A Review: Introduction To Vitamin B12 & Its Association With R.O Water

Vitamin B12:

Any of a group of substance (the vitamin B complex) which are essential for the working of certain enzymes in the body and, although not chemically related, are generally found together in the same foods. They include Thiamine (Vitamin B1), Riboflavin (Vitamin B2), Pyridoxine (Vitamin B6), and Cyanocobalamin (Vitamin B12). Vitamin B12 is also known as cobalamine, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. There is no upper intake level for vitamin B12 because its absorption and retention is limited. Usually the excess vitamin is excreted with urine. Only a few microbes can synthesis vitamin B12 but human can obtain this vitamin through food, due to bioaccumulation process. Deficiency of vitamin B12 & folic acid, which are group B vitamins, results in megaloblastic anaemia characterized by the presence of large red cell precursor in bone marrow & their large & short lived progeny in peripheral blood. EX: Vitamin B12, folic acid. Cynocobalamin & hydrocobalamin are complex cobalt containing compound present in diet (referred as vitamin B12). Vitamin B12 is required for the development, myelination, and function of the central nervous system; healthy red blood cell formation; and DNA synthesis[6,9,10]. Vitamin B12 functions as a cofactor for two enzymes, methionine synthase and L-methylmalonyl-CoA mutase[6-8,10]. Methionine synthase catalyzes the conversion of homocysteine to the essential amino acid methionine [6,7]. Methionine is required for the formation of S- adenosylmethionine, a universal methyl donor for almost 100 different substrates, including DNA, RNA, proteins, and lipids [8,10]. L-methylmalonyl-CoA mutase converts L-methylmalonyl-CoA to succinyl-CoA in the metabolism of propionate, a short-chain fatty acid [7]. Vitamin B12 status is typically assessed by measurements of serum or plasma vitamin B12 levels. The cut off between normal vitamin B12 levels and deficiency varies by method and laboratory, but most laboratories define subnormal serum or plasma values as those lower than 200 or 250 pg/mL (148 or 185 pmol/L) [7]. Levels of serum methylmalonic acid (MMA), a vitamin B12-associated metabolite, are the most sensitive markers of vitamin B12 status, and an MMA level greater than 0.271 micromol/L suggests vitamin B12 deficiency [11-13]. However, MMA levels also rise with renal insufficiency and tend to be higher in older adults [11,14,15]. Another marker is total plasma homocysteine levels, which rise quickly as vitamin B12 status declines; a serum homocysteine level higher than 15 micromol/L, for example, suggests vitamin B12 deficiency [16]. However, this indicator has poor specificity because it is influenced by other factors, such as low folate levels and, especially, by declines in kidney function[11]. Experts suggest that if a patient’s serum vitamin B12 level is less than 150 pg/ml (111 pmol/L), the patient’s serum MMA levels should be checked to confirm a diagnosis of vitamin B12 deficiency [12,14]. Vegetarians and the elderly are at higher risk of vitamin B12 deficiency. Among the elderly, vitaminB12 deficiency occurs in about 20% of the population; more than 60% of these deficiencies are due to food-cobalamin malabsorption syndrome1 caused by gastrointestinal problems. Deficiency related to a lack of intrinsic factor results in severe neurologic damage and life-threatening anemia; therefore, such individuals require medical treatment including vitamin B12 injections. Economic status, age, and dietary choices all influence the occurrence of vitamin B12 deficiency. Generally, when anemia is present, vitamin B12 levels are measured, but recent evidence suggests that while symptoms of B12 deficiency might be subtle, it can still cause metabolic and neurologic abnormalities such as hyper-homocysteinemia, cognitive function decline, or depression. Several studies have shown that folic acid in combination with B12 lowers homocysteine levels, but what has not been quantified is the contribution of vitamin B12 alone to the lowering of homocysteine levels.

DAILY REQ: 1-3µg, pregnancy & lactation 3-4µg

Metabolic functions:

• Essential for the conversion of homocysteine to methionine.
• Purine & Pyrimidine synthesis is affected primarily due to defective ‘one carbon’ transfer because of folate trap.
• Essential for cell growth and multiplication.

Chemistry & Structure:

Cobalamin is analogous to heme in its structure having as its base a tetrapyrrole ring. Instead of ion as a metal cofactor for heme, cobalamin has cobalt in a coordination state of six with a benzimidazole group nitrogen coordinated to one axial position, the four equatorial positions coordinated by the nitrogen of the four pyrrole group and the sixth position occupied by either a deoxyadenosine group, a methyl group or a CN-group in the commercially available form in vitamins tablets.

Source of vitamin B12:

Vitamin B 12 is naturally found in animal products, fish, meat, poultry, egg, milk, and milk products [1]. Vitamin B12 is not generally present in plant food, but fortified breakfast cereals are a readily available source of vitamin B12 with high bioavailability. Some nutritional yeast product also contains vitamin B12 [2]. Vitamin B12 is usually present as cyanocobalamin [3], a form that the body converts to the active form methyl cobalamin and 5-deoxyadenosylcobalamin. Dietary supplements can also contain methylcobalamin and other form of Vitamin B12. Body’s ability to absorb vitamin b12 from dietary supplements is limited by the capacity of intrinsic factor. Only about 10mcg of 500mcg oral supplement is actually absorbed in healthy people. Deficiency linked to improper absorption rather than low consumption [4].

*DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for vitamin B12 is 2.4 mcg for adults and children aged 4 years and older [18]. FDA does not require food labels to list vitamin B12 content unless vitamin B12 has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

The U.S. Department of Agriculture’s Food Data Central [17] lists the nutrient content of many foods and provides a comprehensive list of foods containing vitamin B12 arranged by nutrient content and by food name.

Dietary supplements

1. Vitamin B12 is available in multivitamin/mineral supplements, in supplements containing other B-complex vitamins, and in supplements containing only vitamin B12.
2. Multivitamin/mineral supplements typically contain vitamin B12 at doses ranging from 5 to 25 mcg [19]. Vitamin B12 levels are higher, generally 50–500 mcg, in supplements containing vitamin B12 with other B-complex vitamins and even higher, typically 500– 1,000 mcg, in supplements containing only vitamin B12.
3. The most common form of vitamin B12 in dietary supplements is cyanocobalamin [6,8,19,20]. Other forms of vitamin B12 in supplements are adenosylcobalamin, methylcobalamin, and hydroxocobalamin [19].
4. No evidence indicates that absorption rates of vitamin B12 in supplements vary by form of the vitamin. These rates are about 50% at doses (less than 1–2 mcg) that do not exceed the cobalamin-binding capacity of intrinsic factor and are substantially lower at doses well above 1–2 mcg [20,21]. For example, absorption is only about 2% at doses of 500 mcg and 1.3% at doses of 1,000 mcg [21].
5. In addition to oral dietary supplements, vitamin B12 is available in sublingual preparations as tablets or lozenges [19]. Evidence suggests no difference in efficacy between oral and sublingual forms [22,23].

Prescription medications

1. Vitamin B12, in the forms of cyanocobalamin and hydroxycobalamin, can be administered parenterally as a prescription medication, usually by intramuscular injection [7]. Parenteral administration is typically used to treat vitamin B12 deficiency caused by pernicious anemia as well as other conditions (e.g., tropical sprue, pancreatic insufficiency) that result in vitamin B12 malabsorption and severe vitamin B12 deficiency [10].
2. Vitamin B12 is also available as a prescription nasal gel spray. This formulation appears to be effective in raising vitamin B12 blood levels in adults and children [24,25]. A small clinical study with 10 participants (mean age 81 years) found that the bioavailability of a 1,000 mcg cobalamin dose was 2% with intranasal administration, which is similar to the bioavailability of an oral dose [26].

Food rich in B12:

• Animal products (meat, fish, poultry)
• Not usually denatured by cooking
• Great sources: Liver, kidney [5]

Recommended Intakes

Intake recommendations for vitamin B12 and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the National Academies of Sciences, Engineering, and Medicine [6]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and sex, include:

Recommended Dietary Allowance (RDA):

Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.

Adequate Intake (AI):

 Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.

Estimated Average Requirement (EAR): Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals.

Tolerable Upper Intake Level (UL):

Maximum daily intake unlikely to cause adverse health effects.

For adults, the main cSriterion that the FNB used to establish the RDAs was the amount needed to maintain a healthy hematological status and serum vitamin B12 levels. For infants aged 0 to 12 months, the FNB established an AI that is equivalent to the mean intake of vitamin B12 in healthy, breastfed infants.

Deficiency of Vitamin B12:

Causes of vitamin B12 deficiency include difficulty absorbing vitamin B12 from food, lack of intrinsic factor (e.g., because of pernicious anemia), surgery in the gastrointestinal tract, prolonged use of certain medications (e.g., metformin or proton pump inhibitors, discussed in more detail below in the section on interactions with medications), and dietary deficiency [10,12]. Because people who have difficulty absorbing vitamin B12 from food absorb free vitamin B12 normally, their vitamin B12 deficiency tends to be less severe than that of individuals with pernicious anemia, who cannot absorb either food-bound or free vitamin B12. Certain congenital conditions, such as hereditary intrinsic factor defects and congenital vitamin B12 malabsorption (Imerslund-Gräsbeck disease), can also cause severe vitamin B12 deficiency [10]. The effects of vitamin B12 deficiency can include the hallmark megaloblastic anemia (characterized by large, abnormally nucleated red blood cells) as well as low counts of white and red blood cells, platelets, or a combination; glossitis of the tongue; fatigue; palpitations; pale skin; dementia; weight loss; and infertility [7,10,12]. Neurological changes, such as numbness and tingling in the hands and feet, can also occur [12]. These neurological symptoms can occur without anemia, so early diagnosis and intervention is important to avoid irreversible damage [27]. In addition, some studies have found associations between vitamin B12 deficiency or low vitamin B12 intakes and depression [28-30]. In pregnant and breastfeeding women, vitamin B12 deficiency might cause neural tube defects, developmental delays, failure to thrive, and anemia in offspring [12]. Because the body stores about 1 to 5 mg vitamin B12 (or about 1,000 to 2,000 times as much as the amount typically consumed in a day), the symptoms of vitamin B12 deficiency can take several years to appear [12,31]. Vitamin B12 deficiency with the classic hematologic and neurologic signs and symptoms is uncommon [16]. However, low or marginal vitamin B12 status (200–300 pg/mL [148– 221 pmol/L]) without these symptoms is much more common, at up to 40% in Western populations, especially in those with low intakes of vitamin B12-rich foods [14,16]. The prevalence of vitamin B12 deficiency varies by cutoff level and biomarker used. For example, among adults aged 19 and older who participated in NHANES between 1999 and 2004, the rate of low vitamin B12 levels in serum was 3% with a cutoff of less than 200 pg/mL (148 pmol/L) and 26% with a cutoff of less than 350 pg/mL (258 pmol/L) [32].

Approximately 21% of adults older than 60 had abnormal levels of at least one vitamin B12 biomarker [32]. Typically, vitamin B12 deficiency is treated with vitamin B12 injections, because this method bypasses any barriers to absorption. However, high doses of oral vitamin B12 might also be effective. A 2018 Cochrane review included three Randomized Controlled Trials (RCTs) that compared very high doses (1,000–2,000 mcg) of oral with intramuscular vitamin B12 for vitamin B12 deficiency in a total of 153 participants [33]. The evidence from these studies, although of low quality, showed that the ability of high oral doses of vitamin B12 supplements to normalize serum vitamin B12 was similar to that of intramuscular vitamin B12.

Groups at Risk of Vitamin B12 Inadequacy:

The prevalence of subclinical functional vitamin B12deficiency is higher than hitherto assumed when sensitive and relatively specific markers are used—such as MMA, holoTC, and homocysteine [34,35]. Risk groups for vitamin B12 deficiency include :

• Patients with unexplained anemia.
• Patients with unexplained neuropsychiatric symptoms.
• Patients with gastrointestinal manifestations, including stomatitis, anorexia, and diarrhea.
• Elderly people [35]
• Vegetarians [36]
• Patients with gastrointestinal disorders, crohn's disease or infection with helicobacter pylori, or patients with stomach resection [37]. The rate of people in the risk population who will develop clinical symptoms because of vitamin b12 deficiency has thus far not been studied systematically.

The following groups are among those most likely to be vitamin B12 deficient:

Older adults

Depending on the definition used, between 3% and 43% of community-dwelling older adults, especially those with atrophic gastritis, have vitamin B12 deficiency based on serum vitamin B12 levels [38,39]. The deficiency rate at a cutoff of less than 211 mcg/L (156 pmol/L) at admission to a long-term care facility, according to one study, was 14%, and 38% of these older adults had levels lower than 407 pg/mL (300 pmol/L) [39]. Conditions associated with vitamin B12 inadequacy include pernicious anemia, present in about 15% to 25% of older adults with vitamin B12 deficiency [40]. Atrophic gastritis, an autoimmune condition affecting 2% of the general population but 8–9% of adults aged 65 and older, decreases production of intrinsic factor and secretion of hydrochloric acid in the stomach and thus decreases absorption of vitamin B12 [40,41]. A third condition associated with vitamin B12 deficiency in older adults is Helicobacter pylori infection, possibly because this bacterium causes inflammation that leads to malabsorption of vitamin B12 from food [42].

Individuals with pernicious anemia

Pernicious anemia is an irreversible autoimmune disease that affects the gastric mucosa and results in gastric atrophy [6,43]. This disease leads to attacks on parietal cells in the stomach, resulting in failure to produce intrinsic factor and malabsorption of dietary vitamin B12, recycled biliary vitamin B12, and free vitamin B12 [6,11,16]. Therefore, without treatment, pernicious anemia causes vitamin B12 deficiency, even in the presence of adequate vitamin B12 intakes. Pernicious anemia is the most common cause of clinically evident vitamin B12 deficiency around the world [16,43]. The incidence of pernicious anemia in the United States is an estimated 151 per 100,000, and this condition is more common in women and in people of European ancestry [43].

Individuals with gastrointestinal disorders

Individuals with stomach and small intestine disorders, such as celiac disease and Crohn’s disease, may be unable to absorb enough vitamin B12 from food to maintain healthy body stores [7,8,44]. But although rates of vitamin B12 deficiency are higher in people with celiac disease than other people [45], the evidence for whether rates of vitamin B12 deficiency are higher in people with Crohn’s disease is mixed [44,46,47]. Vitamin B12 deficiency in people with Crohn’s disease is typically treated with intramuscular cobalamin injections, but high doses of oral cyanocobalamin therapy (e.g., 1,000 mcg/day) might be equally effective [48].

Individuals who have had gastrointestinal surgery

Surgical procedures in the gastrointestinal tract, such as for weight loss or to remove all or part of the stomach, can cause a complete or partial loss of cells that secrete hydrochloric acid and cells that secrete intrinsic factor [49,50]. Thus, these procedures reduce the amount of vitamin B12, particularly food-bound vitamin B12, that the body absorbs [49,50]. High doses (1,000 mcg/day) of oral methylcobalamin supplements appear to be as effective as hydroxycobalamin injections in normalizing vitamin B12 values in patients who have undergone Roux-en-Y gastric bypass surgery [51].

Vegetarians

Vegans who consume no animal products and vegetarians who consume some animal products (e.g., dairy products, eggs, or both) but not meat have a higher risk of developing vitamin B12 deficiency because natural food sources of vitamin B12 are limited to animal foods [8,52]. Consumption of foods fortified with vitamin B12 (such as fortified nutritional yeasts) as well as vitamin B12 supplements can substantially reduce the risk of deficiency [52].

Infants of vegan women

Exclusively breastfed infants of women who consume no animal products might have very limited reserves of vitamin B12 and can develop vitamin B12 deficiency, sometimes very early in life [53]. The infant’s deficiency can be severe, especially if the mother’s deficiency is severe or caused by pernicious anemia; sometimes, the mother’s own deficiency is clinically mild and not recognized. Undetected and untreated vitamin B12 deficiency in infants can result in neurological damage, failure to thrive, developmental delays, and anemia [7,53,54]. The reasons include the small amounts of vitamin B12 in the breast milk of vegan mothers as well as the limited amounts of vitamin B12 crossing the placenta in these women during fetal development.

Excessive consumption of Vitamin B12:

The FNB did not establish a UL for vitamin B12 because of its low potential for toxicity [6]. Even at large doses, vitamin B12 is generally considered to be safe because the body does not store excess amounts.

Vitamin B12 deficiency symptoms:

Symptoms of a vitamin B12 shortage might be neurological, psychological, or physical. The signs of a vitamin B12 shortage might appear gradually and progressively worsen. Despite having low levels of vitamin B12 in their systems, some people may not exhibit any symptoms. Without anaemia, those with vitamin B12 insufficiency may experience neurological symptoms or damage (lack of red blood cells).

General physical symptoms of vitamin B12 deficiency can include:

• Feeling very tired or weak.
• Experiencing nausea, vomiting or diarrhea.
• Not feeling as hungry as usual.
• Weight loss.
• Having a sore mouth or tongue.
• Having yellowish skin.   

       
           
       
    Fig-1 Symptoms of B12 [59]

Neurological symptoms of vitamin B12 deficiency can include:

• Numbness or tingling in your hands and feet.
• Vision problems.
• Having a hard time remembering things or getting confused easily.
• Having a difficult time walking or speaking like you usually do.
• If neurological problems develop from vitamin B12 deficiency, they may not be reversible.

Psychological symptoms of vitamin B12 deficiency can include:

• Feeling depressed.
• Feeling irritable.
• Experiencing a change in the way you feel and behave.

Vitamin B12 plays a complex role in your body. This is why B12 deficiency has so many potential symptoms. There are four main categories of vitamin B12 complications. A complication is a problem caused by a medical condition or treatment.

Disease associated with B12

B12 and Cardiovascular Disease

Obesity, hypertension, and hypercholesterolemia are nutritional risk factors for CVD. Increased tHcy levels are also regarded as a risk factor, however it is not apparent whether tHcy is a risk factor that can be changed or if it is a separate marker of the illness process. The benefits of folate supplementation with or without the inclusion of vitamins B12 and B6 are a major focus of study into CVD and tHcy. There have been few studies specifically looking at the connection between CVD and vitamin B12. Increased plasma homocysteine levels have been recognized as an important risk factor for CVD Supplementation with folic acid and other B vitamins, a relatively inexpensive way of reducing plasma homocysteine levels, might be a way to lower CVD risk [6,7]. Several studies have shown that folic acid in combination with B12 lowers homocysteine levels, but what has not been quantified is the contribution of vitamin B12 alone to the lowering of homocysteine levels.

B12 and Cerebrovascular Disease

Studies of the effect of dietary intakes of vitamin B12 on risk of stroke have not yielded consistent results. One study14 indicated that intakes of folate and vitamin B6, but not vitamin B12, were significantly associated with decreased cerebrovascular mortality, whereas intakes of folate and vitamin B12, but not vitamin B6, were inversely associated with the risk of ischemic stroke [15]. Quinlivan and colleagues [16] demonstrated that following supplementation with increasing doses of folic acid, the dependency of plasma homocysteine levels on folate diminished, and the main determinant of plasma homocysteine levels then became vitamin B12. These researchers suggested that fortification of food with both folic acid and vitamin B12 could lower homocysteine levels more effectively, providing a potential benefit in vascular disease risk reduction.

B12 and Cancer

Synthesis and repair of DNA is a well-known function of folic acid. Ames [28] notes that folate deficiency, and possibly vitamin B12 and B6 deficiencies, are related to cancer via the incorporation of uracil, rather than the appropriate base, into human DNA, resulting in chromosomal breaks. A small study [29] provided some evidence of a modest relationship between intake of B vitamins and cervical cancer. A case-control study among Hawaiian women suggested a protective role for B vitamins in cervical cancer, owing to a reduction in premalignant cervical lesions with high nutrient intakes.

B12 and Osteoporosis

Dietary factors associated with the development of osteoporosis include inadequate protein, calcium and vitamin D. More recently, there has been interest in the effect of other nutrients, including vitamin B12 on bone health. Elevated tHcy has been associated with an increased risk of bone fractures, however it is not clear whether this is related to tHcy per se, to the level of vitamins B12, B6 or folate which are required for its metabolism, or to other causes of elevated tHcy such as environmental factors or underlying disease. A recent systematic review found that there is evidence for the association between tHcy and increased fracture risk, but less conclusive evidence for tHcy and low Bone Mineral Density (BMD) or for the association between vitamin B12 and either fracture risk or low BMD [77]. Intervention trials of the association between B vitamin supplementation have also shown mixed results. Positive effects of the supplementation of B vitamins on BMD have been found in a subgroup of osteoporotic patients with high tHcy and stroke patients at risk for osteoporosis [78,79], but none in a group of healthy older people or from the secondary analysis of the HOPE Trial for CVD reduction [80,81].

B12 and neuropsychiatric disorders

Vitamin B12 deficiency is a common cause of neuropsychiatric symptoms in elderly persons. Malabsorption accounts for the majority of cases. Vitamin B12 deficiency has been associated with neurologic, cognitive, psychotic, and mood symptoms, as well as treatment-resistance. Clinician awareness should be raised to accurately diagnose and treat early deficiencies to prevent irreversible structural brain damage, because current practice can be ineffective at identifying cases leading to neuropsychiatric sequelae. This clinical review focuses on important aspects of the recognition and treatment of vitamin B12 deficiency and neuropsychiatric manifestations of this preventable illness in elderly patients. Various disorders associated with Vitamin B12 deficiency are:

• Psychosis
• Mood disorders
• Mania
• Cognitive Impairment
• Delirium

Diagnosis:

It can be difficult to diagnose vitamin B12 deficiency because symptoms are not always present or the symptoms can be similar to other nutritional deficiencies. Healthcare providers will usually do routine blood tests to check for vitamin B12 deficiency in people who have a high risk of developing it. The tests used to diagnose vitamin B12 deficiency are a complete blood count (CBC) and a vitamin B12 blood test level. A person is diagnosed with vitamin B12 deficiency if the amount of vitamin B12 in their blood is less than 150 per mL. The diagnosis of a vitamin B12 deficiency is typically made by a pathologist doing a blood or urine test, preferably in the doctor's office. In order to determine the body's overall vitamin B-12 storage, this test primarily analyses the level of vitamin B-12 in the

blood or urine. The test often evaluates one, occasionally even both, of the following.

• Overall Vitamin B-12
• Holotranscobalamin (holoTC)
• Methylmalonic acid (MMA)

       
           
       
    Fig-2 Vitamin B12 Tests

The tests used to measure vitamin B12 deficiency are as follows:

• Complete Blood Count (CBC)
• Blood test
• Urine test
• Folate test
• Methylmelonic Acid test

Blood Test:

The blood test is a straightforward procedure whereby the pathologist often takes blood from the vein after cleansing the area, tying a rubber or elastic band over it, and drawing blood with a needle. After the blood has been extracted, the region is lightly compressed and a bandage is applied to halt the bleeding gradually. Although the vitamin B12 test alone does not necessitate adhering to any specific food timing, in the event that your doctor is checking other components in the blood, he or she may ask you to refrain from eating or drinking for approximately six to eight hours prior to your test and make sure you are adequately hydrated.

Urine Test:

You can perform a urine test by gathering a sample in a jar and mailing it to the lab. In some cases, this urine test can be performed at home using test strips similar to those used for pregnancy tests. This test strip must be dipped in the urine sample, and the findings are then interpreted in accordance with the guidelines provided in the brochure that is included. The majority of urine tests look for MMA, or methylmalonic acid, which has been linked to the beginning stages of a vitamin B-12 shortage. The recommended laboratory evaluation for patients with suspected vitamin B12 deficiency includes a complete blood count and serum vitamin B12 level.2,[19–21]. A level of less than 150 pg per mL (111 pmol per L) is diagnostic for deficiency.1,2 Serum vitamin B12 levels may be artificially elevated in patients with alcoholism, liver disease, or cancer because of decreased hepatic clearance of transport proteins and resultant higher circulating levels of vitamin B12; physicians should use caution when interpreting laboratory results in these patients[22,23]. In patients with a normal or low-normal serum vitamin B12 level, complete blood count results demonstrating macrocytosis, or suspected clinical manifestations, a serum methylmalonic acid level is an appropriate next step [1,2,6,18] and is a more direct measure of vitamin B12's physiologic activity. Table 3 lists the relative sensitivities and specificities of various laboratory tests.

Treatment:

Vitamin B12 can be used to correct a vitamin B12 shortage. It is frequently treated with cyanocobalamin, a synthetic vitamin B12 form. Depending on the underlying reason of the shortage, the patient may just require treatment until their vitamin B12 levels return to normal, or they may require lifelong vitamin B12 medication. Some people require ongoing B12 supplemental therapy. The cause of the insufficiency is typically what determines this. Even if your symptoms are better, you might need to keep taking B12 pills.

Treatment options for vitamin B12 deficiency include:

• Vitamin B12 oral supplements.
• Intramuscular injections of vitamin B12 (a shot that goes into the muscle).
• Nasal spray with vitamin B12.
• Nasal spray with vitamin B12.

Drug used for the treatment of Vitamin B12 deficiency are as follows:

Adenosylcobalamin

The active form of vitamin B12, adenosyl cobalamin, is a water-soluble vitamin that is used as a dietary supplement to treat stomatitis, pernicious anemia, vitamin B12 deficiency, depression, panic attacks, and anxiety.

Hydroxocobalamin

Vitamin B12 is available naturally as hydroxocobalamin, which is prescribed to treat anemia and vitamin B12 insufficiency.

Mecobalamin

MeCbl is gradually taking the place of older B12 preparations like cyanocobalamin and hydroxocobalamin in the treatment of vitamin B12 insufficiency.[61]

Interaction with medication

Vitamin B12 has the potential to interact with certain medications. In addition, several types of medications might adversely affect vitamin B12 levels. A few examples are provided below. Individuals taking these and other medications on a regular basis should discuss their vitamin B12 status with their healthcare providers.

Gastric acid inhibitors

Gastric acid inhibitors include proton pump inhibitors, such as omeprazole (Prilosec®) and lansoprazole (Prevacid®), and histamine 2-receptor antagonists, such as cimetidine (Tagamet®) and ranitidine (Zantac®). These drugs are used to treat gastroesophageal reflux disease and peptic ulcer disease. They can interfere with vitamin B12 absorption from food by slowing the release of gastric acid into the stomach and thereby lead to vitamin B12 deficiency [55-57].

Metformin

Metformin, an antihyperglycemic agent used as first-line treatment for prediabetes and diabetes, might reduce the absorption of vitamin B12 and significantly reduce serum vitamin B12 concentrations [57].

Association of vitamin b12 deficiency and use of reverse osmosis processed water for drinking:

Importance of Vitamin B12 in the production of DNA and RNA is been well established. Deficiency of Vitamin B12 causes macrocytic anaemia, peripheral neuropathy, dementia, weight loss, neural tube birth defects and various other adverse health effects. Recently increased prevalence of Vitamin B12 deficiency is been identified in various studies across different parts of India[62-64]. Easy availability of diagnostic facility to identify B12 deficient individuals, who were otherwise unidentified earlier as well as increased awareness among public causing voluntary testing of B12 levels may be some of the reasons for recently increased prevalence. Pure vegetarian diet lacking in milk or dairy product is one of the most commonly identified risk factors for development of Vitamin B12 deficiency. Along with life style changes, changes have kept on occurring in people’s dietary habits and type of drinking water over period of time; there is a possibility that some of these changes may be associated with recently increasing Vitamin B12 deficiency. One of the frequently questioned such factors is use of drinking water processed by Reverse Osmosis (RO) technology. With population growth and exploitation of available water sources causing scarcity of safe drinking water, mainly in developing countries, public based RO plants and home based RO units are being increasingly used. RO system very effectively removes dissolved solids as well as many microorganisms making water palatable and relatively safe to use [65-67]. With increased use of RO processed demineralised water, many adverse health effects are also has been increasing identified. Increased cardiovascular morbidity and mortality is now has been well established due to use of demineralised water low in calcium and magnesium [68-70]. Recent studies also suggest association of drinking soft water with higher risk of fractures in children, neurodegenerative diseases, gastric and duodenal ulcers, chronic gastritis and goiter. Several complications has been recognized in newborns and infants, including low birth weight babies, pre-term births, jaundice, anaemia, fractures and growth disorders.

Study in rats has shown increased occurrence of anaemia in rats fed with demineralised water [69]. Looking at various adverse health effects of drinking demineralized water, there is possibility that it may also be one of the newly associated factors for increasing incidence and prevalence of Vitamin B12 deficiency. Yet, it has not been proven so far by any scientific studies to the best of our knowledge.