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Anaemia (also spelt as anemia) is a condition where you don’t have enough healthy red blood cells circulating in the bloodstream. There are different types of anaemia, for example iron deficiency anaemia (anaemia that happens due to severely low levels of iron in the body) and vitamin B12 deficiency anaemia (anaemia that occurs due to vitamin B12 deficiency).
In this blog we will explore the relationship between low vitamin B12 and anaemia, symptoms of vitamin B12 deficiency and important things to know about its diagnosis and treatment.
Vitamin B12 and anaemia: What is the link?
Vitamin B12 deficiency is one of the major causes of megaloblastic anaemia, a condition where your bone marrow produces abnormally large and underdeveloped red blood cells.
So, how does vitamin B12 deficiency cause anaemia? Vitamin B12 does some incredible work in the body. Among many things, B12 is essential for the production of red blood cells.
The bone marrow – a spongy, yellow tissue present inside of certain bones – is in charge of producing the main blood cells, which are red blood cells (RBCs), white blood cells and platelets. Vitamin B12, along with folate and iron, plays an important role in the development and maturation of red blood cells.
Insufficient B12 leads to the formation of RBCs that are large, structurally deformed, underdeveloped and fragile. These RBCs are too large to pass from the bone marrow to the bloodstream, leading to anaemia and associated symptoms.
Red blood cells carry oxygen to different parts of the body with the help of a protein called haemoglobin. A deficiency in healthy, fully-developed red blood cells causes fatigue, lethargy, shortness of breath, paleness of the skin and other symptoms typically associated with anaemia.
“Vitamin B12 helps in the formation of healthy red blood cells. Its deficiency can lead to RBCs that are immature, unusually large and easy to break. This leads to vitamin B12 deficiency anaemia.”
What causes vitamin B12 deficiency anaemia?
Inadequate vitamin B12 in your diet, use of certain medicines and poor absorption of B12 in the intestines can cause B12 deficiency and the resulting anaemia.
1. Diet low in vitamin B12
Vitamin B12 is naturally present in animal-based foods, such as diary, eggs, fish, meat, and poultry. Since it is not present in plant-based foods, people who are on a strict vegetarian diet are likely to be deficient in this water-soluble vitamin.
While inadequate intake might look like quite an obvious cause, there are many other compelling and often overlooked reasons that might lead to B12 shortage in your body. Being aware of these reasons will help in understanding your diagnosis and treatment route.
2. Lack of Intrinsic factor
Intrinsic factor (IF) is a protein that helps in vitamin B12 absorption in the small intestine. It is produced by the cells that line the stomach. Lack of, or failure to utilise intrinsic factor effectively will impair the absorption of vitamin B12.
So, what decreases the production of intrinsic factor in the body? Before we get to this part, let us look at how exactly is vitamin B12 absorbed in the body.
a) In food, vitamin B12 is bound to protein. So, it must be separated from this dietary protein before it can move towards small intestine for absorption.
b) Gastric juices (hydrochloric acid and enzyme pepsin), secreted by the stomach, sets B12 free from dietary protein.
c) Free B12 now binds to haptocorrin, a protein secreted in saliva, bile and pancreatic fluid. Haptocorrin protects B12 from the acidic environment in the stomach.
d) This haptocorrin-B12 complex makes its way through the parts of the small intestine, where the pancreas secretes enzymes that digest haptocorrin protein. This reaction releases B12.
e) This newly available B12 now binds to intrinsic factor, a protein produced by the cells in the stomach lining.
f) B12-Intrinsic factor complex now moves through the small intestine and reaches the ileum, the last part of your small intestines that has receptors for intrinsic factor. In the presence of calcium and an alkali environment, intrinsic factor-B12 now binds to the ileum and B12 is ready to be absorbed in the bloodstream.
Health conditions that adversely affect any of these steps can restrict B12 absorption in the small intestines, leading to deficiency.
What reduces intrinsic factor?
Pernicious anaemia is one of the main causes that decrease intrinsic factor in the body. It is a type of anaemia caused by vitamin B12 deficiency and happens due to lack of intrinsic factor.
Pernicious anaemia can be caused by an autoimmune response where your immune cells attack and destroy stomach cells (gastric parietal cells) that produce intrinsic factor, a protein that is required for the absorption of B12.
Other conditions that reduce intrinsic factor are atrophic gastritis (thinning of stomach lining) and gastrectomy (surgery that removes all or part of the stomach). Rarely, babies are born with a genetic condition that prevents them from producing intrinsic factor. This condition is called congenital pernicious anaemia.
3. Malabsorption in small intestines
Certain health conditions lead to reduced absorption of vitamin B12 in the small intestines, leading to vitamin B12 deficiency anaemia.
a) Crohn's disease: It is an inflammatory bowel disease that causes chronic inflammation of the digestive tract. This painful disorder leads to abdominal pain, fatigue, diarrhoea and nutritional deficiencies. People with Crohn’s disease often develop vitamin B12 deficiency.
b) Celiac disease: It is an autoimmune disorder where eating gluten triggers your immune cells to attack and damage the small intestine. Gluten is a protein found in wheat, barley and rye. This immune response damages the villi, small finger like structures that line the inside of the small intestines and help in absorption of nutrients.
People with celiac disease are commonly deficient in vitamins and minerals, including B12, folate, B6, vitamin D, iron, magnesium and calcium. This increases their risk of developing vitamin deficiency anaemia, arthritis, bone pain and other health conditions.
c) Gastric bypass weight loss surgery: In this surgery, the part of the stomach that produces acid and intrinsic factor is bypassed and is no longer utilized to digest the food. Since both acid and intrinsic factor help in proper absorption of vitamin B12, this can lead to poor vitamin B12 absorption.
d) Surgery that removes all or part of the small intestine: Your small intestine is divided into three parts: duodenum (first part that starts where stomach ends), jejunum (middle part), and ileum (the last section of small intestine that extends into large intestine).
Intrinsic factor binds to B12 in the duodenum, whereas B12 is absorbed in the end part of the ileum. So, any surgery that removes any or all parts of the small intestine can lead to poor absorption. People with Crohn’s may have to undergo surgery that removes the end part of the ileum, where B12 is absorbed.
e) Small intestinal bacterial overgrowth (SIBO): The small intestine doesn’t house as many bacteria as the colon does. It also has lesser varieties of bacteria than the colon. Since small intestine is the site where your food is digested and absorbed, too much growth of bacteria in this part of the digestive tract will create unnecessary competition with the body for nutrients, creating nutritional deficiencies, including that of vitamin B12.
Your body has a defensive mechanism that keeps a check on the number and type of bacteria thriving in the small intestine. Acid and enzymes produced by the stomach, bile, the downward contraction of the intestinal muscles and one-way valve between small intestine and large intestine - all work together in moving bacteria downward from small to large intestine, thus preventing SIBO.
Change in the motility of the small intestine (where the food and bacteria don’t move through the digestive tract as fast as they should) is the main reasons for excessive growth of bacteria.
Frequent use of antibiotics, antacids, history of abdominal and intestinal surgeries and low stomach acid, can change the number as well as the type of bacteria in the small intestine.
In addition, certain conditions such as Chron’s disease, diabetes, hypothyroidism, scleroderma, diverticulosis, chronic pancreatitis and Celiac disease can cause SIBO. Adhesions caused by previous surgeries, obstructions or injuries in the small intestine also contribute to SIBO. 
f) Tapeworm infection: The fish tapeworm (Diphyllobothrium latum) is a parasite found on fish. Eating raw and undercooked fish that is infected with the parasite can cause tapeworm infection.
Tapeworm absorbs the nutrition, leading to vitamin B12 deficiency and anemia.
g) Tropical sprue: It is a rare digestive disease where the small intestine loses its ability to absorb nutrients, leading to malabsorption. While it’s not clear what causes tropical sprue, viral, bacterial or parasitic infections may cause inflammation and swelling in the intestines, making it difficult to absorb nutrients, especially B12 and folic acid. 
h) Certain medications: Long-term use of certain medicines is known to cause vitamin B12 and other nutritional deficiencies. Proton pump inhibitors (PPIs) and H2 blockers (drugs that are used to treat acid reflux, peptic ulcers and H.pylori), metformin (diabetes medicine) and anti-seizure drugs may trigger vitamin B12 deficiency.
While it is not exactly clear why chronic use of metformin may cause vitamin B12 shortage, research suggests it may impact how your body absorbs vitamin B12. [3-5] Both vitamin B12 deficiency and diabetes are linked with neurological symptoms, such as peripheral neuropathy and dementia.
Elderly persons often have conditions that can lead to malabsorption of vitamin B12 in one way or another. People in their old age are more vulnerable to developing atrophic gastritis, where the thinning of stomach lining leads to little or no production of hydrochloric acid and intrinsic factor, required for B12 absorption.
“While poor dietary intake is one of the reasons for vitamin B12 deficiency, lack of intrinsic factor (a protein that helps in B12 absorption in the small intestine which is reduced by pernicious anaemia and thinning of stomach lining), and poor absorption in the small intestine (caused by conditions such as age, Crohn’s, Celiac, HIV, excessive bacterial growth in the small intestine, tapeworm infection, surgeries of stomach and small intestine and chronic use of certain medicines) cause vitamin B12 deficiency.”
How is vitamin B12 deficiency anaemia diagnosed?
Your doctor will diagnose vitamin B12 deficiency anaemia with the help of blood test results, your medical history and symptoms, and your family history.
Looking at symptoms Vitamin B12 is required for a number of processes such as:
- DNA synthesis
- Production and maintenance of myelin sheaths, protective coating around the nerves that helps in nerve transmission.
- Synthesis of neurotransmitters
- Formation of healthy red blood cells
That’s why vitamin B12 deficiency results in a number of blood, neurological and psychiatric symptoms such as:
- Anaemia with symptoms such as pale skin, fatigue, dizziness, shortness of breath, irregular heartbeat and rapid heart rate
- Mouth ulcers, canker sores, and smooth tongue.
- Poor reflexes, muscle weakness, poor co-ordination, change in the way you walk
- Pins and needles sensation in hands, feet, arms or legs, a sign of nerve damage
- Blurred vision, caused by damage to the optic nerve that sends signals to the brain
- Mental confusion and memory issues
- Unexplained weight loss
- Ringing in ears
Are you at a risk of developing vitamin B12 deficiency anaemia?
Important risk factors include:
- Family history of pernicious anaemia
- Surgical history that involved removing some or all parts of the stomach.
- Surgical history that involved removing some or all parts of the small intestine.
- Autoimmune disorder such as Addison's disease, type 1 diabetes, Graves' disease, or vitiligo.
- Health conditions such as Crohn's disease, Celiac disease and HIV.
- Long term use of antibiotics, anti-seizure medicines, metformin and antacids.
- Strict vegetarian diet
- Old age
- Pregnant and breastfeeding women
Your doctor may order a couple of blood tests to determine your levels of B12.
CBC: One of the most important tests to diagnose vitamin B12 deficiency is a complete blood count or CBC, that looks at the amounts of haemoglobin, red blood cells, white blood cells, platelets, and haematocrit in the blood.
CBC also gives insights into another critical parameter – mean corpuscular volume (MCV). It tells you about the size of your red blood cells.
Large and underdeveloped red blood cells could mean your anaemia is caused by vitamin B12 or folate deficiency. In a more severe B12 or folate deficiency, the numbers of white blood cells and platelets may also drop.
B12 and folate levels: If your B12 and folate levels fall below the required range, it is a sure sign that you are deficient.
It is important to note that taking folic acid supplements can mask vitamin B12 deficiency. This might help with the symptoms of vitamin B12 deficiency anaemia but make the neurological symptoms worse.
Antibodies for intrinsic factor: This may help in the diagnosis of pernicious anaemia, where the body makes antibodies that attack intrinsic factor producing stomach cells.
Homocysteine and methylmalonic acid (MMA) levels: High levels of these two substances indicate vitamin B12 deficiency. MMA blood test is extremely useful in people who are deficient, and show B12 deficiency symptoms for those who have normal levels of vitamin B12 in their blood. This is known as functional vitamin B12 deficiency. 
In people who consume high amounts of alcohol or those with cancer and liver disorders often have elevated levels of B12. This happens because these conditions impact the levels a transport protein (transcobalamin II). This protein binds to B12 after it has been absorbed into the bloodstream and ferries it to tissues throughout the body.
“Your doctor will assess whether you have low B12 levels through physical exam, symptoms, CBC, blood tests to determine B12 and folate levels in the blood, intrinsic antibodies test and MMA test, especially if you have normal B12 but still show signs of vitamin B12 deficiency.”
B12 deficiency anaemia treatment
Vitamin B12 deficiency anaemia is easy to treat by taking supplements or making changes to your diet. It is found in beef, liver, chicken, shellfish, fish, eggs, dairy products and fortified foods.
Vitamin B12 supplements are helpful in reversing deficiency in vegans and vegetarians.
What if you have low levels of intrinsic factor due to pernicious anaemia? Or you have had gastric bypass surgery that decreases the production of intrinsic factor in the stomach? Would it help to take oral supplements? In such cases, intramuscular injections can be extremely useful. However, some experts maintain that taking high doses of vitamin B12 supplements can be effective, irrespective of your intrinsic factor status.
Another effective way of correcting your vitamin B12 deficiency anaemia is to take liposomal vitamin B12 supplements.
Liposomal supplements are designed in such a way that the enclosed nutrients are directly delivered to the cells without getting degraded in the digestive tract. Small, round, bubble-like structures carry the nutrients within their fold and protect them from degradation by gastric juices and oxidative stress.
- Aroda et al. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016
- Tropical Sprue. National Organization for Rare Disorders
- Oren Zaidel and Henry C. Lin. Uninvited Guests: The Impact of Small Intestinal Bacterial Overgrowth on Nutritional Status. NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #7
- Alvarez et al. Vitamin B12 deficiency and diabetic neuropathy in patients taking metformin: a cross-sectional studyy. Endocrine Connections. 2019.
- Kim et al. Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes. Medicine (Baltimore). 2019
- Alpaslan Cosar and Osman Metin Ipcioglu. Detection of functional vitamin B12 and folate deficiencies, while serum levels are normal. Blood Transfus. 2014 Jan