Vitamin B12 Deficiency



Chronic Fatigue Syndrome (CFS) or Myalgic Encephalomyelitis (ME)

Chronic Fatigue Syndrome (CFS) or Myaligic Encephalomyelitis (ME) is an ill defined disease that is characterized by a post exercise tiredness or malaise. The condition usually lasts for more than six months and in affected individuals is very disabling. Symptoms include muscle soreness, inability to concentrate (brain fog), headaches and severe mental and physical fatigue. In addition these symptoms may be accompanied by sensitivity to light, sounds and smells, digestive disturbances, depression, painful and often slightly swollen lymph nodes, and it may also be accompanied by cardiac and respiratory problems.


Causes of CFS

A wide variety of immune, endocrine, cardiovascular and central nervous abnormalities have been reported in CFS. Among the causes suggested for CFS include damage to parts of the brain governing cognition, memory, mood, energy and perception, an altered stress response, an unbalanced immune system, a hidden chronic infection, excessive production of free radicals, reduced intracellular glutathione, abnormal sympathetic nervous system activity, cardiac dysfunction and others. Many CFS sufferers are found to have sub-normal levels of vitamin D in their serum. Several researchers believe that CFS is a mitochondrial disease in which excessive, uncontrolled production of nitric oxide damages proteins in the mitochondria, and particularly in the electron transport chain. Whilst the exact cause of CFS may vary, a major group of CFS sufferers have also been found to have one or more mutations in the enzymes responsible for methylation. In these individuals it would appear that whilst they were able to exist as relatively healthy individuals, often not knowing that they had methylation associated mutations, some initiating factor such as a prolonged viral infection (HSV, Ross River, EBV, retrovirus, mycoplasma, rubella, candida albicans) (and possibly Lyme disease), excessive exercise,  Incomplete dietary supplementation, particularly with vitamin B12 and vitamin B2, combined with low vitamin D levels results in gradual loss of their vitamin B12 supplies leading to the CFS symptomology being apparent, and the subsequent discovery of their poor methylation status. CFS/ME individuals generally score very highly on symptoms of vitamin B12 deficiency, which would contribute to low methylation, and mitochondrial dysfunction.


Mitochondrial dysfunction and CFS/ME

Many studies have now shown that CFS/ME can be regarded as a mitochondrial dysfunction disease, with similar characteristics to genetically acquired mutations in vitamin B12 processing. Increased levels of reactive oxygen species (ROS) found in CFS have been shown to cause mitochondrial damage, similar to that observed in vitamin B12 deficiency, as too are primary defects in energy metabolism. The increased levels of ROS found in CFS patients could in turn account for the reduced methylation deficiency due to partial inactivation of methionine synthase, a known activity of elevated NO..


Genetic Linkage

Recently it has been postulated  that CFS may be related to defects in either folate metabolism and/or the methylation cycle, with a high incidence of sufferers have genetic mutations in the MTHFR, MTR, MTRR, MTS, NOS, DAO, BHMT, MAO, BHMT, COMT and/or SHMT genes. In addition many CFS individuals have genetically similar vitamin D receptor genes. It is possible that CFS sufferers have had these "inborn errors of metabolism" for much of their life, without experiencing any significant problem until some precipitating event such as stress or a chronic infection has triggered chemical changes inside the body thereby resulting in CFS. Closer inspection of the frequencies of these genetic alleles in CFS/ME sufferers and comparison to the general population has shown that it is only mutations in COMT and BHMT that are overly expressed in CFS/ME individuals, possibly casting a doubt on the genetic association with CFS/ME. A description of the associated genes and function can be found at the following web-site LINK


Biochemical Abnormalities in CFS/ME - Vitamin B12 deficiency and Vitamin B2 deficiency

Biochemical analysis of the blood and urine of CFS/ME individuals reveals many abnormalities, which in themselves suggest the true cause of both the generation and maintenance of the CFS/ME condition. Generally CFS/ME patients show high levels of oxalate in their urine, which in itself can not only cause some of the associated medical conditions of CFS/ME, but can discourage these individuals from eating high oxalate (and also high folate) containing foods, thereby leading to folate insufficiency. Serologically the majority of individuals have low range iron and ferritin levels, which may in itself lead to reduced activity of heme containing enzymes, and reduced function of the cytochrome system. Accompanying the reduced iron/ferritin levels there can be a condition called porphyria .in which various pyrole metabolites occur in the urine, which suggests an incomplete synthesis of the heme molecule. Close inspection of Organic Acids data shows that generally there is an increase in the levels of unprocessed short, medium and long chain fatty acids, which is commensurate with the weight gain seen by many people with CFS/ME and would appear to be incongruous with the chronic fatigue and post exercise malaise felt by many CFS/ME sufferers. Many CFS/ME individuals show signs of faulty energy metabolism in the Krebs (CAC) cycle, with elevated levels of succinic acid and citrate being common. All CFS sufferers that we have data for are deficient in both Adenosyl and Methyl B12. Around 80% show concomitant deficiency in functional vitamin B2.  Elevation in levels of lactate are also common, which may be a result of anaerobic metabolism during exercise, or alternatively improper processing of sugars, thereby adding to the observed fault in the Krebb's cycle. Metabolic markers can also be used to "look" at problems in the synthesis and processing of neurotransmitters. Here it can be seen that elevated levels of homovanillic acid (HVA)(a by-product of dopamine breakdown) are common as too is an elevation in the ratio of  HVA:Vanillylmandelic acid suggesting a problem in the processing of dopamine to nor-epinephrine and epinephrine. Many CFS/ME individuals have high levels of 5-HydroxyIndole acetic acid (HIAA) (a serotonin break-down product) and many  have a high Quinolic acid:HIA ratio. Reports indicate that the ratio of GSH:GSSG is low suggesting that the concentration of reduced glutathione in the cells is also low.


Current concepts on the development of CFS/ME

Currently it is thought that CFS/Me manifests itself in 2 main areas, the muscles and the brain. Evidence suggests that the post exercise muscle fatigue experienced in CFS is a result of uncontrolled, over-production of oxidizing agents such as nitric oxide and histamine in the muscles. The reduced capacity of the body to methylate, due to methylcobalamin/5MTHF deficiency, means that the CFS/ME sufferers have trouble in inactivating histamine, thereby prolonging its inflammatory effect in the muscles. The reduced level of intracellular glutathione (the body's natural anti-oxidant), which results from undermethylation, best replica watches lack of cystathione B-synthase activity or glutathione reductase activity, leads to increased damage of mitochondria, the electron transport chain and muscle fibres due to attack by nitric oxide and other strong oxidizing agents. This increased damage of actin and myosin filaments can be detected by increased levels of 3-methylhistidine in the urine of CSF/ME individuals following exercise. Low levels of SAM (due to undermethylation) leads in turn to a reduced production of creatine and creatine phosphate (an alternative short term energy supply) as well as reduced levels of carnitine, thus lowering the capacity to transport fatty acids into the mitochondria for energy production. Concurrent with the lack of methylcobalamin, there is also a reduced level of adenosylcobalamin, which in itself causes mitochondrial damage and a reduced ability to process ketones and odd chain fatty acids for energy in the muscle mitochondria.

In the brain, the lack of methylation activity leads to a reduction in the production of phosphorylcholine, choline and acteylcholine, as choline is converted to betaine to act as a methyl donor for SAM. In concert with the reduced amount of the neurotransmitter acetylcholine, lack of methylation leads to the production of improperly folded myelin basic protein thereby compromising the neuronal myelin sheath. The lack of adenosylcobalamin leads to the production of methylmalonic acid,(MMA), with extremely high levels often being apparent in the serum and urine of CFS/ME sufferers. Apart from the pro-inflammatory properties of MMA itself, the high levels of MMA can in turn lead to the incorporation of improper phospho- and sphingo-lipids into the myelin sheath. It has recently been shown that methylation is an essential part of the production of short term memory, and CFS/ME individuals often experience poor short term memory, difficulty concentrating and a lack of spatial awareness and brain fog.


The compromised folate cycling and methylation pathways resulting from the methylation mutations, combined with vitamin B12 deficiency also affects the ability of the body to produce a functionally intact gastro-intestinal tract, with the result that CFS/ME sufferers often have poor absorption of water soluble vitamins and have increased susceptibility to dietary allergens and toxins..


CFS Treatment and Vitamin B12

Many, many different treatments have been tried in an attempt to cure CFS, with little success. These treatments have included non-prescription pain medications, rest, anti-depressants, psychological counseling, cognitive behavioural therapy, genetic testing, sleeping tablets, and a whole bunch of alternative "natural" remedies, such as St John's Wort, borage seed oil, garlic, ginko, ginger, quercetin, spirulina, and shitaki mushrooms. Other remedies have tried to address various aspects of metabolic insufficiency and have included  high dose folate, or more recently 5MTHF, N-acetyl-cysteine, reduced glutathione, L-carnitine, betaine, and magnesium, Despite these attempts, the majority of people do not get better rapidly. Confounding the situation is the fact that nearly all of the people who get CFS were perfectly healthy before they succumbed to the disease and were not dependent upon any of these metabolic supplements, nor were using these classical or alternative remedies.


Recently, it has been found that many people have obtained significant benefit from repeated high dose treatment with high levels of vitamin D3, plus vitamin B2, and adenosylcobalamin and methylcobalamin. It is believed that this repeated high dose supplementation is required to stock both the body's methylcobalamin levels and also the adenosylcobalamin. Over time, and with the addition of high dose vitamin D supplementation the subjects appear to slowly return to their pre-CFS status. Restoration of brain function is very slow presumably because of the time required to repair the damaged myelin basic protein and the damaged myelin sheath which surrounds the nerves.  It has been found that it is almost  impossible to achieve sufficient levels of adenosyl and methyl cobalamin in the serum for replenishment of vitamin B12 levels in serum, tissue and the central nervous system using  high dose sub-lingual, or high dose oral tablets.


High dose supplementation has been greatly aided by topical administration of a special oil formulation containing Ado and MeCbl. Supplementation by injection of CN-Cbl or OHCbl has only been shown to be marginally effective. It is believed that the reason that supplementation with CN-Cbl or OHCbl is ineffective is because the high oxidizing environment within the cells of chronically B12 deficient individuals (such as in CFS/ME) prevents conversion of OHCbl and particularly CNCbl, to Ado or Me CBl For this reason it seems to be necessary to administer the two active forms of vitamin B12, namely adenosyl and methylcobalamin, and in addition vitamin B2 with Iodine, Selenium and Molybdenum, all of which are required to activate vitamin B2..


Dietary Supplementation for CFS

During the development of CFS/ME reduced methylation, due to the lack of folate and eventually vitamin B12, results in poor gastrointestinal health with the result that CFS/ME sufferers can also be low in B group vitamins. Poor GI health would also be a result of lower production of gut melatonin, an essential hormone for maintaining gut maturation and development. The absolute requirement for methylation by the body can lead eventually to changes in the levels of the essential membrane lipid, phosphorylcholine, as it is sacrificed to provide methyl groups for the body using the alternative methylation substrate, betaine, which can be derived from choline or /phosphorylcholine. Suggested dietary supplementation, to be taken in conjunction with folate or 5MTHF and Ado/Me Cbl aims to overcome these deficiencies and restock the body with phosphorylcholine, choline and acetylcholine, and to provide adequate supplies of B group vitamins. One of the best dietary sources of phosphorylcholine is lecithin, with the best source of lecithin being beef liver, eggs, toasted wheat germ, beef, brussel sprouts, broccoli, salmon, skim milk and peanut butter..


Further reading on CFS

Mitochondrial dysfunction and CFS 


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The statements on this site compose a compendium of generally recognized signs of vitamin B12 deficiency, and problems that can then ensue They also are formulated from a summary of relevant scientific publications. In addition they may contain some forward looking statements of a general nature.
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