Anemia is defined as the decline in the number of the normal number of (RBCs) Red Blood Cells or less than the normal quantity of hemoglobin in the blood of the individual at the specific age and life phase; due to which the oxygen carrying capacity of the blood gets reduced (Medicine Net- definition of Anemia, 2000). WHO defines anemia by fall in the hemoglobin below the threshold limit for explicit age and body stage as limit in g/dL for- children (0.5 to 5 years) is 11, children (5 to 12 years) is 11.5, children 12 to 15 years) is 12, women non-pregnant (>15 years) is 12, pregnant women is 11 and men (>15 years) is 13 (WHO, 2008).
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Anemia can be categorized according to the morphological size of the Red Blood Corpuscles, diagnosed by the microscopic examination of peripheral blood smear through the test called Mean Corpuscular Volume (MCV). The normal size of RBCs is 80-100 femtolitre (fl.) and anemic then called Normocytic anemia but if the cells are smaller than normal 80 fl and anemic then named Microcytic anemia & if larger than 100fl. then anemia is classified as Macrocytic anemia. In the Macrocytic anemic condition the most common etiology is Megaloblastic anemia which is due to insufficiency of Vitamin B12 or folic acid or both. The deficiency of Vitamin B12 or folate can be either due to inadequate intake or scanty absorption by the body. Vitamin B12 deficiency produce neurological symptoms, but the folate deficiency does not produce such effect. The lack of intrinsic factor required to absorb Vitamin B12 from the diet causes the Megaloblastic anemic and the condition is called pernicious anemia. The shortage of intrinsic factor may arise from an auto immune condition aiming the parietal cells or the gastric lining (atrophic gastritis) that produce intrinsic factor or against intrinsic factor itself- which lead to poor absorption of the Vitamin B12. The removal of the functional portion of the stomach can be caused during the process of gastric bypass surgical procedure leads to reduced Vitamin B12 or folate absorption.
Prevalence of condition
Pernicious anemia accounts for about 80 % of megaloblastic anemia due to impaired absorption of vitamin B12. Parietal cell antibody and antibodies to intrinsic factor are found in nearly all cases. 90% of patients have antibodies to parietal cells and their components; including antibodies to intrinsic factor and proton pump H, K-ATPase (Burman & Mardh et.al., 1989). About 50 percent of the patients have thyroid antibodies (Clinical Knowledge Summaries, 2008). Pernicious anemia may be associated with simple gastric atrophy in 15% of people age 40-60 and 20 to 30% of the older population. Pathology shows that gastritis with all layers of the body and fundus atrophied. The antrum is spared in more than 80% of patients (Merck Manual).
The prevalence of the pernicious anemia in general population is not known and is difficult to ascertain because of diverse etiologies and different assays that is radioassay or chemoilluminescence. The incidence of the disease is 1:10,000 in northern Europe. The disease occurs in all races. The peak age is 60 and the condition is more common in those with blue eyes, early graying, a positive family history and blood group A. The condition has female : male ratio of 1.6 : 1.0 (Clinical Knowledge Summaries, 2008). Pernicious anemia may be first diagnosed incidentally during the investigation of reversible diarrhea (Marty, 1984).
The recent WHO review has shown that the majority of the data on the prevalence of folate and Vitamin B12 deficiencies has been derived from relatively small and local surveys and these along with the national surveys data from few of the countries suggest that both of these deficiencies may be a public health problem that could affect many million of people throughout the world. Low blood concentrations of the vitamins occur across the population groups and in countries in various stages of development. There is strong evidence of careless relationship between low maternal folate intake or lower status and increased risk of neural tube defects- and for protective effect of folic acid supplementation or consumption of fortified foods, in the preconception period, against the neural defects. This association has been confirmed in two randomized clinical trials, in large scale supplementation trials in China, and from post-fortification data of the countries like United States of America, Chile and Canada (WHO, 2008).
The evidence of the relation between the serum or plasma folate concentrations and cognitive function is weaker in children than in adults. Some studies have reported lower scores in the school children with low folate status (Borjel & Nilsson et.al., 2005). African -American populations are known to have an earlier age presentation (Chanarin, 1979). According to WHO review in United Kingdom among pregnant women 15.2 percent are anemic, among non-pregnant women of reproductive age about 8.8 percent are anemic, and among pre-school age children 8 percent are anemic. (WHO- Global database on Anemia)
Path physiology of condition
Structure of Vitamin B12
Vitamin B12 structurally is a complex molecule in which a cobalt atom is present in a corrin ring. Basically, Vitamin B12 is present in the animal protein.
Vitamin Storage in the Body
Liver stores about half of the total body stores of about 2-5 milligrams. The recommended daily intake for adults is 2 mcg/d, pregnant and lactating women is 2.6mcg/d; while children require 0.7mcg/d and adolescents up to 2mcg/day. Vitamin B12 is highly conserved through the entero-hepatic circulation, cobalamin deficiency from mal-absorption develops after 2 to 5 years and the deficiency from dietary inadequacy in vegetarians develops after 10 to 20 years.
Vitamin Absorption mechanism
The low pH of stomach cleaves cobalamin from the ingested dietary proteins. The free cobalamin binds to the gastric R binder (a glycoprotein in saliva) and the complex travels to the duodenum and jejunum, where pancreatic peptidases digest the complex and release cobalamin. The free cobalamin is capable then to bind with gastric intrinsic factor (IF), a glycoprotein produced by the gastric parietal cells, the secretion of which parallels that of hydrochloric acid. That is why in states of achorhydria, IF secretion is reduced, leading to cobalamin deficiency. Significantly, only 99 percent of the ingested cobalamin requires intrinsic factor for absorption. Up to 1 percent of free cobalamin is passively absorbed through the terminal ileum. Due to this logic oral replacement of the Vitamin B12 with large quantities is suggested for Pernicious anemic conditions (Weir & Scott et.al, 1998).
As the intrinsic factor binds with Vitamin B12, resistance develops for further digestion of Vitamin B12. The complex travels to the distal ileum and binds to specific mucosal brush border receptor, Cublin- which facilitates the internalization of the cobalamin IF complex in an energy dependant process. Once internalized, IF is removed and cobalamin transferred to the other transport proteins – transcobalamin I, II, III (TCI, TCII, TCIII). About 80% of cobalamin is bound to TCI/III, whose function in the cobalamin metabolism is unidentified. The remaining 20 percent binds with TCII, which is the physiological transport protein produced by endothelial cells. Its half life is 6-9 minutes; therefore the deliverance to target tissues is fast.
Cobalamin TCII complex is secreted into the portal blood where it is taken up mainly in the liver and bone marrow and some other tissues. The phase when it reaches the cytoplasm, cobalamin is liberated from the complex by lysosomal degradation. The enzyme mediated reduction process of the cobalt occurs by cytoplasmic methylation to form methylcobalamin or by mitochondrial adenosylation to form adenosylcobalmin- which are the two main active forms of cobalamin (Weir & Scott, 1999).
Role of Vitamin B12 in bone marrow function
Methylcobalamin in the cytoplasm- acts as cofactor for the methionine synthesis by allowing transfer of a methyl group from 5-methyltetrahydrofolate (5-methylTHF) to homocysteine (HC), forming methionine and demethylated tetrahydrofolate (THF). This results in decrease in the level of homocysteine in the serum, which appears to be toxic to the endothelial cells. Methionine is further metabolized to S-adenosylmethinine. THF is utilized in the DNA synthesis. The polyglutamate converted form of THF participated in the purine synthesis and the conversion of deoxyuridylate (dUTP) to deoxythymidine monophospahe (dTMP), which is then phosphorylated to deoxythymidine triphosphate (dTTP). dTTP is required for DNA synthesis, thus in VitaminB12 deficiency- the formation of dTTP and the accumulation of 5-methyl THF is inadequate, trapping folate in tits unusable form, thereby leading to impeded DNA synthesis. RNA contains dTP (deoxyuracil triphosphate) instead of dTTP, allowing for protein synthesis to proceed uninterrupted and resulting in macrocytosis and cytonuclear dissociation.
After folate deficiency, as same mechanisms are responsible to cause macrocytosis and cytonuclear dissociation that is why both deficiencies lead to Megaloblastic anemia and disordered maturation in the granulocytic linkages, therefore folate supplementation can reverse the hemotologic abnormalities of Vitamin B12 deficiency but has no impact on the neurological abnormalities of vitamin B12 deficiency.
Pernicious anemia is commonly seen in individuals having atrophic gastritis, auto immune destruction of gastric parietal cells which leads to lack of intrinsic factor for the absorption of Vitamin B12 and this ultimately give rise to Vitamin B12 deficiency (Kumar, 2007). The loss of the ability to absorb Vitamin B12 is the most common cause of adult vitamin B12 deficiency. Vitamin B12 and folate co enzyme are required for the thymidylate and purine synthesis, thus their deficiency results in retarded DNA synthesis. In folate and Vitamin B12 deficiency – the defect in DNA synthesis affects other rapidly dividing cells also, which may be manifested as glossitis, skin changes and flattening of the intestinal villi (Masnou & Llavat et.al., 2007). The synthesis of DNA may also be delayed when certain chemotherapeutic agents like folate anstagonists (methotrexate), purine antagonists (6-mercaptopurine) and pyrimidine antagonists are used. In addition to non explicit symptoms of anemia, exact features of Vitamin B12 deficiency include peripheral neuropathy and subacute combined degeneration of the spinal cord, which results in balance difficulties from posterior column spinal cord pathology (Niranjan, 2006).
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Most of the microorganisms even including bacteria and algae- synthesize vitamin B12 and they form the only main source of this vitamin (Chanarin, 1979). The Vitamin B12 synthesized in the microorganisms enters the human food chain through amalgamation into the food of the animal origin. In many animals, gastrointestinal fermentation supports the growth of these Vitamin B12 forming microorganisms and consequently the vitamin is absorbed into the animal tissues. This is principally accurate for the liver- where the vitamin B 12 is stored in the large quantities. The products from the herbivorous animals like milk, meat and eggs thus comprise the significant dietary source of the vitamin, unless the animal is surviving in one of the many regions in the world which is geochemically deficient in cobalt (Smith, 1987).
Milk from cows and humans contains binders with very high affinity for Vitamin B12, though whether they hamper or promote intestinal absorption is not totally clear. Omnivores and carnivores, including humans derive dietary vitamin B12 almost exclusively from animal tissues or products like milk, butter, cheese, eggs, meat, poultry etc. This appears that the vitamin B12 derived from the microflora in any appreciable quantities, although vegetable fermentation preparations have been reported as being possible sources of vitamin B12 (Berg & Dagnelie et.al., 1988). About ½ pint of milk contains 1.2µg, a slice of vegetarian cheddar cheese 40gm contains 50µg, 1 boiled egg contains 0.7µg of Vitamin B12. The process fermentation in order to prepare yoghurt destroys much of the B12 present. Boiling milk can also destroy much of the vitamin B12 present in it (Vegatarian Society England- Information Sheet).
The treatment of vitamin B12 deficiency linked anemia is not permanent as the temporary cure and the cessation of the anemia related symptoms depends on the repletion of the Vitamin B12. The most accessible or inexpensive method to replenish vitamin B12 is through dietary supplementation in the of sublingual B12 tablets available widely throughout the world. The oral and sublingual B12 are absorbed equally well but in the study subjects were not selected to be having pernicious anemia. Anemic patients may need sublingual cyanocobalamin or methylcobalamin tablets which permits absorption through the mucous membrane of the mouth thus bypassing the gastrointestinal tract completely therefore no risk of intrinsic factor discrepancy (Sharabi & Sulkes et.al., 2003).
In some studies oral tablets were used but they were required in very high doses to treat pernicious anemia were required (Lederle, 1998). The effectiveness of the high dose of vitamin B12 tablets to treat ordinary pernicious anemia is very well established. High oral administration allows B12 to be absorbed in places other than the terminal ileum. In a study it was found that oral B12 repletion was more effective than injections (Butler & Vidal, 2006). Innovative alternative methods of administering B12, including nasal sprays and behind the ear patches. In small study in mid 1997 with just 6 participants found that the intranasal administration of B12 led to increases in plasma cobalamin even up to 8 times of the given patient’s baseline measurement (Slot & Merkus et.al., 1997).
Evidence from epidemiological studies
According to the epidemiological study conducted in 2005 Pernicious anemia is more common in type diabetics than in non-diabetic subjects, but it is clinically silent until its end stage. The high prevalence of latent Pernicious anemia in Diabetes mellitus type 1 patients leads to the recommendation of screening using serum pepsinogen 1 concentrations (Nuria & Lusia, 2005).
The risk of cancers of buccal cavity, stomach and colon along with lymphoma and leukemia is shown to be increased in case reports of patients in hospital based and cross sectional studies in a cohort study of 1993. Even the cancer of esophagus and pancreas also remain elevated throughout the study and the follow-up period (Hsing & Hansson et.al., 1993).
The epidemiological study conducted in 1996 among U.S. population has shown that undiagnosed pernicious anemia is a common finding in the elderly people of United States with undiagnosed and untreated pernicious anemia and is having possibility for masked cobalamin deficiency (Carmel, 1996).
The study conducted in 2003 to find the link between infection of H.Pylori and the gastric autoimmune diseases like pernicious anemia. This epidemiological study has depicted that the frequent detection of H pylori in subjects with early gastric autoimmunity indicated by parietal cell antibodies suggests that- H. pylori could have crucial role to play in the induction and the maintenance of the autoimmunity at the gastric level (Fabio & Beatrice et.al., 2003).
As the totally vegetarians do not consume any animal products, they are at high risk of developing vitamin B12 deficiency. It is generally agreed that in some communities the only source of vitamin B12 is from contamination of food by microorganisms. When vegetarians move to countries where there are high standards of hygiene and the rules of sanitation are stringent, there is good evidence that risk of vitamin B12 deficiency increases in adults and particularly in children born to and breastfed by women who are strict vegans.
As standards of hygiene improve in developing countries, there is a concern that the prevalence of vitamin B12 deficiency might occur or increase. This should be ascertained by estimating plasma vitamin B12 levels, preferably in conjunction with plasma levels in representative adult populations and in infants. Further research needs include –
- Ascertaining the contribution that fermented vegetable foods make to the vitamin B12 status of vegans communities.
- Investigating the prevalence of atrophic gastritis in developing countries to determine its extent in exacerbating vitamin B12 deficiency.
- Relation of pernicious anemia with the fatal or other chronic diseases like those of endocrinal, cardiac or renal system.
- Dietary or supplementary innovative methods are still to be researched to find easy suitable methods to manage vitamin B12 deficiency.
- To find permanent cure of the disease by some biological stem cell therapy method or repair of the gastric lining to cover up the deficiency of intrinsic factor and break down the pathological cycle of vitamin B12 deficiency anemia.
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