B12 reference ranges are too low Can this be affecting you?

B12 reference ranges are too low Can this be affecting you? What is Vitamin B12 A water-soluble vitamin naturally present in some foods Cobalamins B12 exists in several forms and contains cobalt, thus compounds with B12 activity are called Cobolamins B12 is produced in the gut of animals to get it from your diet you have to eat meat, poultry, fish, eggs, dairy products Methylcobalamin & 5-deoxyadenosylcobalamin Two active B12 forms in human metabolism In mammals, vitamin B12 provides co-factors for two enzymes - methionine synthase - L-methylmalonylCoA mutase 1

Functions of Vitamin B12 Functions:! Erythrocyte formation! Neurological functions! DNA synthesis! Participates in the production of SAM! Lowers plasma and brain levels of homocysteine! Has anti-inflammatory properties Other Vitamin B12 Forms Methylcobalamin is essential for folate metabolism and is essential for the formation of choline containing phospholipids. It protects against NMDA glutamate receptor activity, regulates circadian rhythms, improves concentration, alertness and sleep quality. Hydroxycobalamin is a potent nitric oxide scavenger. It detoxifies cyanide so it is really good for smokers, cytoprotective and helps to recycle methionine. Adenosylcobalamin is required for the formation of succinyl CoA, which is involved in the formation of neural lipids. Cofactor for the methylmalonyl CoA mutase and methionine synthase enzymes. It is essential for energy metabolism, and required for normal myelin sheath production and nucleotide production. Deficiency gives rise to nerve and spinal cord degeneration. Cyanocobalamin is a synthetic form of Vitamin B12 of low biological activity, and has to be converted in the liver to a more active form. It contains cyanide and over time may have toxic effects. 2

B12 Metabolism (1) A member of corrin family: Cobalamin Serum Corrin 40 ~ 50% may be inactive B12 analogs with no function but competing with B12 for serum B12 binding capacity Human body does not synthesize cobalamin Major Source Food of animal origin: Meat, fish and dairy Bacteria synthesize B12 B12 Metabolism (2) http://www.ausnathealth.com.au/vitamin-b12-chemical-compound-sustains 3

http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3650358/ Gherasim C, et al. Navigating the B12 Road: Assimilation, delivery and disorders of cobalamin. J Biol Chem, 2013, 288:13186-13193; Whitehead VM, Acquired and inherited disorders of cobalmin and folate in children. BJH, 2006, 134, 125-136 B12 Metabolism (3) - digestion and absorption 4

B12 Metabolism (4) Cobalamin is digested from dietary protein and absorbed at the distal ileum as two active forms: Methylcobalamin Involved in erythrocyte maturation It is involved in methylation It enters into folate metabolism for formation of methionine that is essential for effective erythropoiesis (deficiency: anemia) Adenosylcobalamin Involved in myelination and neuronal function It is involved in methylmalony-coa mutase for synthesis of neuronal lipids to form myelin (deficiency: neuronal degeneration) So what can affect B12? Pernicious anaemia GIF (TCN3) Gene GIF = Gastric intrinsic Factor = serum cobalamin levels, methylcobalamin, adensoylcobalamin = impairement in methionine synthase (MTR), L-methylmalonyl-CoA mutase (MUT) enzymes Atrophic gastritis inflammation and deterioration of stomach lining Antacids/proton pump inhibitors reduce HCL ie: nexium, omeprazole (prilosec), rabeprazole (Aciphex) Gastric surgery ie: gastric bypass, stomach resections h"p://www.racgp.org.au/download/documents/afp/2011/september/201109oh.pdf 5

So what can affect B12? Gastrointestinal disorders like Crohns disease, coeliac disease, chronic pancreatitis, ileal disease, parasitic infections Alcohol Exposure to nitrous oxide it irreversibly oxidises the cobalt atom of B12 making it inactive. Inhibits methionine synthetase Mercury interferes with B12 s ability to cross the blood brain barrier Genetic disorders more later. Low dietary intake veganism, lacto-ovo vegetarianism, low animal source food intake, low stores and intake by breastfed infants. Other medications colchicine, histamine 2 receptor antagonists (H2RA) like Zantac, tagamet, pepcid, antacids Mylanta, metformin h"p://www.racgp.org.au/download/documents/afp/2011/september/201109oh.pdf, h"p://www.ncbi.nlm.nih.gov/pubmed/2803507, So who is more at risk? Vegetarians and vegans People over 60 years of age Anyone who has had any form of gastric surgery Anyone using proton pump inhibitors and drugs affecting B12 Anyone who uses nitrous oxide People with eating disorders People with Gastrointestinal disorders Babies born to and breast fed by women who are deficient in B12 h"p://www.racgp.org.au/download/documents/afp/2011/september/201109oh.pdf, h"p://www.ncbi.nlm.nih.gov/pubmed/2803507, 6

B12: Vegetarians at Risk (1) Foods Support B12 a. The adult RDA for vitamin B12 is 2.4 µg/day. b. The efficiency of absorption from liver is approximately 11% compared with 50% for other foods. http://naldc.nal.usda.gov/download/44472/pdf B12: Vegetarians at Risk (2) All vegans and anyone who does not regularly consume animal-based foods, and whose diets are un-supplemented or unfortified, will eventually develop vitamin B12 deficiency " 52% vegans and 7% vegetarians were classed as vitamin B12-deficient (the European Prospective Investigation into Cancer and Nutrition (EPIC)-Oxford cohort study) " No significant association between age or duration of subjects adherence to a vegetarian or vegan diet h"ps://www.mja.com.au/open/2012/1/2/vitamin- b12- and- vegetarian- diets 7

B12 Deficiency Signs and Symptoms Dementia Ataxia, falls Parasthesia and weakness in peripheral nerves Weakness, dizziness Numbness Tingling, pins and needles Confusion Depression, psychosis Megaloblastic macrocytic anaemia Mild or moderate leukopaenia or thrombocytopaenia High homocysteine, low methionine Multiple sclerosis like symptoms Chronic Fatigue Infertility Enlarged red blood cells (macrocytosis) Low platelets Megaloblastic anemia. Abnormal white cell (neutrophils) Vision loss Leg pains B12 Deficiency Signs and Symptoms Mental Changes Irritability Apathy Sleepiness Suspiciousness (paranoia) Personality changes Depression (including postpartum depression) Memory loss Dementia, intellectual deterioration Clumsiness Hallucinations Vioilent behaviour In children, developmental delay and/or autistic behaviour Neurological signs and symptoms Abnormal sensations ie: pain, tingling, numbness of legs, arms, trunk Diminished sense of touch, pain and/or temperature Loss of position sense (awareness of body position) Weakness of limbs Tremor Symptoms mimicking Parkinsons disease or MS Spasticity of muscles incontinence (urine or stool) Paralysis Vision changes Damage to the optic nerve neuritis, inflammation, atrophy Sally M. Pacholok, Jeffrey Stuart. Could it be B12? An Epidemic of Misdiagnosis, Quill Driver Books, California, 2011 8

B12 Deficiency Signs and Symptoms Vascular Problems Transient ischemic attacks (TIA s) Cerebral vascular accident Coronary artery disease Myocardial infarction Congestive heart failure Palpitations Orthostatic hypotension Deep vein thrombosis Pumonary embolism Other Shortness of breath Generalised weakness Chronic fatigue or tiredness Loss of appetitie/weight loss Epigastric pain Osteoporosis Increased susceptibilty to infection Failure to thrive in infants Vitiligo Premature greying of hair Burning feet Sally M. Pacholok, Jeffrey Stuart. Could it be B12? An Epidemic of Misdiagnosis, Quill Driver Books, California, 2011 Testing # Serum B12 test measures the level of vitamin B12 in the blood serum # Methylmalonic acid (MMA) test measures methylmalonic acid # Homocysteine blood homocysteine # Holotanscobalamin (holoctc) test When someone is severely B12 deficient : - Serum B12 is low - MMA is elevated - Hcy is elevated 9

Current Reference Ranges: # US Reference Ranges: 200-900 picogram per milliliter (pg/ml)/ 150-650pmol/L # Australia Reference Ranges: > 250 picomole per litre (pmol/l) # Japan Reference Ranges: 500 1300 picogram per milliliter (pg/ml) h"p://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02485.x/abstract Current Reference Ranges: Considered too Low The evidence h"p://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02485.x/abstract 10

B12 Deficiency : A Common Event Underestimated due to Misunderstanding: Deficiency only likely in strict vegetarians or patients It takes ~20 years for B12 storage to be exhausted Developed Countries: Based on large surveys in the UK & US 20% in those aged > 60 years old had marginal status. Developing Countries Starting in early life and persisting across lifespan Due to low consumption of animal-source foods h"p://ajcn.nutrition.org/content/89/2/693s.long Current Reference Ranges: Considered too Low The proscription that cobalamin deficiency should not be diagnosed unless megaloblastic changes are found is akin to requiring jaundice to diagnose liver disease. Carmel. Carmel goes on to say: Even in patients with clinical pernicious anaemia, up to 28% do not Have anaemia and up to 33% have normal mean corpuscular volume Hooshmand et al, found that in 274 community elderly, raised baseline thcy is associated with cognitive decline over 7 years and that holotranscobalamin are protective against cognitive decline. h"p://www.ncbi.nlm.nih.gov/pubmed/10774470 h"p://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02485.x/abstract h"p://www.ncbi.nlm.nih.gov/pubmed/21593511 h"p://www.ncbi.nlm.nih.gov/pubmed/12974873, h"p://www.ncbi.nlm.nih.gov/pubmed/22077644 11

Current Reference Ranges: Considered too Low In the VITACOG trial assessed brain atrophy over 2 years in elderly Subjects with mild cognitive impairment. Lowering thcy by 30% and increasing plasma B12 from a mean of 330 to 672 pmol/l was associated with an average slowing of brain atrophy of 30%. Vogiatzoglou et al defined a vitamin B12 replete group as individuals With vitamin B12 > 400 pmol/l. David Smith and Helga Refsum from the Department of Pharmacology, University of Oxford said: we suggest that physicians should consider treating patients who show symptoms particularly in the low normal range up to 300pmol/L. h"p://www.ncbi.nlm.nih.gov/pubmed/20838622 h"p://www.ncbi.nlm.nih.gov/pubmed/?term=vogiazoglou+a.+determinants+of+plasma+methylmalonic+acid+in+a+large+population Current Reference Ranges: Considered too Low Older studies 1973 Ellis et al found that there was a statistical significance with respect to wellbeing and happiness when B12 levels went from 264.4 pmol/l To 1476 pmol/l. They concluded that B1 had a tonic effect 1991 Ohta T et al found that the sleep/wake cycle was improved Dramatically with serum B12 levels in the high range of 795 pmol/l+ 1991 - Dommisse et al states that The one major step that would bring B12 deficiency back into the mainstream of medicine and psychiatry would be the general recognition that normal range should be regarded as 600-2000 pg/ml. Below 550 to 600pg/ml, deficiencies start to appear in the CSF. h"p://www.ncbi.nlm.nih.gov/pubmed/?term=ellis+fr.+a+pilot+study+of+vitamin+b12+in+the+treatment+of+tiredness h"p://www.ncbi.nlm.nih.gov/pubmed/?term=ohta+t%2c+ando+k.+treatment+of+persistent+sleep+wake+schedule+disorders+in+ adolescents+with+methylcobalamin h"p://www.ncbi.nlm.nih.gov/pubmed/2041487 12

B12 & Methylenetetrahydrofolate Reductase (MTHFR) http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2777484 B12: Related Genes (1) - Tcn B12 or cobalamin uptake and transport involve three transporters: $ Tcn1 Transcobalamin 1 $ Tcn2 Transcobalamin 2 $ Tcn 3 Gastric intrinsic factor (Gif) Gif and B12 Deficiency # A stomach specific protein # Essential for B12 absorption from the gut lumen to blood # Decreased production leads to B12 deficiency Causes: Genetic: Tcn3 mutation Non-Genetic: " Anemia " Gastric surgery " Gastric ulcers " Alcohol consumption 13

14/04/2015 B12: Related Genes (2) Eight Complement Groups Eight Genes o o o o o o o o MMAA MMACHC MMAB MMADHC MTR MTRR MUT LMBRD1 http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2995210/pdf/ S1462399410001651a.pdf B12: Related Genes (2) http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2995210/pdf/s1462399410001651a.pdf 14

Cbl-A Cbl-B Genetic disorders of cobalamin transport and metabolism MMAA Gene (methylmalonic aciduria type A MMAB gene (methylmalonic aciduria type B) % AdoCbl, & MMA, metabolic acidosis, %Methionine, & glycine, ammonia. No megaloblastic anemia % AdoCbl, & MMA, metabolic acidosis, %Methionine, & glycine, ammonia, no megaloblastic anemia. Cbl-C MMACHC gene % AdoCbl, & MMA, % MeCbl, megaloglastic anemaia. Cbl-D Cbl-E Cbl-F MTRR- (methionine synthase reductase deficiency Cbl-G MTR As per Cbl-E % AdoCbl, & MMA, % MeCbl % MeCbl, & MMA, metabolic % acidosis, increased ammonia, % glycine, % methionone % megaloblatic anaemia. % AdoCbl, & MMA, % MeCbl, megaloglastic anemaia. http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3650358/ http://www.scribd.com/doc/230760936/inborn-errors-of-folate-and-cobalamin-peds#scrib Gherasim C, et al. Navigating the B12 Road: Assimilation, delivery and disorders of cobalamin. J Biol Chem, 2013, 288:13186-13193; Whitehead VM, Acquired and inherited disorders of cobalmin and folate in children. BJH, 2006, 134, 125-136 Genetic disorders of cobalamin transport and metabolism TCN Transcobalamin % transcobalamin, % immunoglobulins, & MMA, GIF (TCN 3) MUT Gastric Intrinsic Factor L-metylmalonyl- CoA mutase & homocysteine, methylmalonic aciduria, homocystinuria, megaloblastic anemia. Methylmalonic aciduria, metabolic acidosis, methylmalonic acidemia, megaloblastic anemaia, homocystinuria/hyperhomocysteinemia. http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3650358/ http://www.scribd.com/doc/230760936/inborn-errors-of-folate-and-cobalamin-peds#scrib Gherasim C, et al. Navigating the B12 Road: Assimilation, delivery and disorders of cobalamin. J Biol Chem, 2013, 288:13186-13193; Whitehead VM, Acquired and inherited disorders of cobalmin and folate in children. BJH, 2006, 134, 125-136 15

B12 Genes: Nutraceutical Supports Hydroxycobalamin When there is dizziness/low blood pressure (perhaps an indication of high nitric oxide/hydrogen sulphide levels can t test NO here yet (May cause acneiform dermatitis small papules/pustules on the face, upper parts of the back and chest. Go away within a week of stopping.) Adenosylcobalamin When You see increased MMA in bloods or have MMAA, MMAB, MMADHC, MUT mutations Methylcobalamin Especially when neurological symptoms. (Caution in homozygous COMT, or those people likely to get cranky easily. Great if sleep is bad, constipation predominates, increased oxidative stress TCN mutations Problem getting B12 into the cell so consider nasal delivery of B12. May see increase in B12 in bloods. Case studies Case 1-38 year old female homozygous C677T MTHFR Presents with fatigue 5/10, has to sleep sitting up or she will go numb in the hands and feet (had not gone to bed laying flat for 8 months). Alternating constipation and diarrhea (this had been lifelong), vertigo for 10 years. Saw a neurologist. Swollen under the eyes. Tingling, numbness in her arms and hands. Couldn t hold a shopping basket for more than a few minutes. She could feel her blood pulsing through her body. Felt very stiff and inflamed. Could not exercise as she couldn t walk for more than 20 steps because she felt exhausted (absolute muscle weakness). Serum Vitamin B12 was 402pmol/L, active B12 47pmol/L She took a compounded : Combination of adenosylcobalamin (2,000mcg /methylcobalamin 2.5mcg) Three weeks later she was sleeping lying down, sleeping all the night, going to the toilet every day, the blood pulsing was gone, back pain had gone, she was starting to get her memory back. Her blood sugar was better and she wasn t as fatigued. Still working with her 1 year later and she can now exercise for an hour at a time and feels the best she has for decades. 16

Case studies Case 2-40 year old female Compound heterozygous MTHFR Presents with anxiety, depression since teens. Has been on antidepressants since she was 18 and had what she described as episodes 2-3 x per year. Low energy, constantly having to sleep every afternoon with mood crashes, feeling of isolation and addictive personality. Vitamin B12 was 418pmol/L She took a compounded : Methylcobalamin 2mg daily, zinc, B6, multivitamin, phospholipid complex. Within 8 weeks Mood - more energy, not depressed, able to do alot more. Not getting mood crashes. Anxiety pretty much gone- not as easily overwhelmed. energy - 8.5/10. Not napping. Energy not as dippy. Need for food diminished significantly. Bowels going every day since on the B125. Need for food - not really as bad. Case studies Case 3-82 year old female Over a couple of weeks she started walking quite strangely according to her son. She started to veer to one side, she started to get a lot more forgetful, had just been diagnosed with dementia, at times she slurred her speech. I wrote a letter to her Dr asking if he could please check her vitamin B12 levels. He did and they were 159 pmol/l. She was given hydroxocobalamin injections weekly for 6 months and almost all the symptoms completely resolved. 17

Case studies Case 4 11 year old boy Presented with severe anxiety, mood changes and aggression. Insomnia where it would often take him 3 hours to get to sleep. He was fighting with his brothers a lot and getting into trouble at school. He did a lot of exercise and would get cramps a lot. Very constipated. Vitamin B12 levels 339 pmol/l, Folate 36.8 He took a compounded methylcobalamin 1,000mcg, along with magnesium and glycine. Within 2 weeks he had seen big improvements. Getting to sleep was taking him a maximum of 30 minutes, he was feeling less stressed and he was going to the toilet every day. So what conclusions can we make? We can t rely on test results solely We mustn't think that because someone has Vitamin B12 within the reference range they are not Vitamin B12 deficient. Neurological signs/symptoms get better when Vitamin B12 is in the high range i.e: tiredness, depression, insomnia, sleep-wake cycles Decrease in B12, produces a decrease in SAM so methylation is impaired, neurotransmitters, phospholipids, myelin and receptors are impaired 18