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Vitamin B12 Deficiency: The Hidden Condition Behind Extreme Fatigue & Mystery Symptoms

Vitamin B12 Deficiency: The Hidden Condition Behind Extreme Fatigue & Mystery Symptoms

When you consume proper quantities of B vitamins, you’re likely to benefit from improved brain function, higher energy, and greater health and wellness throughout your body, from the cellular level to the larger systems in the body. In contrast, B vitamin deficiencies can negatively affect the brain, causing fatigue, unreliable memory, mental confusion, difficulty balancing, and weak muscles (1), similar to maladies reported in cases of "mystery symptoms." The brain isn't the only casualty in a B vitamin deficiency, as B vitamins affect so many areas of human health that even a mild deficiency can have wide-ranging effects.

The human body can't make its own B vitamins; they must be broken down and absorbed from food sources to get into the system properly. Eight B vitamins have been identified, each with its own roles. One thing is sure, these nutrients are vital to human health; without them, the body has difficulty functioning! Consider some functions that B vitamins are involved in (1):

  • B1 makes chemical messengers (used in the brain), fatty acids, and hormones

  • B1 helps carbohydrates get broken down into glucose for energy

  • B3 assists in the growth and maintenance of cells, DNA expression within cells, and communication between cells

  • B6 participates in more than 100 processes involving enzymes

  • B9 (folate) helps form the central nervous system during gestation; it is vital for replicating DNA and is required for the division of cells

  • B12 participates in making red blood cells and helps maintain brain function

  • Several B vitamins are cofactors to enzymes critical to cellular energy production

Vitamin B12 Deficiency Often Undiagnosed

Vitamin B12 deserves special mention because the lack of it drives chronic or extreme fatigue in many, and frequently gets missed as a diagnosis, or is misdiagnosed altogether. Fortunately, the mystery behind vitamin B12 deficiency is slowly being illuminated through improved testing techniques and a growing body of research and anecdotal information. Integrative medicine doctors such as those at Temecula Center for Integrative Medicine (TCIM) are well-placed to properly diagnose this condition early, providing standard and complementary non-medicinal treatments to address the root cause.

Roles of Vitamin B12

B12 is built around a bit of cobalt, so it is called cobalamin. There are many forms of B12, being broken down, rearranged, and used all around the body at any given time. The forms methylcobalamin, adenosylcobalamin, and hydroxocobalamin are active and immediately usable without conversion. Vitamin B12 is a key player in producing energy and plays many vital roles in human health. It helps make red blood cells which prevents anemia, helps create and maintain DNA, and is crucial for developing and maintaining the central nervous system (brain and spinal cord). Vitamin B12 also acts as a vital cofactor in the conversion of homocysteine into methionine, which ultimately produces molecules involved in energy production, liver function, and chemical messaging (2).

Symptoms of Vitamin B12 deficiency

Due to all the human processes B12 is involved in, a deficiency may include the following wide-ranging symptoms (3, 4):

  • Feeling weak or tired (can be extreme fatigue)

  • Heartbeat irregularities such as palpitations or a racing heart

  • Losing weight; weak appetite; nausea or vomiting

  • Tingling or numbness in hands or feet (indicative of nerve damage)

  • Mental depression, confusion, difficulty concentrating

  • Difficulty with balance

  • Problems with memory

  • Mouth and tongue become red, glossy, or sore

  • Feeling irritable

  • Developing pale or yellow skin (jaundice)

  • Breathing difficulties

  • In babies developmental milestones are delayed (failure to thrive)

Determining B12 Deficiency Through Testing

Perhaps the most confounding thing about vitamin B12 is deciding the point at which someone is deemed deficient. Amidst the controversy surrounding testing, current deficiency estimates for vitamin B12 in adults vary wildly depending on what testing is adopted. Estimates proclaim that as many as 26% of patients are deficient in vitamin B12 but aren't diagnosed because of reliance on only the serum (blood) B12 test results (5).

As issues surrounding B12 testing began to mount, a medical inquiry was conducted to examine the problem and formulate solutions. A roundtable in 2011 examined a large dataset and determined that two or more tests can help accurately reflect B12 deficiency better than relying on a serum B12 test alone (6, 7).

The crux of the issue is that vitamin B12 serum tests can include many false positives and negatives (8). A false positive means that a person appears to have sufficient vitamin B12 when they don't. A cross-reaction that occurs during the testing can create a false positive and sometimes involves someone taking supplements close in time to the test. A false negative means a person appears to have less vitamin B12 in their system than they actually do, which can happen due to issues performing the test.

Additionally, some people will experience vitamin B deficiency symptoms even though their blood tests are well above the "cutoff" for a deficiency (9). Most serum B12 ranges have a lower limit of 200 pg/mL, meaning below 200 is considered a deficiency. However, it is not uncommon for people to report vitamin B12 symptoms who have scores in the 300s. The current literature on this phenomenon indicates a difference between having enough circulating vitamin B12 in the system and how well the B12 is being used. Something can block the proper breakdown or absorption of the B12, constituting a "functional deficiency."

Because of the past issues in B vitamin testing listed above, integrative medicine doctors are alert to reports of B12 deficiency symptoms and routinely offer additional tests to help detect deficiencies in the amount of circulating vitamin B12 and deficiencies that affect its utilization (functional deficiencies).

Two serum tests that can pick up functional vitamin B12 deficiencies are the homocysteine and methylmalonic acid (MMA) tests.

1) Homocysteine test - Foods (especially meats) containing methionine are converted into homocysteine. Homocysteine can be converted back into methionine but requires vitamins B6, B9 (folate), and B12. A high homocysteine score can indicate a lack of one or all three vitamins (or kidney impairment) (10). Elevated homocysteine is associated with increased risks of heart attack, stroke, and dementia (11).

2) Methylmalonic acid (MMA) test - MMA is involved in energy production. Vitamin B12 converts MMA to another substance. Fewer conversions happen if there is not enough vitamin B12, so more MMA remains in the blood (unconverted) and can be picked up by the test. A high MMA score indicates low vitamin B12. In studies, elevated MMA is an early indicator of B vitamin deficiency (6, 12), even as B12 blood tests taken simultaneously show results in normal ranges.

Determining Nutrient Status Using Specialty Testing - Besides blood testing, specialty tests on the market will test the status of many nutrients. Results from blood and urine tests can show vitamin, mineral, and antioxidant deficiencies, evidence of malabsorption, and indications of imbalanced neurotransmitters (chemicals used for communication in the brain). Sometimes genetic testing can be added to these specialty tests, providing positive identification of genetic influences on B12 status.

Causes of Vitamin B12 Deficiency

One can become deficient in vitamin B12 due to a deficient diet. Humans can't make vitamin B12, so foods that contain vitamin B12 must be eaten frequently to maintain a good supply.

Depletion or lack of absorption can also cause a deficiency. Many factors can contribute:

  • Certain medical conditions - Several medical conditions prevent vitamin B12 absorption. Those with celiac disease and Crohn's are particularly susceptible (13).

  • Surgeries - Surgeries on the gastrointestinal system, such as gastric bypass (Roux-en-Y bypass surgery) and bowel resections, can eliminate the surface through which B vitamins are absorbed (13).

  • Stress - The body uses more energy under physical or psychological stress, depleting resources including antioxidants and B vitamins. Unfortunately, stress can also cause digestion to slow down as the body diverts blood to areas of the body in preparation for "fight or flight," reducing the amount of nutrients coming into the system.

  • Certain medications - Many medications are associated with B vitamin nutrient depletion or blockage of absorption, including some antibiotics, oral contraceptives, proton pump inhibitors (Pepsid, Nexium), anti-epileptic, anti-diabetic (Metformin), and anti-inflammatory drugs (prednisone) (14). A comprehensive, searchable list is linked here.

  • Lack of certain proteins or enzymes - Intrinsic factor (IF) is essential in vitamin B12 absorption. IF is a protein that binds to vitamin B12 in the small intestine, making it possible for the body to absorb it. Without IF, B12 would not be absorbed through the small intestine wall and would pass out of the system. Genetic mutations can cause a lack of IF.

There are also enzymes necessary for the utilization of vitamin B12. A genetic area that codes for methylenetetrahydrofolate reductase (MTHFR) creates enzymes that convert the raw form of vitamin B12 from the diet to the active form that the body can readily use. Gene mutations in the MTHFR area reduce the efficiency of the conversion from inactive to active vitamin B12. Even if people eat enough foods with vitamin B12, genetic mutations in the MTHFR area can prevent having adequate levels of activated vitamin B12 for the body to use.

  • Weak or low stomach acid - Vitamin B12 is found mainly in meat, and those who have difficulty breaking down the proteins in meat may develop a deficiency. Proton pump inhibitors and acid-reducers slow the breakdown of B12-containing animal proteins, so they must be used with abundant caution. Weak stomach acid can exist for various reasons, including H. pylori infection, stomach surgery, and nutritional deficiencies.

  • Antibodies attacking intrinsic factor - An autoimmune disease called pernicious anemia creates antibodies against intrinsic factor (IF), causing it to fail to get vitamin B12 absorbed across the small intestine wall.

Risk Factors for Vitamin B12 Deficiency

Advancing Age - Stomach acid strength goes down as we age, affecting the ability to extract vitamin B12 from meat in the diet (13).

MTHFR genetic mutations - In the US, estimates claim up to 40% of White and Hispanic people have a type of MTHFR mutation (C677T) which is associated with elevated homocysteine (15, 16) and prevents the conversion of inactive B12 to active B12.

Gastrointestinal diseases - Celiac disease, leaky gut, Crohn's disease, and other bowel issues are typically associated with malabsorption issues (13), which increase the risk of vitamin B12 deficiency.

Gastrointestinal surgeries - Bowel surgery, gastric bypass, and other stomach and intestine surgeries can remove areas that help absorb nutrients or secrete substances necessary for the breakdown or absorption of nutrients (13).

Certain autoimmune diseases - The autoimmune diseases pernicious anemia and atrophic gastritis both reduce intrinsic factor, which is necessary for vitamin B12 to be appropriately absorbed (13,17).

Complications of B12 Deficiency

Some vitamin B12 can be stored in the liver if there is an excess in the diet, so it may take a while to become deficient. Once deficient, it can result in severe consequences. Vitamin B12 deficiency can drive elevated homocysteine, which is associated with a higher risk of cardiovascular diseases, Alzheimer's, and dementia (13). Lack of vitamin B12 disrupts red blood cell processes, causing fewer red blood cells and distorted, larger-then-normal cell shapes, and can result in Megaloblastic anemia, as it (17). Some evidence exists for higher risks of gastric, colorectal, and prostate cancers (13).

Nerve damage can occur as it's difficult for nerves to maintain a healthy status without vitamin B12 (18).

Treatments for Vitamin B12 Deficiency

1) Increase consumption of foods containing vitamin B12.

The molecule within vitamin B12, cobalamin, is made only by certain microorganisms and travels up the food chain, landing in the tissues of animals (8). Some mushrooms and algae also contain this essential vitamin (8).

Beef, organ meats, pork, poultry, eggs, and dairy are high in vitamin B12. Potatoes and spinach have some vitamin B12. A good list of high B12 sources is linked here.

2) Supplement with vitamin B12.

  • Oral supplements - Vitamin B12 supplements are available in liquid form, chewable tablets, or capsules. Methylcobalamin, hydroxocobalamin, and adenosylcobalamin are the activated forms of B12 that the body does not have to convert to utilize.

  • Intrinsic factor supplement - If vitamin B12 supplements do not raise serum B12 levels (or lower MMA levels), consider taking intrinsic factor.

  • Bolster stomach acid - To help break down meat to liberate the vitamin B12, consider taking betaine hydrochloric acid supplements (HCl), which the body uses as stomach acid to break down proteins.

3) Bypass digestion with IV or intramuscular vitamin B12.

If there is a severe deficiency, vitamin B12 can be directly introduced into the system, completely bypassing digestion. Bypassing digestion can be helpful in cases where malabsorption is a serious issue, for example, Crohn's and celiac disease.

Intramuscular vitamin B12 injection- Delivered by needle into a muscle, vitamin B12 can be utilized by the body immediately. TCIM provides this extremely valuable service through its shot clinic.

Myers' Cocktail IV therapy- Vitamin B12 can also go directly into the bloodstream intravenously (IV). TCIM's IV clinic provides Myers' Cocktail, a wonderful IV mixture of B vitamins, magnesium, zinc, and glutathione.

4) Heal the gut.

Disorders that affect digestion and absorption can be entirely or partially corrected by providing the gut with all it needs to heal. Working with a doctor and nutritionist can bring the digestive tract to its healthiest state possible. "Taking the long view" can minimize symptoms in autoimmune and other disorders, preventing additional nutritional deficiencies.

Seek Us Out for Fatigue, Chronic Fatigue, or "Mystery Symptoms"

A hidden vitamin B12 deficiency can be identified quickly if one knows what to look for! Our team is privileged to help those with odd symptoms or grinding fatigue find the root cause (or causes) and address it. Training in integrative medicine gives our doctors an edge in identifying symptoms, using the proper tests to diagnose, and providing natural, evidence-based therapies to address the real underlying issue. Come and see the difference our experience and training can offer.


Jonathan Vellinga, M.D.

Jonathan Vellinga, MD is an Internal Medicine practitioner with a broad interest in medicine. He graduated Summa cum laude from Weber State University in Clinical Laboratory Sciences and completed his medical degree from the Medical College of Wisconsin.​

Upon graduation from medical school, he completed his Internal Medicine residency at the University of Michigan. Dr. Vellinga is board-certified with the American Board of Internal Medicine and a member of the Institute for Functional Medicine.




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