VITAMIN B12 UPDATE. Rosemary S. Browne, MD Southern Arizona VA Healthcare System College of Medicine The University of Arizona

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1 VITAMIN B12 UPDATE Rosemary S. Browne, MD Southern Arizona VA Healthcare System College of Medicine The University of Arizona Learning Objectives: Relate the history of Vitamin B12 since the beginning of the last century - from classic deficiency and early treatment methods to structural analysis and synthesis. Describe several ways that older adults can become B12 deficient. Summarize the current understanding of the relationship between Vitamin B12, depression and dementia. DISCLOSURE OF COMMERCIAL SUPPORT Rosemary S. Browne, MD does not have a significant financial interest or other relationship with manufacturer(s) of commercial product(s) and /or provider(s) of commercial services discussed in this presentation. 1

2 Arizona Geriatric Society 8 th Annual Spring Mental Health and Aging Conference Vitamin B12 Update Rosemary S. Browne MD Medical Director, Home Based Primary Care Southern Arizona VA Health Care System Associate Professor of Medicine University of Arizona Friday, April 24, 2015 Learning Objectives Review the history of Vitamin B12 and its place in the history of medicine Discuss the biochemistry of Vitamin B12 List the known disease processes involving Vitamin B12 deficiency Describe the several ways that older adults can become B12 deficient Summarize the current evidence associating Vitamin B12 with dementia and depression LECTURE FORMAT History of Vitamins The Story of Pernicious Anemia Biochemistry of B12 Known disease processes related to Vit B12 Diagnosis and Treatment B12 deficiency in older adults B12, Depression and Dementia 2

3 A Very Brief History of Vitamins 400 BC Hippocrates If we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health James Lind Scurvy Vitamin C 1890s Christiaan Eijkman Beriberi Thiamine (B1) 1860s Louis Pasteur Microbes 1911 Casimir Funk Vital amines Pernicious Anemia 1914 Goldberger Pellagra Niacin (B3) Annie Oakley (d.1926) Alexander Graham Bell (d. 1922) 3

4 History of Pernicious Anemia 1855 Thomas Addison Edinburgh Idiopathic Anemia 1870s Biermer Zurich Pernicious Anemia Whipple USA ANEMIA CURED IN DOGS BY NEW LIVER EXTRACT Rochester Times, Monday October 5, 1931 Minot and Murphy JAMA 1931 *1934 Nobel Prize in Physiology and Medicine * The Unsung Hero Dr. William Castle *2 More Nobels for B12* Dorothy Crowfoot Hodgkins Oxford 1964 Nobel Prize in Chemistry R.B. Woodward Harvard 1965 Nobel Prize in Chemistry 1996 stamp Vitamin B1 Vitamin B2 Other Vitamins are relatively simple... Vitamin D Vitamin A Vitamins E & K Vitamin C 4

5 Vitamin B12 R = OH R = CH3 R = 5'-deoxyadenosine R = CN aquacobalamin methylcobalamin adenosylcobalamin cyanocobalamin Molecular Similarities Biochemistry B12 is needed for two specific reactions: To move around CH3 groups (methionine synthase) Used in cells with rapid turnover, to help to create DNA To move around adenosine groups (methylmalonylcoa mutase) Makes succinyl Co A, for citric acid cycle 5

6 B12 and folate deficiency lead to: elevated homocysteine levels elevated tetrahydrofolate- CH3 low levels of methionine B12 deficiency alone leads to: elevated methylmalonic acid B12 Deficiency Clinical Manifestations Megaloblastic Anemia Demyelinating Neurologic Disease Glossitis, thrombosis, malabsorption, infertility?dementia/depression Megaloblastic Anemia 6

7 Neurological Issues Neurological disease often is more subtle and can occur long before anemia Lower extremity more than upper extremity symmetric paresthesia and numbness gait ataxia and muscle weakness then, incontinence, memory loss Both neuropathy and myelopathy Subacute Combined Degeneration Dorsal columns impaired position and vibration sense, ataxia Corticospinal columns weakness, spasticity, hyperreflexia B12 Deficiency Who is at Risk? Caucasians of northern European descent Autoimmune diseases such as vitiligo and thyroid disease Females Older Adults 10 24% Why are Older Adults at Risk? Complex B12 Absorption 7

8 Common Etiologies for B12 Deficiency Inadequate dietary intake veganism, chronic alcoholism Lack of acid pepsin in the stomach o induced antacids, H2 receptor antagonists, and proton pump inhibitors o innate achlorhydria/ gastric atrophy o Helicobacter pylori infection Lack of gastric secretion of a functional intrinsic factor Pancreatic exocrine failure insufficient pancreatic proteases A poorly functioning ileum o malfunctioning Cbl IF receptors o villous atrophy (Crohn s, sprue) o Bacterial overgrowth competing for B12 o Diphyllobothrium latum o Long term ingestion of biguanides Gastric surgery/reconstruction for obesity (bariatric surgery) Sjogren's syndrome Diagnosing B12 Deficiency Different lab determinations of normal Methodologic problems with B12 assays (50% lows are false positive results) Confirm clinical suspicions, despite low normal values of B12, by getting methylmalonic acid (MMA) and homocysteine levels 98% are markedly elevated in untreated patients MMA reduces with treatment MMA falsely elevated with renal failure (more like 300 than 500) Treatment Most with B12 deficiency have malabsorption, and will require high dose oral or parenteral replacement 1000 micrograms IM 10 % retained get it several times a week for 1 2 weeks, then weekly, then monthly High dose oral is effective ( mcg) and may reduce MMA more effectively (Cochrane review 2009) Anemia will respond briskly Neuropathy will improve with treatment depending on the severity and duration of the deficiency B12 now comes in oral sprays, patches, sublingual effectiveness not studied 8

9 B12 by the numbers Estimated Average Requirements 2 3 μg/day (2.4 DRI) Normal diet 4 7 μg/day Dietary Sources animal foods Vegans the awful truth Storage 2 5 mg Liver storage 50% Effective enterohepatic circulation Intestinal organisms make plenty of B12 that is not absorbed It takes 5 years to be come B12 deficient Vitamin B12 and Cognitive Function Results/Conclusions There does appear to be an association between elevated homocysteine levels and onset of dementia (low quality evidence) Treatment with Vitamin B12 does not appreciably change cognitive function (moderate quality evidence) Treatment with Vitamin B12 in patients with MCI seems to slow the rate of brain atrophy (low to moderate quality evidence) Oral Vitamin B12 is as effective as parenteral Vitamin B12 in patients with confirmed B12 deficiency (moderate quality evidence) 9

10 B12 and Cognition Cochrane Review Jan 2009 No evidence of the efficacy of vitamin B12 supplementation for cognitive function 3 studies with cognitive impairment, low B12 Vit B 12 supplementation did not help cognition Meta analysis of 11 trials with cognitive data on 22,000 individuals Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognitive function or on cognitive aging. Clarke, 2014 Cognitive Aging: A Report From the Institute of Medicine April 2015 The medical literature does not convincingly support any vitamin supplementation to prevent cognitive decline. B12 and Depression community dwelling individuals > age 55 with depressive symptoms (N=278) found that vitamin B 12 deficiency was independently associated with depression The Rotterdam Study. Am J Psychiatry 2002 community dwelling older women (N=700), which found a twofold risk of severe depression in elderly women with metabolically significant (elevated MMA levels) vitamin B 12 deficiency. The Women's Health and Aging Study. Am J Psychiatry 2000 community based, cross sectional study in Chinese elderly persons (N=669), reported that vitamin B 12 deficiency (<180 pmol/liter) was significantly associated with depressive symptoms (odds ratio [OR]: 2.68), independent of folate and homocysteine levels. J Am Geriatr Soc 2009; 57: cross sectional and prospective study, in Korean people older than age 65, without depression (N=521) found that lower baseline vitamin B 12 and folate levels, and raised Hcy levels, were risk factors that predicted onset of late life depression. Br J Psychiatry 2008; 192: Conclusions B12 deficiency does not appear to cause dementia or depression B12 deficiency seems to worsen the symptoms of depression, and might accelerate cognitive decline Oral B12 supplements might help with other therapies for depression, and might slow cognitive decline Oral B12 supplementation is a low risk, potentially high yield intervention, for those with documented B12 deficiency There is no evidence for screening for B12 deficiency for any disease 10

11 From: The Neuropsychiatry of Vitamin B12 Deficiency in Elderly Patients The Journal of Neuropsychiatry and Clinical Neurosciences FIGURE 1. Recommendations for Cobalamin Screening and Supplementation Cbl: serum cobalamin; MMA: serum methylmalonic acid. apo (oral) supplementation is preferred unless it has been proven ineffective or compliance is limited; an alternative, parenteral approach is cyanocobalamin 1,000 mcg IM daily for 1 week, then weekly for 1 month, and monthly thereafter. Copyright American Psychiatric Association. All rights reserved. So B12 it! 11