Vitamin B12 deficiency

Vitamin B12 deficiency, also known as cobalamin deficiency, is the medical condition of low blood and tissue levels of vitamin B12.[4] Serum vitamin B12 levels are typically below 120–180 pmol/L (170–250 pg/mL) in adults.[2] Tissue deficiency resulting in signs and symptoms occurs in nerve cells, the bone marrow, and epithelial cells.[4] In mild deficiency, a person may feel tired and have a reduced number of red blood cells (anemia).[1] In moderate deficiency, soreness of the tongue may occur, and the beginning of neurological symptoms, including abnormal sensations such as pins and needles.[1] Severe deficiency may include symptoms of reduced heart function as well as more severe neurological symptoms, including changes in reflexes, poor muscle function, memory problems, decreased taste, and psychosis.[1] Infertility may occur.[1][5] In young children, symptoms include poor growth, poor development, and difficulties with movement.[2] Without early treatment, some of the changes may be permanent.[6]

Vitamin B12 deficiency
Other namesHypocobalaminemia, cobalamin deficiency
Cyanocobalamin
SpecialtyNeurology, hematology
SymptomsDecreased ability to think, depression, irritability, abnormal sensations, changes in reflexes[1]
ComplicationsMegaloblastic anemia[2]
CausesPoor absorption, decreased intake, increased requirements[1]
Diagnostic methodBlood levels below 120–180 pmol/L (170–250 pg/mL) in adults[2]
PreventionSupplementation in those at high risk[2]
TreatmentSupplementation by mouth or injection[3]
Frequency6% (<60 years old), 20% (>60 years old)[1]

Causes are categorized as decreased absorption of vitamin B12 from the stomach or intestines, deficient intake, or increased requirements.[1] 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.[1] Medications that may decrease absorption include proton pump inhibitors, H2-receptor blockers, and metformin.[7] Decreased intake may occur in vegetarians and the malnourished.[1][8] Increased requirements occur in people with HIV/AIDS, and in those with shortened red blood cell lifespan.[1] Diagnosis is typically based on low serum levels of vitamin B12. Elevated methylmalonic acid levels may also indicate a deficiency.[2] A type of anemia known as megaloblastic anemia is often but not always present.[2]

Treatment consists of using vitamin B12 by mouth or by injection; initially in high daily doses, followed by less frequent lower doses as the condition improves.[3] If a reversible cause is found, that cause should be corrected if possible.[9] If no reversible cause is found - or when found it cannot be eliminated - lifelong vitamin B12 administration is usually recommended.[10] Vitamin B12 deficiency is preventable with supplements containing the vitamin: this is recommended in pregnant vegetarians and vegans, and not harmful in others.[2] Risk of toxicity due to vitamin B12 is low.[2]

Vitamin B12 deficiency in the US and the UK is estimated to occur in about 6 percent of those under the age of 60, and 20 percent of those over the age of 60.[1] In Latin America, about 40 percent are estimated to be affected, and this may be as high as 80 per cent in parts of Africa and Asia.[1]

Signs and symptoms

Vitamin B12 deficiency can lead to anemia and neurological disorders.[11] 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, gastrointestinal 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 type of vitamin B 12 deficiency anemia 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.[12] 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.[13]
  3. Neurological symptoms: Sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation), subacute combined degeneration of spinal cord, seizures,[14][15][16][17] or even symptoms of dementia[18] and or other psychiatric symptoms may be present. Deficiency symptoms in children include developmental delay, regression, irritability, involuntary movements and hypotonia.[19]

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 column 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 blood abnormalities, and the chance of complete reversal decreases with the length of time the neurological symptoms have been present. Elderly people are at an even higher risk of this type of damage.[20] In babies a number of neurological symptoms can be evident due to malnutrition or pernicious anemia in the mother. These include poor growth, apathy, having no desire for food, and developmental regression. While most symptoms resolve with supplementation some developmental and cognitive problems may persist.[21][22]

Only a small subset of dementia cases have been found to be reversible with vitamin B12 therapy.[23] Tinnitus may be associated with vitamin B12 deficiency.[24]

Effect of folic acid

Large amounts of folic acid can correct the megaloblastic anemia caused by vitamin B12 deficiency without correcting the neurological abnormalities, and could also worsen the anemia and the cognitive symptoms associated with vitamin B12 deficiency.[2] 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 folate than they realize.[25] To avoid this potential problem, folic acid intake from fortified food and supplements should not exceed 1,000 μg daily in healthy adults.[2]

Causes

Inadequate intake

Inadequate dietary intake of animal products (eggs, meat, milk, fish) and some edible algae.[26] B12 isolated from bacterial cultures is also added to many fortified foods, and available as a dietary supplement.[27] Vegans, and to a lesser degree vegetarians, may also be at risk for B12 deficiency due to inadequate dietary intake of B12, if they do not supplement. 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.

Alcoholism - if a "diet" of excessive alcohol intake is substituted for a diet adequate in sources of B12.

Impaired absorption

Increased need

Increased needs by the body can occur due to AIDS and hemolysis (the breakdown of red blood cells), which stimulates increased red cell production.[1]

Mechanism
MRI image of the brain in vitamin B12 deficiency, axial view showing the "precontrast FLAIR image": note the abnormal lesions (circled) in the periventricular area suggesting white matter pathology.
MRI image of the cervical spinal cord in vitamin B12 deficiency showing subacute combined degeneration. (A) The midsagittal T2 weighted image shows linear hyperintensity in the posterior portion of the cervical tract of the spinal cord (black arrows). (B) Axial T2 weighted images reveal the selective involvement of the posterior columns.

Physiology

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 this 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.[38] However, the rate at which B12 levels may change when dietary intake is low depends on the balance between several variables.[39]

Pathophysiology

Vitamin B12 deficiency causes particular changes to the metabolism of two 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, homocysteine concentrations increase, and the replenishment of tetrahydrofolate stops.[40] 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.

Nervous system

Early changes include 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 occur in dorsal parts of the spinal cord and to pyramidal tracts in lateral cords and is called subacute combined degeneration of spinal cord.[41] Pathological changes can be noticed as well in the posterior roots of the cord and, to lesser extent, in peripheral nerves.

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.

MRI of the brain may show periventricular white matter abnormalities. MRI of the spinal cord may show linear hyperintensity in the posterior portion of the cervical tract of the spinal cord, with selective involvement of the posterior columns.

Diagnosis

The diagnosis is frequently first suspected when a routine complete blood count shows anemia with an elevated MCV. In addition, on the peripheral blood smear, macrocytes and hypersegmented polymorphonuclear leukocytes may be seen.

Diagnosis is typically confirmed based on vitamin B12 blood levels below 120–180 pmol/L (170–250 pg/mL) in adults.[2] Elevated serum homocysteine (over 12 μmol/L) and methylmalonic acid (over 0.4 micromol/L) levels are considered more reliable indicators of B12 deficiency than the concentration of B12 in blood.[2][42]

If nervous system damage is present and blood testing is inconclusive, a lumbar puncture to measure cerebrospinal fluid B-12 levels may be done.[43]

On bone marrow aspiration or biopsy, megaloblasts are seen.

Treatment
Hydroxocobalamin injection is a clear red liquid solution.

B12 can be supplemented by pill or injection and appears to be equally effective in those with low levels due to deficient absorption of B12.[3]

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.[44] Even pernicious anemia can be treated entirely by the oral route.[45][46][47] 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

Vitamin B12 deficiency is common and occurs worldwide. In the US and UK, around 6 percent of the general population have the deficiency; in those over the age of sixty, around 20 percent are deficient. In under-developed countries, the rates are even higher: across Latin America 40 percent are deficient; in some parts of Africa, 70 percent; and in some parts of India, 70 to 80 percent.[1]

History

Adapted from:[48]

  • 1849 - Thomas Addison first described a case of pernicious anemia.[49]
  • 1877 - William Osler and William Gardner first described a case of neuropathy in this condition.[48]
  • 1878 - Hayem first described large red cells in the peripheral blood in this condition, which he called "giant blood corpuscles", now called macrocytes.[48]
  • 1880 - Paul Ehrlich first identified megaloblasts in the bone marrow in this condition.[48]
  • 1887 - Ludwig Lichtheim first described a case of myopathy in this condition.[48]
  • 1926 - George Minot shared the 1934 Nobel Prize with William Murphy and George Whipple, for discovery of an effective treatment for pernicious anemia using liver concentrate, later found to contain a large amount of vitamin B12.[50]
  • 1929 - William Castle demonstrated that gastric juice contained an "intrinsic factor" which when combined with meat ingestion resulted in absorption of the vitamin in this condition.[48]

Other animals

Ruminants, such as cows and sheep, absorb B12 synthesized by their gut bacteria.[51] Sufficient amounts of cobalt and copper need to be consumed for this B12 synthesis to occur.[52]

In the early 20th century, during the development for farming of the North Island Volcanic Plateau of New Zealand, cattle suffered from what was termed "bush sickness". It was discovered in 1934 that the volcanic soils lacked the cobalt salts essential for synthesis of vitamin B12 by their gut bacteria.[53][52] The "coast disease" of sheep in the coastal sand dunes of South Australia in the 1930s was found to originate in nutritional deficiencies of the trace elements, cobalt and copper. The cobalt deficiency was overcome by the development of "cobalt bullets", dense pellets of cobalt oxide mixed with clay given orally, which then was retained in the animal's rumen.[52][54]

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Further reading
  • Greer JP (2014). Wintrobe's Clinical Hematology Thirteenth Edition. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins. ISBN 978-1-4511-7268-3. Chapter 36: Megaloblastic anemias: disorders of impaired DNA synthesis by Ralph Carmel. The gold standard of clinical hematology textbooks since 1942.
  • Hunt, A.; Harrington, D.; Robinson, S. (4 September 2014). "Vitamin B12 deficiency". BMJ. 349. g5226. doi:10.1136/bmj.g5226. PMID 25189324.
  • 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.
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