadamia, olive, canola, and safflower oil
- Polyunsaturated long-chain fats – are found in seeds, nuts (including peanuts), and some vegetable oils, avocados, meat, eggs, fish, oily fish, and marine oils.
(Omega-3 and omega-6 are both long-chain fatty acids. Omega-3s tend to be anti-inflammatory while high levels of omega-6s are pro-inflammatory.)
Some long-chain fat consumption is needed and should come from foods like butter, walnuts, or flaxseed oil, fatty fishes (sardines, salmon, mackerel). Lean fatty meats and non-fat milk are used as protein sources.
Since exercise places a large demand on fatty-acid produced energy, MCT (0.15–0.2 g/kg weight) is usually mixed with a glucose solution (e.g., Gatorade®) prior to exercise, and then a high carbohydrate/protein snack (3:1 carb/protein) taken afterward.
Relapses after exercise, fasting, and illness are treated by drinking carbohydrate-rich fluids and taking extra MCT every 3–4 hours. If that doesn’t work, the patient needs intravenous fluids.
Medium Chain Fatty Acid Foods – medium-chain fatty acids have shorter carbon chains (6-12) and are metabolized differently. I couldn’t find much information on medium-chain fatty acid foods either, but webpages tended to note milk, butter (particularly grass-fed), cheese, yogurt, coconut oil, goat milk, and palm kernel oil). (Some of these (butter, cheese) overlap with long-chain fatty acid foods presumably because they are rich in both). With @65% of the fatty acids in coconut oil taking the form of MCTs, coconut oil may have the highest MCT content of any food and some doctors believe coconut oil is a good choice.
It appears, though, that most medium-chain intake in long-chain fatty acid-restricted diets occurs through supplementation with something like MCT oil.
- Muscle biopsies reveal abnormalities in fatty acid metabolism in fibromyalgia. Carnitine is necessary to transport long-chain fatty acids into the mitochondria. Shorter chain fatty acids, on the other hand, are able to simply enter the mitochondria.
- Low carnitine palmitoyltransferase activity suggested that long-chain fatty acids were not being metabolized correctly – thus impeding them from entering and providing fuel for the mitochondria. About a third of the patients also had another biochemical mitochondrial abnormality.
- The authors reported that a low long-chain fatty diet plus mitochondrial supplements helped. Long-chain fatty acids are found in foods like olive oil and other vegetable oils, nuts, nut butter, oily fish, fatty meats, dairy fat, avocados.
- Medium-chain fatty acids take the place of long-chain fatty acids in the restricted long-chain fatty acid diet. These fatty acids are commonly found in coconut oil and MCT oil and some other foods. Lean meats and non-fat milk products are used for protein and carbohydrates make up from 50-70% of the diet.
- MCT oil is often used to add these fatty acids to the diet. MCT is easily absorbed and may be able to help with gut problems and inflammation. It should be taken in small amounts at first (1 tsp/day) to allow the stomach to adjust to it.
- Since exercise places a large demand on fatty-acid produced energy, MCT oil is usually mixed with a glucose solution (e.g., Gatorade®) prior to exercise, and then a high carbohydrate/protein snack (3:1 carb/protein) taken afterward.
- Relapses after exercise, fasting, and illness are treated by drinking carbohydrate-rich fluids and taking extra MCT every 3–4 hours.
One doctor warns to start MCT supplementation slowly (1 teaspoon/day and working up to 1-several tablespoons/day) as MCT oil can produce stomach problems (loose stools, diarrhea, gas, bloating, abdominal pain) if the stomach is not used to breaking it down.
Carnitine Issues in Chronic Fatigue Syndrome (ME/CFS)
Carnitine issues seem to be inherent in long-chain fatty acid disorders. While some studies have shown evidence of reduced carnitine levels in ME/CFS, others have not. The most complete study – an Australian study, “Long-chain acylcarnitine deficiency in patients with chronic fatigue syndrome. Potential involvement of altered carnitine palmitoyltransferase-I activity“, found that reductions in two carnitines: oleyl‐l‐carnitine (C18:1) and linoleyl‐l‐carnitine (C18:2), were highly correlated with fatigue levels in ME/CFS.
That suggested the CPT-1 enzyme that binds fatty acids and carnitine together for entry into the mitochondria was punking out. The authors proposed supplementing omega‐3 fatty acids in combination with l‐carnitine in order to boost CPT-1 activity. Omega 3 fatty acids can be helpful because they already exist in a form the mitochondria can use.
The Peroxisome Connection
Recently, the Lipkin metabolomic study suggested that both low carnitine levels and low peroxisome activity are present in ME/CFS. Both carnitine and peroxisomes, interestingly, are involved in the breakdown or transport of long-chain fatty acids into the mitochondria.
After the peroxisomes break down, these fatty acids carnitine transports them into the mitochondria. The breakdown of either factor could starve the mitochondria of the fuel it needs.
Given the role peroxisomes play in breaking down long chain fatty acids, it would be good to know more about fatty acid metabolism in ME/CFS.
Long-chain fatty acid oxidation disorders are just one of quite a few fatty acid metabolism disorders, and many more metabolic disorders exist. Preliminary results suggest that several inborn errors of metabolism may be more common in ME/CFS/FM than we think.
The authors of the carnitine polymerase transferase study in fibromyalgia, unfortunately, didn’t quantify how much their patients improved. Nor do we know how widespread the deficiency is in FM. In short, the study was hardly the epitome of rigor. It seemed like more of a “let’s get this information out into the scientific literature in hopes that someone will follow up on it” kind of study.
What we do know is that muscle biopsies did find evidence of carnitine polymerase transferase deficiency in some FM patients and that a dietary modification in combination with supplementation appeared to help. It was also clear that plasma carnitine levels missed almost all of the carnitine deficiencies found in this group.
That dietary modification presents an abrupt shift from the high-fat, moderate protein, low carbohydrate diets often prescribed for ME/CFS/FM to a lower fat, moderate protein, higher carbohydrate diet.
As exertion places strong demands on energy production a pre-exertion recipe has been developed. It includes MCT oil mixed with a glucose solution (e.g., Gatorade® (or oral rehydration solution?)) prior to exercise and then a high carbohydrate/protein snack (3:1 carb/protein) taken afterward.
Similarly, relapses after exercise, fasting, and illness are treated by drinking carbohydrate-rich fluids and taking extra MCT every 3–4 hours.