Vitamin B12 deficiency

Vitamin B₁₂ deficiency, also known as cobalamin deficiency, is the medical condition in which the blood and tissue have a lower than normal level of vitamin B₁₂. Symptoms can vary from none to severe. Mild deficiency may have few or absent symptoms. Deficiency may occur more in elderly people due to impaired intestinal absorption, children, premenopausal women, and pregnant women, whose diets are low in animal foods. In healthy adults, vitamin B12 deficiency is not common, mainly because body stores of the vitamin are substantial and turnover is slow, with dietary intake of only 2.4 μg per day as sufficient to maintain adequate levels.
In moderate deficiency, symptoms develop slowly over years, with various neurological symptoms possibly including sensory loss, abnormal balance and reflexes, or memory and cognitive impairment. Severe deficiency may include symptoms of reduced heart function, as well as more severe neurological symptoms, and suppression of bone marrow. If left untreated, some of these changes can become permanent. Temporary infertility, reversible with treatment, may occur. A late finding type of anemia known as megaloblastic anemia is often but not always present. In exclusively breastfed infants of vegan mothers, undetected and untreated deficiency can lead to poor growth, poor development, and difficulties with movement.
Causes are usually related to conditions that give rise to malabsorption of vitamin B₁₂ particularly autoimmune gastritis in pernicious anemia. Other conditions giving rise to malabsorption include surgical removal of the stomach, chronic inflammation of the pancreas, intestinal parasites, certain medications such as long-term use of proton pump inhibitors, H2-receptor blockers, and metformin, and some genetic disorders.
Deficiency can also be caused by inadequate dietary intake such as with the diets of vegetarians, and vegans, and in the malnourished. Deficiency may be caused by increased needs of the body for example in those with HIV/AIDS, and shortened red blood cell lifespan. Diagnosis is typically based on blood levels of vitamin B₁₂ below 148–185 pmol/L in adults. Diagnosis is not always straightforward as serum levels can be falsely high or normal. Elevated methylmalonic acid levels may also indicate a deficiency. Individuals with low or marginal values of vitamin B₁₂ in the range of 148–221 pmol/L may not have classic neurological or hematological signs or symptoms, or may have symptoms despite having normal levels.
Treatment is by vitamin B₁₂ supplementation, either by mouth or by injection. Initially in high daily doses, followed by less frequent lower doses, as the condition improves. If a reversible cause is found, that cause should be corrected if possible. If no reversible cause is found, or when found it cannot be eliminated, lifelong vitamin B₁₂ administration is usually recommended. A nasal spray is also available. Vitamin B₁₂ deficiency is preventable with supplements, which are recommended for pregnant vegetarians and vegans, and not harmful in others. Risk of toxicity due to vitamin B₁₂ is low.
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. In Latin America, about 40 percent are estimated to be affected, and this may be as high as 80 percent in parts of Africa and Asia. Marginal deficiency is much more common and may occur in up to 40% of Western populations.

Signs, symptoms and complications

Vitamin B₁₂ deficiency appears slowly and worsens over time, and can often be confused with other conditions. It may often go unrecognized, as the body becomes used to feeling unwell.
Vitamin B₁₂ deficiency can lead to anemia, neurologic, and digestive dysfunctions. A mild deficiency may not cause any discernible symptoms, but at levels moderately lower than normal, a range of symptoms such as feeling tired, weak, lightheadedness, headaches, dizziness, rapid breathing, rapid heartbeat, cold hands and feet, low-grade fevers, tremor, cold intolerance, easy bruising and bleeding, pale skin, low blood pressure, sore tongue, upset stomach, loss of appetite, weight loss, constipation, diarrhea, severe joint pain, feeling abnormal sensations including numbness or tingling to the fingers and toes, and tinnitus, may be experienced. A wide range of associated symptoms may include angular cheilitis, mouth ulcers, bleeding gums, hair loss and thinning, premature greying, a look of exhaustion and dark circles around the eyes, as well as brittle nails.
Severe vitamin B₁₂ deficiency can damage nerve cells. If this happens, vitamin B₁₂ deficiency may result in sense loss, loss of sensation in the feet, difficulty walking, poor balance, blurred vision, changes in reflexes, muscle weakness, decreased smell and taste, decreased level of consciousness, mood changes, memory loss, depression, irritability, clumsiness, disorientation, dementia and, in severe cases, psychosis. Tissue deficiencies may negatively affect nerve cells, bone marrow, and the skin.
A further complication of severe deficiency is the neurological complex known as subacute combined degeneration of spinal cord. also myelosis funicularis, or funicular myelosis. This complex consists of the following symptoms:

Impaired perception of deep touch, pressure and vibration, loss of sense of touch, very annoying and persistent paresthesias
Ataxia of dorsal column type
Decrease or loss of deep muscle-tendon reflexes
Pathological reflexesBabinski, Rossolimo and others, also severe paresis.

The presence of peripheral sensory-motor symptoms or subacute combined degeneration of the 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 with others.
Vitamin B₁₂ is essential for the development of the brain. Its deficiency can cause neurodevelopmental problems, which can be partly reversible with early treatment. Only a small subset of dementia cases are reversible with vitamin B₁₂ therapy. Tinnitus may be associated with vitamin B₁₂ deficiency.
Vitamin B₁₂ deficiency may accompany certain eating disorders or restrictive diets.

Pernicious anemia

Pernicious anemia is a disease caused by an autoimmune response that produces antibodies that attack the parietal cells in the stomach lining, preventing them from creating intrinsic factor needed for the absorption of vitamin B₁₂. It occurs in only about 2-3% of the population over the age of 65. It is the main and most common cause of vitamin B₁₂ deficiency anemia in developed countries, and is characterized by a triad of symptoms:

Anemia with bone marrow promegaloblastosis. This is due to the inhibition of DNA synthesis.
Gastrointestinal symptoms: alteration in bowel motility, such as mild diarrhea or constipation, and loss of bladder or bowel control. These may be due to defective DNA synthesis inhibiting replication in a site with a high turnover of cells. This may also result from the autoimmune attack on parietal cells of the stomach. There is an association with "watermelon stomach" and pernicious anemia.
Neurological symptoms: Sensory or motor deficiencies, subacute combined degeneration of spinal cord, or seizures. Deficiency symptoms in children include developmental delay, regression, irritability, involuntary movements, and hypotonia.

In babies, neurological symptoms can occur from 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.

Metabolic risk in offspring

Vitamin B₁₂ is a critical micronutrient essential for supporting the increasing metabolic demands of the foetus during pregnancy. B₁₂ deficiency in pregnant women is increasingly common and has been shown to be associated with major maternal health implications, including increased obesity, higher body mass index, insulin resistance, gestational diabetes, and type 2 diabetes in later life. A study in a pregnant white non-diabetic population in England, found that for every 1% increase in BMI, there was 0.6% decrease in circulating B₁₂. Furthermore, an animal study in ewes demonstrated that a B₁₂, folate and methionine restricted diet around conception, resulted in offspring with higher adiposity, blood pressure and insulin resistance which could be accounted for by altered DNA methylation patterns.
Both vitamin B₁₂ and folate are involved in the one-carbon metabolism cycle. In this cycle, vitamin B₁₂ is a necessary cofactor for methionine synthase, an enzyme involved in the methylation of homocysteine to methionine. DNA methylation is involved in the functioning of genes and is an essential epigenetic control mechanism in mammals. This methylation is dependent on methyl donors such as vitamin B₁₂ from the diet. Vitamin B₁₂ deficiency has the potential to influence methylation patterns in DNA, besides other epigenetic modulators such as micro, leading to the altered expression of genes. Consequently, an altered gene expression can possibly mediate impaired foetal growth and the programming of non-communicable diseases.
Vitamin B₁₂ and folate status during pregnancy is associated with the increasing risk of low birth weight, preterm birth, insulin resistance and obesity in the offspring. In addition it has been associated with adverse foetal and neonatal outcomes including neural tube defects The mother's B₁₂ status can be important in determining the later health of the child, as shown in the Pune maternal Nutrition Study, conducted in India. In this study, children born to mothers with high folate concentrations and low vitamin B₁₂ concentrations were found to have higher adiposity and insulin resistance at age 6. In the same study, over 60% of pregnant women were deficient in vitamin B₁₂, which was considered to increase the risk of gestational and later diabetes in the mothers. Increased longitudinal cohort studies or randomised controlled trials are required to understand the mechanisms between vitamin B₁₂ and metabolic outcomes, and to potentially offer interventions to improve maternal and offspring health.