tools for Vitamin B12 deficiency

Vitamin B₁₂ deficiency

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

Vitamin B₁₂ deficiency or hypocobalaminemia typically features a low blood level of vitamin B₁₂ however functional B₁₂ deficiency can occur at any serum level;^[1] with or without anaemia and/or macrocytosis.^[2] The deficiency is common to all age groups and is sometimes diagnosed late due to the lack of a gold standard assay and its complex aetiology. Neuropsychiatric symptoms can precede hematologic signs and are often the presenting manifestation of B₁₂ deficiency.^[2][3][4][5] B₁₂ deficiency can cause permanent damage to nervous tissue if left untreated longer than 6 months.^[6] B12 assays may be vulnerable to interference resulting in normal values despite severe B₁₂ deficiency.^[7] The standard CBLA B12 test Vitamin B₁₂ itself was discovered through investigation of pernicious anemia, which is an autoimmune disease that destroys parietal cells in the stomach that secrete intrinsic factor. Pernicious anemia and b12 deficiency, if left untreated, can be fatal.^[8] Once identified, however, the blood level can be raised very easily but the nerve deterioration can continue if the medication is not of the requisite dosage. It cannot be cured and ongoing treatment is required. Humans obtain almost all of their vitamin B₁₂ from dietary means. Pernicious anemia is usually the result of insufficient secretion of intrinsic factor within the stomach.^[9] Other more subtle types of vitamin B₁₂ deficiency have been elucidated, including the biochemical effects, over the course of time in significant numbers.

The results of the Framingham Offspring Study indicate that B₁₂ deficiency may be more common than was previously believed. Deficiency is most significantly linked to improper absorption rather than low consumption, as many who consume high amounts of B₁₂ may still experience deficiency.

Storage and levels[edit]

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 viaenterohepatic 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.^[9]However, the rate at which B₁₂ levels may change when dietary intake is low depends on the balance between several variables.^[11]

Symptoms and pathomorphology[edit]

Vitamin B₁₂ deficiency can lead to vitamin B12 deficiency anemia and neurologic dysfunction. 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 symptoms of Vitamin B₁₂ deficiency can be broken down into the following pathomorphology, signs, and symptoms:^[12]

Metabolic[edit]

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;
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.^[13]

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[edit]

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.^[14]

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.^[15]

Clinical symptoms[edit]

The main syndrome of vitamin B₁₂ deficiency is Biermer's disease (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.^[specify] 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.^[16]
3. Neurological symptoms: Sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation), subacute combined degeneration of spinal cord, seizures,^{[17][18][19][20]} or even symptoms of dementia ^[21] 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 ofmethionine 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.

Vitamin B₁₂ deficiency symptoms also include shortness of breath and increased pallor.

Psychological symptoms and mental disorders[edit]

Vitamin B₁₂ deficiency can also cause symptoms of mania and psychosis, fatigue, memory impairment, irritability, depression and personality changes.^{[22][23][24][25][unreliable source?]} In infants symptoms include irritability, failure to thrive, apathy, anorexia, and developmental regression.^[26][27]

Association of low B₁₂ with diseases not classically due to vitamin deficiency[edit]

A number of diseases not classically thought to be caused by B₁₂ deficiency are epidemiologically associated with it, raising questions of whether B₁₂ status is an independent risk-factor, or a partial causal agent in these states. None of these causal connections have been proved, and all are under active investigation.

B₁₂ status may be associated with the onset and cause of Alzheimer's disease. Some studies have found no relationship,^[28] while several recent studies^[29][30][31] indicate a relationship between B₁₂, homocysteine, and Alzheimer's. B₁₂ status is routinely measured at the time of Alzheimer's diagnosis, and there is some indication that ongoing measurements may be useful to detect the development of a severe deficiency.^[32] In addition to checking serum B₁₂, checking the levels of other compounds (particularlymethylmalonic acid) may be necessary to accurately detect a deficiency state, because serum levels do not necessarily correlate with efficient utilization of B₁₂.

A relationship between clinical depression levels and deficient B₁₂ blood levels in elderly people is documented in the literature.^[33][34]

Causes[edit]

• 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 asChlorella^[35][36][37] and Susabi-nori (Porphyra yezoensis).^[38][39][40] B₁₂ isolated from bacterial cultures is also added to many fortified foods, and available as a dietary supplement ^[41] 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 intake.^[10] 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.^[42] 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.^{[citation needed]}
• 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.^[43]
• Coeliac disease may also cause impaired absorption of this vitamin, though this is due not to loss of intrinsic factor, but rather damage to the small bowel.^{[citation needed]}
• 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 theadjustable gastric band type do not appear to affect B₁₂ metabolism significantly).^{[citation needed]}
• 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.^{[citation needed]}
• The diabetes medication metformin may interfere with B₁₂ dietary absorption.^[44]
• Hereditary causes such as severe MTHFR deficiency, homocystinuria, and transcobalamin deficiency.^{[citation needed]}
• Some studies have shown that giardiasis, or similar parasitic infections may be a cause of vitamin B₁₂ deficiency.^[45]
• Malnutrition of alcoholism.
• Nitrous oxide abuse.^[46]

Diagnosis[edit]

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.^[47] Some researchers propose that the current standard norms of vitamin B₁₂ levels are too low.^[48] 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).^[49]

Serum vitamin B₁₂ tests results are in pg/mL (picograms/millilitre) or pmol/L (picomoles/litre). 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.^[50] 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/ml 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.^[51]

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.^[52]

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

Treatment[edit]

Hydroxocobalamin injection USP (1000 mcg/mL) is a clear red liquid solution of hydoxocobalamin which is available in a 30 mL brown glass multidose vial packaged in a paper box. Shown is 500 mcg B-12 (as 1/2 cc) drawn up in a 1/2 cc U-100 27 gauge x 1/2" insulin syringe, as prepared for subcutaneous injection.

B₁₂ can be supplemented in healthy subjects by oral pill; sublingual pill, liquid, or strip; intranasal spray; transdermal patch or by injection. B₁₂ is available singly or in combination with other supplements. B₁₂ supplements are available in forms includingcyanocobalamin, hydroxocobalamin, methylcobalamin, and adenosylcobalamin (sometimes called "cobamamide" or "dibencozide"). Oral treatments involve giving 250 µg to 1 mg of B₁₂ daily.^[53]

Vitamin B₁₂ can be given as intramuscular or subcutaneous injections of hydroxycobalamin, methylcobalamin, orcyanocobalamin. Body stores (in the liver) are partly repleted with half a dozen injections in the first couple of weeks (full repletion of liver stores requires about 20 injections) and then maintenance with monthly injections throughout the life of the patient. Vitamin B₁₂ can also be easily self-administered by injection by the patient, using the same fine-gauge needles and syringes used for self-administration of insulin.

B₁₂ has traditionally been given parenterally (by injection) 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.^[54] By contrast, the typical Western diet contains 5–7 µg of B₁₂ (Food and Drug Administration (FDA) Daily Value^[55]). It has been appreciated since the 1960s that B₁₂ deficiency in adults resulting from malabsorption (including loss of intrinsic factor) can 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. In two studies, oral treatment with 2 mg per day was as effective as monthly 1 mg injections.^[56][57]

Hypokalemia, an excessively low potassium level in the blood, is anecdotally reported as a complication of vitamin B₁₂ repletion after deficiency.^{[citation needed]} Excessive quantities of potassium are used by newly growing and dividing hematopoietic cells, depleting circulating stores of the mineral.

Research has established the effectiveness of other routes of B₁₂ administration, primarily intranasal and sublingual dosing, but neither has been proven to be superior to oral dosing; recommendations are based on a consumers individual circumstances.^[58] The sublingual route, in which B₁₂ is absorbed under the tongue, is manufactured in a variety of forms, such as lozenges, pills, and lollipops. A 2003 study found no significant difference in absorption for serum levels from oral vs. sublingual delivery of 500 µg (micrograms) of cobalamin,^[59] although the study measured only serum levels as opposed to tissue levels, which is more reflective of B₁₂ levels. Sublingual methods of replacement may be effective only because of the typically high doses (500 micrograms), which are swallowed, not because of placement of the tablet. As noted below, such very high doses of oral B₁₂ may be effective as treatments, even if gastro-intestinal tract absorption is impaired by gastric atrophy (pernicious anemia).

Naturally occurring sources[edit]

Vitamin B₁₂ can be found in large quantities in animal products, including meat, poultry, fish, seafood, eggs, and dairy products; and the consumption of these products is the most longstanding method by which human beings have taken vitamin B₁₂ into their systems. Bioavailability of B₁₂ in eggs is low (<9%) compared to other animal food sources.^[60]B₁₂ vitamin levels in different dietary sources are listed by the recommended dietary allowance per 100g serving of a particular food source.^[61] Some animal foods that have high vitamin B₁₂ content per 100g serving (% in RDA) are as follows:^[62] mussels 1267%, mackerel 317%, herring 312%, salmon 302%, liverwurst sausage 224%, crab 192%, tuna 181%, goose liver 157%, emu steak 156%, bluefish 104%, beef (lean fat part) 103%, New England clam chowder 80%, lobster 67%, lamb (shoulder part) 62%, Swiss cheese 56%, Manhattan clam chowder 55%, chicken eggs 33%.^{[citation needed]}

Fermented foods and unconventional bacterial sources[edit]

Since B₁₂ is produced by bacteria, it is possible that it can be obtained in some bacterially fermented foods such as traditional Korean foods. However, this has not yet be rigorously proven.^[63][64]

Certain makers of kombucha cultured tea, such as GT's Kombucha, list vitamin B₁₂ as naturally present in their product. One brand purports to contain 20 percent of the Daily Value of B₁₂ in a single bottle,^[65] making kombucha a potential "high" food source of B₁₂. Because kombucha is produced by a symbiosis between yeast and bacteria, the possibility that kombucha contains B₁₂ does not contradict current knowledge. But no scientific studies have yet been published confirming the fact, nor whether the B₁₂ in kombucha is the biologically active B₁₂.

A Japanese fermented black tea known as Batabata-cha has been found to contain biologically active B₁₂.^[66] Unlike kombucha which is made by fermenting already prepared tea, Batabata-cha is fermented while still in the tea leaf state.

Unconventional natural sources of B₁₂ also exist, but their utility as food sources of B₁₂ are doubtful. For example, plants pulled from the ground and not washed scrupulously may contain remnants of B₁₂ from the bacteria present in the surrounding soil.^[67] B₁₂ is also found in lakes if the water has not been sanitized.^[68] Certain insects such as termitescontain B₁₂ produced by their gut bacteria, in a way analogous to ruminant animals.^[69] The human intestinal tract itself may contain B₁₂ producing bacteria in the small intestine,^[70] but it is unclear whether sufficient amounts of the vitamin could be produced to meet nutritional needs.

Fortified sources[edit]

Foods fortified with B₁₂ are also sources of the vitamin₁₂. The vitamin is added in supplement form, from commercial bacterial production sources, such as cyanocobalamin. Examples of B₁₂-fortified foods include fortified breakfast cereals, fortified soy products, fortified energy bars, and fortified nutritional yeast. The UK Vegan Society, the Vegetarian Resource Group, and the Physicians Committee for Responsible Medicine, among others, deny that non-animal food sources of vitamin B₁₂ are reliable and recommend that every vegan who is not supplementing consume B₁₂-fortified foods.^[71][72][73] Not all of these may contain labeled amounts of vitamin activity. Supplemental B₁₂ added to beverages in one study was found to degrade to contain varying levels of pseudovitamin-B₁₂. One report has found B₁₂ analogues present in varying amounts in some multivitamins.^[74][75]

Pseudovitamin sources[edit]

So-called pseudovitamin-B₁₂ refers to B₁₂-like analogues that are biologically inactive in humans and yet found to be present alongside B₁₂ in humans,^[76][77] many food sources (including animals^[78]), and possibly supplements and fortified foods.^[74][75] In most cyanobacterium, including Spirulina, and some algae, such as dried Asakusa-nori (Porphyratenera), pseudovitamin-B12 is found to predominate.^[79][80]

Controversial sources in algae with some evidence[edit]

The UK Vegan Society, the Vegetarian Resource Group, and the Physicians Committee for Responsible Medicine, among others, recommend that vegans either consistently eat B₁₂-fortified foods or take a daily or weekly B₁₂ supplement to meet the recommended intake.^[72][73][81]

It is important for vegans, who possess limited food sources of B₁₂, and anyone else wishing to obtain B₁₂ from food sources other than animals, to consume foods that contain little or no pseudovitamin-B₁₂ and are high in biologically active B₁₂. However, there have been no significant human trials of sufficient size to demonstrate enzymatic activity of B₁₂ from nonbacterial sources, such as Chlorella and edible sea algae (seaweeds, such as lavers), although chemically some of these sources have been reported to contain B₁₂that seems chemically identical to active vitamin.^[35][36] However, among these sources, only fresh sea algea such as Susabi-nori (Porphyra yezoensis)^[38][39] have been reported to demonstrated vitamin B₁₂ activity in B₁₂ deficient rats. This has yet to be demonstrated for Chlorella, and no study in rats of any algal B₁₂ source has yet to be confirmed by a second independent study. The possibility of algae-derived active forms of B₁₂ presently remains an active topic of research, with no results that have yet reached consensus in the nutritional community.