Vitamin B12 deficiency

Vitamin B12 deficiency
Cyanocobalamin
Classification and external resources
Specialty	Neurology
ICD-10	E53.8
ICD-9-CM	266.2
DiseasesDB	13905
MedlinePlus	000574
Patient UK	Vitamin B12 deficiency

Vitamin B₁₂ deficiency, also known as hypocobalaminemia, refers to low blood levels of vitamin B₁₂.^[1] A wide variety of signs and symptoms may occur including a decreased ability to think and behavioural and emotional changes such as depression, irritability, and psychosis. Abnormal sensations, changes in reflexes, and poor muscle function can also occur as may inflammation of the tongue, decreased taste, low red blood cells, reduced heart function, and decreased fertility.^[2] In young children symptoms include poor growth, poor development, and difficulties with movement.^[3] Without early treatment some of the changes may be permanent.^[4]

Common causes include poor absorption from the stomach or intestines, decreased intake, and increased requirements. Decreased absorption may be due to pernicious anemia, surgical removal of the stomach, chronic inflammation of the pancreas, intestinal parasites, certain medications, and some genetic disorders. Decreased intake may occur in those who eat a vegan diet or are malnourished. Increased requirements occur in HIV/AIDS and in those with rapid red blood cell breakdown.^[2] Diagnosis is typically based on vitamin B₁₂ blood levels below 120–180 picomol/L (170–250 pg/mL) in adults. Elevated methylmalonic acid levels (values >0.4 micromol/L) may also indicate a deficiency. A type of low red blood cells known as megaloblastic anemia is often but not always present.^[3]

Supplementation is recommended to prevent deficiency in vegetarians who are pregnant.^[3] Once identified it is easily treated with supplementation by mouth or injection.^[5] There are no concerns from excess vitamin B₁₂ among those who are otherwise healthy.^[3] Some cases may also be helped by treating the underlying cause.^[6] Other cases may require ongoing supplementation as the underlying cause is not curable.^[7] Vitamin B₁₂ deficiency is common.^[2] It is estimated to occur in about 6% of those under the age of 60 and 20% of those over the age of 60. Rates may be as high as 80% in parts of Africa and Asia.^[2]

Signs and symptoms

Vitamin B₁₂ deficiency can lead to vitamin B₁₂ deficiency anemia and neurologic dysfunction.^[8] A mild deficiency may not cause any discernible symptoms, but as the deficiency becomes more significant symptoms of anemia may result, such as weakness, fatigue, light-headedness, rapid heartbeat, rapid breathing and pale color to the skin. It may also cause easy bruising or bleeding, including bleeding gums. GI side effects including sore tongue, stomach upset, weight loss, and diarrhea or constipation. If the deficiency is not corrected, nerve cell damage can result. If this happens, vitamin B₁₂ deficiency may result in tingling or numbness to the fingers and toes, difficulty walking, mood changes, depression, memory loss, disorientation and, in severe cases, dementia.

The main syndrome of vitamin B₁₂ deficiency is pernicious anemia. It is characterized by a triad of symptoms:

1. Anemia with bone marrow promegaloblastosis (megaloblastic anemia). This is due to the inhibition of DNA synthesis (specifically purines and thymidine)
2. Gastrointestinal symptoms: alteration in bowel motility, such as mild diarrhea or constipation, and loss of bladder or bowel control.^[9] These are thought to be due to defective DNA synthesis inhibiting replication in a site with a high turnover of cells. This may also be due to the autoimmune attack on the parietal cells of the stomach in pernicious anemia. There is an association with GAVE syndrome (commonly called watermelon stomach) and pernicious anemia.^[10]
3. Neurological symptoms: Sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation), subacute combined degeneration of spinal cord, seizures,^{[11][12][13][14]} or even symptoms of dementia^[15] and or other psychiatric symptoms may be present. The presence of peripheral sensory-motor symptoms or subacute combined degeneration of spinal cord strongly suggests the presence of a B₁₂ deficiency instead of folate deficiency. Methylmalonic acid, if not properly handled by B₁₂, remains in the myelin sheath, causing fragility. Dementia and depression have been associated with this deficiency as well, possibly from the under-production of methionine because of the inability to convert homocysteine into this product. Methionine is a necessary cofactor in the production of several neurotransmitters.

Each of those symptoms can occur either alone or along with others. The neurological complex, defined as myelosis funicularis, consists of the following symptoms:

1. Impaired perception of deep touch, pressure and vibration, loss of sense of touch, very annoying and persistent paresthesias
2. Ataxia of dorsal chord type
3. Decrease or loss of deep muscle-tendon reflexes
4. Pathological reflexes — Babinski, Rossolimo and others, also severe paresis

Vitamin B₁₂ deficiency can cause severe and irreversible damage, especially to the brain and nervous system. These symptoms of neuronal damage may not reverse after correction of hematological abnormalities, and the chance of complete reversal decreases with the length of time the neurological symptoms have been present.

Tinnitus may be associated with vitamin B₁₂ deficiency.^[16]

Psychological

Vitamin B₁₂ deficiency can also cause symptoms of mania and psychosis, fatigue, memory impairment, irritability, depression, ataxia, and personality changes.^[17][18][19] In infants symptoms include irritability, failure to thrive, apathy, anorexia, and developmental regression.^[20][21]

Causes

• Inadequate dietary intake of vitamin B₁₂. Vitamin B₁₂ occurs in animal products (eggs, meat, milk) and recent research indicates it may also occur in some algae, such as Chlorella^[22][23][24] and Susabi-nori (Porphyra yezoensis).^[25][26] B₁₂ isolated from bacterial cultures is also added to many fortified foods, and available as a dietary supplement.^[27] Vegans, and also vegetarians but to a lesser degree, may be at risk for B₁₂ deficiency due to inadequate dietary intake of B₁₂, if they do not supplement. However, B₁₂ deficiency can occur even in people who consume meat, poultry, and fish.^[28] Children are at a higher risk for B₁₂ deficiency due to inadequate dietary intake, as they have fewer vitamin stores and a relatively larger vitamin need per calorie of food intake.
• Selective impaired absorption of vitamin B₁₂ due to intrinsic factor deficiency. This may be caused by the loss of gastric parietal cells in chronic atrophic gastritis (in which case, the resulting megaloblastic anemia takes the name of "pernicious anemia"), or may result from wide surgical resection of stomach (for any reason), or from rare hereditary causes of impaired synthesis of intrinsic factor.
• Impaired absorption of vitamin B₁₂ in the setting of a more generalized malabsorption or maldigestion syndrome. This includes any form of structural damage or wide surgical resection of the terminal ileum (the principal site of vitamin B₁₂ absorption).
• Forms of achlorhydria (including that artificially induced by drugs such as proton pump inhibitors and histamine 2 receptor antagonists) can cause B₁₂ malabsorption from foods, since acid is needed to split B₁₂ from food proteins and salivary binding proteins.^[29] This process is thought to be the most common cause of low B₁₂ in the elderly, who often have some degree of achlorhydria without being formally low in intrinsic factor. This process does not affect absorption of small amounts of B₁₂ in supplements such as multivitamins, since it is not bound to proteins, as is the B₁₂ in foods.^[30]
• Surgical removal of the small bowel (for example in Crohn's disease) such that the patient presents with short bowel syndrome and is unable to absorb vitamin B₁₂. This can be treated with regular injections of vitamin B₁₂.
• Long-term use of ranitidine hydrochloride may contribute to deficiency of vitamin B₁₂.^[31]
• Untreated celiac disease may also cause impaired absorption of this vitamin, probably due to damage to the small bowel mucosa. In some people, vitamin B12 deficiency may persist despite treatment with a gluten-free diet and require supplementation.^[32]
• Some bariatric surgical procedures, especially those that involve removal of part of the stomach, such as Roux-en-Y gastric bypass surgery. (Procedures such as the adjustable gastric band type do not appear to affect B₁₂ metabolism significantly).
• Bacterial overgrowth in parts of the small bowel are thought to be able to absorb B₁₂. An example occurs in so-called blind loop syndrome.
• The diabetes medication metformin may interfere with B₁₂ dietary absorption.^[33]
• Hereditary causes such as severe MTHFR deficiency, homocystinuria, and transcobalamin deficiency.
• One anecdotal study has shown that giardiasis may be a cause of vitamin B₁₂ deficiency,^[34] but larger studies have shown no correlation.^[35]
• Malnutrition of alcoholism.
• Nitrous oxide abuse.^[36]

Mechanism

The total amount of vitamin B₁₂ stored in the body is between two and five milligrams in adults. Approximately 50% is stored in the liver, but approximately 0.1% is lost each day, due to secretions into the gut—not all of the vitamin in the gut is reabsorbed. While bile is the main vehicle for B₁₂ excretion, most of the B₁₂ secreted in bile is recycled via enterohepatic circulation. Due to the extreme efficiency of this mechanism, the liver can store three to five years worth of vitamin B₁₂ under normal conditions and functioning.^[37] However, the rate at which B₁₂ levels may change when dietary intake is low depends on the balance between several variables.^[38]

Metabolic

Vitamin B₁₂ deficiency causes particular changes to the metabolism of 2 clinically relevant substances in humans:

1. Homocysteine (homocysteine to methionine, catalysed by methionine synthase) leading to hyperhomocysteinemia may lead to varicose veins
2. Methylmalonic acid (methylmalonyl-CoA to succinyl-CoA, of which methylmalonyl-CoA is made from methylmalonic acid in a preceding reaction)

Methionine is activated to S-adenosyl methionine, which aids in purine and thymidine synthesis, myelin production, protein/neurotransmitters/fatty acid/phospholipid production and DNA methylation. 5-Methyl tetrahydrofolate provides a methyl group, which is released to the reaction with homocysteine, resulting in methionine. This reaction requires cobalamin as a cofactor. The creation of 5-methyl tetrahydrofolate is an irreversible reaction. If B₁₂ is absent, the forward reaction of homocysteine to methionine does not occur, and the replenishment of tetrahydrofolate stops.^[39]

Because B₁₂ and folate are involved in the metabolism of homocysteine, hyperhomocysteinuria is a non-specific marker of deficiency. Methylmalonic acid is used as a more specific test of B₁₂ deficiency.

Pathomorphology

A spongiform state of neural tissue along with edema of fibers and deficiency of tissue. The myelin decays, along with axial fiber. In later phases, fibric sclerosis of nervous tissues occurs. Those changes apply to dorsal parts of the spinal cord and to pyramidal tracts in lateral cords. The pathophysiologic state of the spinal cord is called subacute combined degeneration of spinal cord.^[40]

In the brain itself, changes are less severe: They occur as small sources of nervous fibers decay and accumulation of astrocytes, usually subcortically located, and also round hemorrhages with a torus of glial cells. Pathological changes can be noticed as well in the posterior roots of the cord and, to lesser extent, in peripheral nerves. Abnormalities might be observed in MRI.^[41]

Diagnosis

MRI image of the brain in an axial view showing the “precontrast FLAIR image”. Note the abnormal lesions (circled) in the per ventricular area suggesting white matter pathology in someone with vitamin B12 deficiency.

Serum B₁₂ levels are often low in B₁₂ deficiency, but if other features of B₁₂ deficiency are present with normal B₁₂ then further investigation is warranted. One possible explanation for normal B₁₂ levels in B₁₂ deficiency is antibody interference in people with high titres of intrinsic factor antibody.^[42] Some researchers propose that the current standard norms of vitamin B₁₂ levels are too low.^[43] One Japanese study states the normal limits as 500–1,300 pg/mL.^[44] Range of vitamin B12 levels in humans is considered as normal: >300 pg/mL; moderate deficiency: 201–300 pg/mL; and severe deficiency: <201 pg/mL.^[45]

Serum vitamin B₁₂ tests results are in pg/mL (picograms/milliliter) or pmol/L (picomoles/liter). The laboratory reference ranges for these units are similar, since the molecular weight of B₁₂ is approximately 1000, the difference between mL and L. Thus: 550 pg/mL = 400 pmol/L.

Serum homocysteine and methylmalonic acid levels are considered more reliable indicators of B₁₂ deficiency than the concentration of B₁₂ in blood.^[46] The levels of these substances are high in B₁₂ deficiency and can be helpful if the diagnosis is unclear.

Routine monitoring of methylmalonic acid levels in urine is an option for people who may not be getting enough dietary B₁₂, as a rise in methylmalonic acid levels may be an early indication of deficiency.^[47]

If nervous system damage is suspected, B₁₂ analysis in cerebrospinal fluid is possible, though such an invasive test should be considered only if blood testing is inconclusive.^[48]

The Schilling test has been largely supplanted by tests for antiparietal cell and intrinsic factor antibodies.

Effect of folic acid

The National Institutes of Health has found that "Large amounts of folic acid can mask the damaging effects of vitamin B₁₂ deficiency by correcting the megaloblastic anemia caused by vitamin B₁₂ deficiency without correcting the neurological damage that also occurs", there are also indications that "high serum folate levels might not only mask vitamin B₁₂ deficiency, but could also exacerbate the anemia and worsen the cognitive symptoms associated with vitamin B₁₂ deficiency".^[3] Due to the fact that in the United States legislation has required enriched flour to contain folic acid to reduce cases of fetal neural-tube defects, consumers may be ingesting more than they realize.^[49] To counter the masking effect of B₁₂ deficiency the NIH recommends "folic acid intake from fortified food and supplements should not exceed 1,000 μg daily in healthy adults."^[3] Most importantly, B₁₂ deficiency needs to be treated with B₁₂ repletion. Limiting folic acid will not counter the irrevocable neurological damage that is caused by untreated B₁₂ deficiency.

Treatment

Hydroxocobalamin injection is a clear red liquid solution of hydroxocobalamin.

B₁₂ can be supplemented by pill or injection and appear to be equally effective in those with low levels due to absorption problems.^[5]

When large doses are given by mouth its absorption does not rely on the presence of intrinsic factor or an intact ileum. Generally 1 to 2 mg daily is required as a large dose.^[50] Even pernicious anemia can be treated entirely by the oral route.^[51][52][53] These supplements carry such large doses of the vitamin that 1% to 5% of high oral doses of free crystalline B₁₂ is absorbed along the entire intestine by passive diffusion.

Epidemiology

A study in the year 2000 indicates that B₁₂ deficiency is far more widespread than formerly believed. The study found that 39 percent of studied group of 3,000 had low values.^[28]

In the developing world the deficiency is very widespread, with significant levels of deficiency in Africa, India, and South and Central America. This is theorized to be due to low intakes of animal products, particularly among the poor.^[54]

B₁₂ deficiency is more common in the elderly.^[54] This is because B₁₂ absorption decreases greatly in the presence of atrophic gastritis, which is common in the elderly.

The 2000 Tufts University study found no correlation between eating meat and differences in B₁₂ serum levels.^[28]

See also

• Beriberi (caused by Vitamin B1 deficiency)

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Further reading

• Pacholok SM, Stuart JJ (2011). Could It Be B12?: An Epidemic of Misdiagnoses. Fresno, CA: Linden Publishing. ISBN 978-1-61035-065-5.
• Hooper M (2012). Pernicious Anaemia: The Forgotten Disease - the causes and consequences of Vitamin B12 Deficiency. London: Hammersmith Press. ISBN 978-1-78161-004-6.

External links

• http://www.webmd.com/a-to-z-guides/vitamin-b12-deficiency-anemia-topic-overview WebMD overview
• Vitamin B12 and Folate at Lab Tests Online