Download PREVALENCE OF VITAMIN B12 DEFICIENCY AND ITS

PREVALENCE
OF
VITAMIN
B12
DEFICIENCY
AND
ITS
IMPLICATION IN INDIA
ABSTRACT: Vitamin B12 is important for our body to work properly. It plays a crucial
role for the normal functioning of brain, nervous system and formation of blood. A person
who lacks vitamin B12 may feel tired, lack of energy, fatigue and may suffer from lack of
appetite, depression, difficulty in maintaining balance, confusion, poor memory, dementia
and soreness of the mouth or tongue. In India the most common cause of vitamin B12
deficiency is vegetarian diet since it is only obtained from animal food. In India, very little
appreciation is been given to vitamin B12 deficiency among the Indian medical professionals
and policy makers. This may be due to various reasons: 1) it is not routinely measured in
clinical practice, 2) despite of low level of circulating vitamin B12, signs for specific
neurological or haematological syndrome consistent with vitamin B12 deficiency are rare, 3)
the reports of prevalence, majority of them are based on clinical data and, therefore, may not
represent community prevalence. This article points out the reason of vitamin B12 deficiency
and the population at risk and how to diagnose them and provide proper treatment.
INTRODUCTION
Vitamin B12 is a water soluble vitamin and it is naturally present in some foods, also
available as dietary supplement and as prescription medication.[26; 1-4] It is also known as
cobalamin and is important for the body to work properly. It is a cobalt containing
compounds which are a biologically active corrinoid with macrocyclic pyrrol rings [2; 3].
Vitamin B12 plays an important role in normal functioning of the brain, nervous system and
for the formation of blood [31; 1]. People who are deficient of vitamin B12 may feel tired or
have lack of energy.[27] It acts as a cofactor that is integral to methylation processes which
are important in reactions related to DNA and cell metabolism, therefore, deficiency of
vitamin B12 may lead to disruption of DNA and cell metabolism which may cause serious
clinical consequences [7; 1].
Intracellularly vitamin B12 is converted to two active coenzymes, methylcobalamin in the
cytoplasm and adenosylcobalamin in the mitochondria. These coenzymes are necessary for
the homeostasis of methylmalonic acid (MMA) and homocysteine [7; 2,3]. Vitamin B12 acts
as a cofactor in the conversion of methylmalonic acid into succinyl-CoA. Methionine is
converted to homocysteine and then homocysteine is further converted to amino acids
cysteine or resynthesized into methionine. [7]
Deficiency of vitamin B12 also leads to elevated levels of homocysteine and methylmalonic
acid. It was found out that MMA concentration were shown to be elevated in nearly every
patient with hematologic or neurologic abnormalities due to vitamin B12 deficiency and
when treated with vitamin B12, MMA concentration was found to be corrected.[28] Elevated
levels of total homocysteine (tHcy) are found to be a risk factor for cardiovascular
disease.[20] Homocysteine causes peroxidation and generation of free radicals which causes
inflammation and acute endothelial dysfunction, which leads to acceleration of
atherosclerotic process predisposing to cardiovascular disease [24; 3]. An elevated level of
homocysteine and deficiency of folate and vitamin B12 are risk factor for birth defects, poor
pregnancy outcomes, and neurocognitive performances [20; 3-5]. Megaloblastic anemia is
commonly seen in vitamin B12 deficient patients. Vitamin B12 deficiency is more common
in elderly patients, but it is often not investigated or unrecognized because of subtle clinical
manifestation[1; 1-4].
In India, very little appreciation is been given to vitamin B12 deficiency among the Indian
medical professionals and policy makers. This may be due to various reasons: 1) it is not
routinely measured in clinical practice, 2) despite of low level of circulating vitamin B12,
signs for specific neurological or haematological syndrome consistent with vitamin B12
deficiency are rare, 3) the reports of prevalence, majority of them are based on clinical data
and, therefore, may not represent community prevalence.[20]
PREVALENCE OF VITAMIN B12 DEFICIENCY IN SURVEYS:
Vitamin B12 deficiency is widespread in developing countries like Africa, India and South
and Central America mostly due to low intake of animal products, particularly among the
poor [28; 48]. Various studies have been performed to find out the prevalence of vitamin B12
deficiency in India.
The prevalence of vitamin B12 depends on various factors such as age, dietary habits and
socio-economic status. So depending upon the different factors various data have been
obtained for vitamin B12 deficiency.
A study performed on the urban population of Delhi showed to have a prevalence of 43%,
this study includes parameters such as age and sex. [18] A Pune study showed the prevalence
of 67%, the study was only performed on men and included parameters such as socioeconomic status, lifestyle, dietary habits and medical history.[20] A study done in BhujKutch showed the prevalence of
44.2%, it only included data from the higher socio-
economic class.[14] Such a high prevalence of vitamin B12 deficiency indicates that there is
immediate need of some action or a policy to prevent it.
The prevalence of vitamin B12 deficiency in US population vary with age groups and was
found to be 3% in those aged 20-39-year-old, 4% in those aged 40-59-year-old, and 6% in
those aged 70-year-old.[10] This shows that compared to the American population, the Indian
population is widely prevalent to vitamin B12 deficiency this may be due to more vegetarian
population and poor lifestyle.
A study performed by Sanket K. et al in Western Maharashtra on 100 patients out of which
33% were vegetarian. The result showed that 6% patients had neuropsychiatric manifestation,
1% patients had depressive illness, 0% patients had dementia, 1% patients had forgetfulness,
0% patients had mania/hallucination and 1% patients had chronic headache [30].
CLINICAL MANIFESTATION OF B12 DEFICIENCY:
Vitamin B12 deficiency can be characterized by fatigue, constipation, megaloblastic anemia,
weakness, weight loss, loss of appetite. [26;1,3,27] It can also cause some neurological
changes like numbness and tingling in the hands and feet.[26;5,28] Other symptoms of
deficiency include depression, difficulty in maintaining balance, confusion, poor memory,
dementia and soreness of the mouth or tongue[26;29].
The neurological symptoms of Vitamin B12 deficiency can also occur without anemia, so
early diagnosis is important to avoid irreversible damage [26,6]. Symptoms of vitamin B12
deficiency in infants includes failure to thrive, developmental delay, megaloblastic anemia
and movement disorder[26;30].
CAUSES OF VITAMIN B12 DEFICIENCY:
Vitamin B12 is mainly derived from animal foods like milk, fish, and dairy. According to
FAO and USFDA 20%-42% of the Indian population are vegetarian since vitamin B12 is
mostly obtained from animal food, vegetarian diet becomes the most common cause of
vitamin B12 deficiency.
Other common causes [7; 5-9]:
1) Impaired gastric absorption
Example: Gastrectomy (partial or total), Pernicious anemia, and Impaired intestinal
absorption for Eg. Ileal resection or disease like tuberculous ileiris and Crohn's
inflammatory bowel disease; Blind loop syndrome, Parasites like bacterial
overgrowth, giardiasis, and fish tapeworm; Luminal disturbance like in case of
chronic pancreatic disease and gastrinoma
2) Decreased intake
Example: Malnutrition, Reduce intake of animal product, strict vegan diet.
3) Pancreatic insufficiency
4) Congenital/ inherited
Example: Intrinsic factor receptor deficiency/defect, Cobalamine mutation (C-g-1
gene), Transcobalamin deficiency, Congenital deficiency of intrinsic factor like in the
case of "juvenile" pernicious anemia.
5) HIV and Haemolysis
6) Drugs such as Alcohol, Metformin, Nitrous oxide, Proton pump inhibitor (E.g.
omeprazole), H2 receptor antagonists (E.g. Ranitidine), Colchicine, Phenytoin,
Macrolide may also lead to vitamin B12 deficiency.
POPULATION AT RISK OF VITAMIN B12 DEFICIENCY:
The main cause that leads to vitamin B12 deficiency is malabsorption from food, dietary
deficiency, pernicious anemia and postsurgical malabsorption [26; 12]. However in many
cases the exact cause of deficiency is unknown. The following population groups are the one
that are most likely to have vitamin B12 deficiency.
Vegetarian diet: population who are strict vegetarian or vegan are the one at greater risk
than Lacto-ovo vegetarians and nonvegetarians who are having vitamin B12 deficiency
because animal products are the main source of vitamin B12 compare to the natural food
sources [26; 5]. Fortified breakfast cereals, milk, yogurt, fruits and cheese are some of the
dietary sources of vitamin B12 for strict vegans.
Women who are pregnant and lactating and follow a strict vegetarian diet and their
infants: during pregnancy vitamin B12 crosses the placenta and is present in breast milk.
Women who consume no animal products when breastfed their infants may have very limited
reserves of vitamin B12 and their infants can develop deficiency within months of birth [26;
5, 43]. If the deficiency is undetected or untreated in infants it can lead to severe and
permanent neurological damage.
In America, The American Dietetic Association recommends taking vitamin B12
supplements for vegans and Lacto-ovo vegetarians during both pregnancy and lactation. This
is to ensure that enough vitamin B12 is transferred to the fetus and infant [26; 44]. Women
who are pregnant and lactating and follow strict vegetarian diets should consult with a
pediatrician regarding supplemental vitamin B12 for their infants and children [26; 5].
History of gastrointestinal surgery: surgery in the gastrointestinal tract, such as surgery to
remove all or a part of stomach, weight loss surgery, often leads to loss of cells that secrete
intrinsic factors and hydrochloric acid [26; 5, 39, 40]. This reduces the amount of vitamin
B12 absorbed from the food [26; 41]. Removal of the distal ileum by surgery can also result
in the reduce ability to absorb vitamin B12. Individual who undergoes such surgical
procedures should be monitored preoperatively and postoperatively for vitamin B12
deficiency [26; 42].
Pernicious anemia: it is a condition which is characterized by a lack of intrinsic factors and
affects 1%-2% of older adults [26; 11]. In this condition, the absorption of vitamin B12 from
the gastrointestinal tract is reduced [26; 3, 5 9, 10]. Intramuscular vitamin B12 is given for
treating pernicious anemia. In the absence of intrinsic factor approximately 1% of the oral
vitamin B12 can be absorbed passively [26; 11], therefore the high dose of vitamin B12 can
also be an effective treatment.
Older adult: an older individual who are suffering from atrophic gastritis which decreases
the secretion of hydrochloric acid in stomach results in decreased absorption of vitamin B12
[26;5,11,32-36]. The decrease levels of hydrochloric acid promote the growth of normal
intestinal bacteria, these bacteria use vitamin B12, further reducing its level.[26;37]
Gastrointestinal disorder: Individual who is suffering from disorders of stomach and
intestine such as celiac disease and Crohn's disease are unable to absorb enough amount of
vitamin B12.[26;12,13] The initial symptoms are cognitive function resulting from early
vitamin B12 deficiency followed by megaloblastic anemia and dementia.
VITAMIN B12 DEFICIENCY IN CARDIOVASCULAR DISEASES:
The most common cause of death in industrialized countries is cardiovascular diseases such
as the United States, and it is rising in developing countries. The various risk factors for
cardiovascular disease include elevated low-density lipoprotein (LDL) levels, low levels of
high-density lipoprotein (HDL), high blood pressure, diabetes and obesity [26;45]
Another risk factor identified for cardiovascular disease is elevated levels of homocysteine.
Homocysteine is derived from methionine that is normally present in the blood. Its elevated
levels are thought to promote thrombogenesis, lipid peroxidation, impair endothelial
vasomotor function and induce vascular smooth muscle proliferation [26;46,47,49]. The link
between elevated levels of homocysteine with coronary heart disease and stroke has been
proof from retrospective, cross-sectional and prospective studies [26;46,49-58].
Metabolism of homocysteine involves vitamin B12, folate, and vitamin B6. In the deficiency
of vitamin B12, homocysteine level is increased due to inadequate function of methionine
synthase [26;6]. Several randomized controlled trials indicate that combination of vitamin
B12 and folic acid supplement with or without vitamin B6 resulted in decreased levels of
homocysteine in people suffering from a vascular disease or diabetes and in young adult
women [26;56-67]. In another study which was conducted on older men and women who
were given multivitamin/ multimineral supplement for 8 weeks experienced a significant
decrease in homocysteine levels [26;68].
Atherosclerosis is accelerated due to inflammation and acute endothelial dysfunction which is
caused by the presence of free radicals, generated through lipid peroxidation mediated by
homocysteine. The theory that there is a positive relation between high homocysteine levels
and coronary artery disease (CAD) was first proved in a clinical study by Wilcken and
Wilcken in 1976 [24;3]. Low vitamin B12 levels and hyperhomocysteinemia is most
common in Indian men and particularly vegetarians and urban residents [24;4]
VITAMIN B12 DEFICIENCY IN DEMENTIA AND COGNITIVE FUNCTION:
Vitamin B12 deficiency causes accumulation of homocysteine in the blood and also
decreases levels of substances which are needed to metabolize neurotransmitters [26;70].
Observational studies have shown a positive relation between elevated levels of
homocysteine and the incidence of Alzheimer's disease and dementia [26;6,47,71]. Low
vitamin B12 levels have also been positively related with decreased cognitive function.
EXCESSIVE VITAMIN B12:
An excessive level of vitamin B12 has no harmful impact on health because of its low
potential for toxicity. The IOM states that "no adverse effects have been associated with
excess vitamin B12 intake from food and supplements in healthy individuals" [26;5].
INTERACTION OF VITAMIN B12 WITH MEDICINS:
There are several medications which interact with vitamin B12 and might adversely affect its
level. Given below are several examples of interactions:
CHLORAMPHENICOL: It is a bacteriostatic antibiotic. Vitamin B12 plays an important role
in red blood cell formation and Chloramphenicol can decrease new blood cells. There for
Chloramphenicol decreases the effect of vitamin B12.
PROTON PUMP INHIBITORS: They are used in the treatment of gastroesophageal reflux
disease and peptic ulcer Eg. Omeprazole and lansoprazole. These drugs suppress the
production of gastric acid leading to malabsorption of vitamin B12 [26;83-85].
H2 RECEPTOR ANTAGONISTS: These drugs are used in the treatment of peptic ulcers, Eg.
Ranitidine, famotidine and cimetidine. They reduce vitamin B12 absorption from foods by
slowing the release of hydrochloric acid into the stomach [26;90].
METFORMIN: Metformin is the most commonly used drug for treatment of type 2 diabetes.
It has been reported that metformin reduces vitamin B12 level by 25%. [13;10,12]. The
possible mechanism through which metformin reduces B12 level includes alterations in
intestinal mobility, alteration in the calcium-dependent uptake by ileal cells of the vitamin
B12 intrinsic factor and increased bacterial overgrowth. Case reports and small studies ha
reported that 10-30% patients taking metformin have reduced vitamin B12 absorption
[26;92,93]. Various studies have suggested that if calcium given as a supplement may help to
improve B12 malabsorption caused by metformin [26;92,93], but not every researcher agree
[26;95].
HOW VITAMIN B12 DEFICIENCY IS DETERMINE:
Several tests are available which reflect the physiological, static and functional status of
vitamin B12. There is still no perfect test for measuring vitamin B12 deficiency. Measuring
the serum cobalamin level remains the favored decision. [7;4]. The other test includes
measurement of methylmalonic acid level, consider as the second line test, it helps to clarify
the false results of underlying biochemical and functional deficiencies. Measurement of
holotranscobalamin level shows an indeterminate “grey area” and therefore should be
followed by methylmalonic acid test. Measurement of homocysteine level also shows B12
deficiency but is less accurate than methylmalonic acid [7;4]. Because of various reference
ranges are available for B12 deficiency, it results in an inability of final definition for clinical
and subclinical deficiency states.
Physiological examination: The physiological parameters which reflects vitamin B12
deficiency includes full blood count (mean cell volume and hemoglobin), blood film,
reticulocyte count and lactate dehydrogenase. Macrocytosis is the most well-known trigger
for checking vitamin B12 level. Bone marrow biopsy can also be done in cases where the
diagnosis is unclear or the patient is not responding adequately to the treatment. Patient who
are concominantly suffering from iron deficiency may not show morphological features of
B12 deficiency until the iron deficiency is resolved. Macrocytosis is absent or masked by
thalassaemia trait [7;5-7].
Serum vitamin B12 level or cobalamin level: It is the most common method used to
evaluate the level of vitamin B12 in serum. It also includes measurement of both serum
holohaptocorrin and serum holotranscobalamin which may mask the actual result or show
false deficient state. This method is cheap compare to other methods and uses an automated
method and competitive-binding immune chemiluminescene [7; 2, 4, 14-17].
Level of Holotranscobalamin: Decrease level of holotranscobalamin in serum are consider
as an early marker for vitamin B12 deficiency in addition to elevated levels of MMA and
homocysteine. Holotranscobalamin is made of vitamin B12 attached to a transport protein
transcobalamin II. It is an active metabolite of vitamin B12 which is readily taken up by all
the cells and represents 6%-20% of total serum vitamin B12 [29;23]. Decrease in level of
holotranscobalamin occurs even before elevation in homocysteine and MMA level occurs
[29;24]. For vitamin B12 deficiency holotranscobalamin level is been consider as most
sensitive marker followed by MMA [29;23,25]. But this test cannot be performed in patients
having renal impairment as its increases in them [29;23]. Due to its high cost and lesser
availability then MMA and homocysteine test make it difficult to acquire wide clinical
acceptance.
Level of Methylmalonic acid: Due to deficiency of vitamin B12, methylmalonic acid gets
accumulated because vitamin B12 is required for the conversion of methylmalonic acid in to
succinyl-CoA. Its elevated level act as the indicator for vitamin B12 deficiency in tissues and
remains persistent for several days even after the replacement therapy is started [7;2]. This
test is been consider as the most representative marker for metabolic vitamin B12
insufficiency. In older patients (>65years) and those with impaired renal impairment the
levels can be falsely increased which me lead to false diagnosis. This method is expensive as
methylmalonic acid is measured by gas chromatography and mass spectrometry.
Total Homocysteine level: Total homocysteine levels in plasma are also increased in vitamin
B12 deficiency at the early course of deficiency. This test is sensitive but cannot be consider
as specific test for B12 deficiency as homocysteine levels are also increased in folic acid
deficiency, B6 deficiency, renal failure and hypothyroidism. The reference range varied with
the different technique used but the most preferred range is >15 μmol/L as high level of
homocysteine [7]. Fig 2 shows the algorithm for the diagnosis of vitamin B12 deficiency
[30;3,14].
Fig 2: Algorithm for the diagnosis of vitamin B12 deficiency
A study done on 406 patients diagnosed with vitamin B12 deficiency showed that 98.4
percent patients had elevated levels of methylmalonic and 95.9 percent had elevated
homocysteine levels. Out of 406 patients 1 patient showed normal level of both metabolites
resulting in 99.8 percent sensitivity when homocysteine and methylmalonic levels are
consider for diagnosing. It was also found that 28 percent patient had normal hematocrit
levels and 17 percent had normal mean corpuscular volumes [30;10]. This study suggest that
methylmalonic acid and homocysteine levels can be consider as the early marker for tissue
vitamin B12 deficiency, even before hematological manifestations occur.
TREATMENT:
The treatment should be started within the few days of confirmed diagnosis. In case of any
neurological conditions the treatment should be started immediately. In case of neurological
disturbance and impaired cognitive state a specialist should be concerned. Neurological
symptoms are also seen in the absence of haematological changes, so the treatment should be
started early to prevent permanent neurological disability. In emergency conditions such as
major anemia with cardiovascular compromise can be treated with packed red cell transfusion
[7; 24]. Table 1: shows the Parenteral and oral treatment for treating vitamin B12 deficiency
in normal and special conditions.
ROUTE OF
CONDITION
DOSE
ADMINISTRATION
Intramuscular treatment
Standard
treatment
for 1000 µg IM three times a
patients
without
any week for two week [7; 4,25]
neurological involvement
For
treating
neurological 1000
symptoms
µg
IM
given
on
alternate days for up to three
weeks or until there is no
improvement [7; 4,25]
For treating irreversible cases 1000 µg IM should be given
for
example
pernicious for lifelong [7; 26,27]
anemia, inflammatory bowel
syndrome and deficiency due
to malabsorption syndrome
Oral treatment
Standard
treatment
neurological
for 1000 µg and 2000 µg daily
and [7; 28]
haematological symptoms
Table 1: Parenteral and Oral treatment for vitamin B12 deficiency.
During pregnancy the treatment can be reviewed when the patient is fully replete and the
causative agent is removed [7; 4, 26, 27]. Oral treatment can be considered when deficiency
is mild or subclinical with no clinical symptom or when the absorption and compliance are
not a problem [7: 4, 28].
Cyanocobalamin and Hydroxocobalamin are the main drugs used for the treatment of vitamin
B12
deficiency.
Methylcobalamin
is
the
active
form
of
Hydroxocobalamin.
Hydroxocobalamin is well tolerated and have rare side effects such as itching, chills, hot
flushes, fever, exanthema, nausea, dizziness and very rarely anaphylaxis [7; 4, 26 27].
Cyanocobalamin is licensed and outlined in the British National Formulary as an oral
preparation which is given at a dose of 50-150 µg daily [7; 25] and its active form is
Deoxyadenosylcobalamin.