Vitamin B12 deficiency

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Vitamin B12 deficiency
Classification and external resources
Cyanocobalamin
ICD-10	E53.8
ICD-9	266.2
DiseasesDB	13905
MeSH	D014806

B12 deficiency is a reduction in vitamin B12 from inadequate dietary intake or impaired absorption. The condition is commonly asymptomatic, but can also present as anemia characterized by enlarged blood corpuscles with characteristic changes in neutrophils, known as megaloblastic anemia.

In serious cases deficiency can potentially cause severe and irreversible damage to the nervous system, including subacute combined degeneration of spinal cord.

The anemia is thought to be due to problems in DNA synthesis, specifically in the synthesis of thymine, which is dependent on products of the MTR reaction. Other blood cell types such as white blood cells and platelets are often also low. Bone marrow examination may show megaloblastic hemopoiesis. The anemia responds completely to vitamin B12; the neurological symptoms (if any) respond partly or completely, depending on prior severity and duration.

Contents 1 Presentation 2 Causes 3 Incidence/prevalence 4 Diagnosis 5 Treatment 5.1 Natural food sources of B-12 6 References

[edit] Presentation

Early and even fairly pronounced deficiency does not always cause distinct or specific symptoms. Common early symptoms are tiredness, a decreased mental work capacity, weakened concentration and memory, and irritability and depression.

Sleep disturbances may occur, because B12 may be involved in the regulation of the sleep wake cycle by the pineal gland (through melatonin).^[1]

Neurological signs of B₁₂ deficiency, which can occur with anemia, include sensory disturbances due to damage to peripheral nerves caused by demyelination and irreversible nerve cell death. Symptoms include numbness and/or tingling of the extremities, impaired sense of smell, loss of appetite, disturbed coordination and, if not treated in time, an ataxic gait especially in the dark when there is less visual reference,^[2] a syndrome known as subacute combined degeneration of spinal cord.

B-12 deficiency can also cause symptoms of mania, psychosis, fatigue, memory impairment, irritability, depression and personality changes.^[2][3][4][5]

Recent studies have devalued a possible connection between B12 deficiency and Alzheimer's dementia, and such a correlation is unlikely as of June 2007.^[6]

Studies showing a relationship between clinical depression levels and deficient B₁₂ blood levels in elderly people are documented in the clinical literature.^[7] and 2002 ^[8]

Bipolar disorder appears to genetically co-segregate with the hereditary B12-deficiency disorder pernicious anemia ^[9][10].

Science Daily reported that "a deficiency of B-vitamins may cause vascular cognitive impairment, according to a new study by the Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University." Aron Troen, PhD, said that: "The vascular changes occurred in the absence of neurotoxic or degenerative changes. Metabolic impairments induced by a diet deficient in three B-vitamins -folate, B12 and B6- caused cognitive dysfunction and reductions in brain capillary length and density in our mouse model."^{[11][12][13][14]}

The following symptoms have been recorded, beginning with those perhaps most likely to be indicative of B12 deficiency.

1. Itchy or tingling tongue. The tongue suddenly itches from time to time without warning. This occurs on the edge of the tongue, along one side or the other or at the tip. Some individuals experience stinging, pain, or tingling instead of itching.

2. White spots in the skin, resulting from melanin becoming absent in the area. These often occur on the outside of the forearm, but may occur in other places. The longer these spots are there, the whiter they get. As time goes by, the spots become very dry and flaky to the extent that small raw spots of skin may be exposed.

3. Sharp stabbing, tingling pain in the palm of one or both hands. This occurs suddenly and for no apparent reason in a spot directly below the ring finger, approximately where the first palm crease is. If B12 deficiency is not treated, a tingling pain may begin to occur along the outside edge of the hand, starting from the wrist. This pain occurs when the wrist is extended.

4. Sores at the corners of the mouth, sometimes extending along the edge of the lip. These are raw spots, not blisters, and they tend to come and go.

5. Nerve shock in the side of the body. It can be felt coming on a few seconds before it hits, and then it hits almost like a mild but deep electric shock and quickly subsides. It can occur at the side of either hip or on either side of the upper body, along the ribs. It can occur consecutively in at least two or three locations, one right after the other.

6. Shortness of breath, but without chest pain. This can occur when walking just a few yards.

7. Eye twitch, usually in one eye or the other. It can occur on the eyelid or just below the eye.

8. Facial pain, usually on only one side of the face at a time. This pain varies so much that it would be difficult to describe all the possibilities. This can present as a dull pain in the cheek bone right underneath an eye, or a sharp shooting pain across the forehead, sometimes coming downward from the scalp to the edge of the nose by the eye.

9. Tingling along the back of one or both thighs, starting at the hips and shooting downward.

10. Memory loss and/or disorientation.

11. Migraine headaches. These may be preceded by a temporary blind spot in the center of the field of vision, usually lasting about ten minutes, and sometimes followed by facial pain under the eyes. After the blind spot vanishes, there may be zigzag streaks through the vision that may last up to hours. Even in the same person, there may be extreme variations in the headaches themselves. They may be quite severe with nausea or they may be virtually nonexistent.

Migraines of most individuals have causes other than B12 deficiency, but migraines of certain individuals diminish or stop completely after they are treated for B12 deficiency.

12. Irritability and/or depression and/or personality changes.

[edit] Causes

• Inadequate dietary intake of vitamin B₁₂. As the vitamin B₁₂ occurs naturally only in animal products (eggs, meat, milk); a vegan diet can produce a deficiency unless one uses supplements or eats enriched food.^[15][16]

• Selective impaired absorption of vitamin B₁₂ due to intrinsic factor deficiency. This may depend on loss of gastric parietal cells in chronic atrophic gastritis (in which case, the resulting megaloblastic anaemia takes the name of "pernicious anaemia"), or on wide surgical resection of stomach (such as in bariatric surgery), or on rare hereditary causes of impaired synthesis of intrinsic factor.Celiac disease which affects around one percent of the European population may cause impaired absorption of this vitamin.

• Impaired absorption of vitamin B₁₂ in the setting of a more generalised 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), as well as bacterial overgrowth (such as in blind loop syndrome).

• Chronic intestinal infestation by the fish tapeworm Diphyllobothrium, that competes for vitamin B₁₂, seizing it for its own use and therefore leaving insufficient amount for the host organism. This is mostly confined to Scandinavia and parts of Eastern Europe (for example, in preparers of gefilte fish, who would acquire the tapeworm by nibbling bits of fish before it was cooked while making the Eastern European delicacy).

• The diabetes medication, metformin may interfere with B12 dietary absorption.^[17]

• Hereditary causes such as severe MTHFR deficiency, homocystinuria, and transcobalamin deficiency.

• Some studies have shown that giardiasis, or similar parasite should be considered as a cause of Vitamin B12 deficiency, this a result of the problems caused within the intestinal absorption system.^[18]

[edit] Incidence/prevalence

Recent research indicates that B12 deficiency is far more widespread than formerly believed. A large study in the US found that 39 percent had low values.^[19] This study at Tufts University used the B12 concentration 258 pmol/l (= 350 pg/liter) as a criterion of "low level". However, recent research has found that B12 deficiency may occur at a much higher B12 concentration (500-600 pg/l). On this basis Mitsuyama and Kogoh ^[20]. proposed 550 pg/l, and Tiggelen et al.^[21] proposed 600 pg/l. Against this background, there are reasons to believe that B12 deficiency is present in a far greater proportion of the population than 39% as reported by Tufts University.

In the developing world the deficiency is very widespread, with significant levels of deficiency in Africa, India, and South and Central America. This is due to low intakes of animal products, particular among the poor. Increased intake of animal products or supplements have been suggested.^[22]

B12 deficiency is even more common in the elderly ^[22]. This is because B₁₂ absorption decreases greatly in the presence of atrophic gastritis, which is common in the elderly.

B12 deficiency is common among vegetarians and vegans who do not take B12 supplements. In vegans the risk is very high because none of their natural food sources contain B12. One American study found blood levels below normal in 92 % of vegans, 64 % of lactovegetarians, 47 % of lacto-ovo vegetarians who did not supplement their diet with B12^{[citation needed]}. However, their complete blood count values did not deviate greatly from those found for nonvegetarians, even though some had been vegans or lactovegetarians for over 10 years.^[23] The study applied the old normal values, so in reality a considerably greater proportion may have been deficient. On the other hand, one must take into account that the study was conducted in 1982 with a group taking no vitamin supplements: today soy drinks are often fortified with vitamin B12.

[edit] Diagnosis

Serum B₁₂ levels are often low in B₁₂ deficiency, but if other features of B₁₂ deficiency are present with normal B₁₂ then the diagnosis must not be discounted. One possible explanation for normal B₁₂ levels in B₁₂ deficiency is antibody interference in people with high titres of intrinsic factor antibody.^[24] Some researchers propose that the current standard norms of vitamin B12 levels are too low^{[citation needed]}. In Japan, the lowest acceptable level for vitamin B12 in blood has been raised from about 200 pg/ml (145 pM) to 550 pg/ml (400 pM).^[20]

There is confusion in units of B12 deficiency when given by various labs in various countries. Where units are presented as pg/liter, or pg/L, they are likely in error. Where they are presented as pg/mL or pmol/L, they are likely correct. The ranges for these two 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, see for example research at the St. Louis University.^[25] The levels of these substances are high in B₁₂ deficiency and can be helpful if the diagnosis is unclear. Approximately 10% of patients with vitamin B12 levels between 200-400pg/l will have a vitamin B12 deficiency on the basis of elevated levels of homocysteine and methylmalonic acid.^{[citation needed]}

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.^[26]

If nervous system damage is suspected, B12 analysis in cerebrospinal fluid can also be helpful, though such an invasive test would be applicable only after unrevealing blood testing.^[27]

The Schilling test can play a role in the diagnosis.

[edit] Treatment

B₁₂ can be supplemented in healthy subjects by oral pill; sublingual pill, liquid, or strip; intranasal spray; or by injection. B₁₂ is available singly or in combination with other supplements. B₁₂ supplements are available in forms including cyanocobalamin, hydroxocobalamin, methylcobalamin, and adenosylcobalamin (sometimes called "cobamamide" or "dibencozide"). Oral treatments involve giving 250 ug to 1 mg of B12 daily.^[28]

Vitamin B₁₂ can be given as intramuscular injections of hydroxycobalamin, methylcobalamin, or cyanocobalamin. Body stores (in the liver) are refilled with half a dozen injections in the first couple of weeks and then maintenance with monthly to quarterly injections throughout the life of the patient.

B₁₂ has traditionally been given parenterally to ensure absorption. However, oral replacement is now an accepted route, as it has become increasingly appreciated that sufficient quantities of B₁₂ are absorbed when large doses are given. This 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 [3]. By contrast, the typical Western diet contains 5–7 µg of B₁₂ (Food and Drug Administration (FDA) Daily Value ^[29]).

Hypokalemia, an excessive low potassium level in the blood, is anecdotally reported as a complication of vitamin B₁₂ repletion after deficiency. Excessive quantities of potassium are used by newly growing and dividing hematopoeitic cells, depleting circulating stores of the mineral.

It has been appreciated since the 1960s that deficiency can sometimes be treated with oral B₁₂ supplements when given in sufficient doses. When given in oral doses ranging from 0.1–2 mg daily, B₁₂ can be absorbed in a pathway that does not require an intact ileum or intrinsic factor. However, with the advent of sublingual and intranasal administration, tablet usage is becoming outdated.^[30][31] Oral absorption is limited so regular intramuscular injections or sublingual/intranasal administration of a cobalamin (preferably methyl- or hydroxycobalamin) is necessary to restore systemic stores to physiological levels.

[edit] Natural food sources of B-12

Vitamin B12 is found in foods that come from animals, including fish, meat, poultry, eggs, milk, and milk products and fortified breakfast cereals. It is made by yeasts and microorganisms.^[32] One half chicken breast, provides some .3 mc grams per serving or 6% of your daily value (DV), 3 ounces of beef, 2.4 mc grams, or 40% of your DV, one slice liver 47.9 mc grams or 780% of your DV, and 3 ounces of molluscs 84.1 mc grams, or 1,400% of your DV, while one egg provides .6 mc grams or 10% of your DV. Other sources include nutritional yeast, fortified soy milks, and fortified energy bars.

[edit] References

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