Vitamin B12 deficiency

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Overview
B12 deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system.

The daily cobalamin (vitamin B12) requirement is 1-2 mcg. An intake of 5-20 mcg/day is usual in Western diet. The total body can store 2-5 mg. 60% of vitamin B12 is efficiently absorbed via the ileum when it is bound to intrinsic factor (IF).

The first deficiency symptom that was discovered was anemia characterized by enlarged blood corpuscles, so-called megaloblastic anemia.

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 cell lines such as white blood cells and platelets are often also low. Bone marrow examination may show megaloblastic hemopoiesis. The anemia is easy to cure with vitamin B12.

Far more serious is the damage to the nervous system that may occur due to deficiency.

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

Neurological signs of B deficiency, which can occur without anemia, include sensory disturbances due to damage to peripheral nerves caused by demyelination and irreversible nerve cell death. Symptoms include numbness, tingling of the extremities, disturbed coordination and, if not treated in time, an ataxic gait, a syndrome known as subacute combined degeneration of spinal cord.

B12 deficiency can also cause symptoms of mania and psychosis.

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

Studies showing a relationship between clinical depression levels and deficient B blood levels in elderly people are documented in the clinical literature. and 2002

Bipolar disorder appears to genetically co-segregate with the hereditary B12-deficiency disorder pernicious anemia.

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.


 * 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. It takes years to develop deficiency after dietary absorption stops.


 * 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 sneaking bits of uncooked fish while making the Eastern European delicacy, now eaten by Jews at Pesach).


 * The diabetes medication, metformin may interfere with B12 dietary absorption..


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

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. 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. proposed 550 pg/l, and Tiggelen et al 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 the 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 beens suggested.

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

B12 deficiency is common among vegetarians. 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-ovovegetarians. The study applied the old normal values, so in reality a considerably greater proportion may have been deficient.

Diagnosis
Deficiency is defined as serum Blevels less than 200 pg/mL (95-100% specific). Borderline B levels are defined between 200 and 400 pg/mL.

Serum B levels are often low in B deficiency, but if other features of B deficiency are present with normal B then the diagnosis must not be discounted. One possible explanation for normal B levels in B deficiency is antibody interference in people with high titres of intrinsic factor antibody. Some researchers propose that the current standard norms of vitamin B12 levels are too low. In Japan, the lowest acceptable level for vitamin B12 in blood has been raised from about 200 picograms/litre (pg/l) = 145  picomol/litre (pm/l) to 550 pg/l = 400 pm/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. The levels of these substances are high in B 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.

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

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.

Manifestations
Megaloblastic anemia w/ineffective erythropoiesis (inc bili/LDH); atrophic glossitis; and subacute combined degeneration of spinal cord:
 * Paresthesias, LE weakness, spasticity, ataxic gait
 * Loss of vibration and position sense
 * Dementia, personality change

Treatment
B can be supplemented in healthy subjects by oral pill; sublingual pill, liquid, or strip; or by injection. B is available singly or in combination with other supplements. B supplements are available in forms including cyanocobalamin, hydroxocobalamin, methylcobalamin, and adenosylcobalamin (sometimes called "cobamamide" or "dibencozide").

Vitamin B 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.

B has traditionally been given parenterally to ensure absorption in the dosage of 1 mg qd x 1 wk, then qwk x 1month, then monthly. However, oral replacement is now an accepted route, as it has become increasingly appreciated that sufficient quantities of B are absorbed when large doses are given although this is a less efficient path for absorption (1%). 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. By contrast, the typical Western diet contains 5–7 µg of B (Food and Drug Administration (FDA) Daily Value ). This method may be more effective than IM Rx, but requires patient compliance.

Hypokalemia, an excessive low potassium level in the blood, is anecdotally reported as a complication of vitamin B 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 B supplements when given in sufficient doses. When given in oral doses ranging from 0.1–2 mg daily, B 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. 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. Recent research indicates that sublingual administration eliminates a deficiency as well as injections (reference will be added) with the advantage of evading the allergy risk.

Laboratory Findings

 * Methylmalonic acid: elevated in B12 deficiency (98% sensitive)
 * Homocysteine: elevated in B12 and folate deficiency


 * Anti-IF Antibodies (AB): highly specific for PA, but sensitivity only 50-84%
 * Anti-parietal cell ABs: less sensitive and much less specific