Vitamin B12 deficiency

Mild deficiencies may have few or absent symptoms. In moderate deficiencies, feeling tired, feeling faint, mouth ulcers, rapid breathing, upset stomach, pallor, hair loss, decreased ability to think and joint pain and the beginning of neurological symptoms, including abnormal sensations such as, numbness and tingling, and tinnitus may occur. Severe deficiencies may include symptoms of reduced heart function, suppression of bone marrow, as well as more various severe neurological symptoms possibly including sensory loss, abnormal balance and reflexes, memory and consciousness impairment, smell and taste problems, depression, irritability, confusion, and psychosis. If left untreated, some of these changes can become permanent. Onset of deficiency may take years to develop. In exclusively breastfed infants of vegan mothers, undetected and untreated deficiency can lead to poor growth, poor development, and difficulties with movement.

In healthy adults, vitamin B₁₂ deficiency is not common, mainly because body stores of the vitamin are substantial and turnover is slow, with relatively low dietary requirements. Risk factors may occur possibly more in elderly people due to impaired intestinal absorption, and in children, premenopausal women, and pregnant women, whose diets are low in animal foods.

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. Diagnosis can be challenging, based on blood tests, and whether if there an unexplained haemotoligcal or neurological symptoms found. Elevated methylmalonic acid levels may also indicate a deficiency.

Treatment is by vitamin B₁₂ supplementation, either by mouth or by injection. If no reversible cause is found, or when found it cannot be eliminated, lifelong vitamin B₁₂ administration is usually recommended. Vitamin B₁₂ deficiency is preventable with supplements, which are recommended for pregnant vegetarians and vegans, and not harmful in others.

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 moderate deficiency can cause various symptoms, such as feeling tired, lightheadedness, cold intolerance, pale skin, sore tongue, upset stomach, loss of appetite, numbness or tingling (pins and needles) of the fingers and toes, and vision, cognitive or psychological problems.

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.

Clinical manifestations, such as low blood pressure, and low-grade fevers, and dark circles around the eyes, may occur.

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:

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.

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:

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. 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" (GAVE) and pernicious anemia.
3. Neurological symptoms: Sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation), 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 (BMI), insulin resistance, gestational diabetes, and type 2 diabetes (T2D) 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 (RNAs), 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 (NTDs) 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.

Cardiometabolic disease outcomes

Multiple studies have explored the association between vitamin B₁₂ and metabolic disease outcomes, such as obesity, insulin resistance and the development of cardiovascular disease. A long-term study where vitamin B₁₂ was supplemented across a period of 10 years, led to lower levels of weight gain in overweight or obese individuals (p < 0.05).

There are several mechanisms which may explain the relationship between obesity and decreased vitamin B₁₂ status. Vitamin B₁₂ is a major dietary methyl donor, involved in the one-carbon cycle of metabolism and a recent genome-wide association (GWA) analysis showed that increased DNA methylation is associated with increased BMI in adults, consequently a deficiency of vitamin B₁₂ may disrupt DNA methylation and increase non-communicable disease risk. Vitamin B₁₂ is also a co-enzyme which converts methylmalonyl-CoA to succinyl-CoA in the one carbon cycle. If this reaction cannot occur, methylmalonyl-CoA levels elevate, inhibiting the rate-limiting enzyme of fatty acid oxidation (CPT1 – carnitine palmitoyl transferase), leading to lipogenesis and insulin resistance. Further to this, reduced vitamin B₁₂ concentrations in the obese population is thought to result from repetitive short-term restrictive diets and increased vitamin B₁₂ requirements secondary to increased growth and body surface area. It has also been hypothesised that low vitamin B₁₂ concentrations in obese individuals are a result of wrong feeding habits, where individuals consume a diet low in micronutrient density. Finally, vitamin B₁₂ is involved in the production of red blood cells, and vitamin B₁₂ deficiency can result in anemia, which causes fatigue and the lack of motivation to exercise.

The investigation into the relationship between cardiovascular disease and vitamin B₁₂ has been limited, and there is still controversy as to whether primary intervention with vitamin B₁₂ will lower cardiovascular disease. Deficiency of vitamin B₁₂ can impair the remethylation of homocysteine in the methionine cycle, and result in raised homocysteine levels. There is much evidence linking elevated homocysteine concentrations with an increased risk of cardiovascular disease, and homocysteine lowering treatments have led to improvements in cardiovascular reactivity and coagulation factors. In adults with metabolic syndrome, individuals with low levels of vitamin B₁₂ had higher levels of homocysteine compared to healthy subjects. It is thus possible that vitamin B₁₂ deficiency enhances the risk of developing cardiovascular disease in individuals who are obese. Alternatively, low levels of vitamin B₁₂ may increase the levels of proinflammatory proteins which may induce ischaemic stroke.

It is important to screen vitamin B₁₂ deficiency in obese individuals, due to its importance in energy metabolism, and relationship with homocysteine and its potential to modulate weight gain. More studies are needed to test for the causality of vitamin B₁₂ and obesity using genetic markers. A few studies have also reported no deficiency of vitamin B₁₂ in obese individuals. Finally, a recent literature review conducted over 19 studies, found no evidence of an inverse association between BMI and circulating vitamin B₁₂.

Previous clinical and population-based studies have indicated that vitamin B₁₂ deficiency is prevalent amongst adults with type 2 diabetes. Kaya et al., conducted a study in women with polycystic ovary syndrome, and found that obese women with insulin resistance had lower vitamin B₁₂ concentrations compared to those without insulin resistance. Similarly, in a study conducted in European adolescents, there was an association between high adiposity and higher insulin sensitivity with vitamin B₁₂ concentrations. Individuals with a higher fat mass index and higher insulin sensitivity (high Homeostatic Model Assessment [HOMA] index) had lower plasma vitamin B₁₂ concentrations. Furthermore, a recent study conducted in India reported that mean levels of vitamin B₁₂ decreased with increasing levels of glucose tolerance e.g. individuals with type 2 diabetes had the lowest values of vitamin B₁₂, followed by individuals with pre-diabetes and normal glucose tolerance, respectively. However, B₁₂ levels of middle aged-women with and without metabolic syndrome showed no difference in vitamin B₁₂ levels between those with insulin resistance (IR) and those without. It is believed that malabsorption of vitamin B₁₂ in diabetic patients, is due to individuals taking metformin therapy (an insulin sensitizer used for treating type 2 diabetes). Furthermore, obese individuals with type 2 diabetes are likely to develop gastroesophageal reflux disease, and take proton pump inhibitors, which further increased the risk of vitamin B₁₂ deficiency.

A literature review conducted in 2011 over seven studies, found that there was limited evidence to show that low vitamin B₁₂ status increased the risk of cardiovascular disease and diabetes. However, the review did not identify any associations between vitamin B₁₂ and cardiovascular disease in the remaining four studies. Currently, no data supports vitamin B₁₂ supplementation on reducing the risk of cardiovascular disease. In a dose-response meta-analysis of five prospective cohort studies, it was reported that the risk of coronary heart disease (CHD) did not change substantially with increasing dietary vitamin B₁₂ intake. Of these five studies, three of the studies stated a non-significant positive association and two of the studies demonstrated an inverse association between vitamin B₁₂ supplementation and coronary heart disease (only one of the studies was significant).

Anemia

Vitamin B₁₂ deficiency is one of the main causes of anemia. In countries where B₁₂ deficiency is common, it is generally assumed that there is a greater risk of developing anemia. However, the overall contribution of vitamin B₁₂ deficiency to the global incidence of anemia may not be significant, except in elderly individuals, vegetarians, cases of malabsorption and some genetic disorders. Anemia is defined as a condition in which there are not enough red blood cells, as the tissues and organs of the body do not get enough oxygen. Megaloblastic anemia caused by vitamin B₁₂ deficiency is characterized by red blood cells that are larger than normal and are unable to deliver oxygen to the body's organs. The clinical case indicates an altered synthesis of DNA, in which vitamin B₁₂ is essential for the production and maturation of red blood cells in the bone marrow. Adult patients often report to medical attention symptoms related to anemia, such as feeling tired and weak, breathlessness, exercise intolerance, feeling faint, headaches, paleness, dry lips and a disturbance of taste.

Pernicious anemia is the most common cause of vitamin B₁₂ deficiency anemia in adults, which results from malabsorption of vitamin B₁₂ due to a lack or loss of intrinsic factor. There are relatively few studies which have assessed the impact of haematological measures in response to B₁₂ supplementation. One study in 184 premature infants, reported that individuals given monthly vitamin B₁₂ injections (100 μg) or taking supplements of vitamin B₁₂ and folic acid (100 μg/day), had higher haemoglobin concentrations after 10–12 weeks, compared to those only taking folic acid or those taking no vitamin B₁₂ injections.

Aging

In the elderly, vitamin B₁₂ deficiency has been associated with the development of macular degeneration, and the risk of frailty. Macular degeneration is the leading cause of severe, irreversible vision loss in older adults. Several risk factors have been linked to macular degeneration, including family history, genetics, hypercholesterolemia, hypertension, sunlight exposure and lifestyle (smoking and diet). It has been shown that daily supplementation of vitamin B₁₂, B₆ and folate over a period of seven years can reduce the risk of age-related macular degeneration by 34% in women with increased risk of vascular disease (n=5,204). However, another study failed to find an association between age-related macular degeneration and vitamin B₁₂ status in a sample of 3,828 individuals representative of the non-institutionalized US population.

Frailty is a geriatric condition which is characterized by diminished endurance, strength, and reduced physiological function that increases an individual's risk of mortality and impairs an individual from fulfilling an independent lifestyle. Frailty is associated with an increased vulnerability to fractures, falls from heights, reduced cognitive function and more frequent hospitalisation. The worldwide prevalence of frailty within the geriatric population is 13.9%, therefore there is an urgent need to eliminate any risk factors associated with frailty. Poor vitamin B status has been shown to be associated with an increased risk of frailty. Two cross sectional studies have reported that deficiencies of vitamin B₁₂ were associated with the length of hospital stay, as observed by serum vitamin B₁₂ concentrations and methylmalonic acid (MMA) concentrations. Furthermore, another study of elderly women, found that certain genetic variants associated with vitamin B₁₂ status (transcobalamin II) may contribute to reduced energy metabolism, consequently contributing to frailty. Given that there are limited studies assessing the relationship between vitamin B₁₂ and frailty status, more longitudinal studies are needed to clarify the relationship.

Neurological decline

Severe vitamin B₁₂ deficiency is associated with subacute combined degeneration of the spinal cord, which involves demyelination of the posterior and lateral columns of the spinal cord. Symptoms include memory and cognitive impairment, sensory loss, motor disturbances, personality changes, disorientation, irritability, dementia, loss of posterior column functions and disturbances in proprioception. In advanced stages of vitamin B₁₂ deficiency, cases of psychosis, paranoia and severe depression have been observed, which may lead to permanent disability if left untreated. Studies have shown the rapid reversal of the neurological symptoms of vitamin B₁₂ deficiency, after treatment with high-dose of vitamin B₁₂ supplementation; suggesting the importance of prompt treatment in reversing neurological manifestations.

Cognitive decline

Elderly individuals are currently assessed on vitamin B₁₂ status during the screening process for dementia. Studies investigating the association between vitamin B₁₂ concentrations and cognitive status have produced inconclusive results. It has been shown that elevated MMA concentrations are associated with decreased cognitive decline and Alzheimer's disease. In addition, low vitamin B₁₂ and folate intakes have shown associations with hyperhomocysteinemia, which is associated with cerebrovascular disease, cognitive decline and an increased risk of dementia in prospective studies.

There are limited intervention studies which have investigated the effect of supplementation of vitamin B₁₂ and cognitive function. A Cochrane review, analysing two studies, found no effect of vitamin B₁₂ supplementation on the cognitive scores of older adults. A recent longitudinal study in elderly individuals, found that individuals had a higher risk of brain volume loss over a 5-year period, if they had lower vitamin B₁₂ and holoTC levels and higher plasma tHcy and MMA levels. More intervention studies are needed to determine the modifiable effects of vitamin B₁₂ supplementation on cognition on people who are not deficient.

Osteoporosis

There has been growing interest on the effect of low serum vitamin B₁₂ concentrations on bone health. Studies have found a connection between elevated plasma tHcy and an increased risk of bone fractures, but is unknown whether this is related to the increased levels of tHcy or to vitamin B₁₂ levels (which are involved in homocysteine metabolism). Results from the third NHANES conducted in the United States, found that individuals had significantly lower bone mass density (BMD) and higher osteoporosis rates with each higher quartile of serum MMA (n= 737 men and 813 women). Given that poor bone mineralization has been found in individuals with pernicious anemia, and that the content of vitamin B₁₂ within bone cells in culture has shown to affect the functioning of bone forming cells (osteoblasts); it is possible that vitamin B₁₂ deficiency is causally related to poor bone health.

Randomized intervention trials investigating the association of vitamin B₁₂ supplementation and bone health have yielded mixed results. One study conducted on osteoporotic risk patients with hyperhomocysteinemia found positive effects between supplementation of B vitamins on BMD. However, no improvement in BMD was observed in a group of healthy older people. Further, controlled trials are needed to confirm the impact and mechanisms vitamin B₁₂ deficiency has on bone mineralization.