Deficiency of vitamin B12 and its relation with neurological disorders: a critical review

B12 is an essential vitamin for human body which reduces the chances of neurological diseases, birth defects, and chronic disorders. It is a vital micro-nutrient for maintaining the brain health. This review sorts out some causes of vitamin B12 (B12) deficiency and develops its link with neurological disorders. The portals include PubMed, Google Scholar, Directory of Open Access Journals (DOAJ), Pak MediNet, and Science Direct were search for literature retrieval. Study of literature revealed that deficiency of this vitamin occurs primarily due to insufficient dietary intake which results in a group of neurological symptoms in adults as well as infants. These neurological disorders include apathy, anorexia, irritability, growth retardation, and developmental regression. It may also involve in delayed myelination or demyelination of neurons. It was concluded that B12 is vital micro-nutrient for healthy brain in children, younger, and elders. Various conditions are responsible for deficiency of B12. A timely and proper supplementation is necessary if it is dietary deficiency.


Introduction
B 12 is a water-soluble complex organic compound. It is required for normal development of animals, human beings, and even several microorganisms (Allen, 2004). Body is unable to synthesize in sufficient amount and must be taken in diet. It has a complex structure and contains a metallic ion along with cobalt. Several of its forms exist. However, cobalamin and cyan cobalamin are the most common forms (Andersen et al., 2010). It is synthesized by microorganisms in cows and sheep. In cows, it is transferred to muscle from rumen and other tissues. Human beings get this vitamin from diet consisting of cows flesh (Selhub, 2002). Other nutritional sources are eggs and dairy products. Strict vegetarians develop deficiency of B 12 and must take fortified supplements (Black, 2008). Being water-soluble, B 12 can flush out from organisms. Further, fat cells or fatty acid unable to stored it. Therefore, daily consumption level or upper intake level (UL) yet to establish (Kanazawa et al., 1983).
Several strong evidences prove that severe B 12 deficiency leads to neuropathy or pernicious anemia, ileal resections, and gastrectomy (Dagnelie et al., 1989;Kozyraki et al., 1999). The pernicious anemia is rarely recorded in dietary B 12 deficient people except young infants with solely breast feeders or strict vegetarians (Dagnelie et al., 1989).

Forms of B 12
If B 12 has mineral cobalt, then it is cobalamin (Fyfe et al., 2004). Other forms include methyl cobalamin, deoxyadenosylcobalamin, hydroxocobalamin, and cyanocobalamin. Methyl cobalamin is the most active circulating form in humans and present in nutrition supplements. The body needs to convert this form into either methyl cobalamin or 5-deoxyandenosylcobalamin for its absorption (Briani et al., 2013) (Fig. 1).

Absorption and metabolism
Digestive system absorbs the cobalamin in three steps: 1. Food protein bounded with B 12 is released by the action of gastric acid and pepsin and then taken by transcobalamin I (TCI) and then transported to the duodenum (Moestrup & Verroust, 2001). 2. An alkalizing action performed by pancreatic juices with its enzymes (tripsin, chymotrypsin and elastase) breakdown TCI and liberates cobalamin which joins an intrinsic factor (IF). The synthesis of this factor is carried out in parietal cells in the fundus and cardia of the stomach (Christensen & Birn, 2002;Nexo, 1998). It protects cobalamin and carries cubilin in the ileum. 3. Finally, IF-cobalamin complex shows tendency of binding towards cubilin and then taken up the enterocyte by a calcium-dependent passive transport mechanism system (Chanarin et al., 1978).
The chemical structure of cobalamin shows 1 cobalt atom with 4 pyrrole rings in corrin ring as a central part (Eschenmoser, 1988). Cobalamin has different names due to attached radical. For example, it is cyanocobalamin when attach atom is cyano radical, a highly stable compound. When attaches with adenosyland methyl radical, it is called adenosylcobalamin and methylcobalamin.
Cobalamin absorbed in ileum through cubilin receptor. It is a complex structure of cubilin, proteinsmegalin and amnion associated transmembrane protein (AMN) (Nykjaer et al., 2001). Its molecular weight is 460 kDa and exists in proximal tubule. Absorption is carried out at acidic pH at 5.4. Three cobalaminbinding proteins (ascobalophilins), one carrier haptocorrin, or R protein are associated with absorption and recorded in mature granulocytes and monocytes of precursor cells. It is also observed in the saliva, bile, gastric acid, and breast milk secreted by exocrine epithelial cells (Nykjaer et al., 2001) (Fig. 2).

Importance of B 12
Being micronutrient, B 12 is essential for production and maintenance of RBCs and myelination of nerve cells. It also aids in neurotransmitter, DNA, and RNA production. Many people supplement the B 12 via injections on a regular basis to a boost in energy level (de Benoist, 2008) (Fig. 3).

Pathophysiology
As origin of B 12 is the bacterial synthesis in rumen of ruminant animals therefore, meat is a good source. After entry in the stomach, B 12 is bounded to R-binders (protein) secreted by the salivary glands and stomach. While passing through the small intestine, pancreatic enzymes cleave B 12 form R-binder and bound with intrinsic factor (IF). This IF is secreted by the parietal cells and glycoprotein in nature. B 12 is then transported to plasma and bind with transcobalamin intracellularly. The absorption is very efficient in the distal ileum (enterohepatic recirculation). It takes many years a vegan person to deplete as long as his intestinal and hepatobiliary systems are intact. The liver is the largest storage site, and total body pool is about 2500 μg in normal adult. Strict vegetarians are at high risk of deficiency. However, bacterial and insect contamination in food stuffs protects them to some extant against deficiency. Contamination of ruminant feces in vegetables and drinking water could also serve as a source of dietary B 12 for vegetarians or economically poor areas of the world. Specific symptoms of deficiency are presented in Fig. 4.

Causes of deficiencies
Deficiency exists among all age, economic classes, races, and sexes. It is the most common nutritional deficiency in the USA (Allen, 2004). Diagnosis at early stage and its remedy is extremely necessary to prevent neurologic disorders, poor outcomes, or premature death (de Benoist, 2008). Some causes of deficiencies are as follows.

Pernicious anemia
Pernicious anemia is the most common cause of B 12 deficiency. It is an auto-immune condition which affects 1 in 10,000 population. In this disease, an intrinsic factor required for absorption of B 12 from food into the gastrointestinal tract is absent. However, the condition is common among people of over 60, in women, with family history and some autoimmune conditions including Addison's disease and vitiligo (Reid, 2010).
Autoimmune AG develops in condition when body produces antibodies against healthy stomach cells normally produced against viruses and bacteria. People with autoimmune AG target acidic juices producing healthy stomach cells. Intrinsic factor is also under influence of these antibodies and causes pernicious anemia. Deficiency of B 12 make impossible to produce enough healthy RBCs (Reynolds et al., 1993). B 12 deficiency also occurs in abdominal tuberculosis when there is involvement of the terminal ileum.

Malabsorption
Absence or deficiency of HCl, pepsin, and haptocorrin (HC), R-protein or factor makes it difficult to B 12 to extract from food in the stomach and transport intact in the small intestine (Wrong et al., 1981). Further, disorder in the stomach lining, and insufficient saliva and gastric juice also arise these circumstances (Katz et al., 1974). Absorption in the intestine requires intrinsic factor, pancreatic juice, and calcium. Deficiency or absence of any of these factors causes malabsorption (Veeger et al., 1962).
Rare genetic disorder can result in absence of transcobalamin. This leads to inadequacy of B 12 for cells. Sometimes, transcobalaminis sufficiently available; however, large amount of biologically inactive B 12 analogs binds with it and prevents actual vitamin B 12 from binding to transcobalamin. Therefore, a deficiency can develop in spite of good absorption (Booth & Heath, 1962). Genetic disorder can also alter the structure and production of specific enzymes which changes B 12 in coenzyme. In this step, genetic disorder prevents necessary metabolic processes from taking place in cells (Hakami et al., 1971) (Fig. 5).

Vegan diet
Some religious belief can also cause the deficiency. For example, the vegetarian people who do not eat the meat due to religious reasons have risk of B 12 deficiency. Vegans usually have low B 12 but higher folate concentrations. Half of the vegans having B 12 deficiencies have a higher risk of developing clinical symptoms (Herrmann & Geisel, 2002).

Diagnosis
Diagnosis can be performed in a number of ways. A typical method is screening the patients for serum B 12 level. However, the level of methylmalonic acid in serum is measured if the suspicion is strong and B12 level is low normal (Budson & Solomon, 2015).

Treatment of deficiency
Supplementation with B 12 is conducted to treat deficiency either orally (if vegan diet) or parenterally (if atrophy gastritis). Monitoring is necessary with treatment, and cognition should return to normal (Budson & Solomon, 2015).

Neurological disorders
People from all age groups are suffered with depression, severe anxiety, and psychiatric disorders. These patients are prescribed costly psychotropic drugs, narcotics, or benzodiazepines; however, actually the problem is B 12 deficiency (Selhub et al., 2008). Some diseases caused by B 12 deficiency are as follows.

Myeloneuropathy
Myelopathy caused by lower concentration of B 12 is subacute combined degeneration because symptoms develop slowly. It is also "combined" because multiple neurological symptoms develop in this degeneration (Aaron et al., 2005). The posterior column of spinal card is major part to damage. This part is the most important which controls and carries sensory information regarding vibrations, light touch, and position to brain. As a consequence of B 12 deficiency, DNA is also damaged and leads to neurological damage; therefore, people feel numbness tingling (Román et al., 2002). The autonomic nerves can also be target of damage as these nerve fibers run through the spinal cord. In addition, it may also diminish vision and sense of smell. People may develop dementia in the final stage (Selhub et al., 2008).
Demyelination B 12 has important immune modulatory and neurotrophic effects in addition to role as cofactor in myelination (Miller et al., 2005). B 12 deficiency and multiple sclerosis (MS) both have pathophysiological condition like inflammatory and neurodegenerative disorder. Resemblances in clinical findings and MRI presentation, it is very difficult to diagnose between B 12 deficiency and MS. Further, decrease in levels of B 12 demonstrated in patient with multiple sclerosis (Miller et al., 2005).

Alzheimer's disease
If a person feels behavior changes and agitation, it could be symptoms of Alzheimer disease. However, it can also be related to low levels of vitamin B 12 . Deficiency produces large amount of mononuclear IL-6 in the peripheral blood. It is associated with slowly onset of Alzheimer disease which worse over time (Burns et al., 2009). In 60 to 70% cases, it causes dementia. The early symptom is short-term memory loss (Politis et al., 2010). The transcobalamin or holo TC level is associated with cognitive function and Alzheimer's disease (Renvall et al., 1989). However, this association with Alzheimer's disease was only present in patients with high homocysteine level. Further, low level of cobalamin in tissue or an interaction between homocysteine and cobalamin could also be the reason (Refsum, 2001). In Alzheimer's disease, dementia is caused by low level of B 12 in serum of elderly persons (Osimani et al., 2005).

Atrophy or Brain shrinkage
The term atrophy means loss or shrinkage of cells. In brain atrophy, neurons and their connections waste away and cause the brain shrinkage than normal size. Infants with atrophy were diagnosed with vitamin B 12 deficiency (de Jager, 2014). Other risk factor is homocysteine (Hcy) accumulation in plasma (Hogervorst et al., 2002;McCaddon et al., 2001). Conversion of Hcy to its metabolites, i.e., S-adenosyl methionine and glutathione depends on three vitamins as cofactors. These vitamins include B 9 (methyl folate), B 12 (cobalamin), and B 6 (pyridoxine) (Morris et al., 2005;Refsum, 2001;Refsum et al., 2006). Suboptimal supply of B-vitamin in diet, remethylation of Hcy through methionine synthase is lowered and Hcy in plasma rise (Birch et al., 2009).

Sub-acute combined degeneration
Sub-acute combined degeneration (SCD) is progressive degenerative disorder which targets the spinal cord. It may also affect the nerves of the eyes and peripheral nervous system (Reynolds et al., 1993). B 12 deficiency is the cause of SCD. In this disorder, damage to myelin sheath is occurred and followed by degeneration in axons (Victor & Lear, 1956). Initial symptoms are numbness, clumsy movements, and tingling sensation. Other symptoms are visual problems, weakness, cognitive disturbances, erectile dysfunctions, and abnormal reflexes in the bladder (Morris et al., 2005). Early B 12 supplementation gives better results. However, delay can reduce the chance of recovery and lost the functionality (Werder, 2010).

Vascular complications
Elevated level of homocysteine in blood could be the risk factor for stroke along with other vascular complications (Tomkin et al., 1971). Quinlivan et al. (2002) demonstrated folic acid, and B 12 fortified food could lower homocysteine levels and reduced the risk of vascular disease.

Neuropsychiatric abnormalities
Psychiatric problems are associated with B 12 deficiency in adults between the ages of 40-90 years and rarely affect people of younger age (Stanger et al., 2003). The psychiatric manifestations include cognitive changes (like memory decline), depression, delusions, hallucinations, and dementia (Engelborghs et al., 2004). The mechanisms behind are instable production of neurotransmitters and elevated homocysteine and methylmalonic acid (MMA) level in B 12 deficient people. Screening and supplementation of B 12 should be considered if there is no other obvious cause of a psychiatric disorder (Zengin et al., 2009).

Infantile seizures
During infancy, epileptic seizures have varied clinical presentations. It may have different outcomes according to etiology. B 12 is also a rear cause of infantile seizures. Infants have the most common symptoms of B 12 deficiency like feeding difficulties, seizures, growth retardation, megaloblastic anemia, developmental delay, hypotonia, microcephaly, lethargy, involuntary movements, irritability, and cerebral atrophy. Rarely, involuntary movements and seizures are the initial symptoms of deficiency. Involuntary movements are also reported after start of B 12 supplementation in few cases. However, no information is present in literature regarding seizures (Benbir et al., 2007).

Poor fetal brain and cognitive development
Vitamin B 12 and folate play a key role in fetus brain development. Both are also crucial for myelination in new born baby in first 2 years and till puberty (Hellegers et al., 1957). As B 12 deficiency constrained in myelination, child develops varied cognitive and intellectual problems depending upon the area of the nervous system affected (Graber et al., 1971). Deficiency of both in pregnant women needs supplements in order to prevent neurological disorders in fetus (Wilson et al., 1999). Elderly people face problem to absorb this vitamin from food sources so its deficiency can be fulfilled with supplements (Rosenberg, 2005). Vegans also face deficiency which may be restored by supplements. Minimum per take uptake to prevent the deficiency provided in Table 1 (IOM, 1998).

Conclusion
It was concluded that B 12 is vital micro-nutrient for maintaining healthy brain in children, youngers, and elders. Various conditions are responsible for B 12 deficiency. A timely and proper supplementation is necessary if it is dietary deficiency. This supplementation can prevent the damage to nervous system. Deficiency may leads to cognitive decline and vascular risk factors in neuropsychiatric disorders. Therefore, recognition and early management reverse deficiency state. Some behavioral or psychological disorders are related to dementia and depression which can be improved with B 12 supplementation.