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 Table of Contents  
SPECIAL ARTICLE
Year : 2017  |  Volume : 5  |  Issue : 2  |  Page : 261-268

B12 deficiency in India


Department of Medicine and Hematology, Government Medical College, Kozhikode, Kerala, India

Date of Web Publication15-Dec-2017

Correspondence Address:
P K Sasidharan
Department of Medicine and Hematology, Government Medical College, Kozhikode, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/amhs.amhs_121_17

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  Abstract 

B12 deficiency is extremely common in India as is Vitamin D, folic acid, or iron deficiency, all because malnutrition is extremely common, even among the rich. The reasons for these are too many and are related to diet, lifestyle, and social and cultural issues. Any one of its varied manifestations can occur in isolation and can be coexisting with other comorbidities. In addition, the symptoms are modified also by the underlying disorder causing its deficiency. In spite of being a common disorder, its recognition is delayed or missed because the manifestations are diverse in nature, affecting all the organs and systems, and is often subclinical. To add to the confusion, laboratory estimations are notoriously unreliable even from the best of centers and doctors tend to rely on laboratory estimate of B12 levels. In this scenario, the doctors in India have to sharpen clinical skill to make a clinical judgment and initiate therapy and advocate a diet plan to give benefit to the patient. The ways and means of picking up those with clinical or subclinical B12 deficiency and the reasons and solutions to the problem are discussed in this article.

Keywords: B12 deficiency, cobalamine, healthy India, malnutrition


How to cite this article:
Sasidharan P K. B12 deficiency in India. Arch Med Health Sci 2017;5:261-8

How to cite this URL:
Sasidharan P K. B12 deficiency in India. Arch Med Health Sci [serial online] 2017 [cited 2018 Sep 22];5:261-8. Available from: http://www.amhsjournal.org/text.asp?2017/5/2/261/220818




  Introduction Top


Our understanding of B12 is incomplete, but one thing is certain that B12 deficiency is extremely common in the Indian subcontinent, due to lack of regular consumption of a balanced diet and other issues. Since the insight into B12 metabolism came from the western literature, we believe that they will give us guidelines on diagnosis and management too. That is foolishness, we should know how to make use of or adapt that insight into our scenario that needs tremendous common sense, which however is lacking due to various issues we face. What is B12, why we have deficiency of it, the concept of balanced diet and what all are lacking in our diet, how to diagnose, how to manage, and the long-term solutions are discussed based on the review of literature and personal experience.


  Know B12 (Cobalamin) Top


History of B12 and its Deficiency

In 1855, Thomas Addison described cases of anemia not responding to iron therapy – he coined the name “pernicious anemia” to describe the pernicious nature of the problem due to protean manifestations and severity of the anemia, the other associated problems these patients had as the neuropsychiatric problems, the lack of response to iron therapy, and the grave prognosis; usually those days, they succumbed to illness in 1–3 years after the diagnosis. In 1908, Whipple reported success of a liver diet in experimental dogs subjected to repeated phlebotomies. Taking clue from this observation, in 1926, George Richards Minot and William P. Murphy subjected 45 patients with pernicious anemia to a liver therapy. The liver therapy included nearly raw liver with mutton/beef and fresh fruits.[1],[2] Now, we know that these would have provided B12 and folic acid (FA). There was a significant improvement in majority and some even recovered completely. For their observations, in 1934, Minot, Murphy, and Whipple shared the Nobel Prize. In 1935, William B. Castle described the intrinsic factor (IF). Castle noticed that all the patients with pernicious anemia were not improving with the liver therapy; some did not even respond at all, many had only partial recovery, whereas some recovered completely. He then hypothesized that there was an extrinsic factor in the liver diet (which we now know as B12), but it needed an IF from the stomach to complete its action. To prove his hypothesis Castle consumed mutton and after that he aspirated his own gastric secretion. He then transferred this gastric aspirate into those pernicious anemia patients who did not improve after consuming the liver diet. There was remarkable recovery in all of them.[3],[4],[5] One great thing to note here is that all these were purely based on meticulous observation and hypothesis, unlike what we see today in the so-called double-blind studies, where everyone is literally blind and dumb to the social issues behind the problem they are studying.

Natural sources of B12

Dorothy Crowfoot Hodgkin determined the chemical structure of the molecule and it was only in 1948 – B12 was isolated.[1],[2] It is now produced industrially by bacterial fermentation – synthesis. Animals, plants, and fungi are incapable of producing it. Meat is the primary source, other animal products such as fish and egg are supposed to provide it as per the literature, but the observation is that those who do not consume meat come with clinical or subclinical deficiency. May be that it is not present in adequate amounts or that, what is present is destroyed by frying of these food items and deep cooking. Green leafy vegetables can give B12 – if the contaminating harmless bacteria are not removed by thorough washing. The only source of B12 in strict vegetarians is the green leafy vegetables, which they either do not take or wash thoroughly for fear of pesticide contamination.

Absorption of B12 is both passive and active; Passive absorption is possible through buccal, duodenal and ileal mucosa but it is very inefficient with only less than 1% of an oral dose absorbed. With 1000 mcg oral or S/L dose – <10 mcg may get absorbed. Active absorption is from the ileum; it is an efficient mechanism and is mediated by IF secreted from the gastric parietal cells [Figure 1].[1],[2],[6]
Figure 1: Absorption of B12: R- Protein, IF- Intrinsic factor, Cub: Cubilin receptor, TC1- Transcobalamin 1, TC2- Transcobalamin 2

Click here to view


B12 in diet is bound to proteins in the diet and the enzymes in saliva, and stomach digests and frees the B12, and soon it combines with cobalamin-binding proteins (haptocorrin - or the R-protein) in the salivary and gastric secretions. Then, this travels down to the duodenum where the pancreatic trypsin in the alkaline pH removes the R-protein and it is now free to combine with the IF secreted from the stomach. The IF–B12 complex is resistant to digestion and it travels down to the ileum where the IF attaches to the cubilin receptors on the enterocyte, and the complex is internalized by the process of endocytosis; in the enterocyte, the IF is catabolized and B12 then combines with the transport protein, transcobalamin 1 (TC1). TC1 transports B12 (cobalalmin) from IF to enterocytes. Finally, the cobalamin is transferred from the enterocyte into the portal circulation where TC2, which carries B12 in circulation, carries it. TC2 delivers B12 to various organs where it is needed [Figure 1].[6]

Enterohepatic circulation of B12

There is a significant enterohepatic circulation for B12. After circulating in blood, part of the B12 is secreted into bile and it binds again with IF, and the process is repeated and finally reabsorbed. Most of it is reabsorbed, and therefore, deficiency develops rapidly if there is malabsorption of B12 at the ileum.[6],[7]

Biochemical functions of Vitamin B12

There are two active forms in the body – methyl cobalamin and adenosylcoblamin. The methyl cobalamin-dependent enzyme is involved in action of methionine synthase-mediated DNA synthesis. This may be the active principle in all the rapidly dividing cells and the epithelial and mucosal surfaces. The Adenosylcobalamin dependent enzyme, Methyl Malonyl Coenzyme A mutase is involved in isomerization of methyl malonyl CoA to succinyl CoA. This metabolic pathway is important for fatty acid synthesis and is involved in myelin sheath synthesis. [6,7] Dysfunction of this pathway could be the metabolic defect behind the neurological manifestations in B12 deficiency.

Cobalamin-Folate-B6 relations[7],[8]

[Figure 2] depicts the biochemical functions of B12 and the relationship between B12, FA, and B6. What we should realize is that there is no B12 without FA; one cannot function in the absence of the other. Even if all these three are available unless there are adequate calories and protein, none of these functions will be adequately met. It goes without saying that the most important prerequisite for B12 and FA is a balanced diet.
Figure 2: Cobalamin-folate- B6 relations

Click here to view



  Why B12 Deficiency in India? Top


Dietary causes of B12 deficiency in India [9]

B12 deficiency in India is primarily due to lack of a balanced diet. Balanced diet should have one source of calories, one source of protein, very high intake of fresh vegetables, and adequate intake of fresh whole seasonal fruits and adequate water (2–2.5 L per day or water sufficient enough to produce at least 1.5 L of urine output). The two basic components of a vegetarian diet are cereals and pulses in the proportion of 4:1. Cereals only should be the source of calories in a vegetarian diet. A vegetarian balanced diet should contain pulses or curd (yogurt) as a source of protein. For growing ages, pregnant and lactating mothers' cereals: pulses ratio should be in 3:1 proportion. Those who consume all food items can combine cereals with any of the pulses or fish, meat, egg, or curd as a source of protein. Strict vegetarians should not be consuming calories in the form of potatoes/tapioca or jackfruits unless they are willing to combine it with egg or curd as a source of protein. Jack fruit-seed and jackfruit together in the same proportion probably is a good combination, but no data are available on that.[9]

A balanced diet with cereals or potato or other items such as tapioca/jackfruit as a source of calories, together with regular intake of meat as a source of protein and regular consumption of fresh fruits and green leafy vegetables, will give adequate B12. Meat is the only definite source of B12 in diet, but the meat should not be deep-fried. A vegetarian diet with any one of the cereals (rice/wheat/ragi/oats) and any one of the pulses (dhals) as a source protein (cereals: pulses = 4:1) and regular consumption of fresh fruits and green leafy vegetables could theoretically give B12 and FA. The harmless bacteria contaminating natural food sources such as green leafy vegetables are the only source of B12 in a strict vegetarian diet. India has the maximum number of vegetarians in the world; however, vegetarianism only means that they do not consume any nonvegetarian food items, but they hardly take any vegetables, including the green leafy vegetables. People are unaware of the need for regular intake of vegetables and fruits too. Some do not even know what exactly are the vegetables and some even consider potatoes and pulses as vegetables. Even if they consume green leafy vegetables, it is often thoroughly washed for fear of pesticide residues or to remove the dirt, and it is always cooked before consumption resulting in loss of FA too. Especially, the fear of pesticide residue on the vegetables is fierce due to media publicity. Even the nonvegetarians do not consume meat regularly as the westerners do. The usual habit is that they take meat only once a week at the most. Most nonvegetarians are nonvegetarians only because they might occasionally consume some fish or egg. Thus, there are a lack of regular consumption of meat and a lack of regular intake of green leafy vegetables. The meat, if at all consumed, is often in the fried form resulting in loss of B12 and producing even toxins such as nitrosamines. Nonvegetarian items such as egg and other dairy products are supposed to contain B12, but in practice, what I have observed is that deficiency exists among majority of those who do not take meat. Both vegetarians and nonvegetarians do not get adequate FA due to lack of raw vegetables and fresh fruits in diet and cooking destroy it. Thus, in India, millions are at risk of B12 deficiency and more so for FA.[9]

Gastric causes of B12 deficiency

Atrophic gastritis

Most important gastric cause is autoimmune atrophic gastritis, due to antiparietal cell antibodies and the consequent lack of IF due to gastric atrophy, or they can even have anti-IF antibodies. This is the originally described pernicious anemia and that is the usual cause of B12 deficiency in a western setup. Autoimmune B12 deficiency (original pernicious anemia) can coexist with other autoimmune disorders such as hypothyroidism/hyperthyroidism, vitiligo, hypoparathyroidism, Addison's disease (hypoadrenalism) or a combination of these, which may be due to systemic lupus erythematosus (SLE). It is mentioned that in some patients, Helicobacter pylori is responsible for autoimmunity as the gastric atrophy improves with H. pylori eradication. However, there is a possibility that gastric atrophy could partly at least be due to the B12 and FA deficiency of any etiology.

Gastric by-pass surgery

It is another cause which might interfere with B12 metabolism and consequent B12 deficiency. Total or partial gastrectomy or gastric mucosal atrophy due to corrosive ingestion can be a cause in some patients. Zollinger–Ellison syndrome can be caused for B12 deficiency as the excess acid that is secreted and the consequent acidic pH in the duodenum would interfere with pancreatic trypsin-mediated digestion and removal of the B12-binding R-protein (HC) preventing B12 from getting attached to the IF. For the same reason, patients with chronic pancreatitis would also have B12 deficiency due to the absence of trypsin. Congenital absence of IF is a rare cause.[1],[2]

Intestinal causes of B12 malabsorption

Terminal ileum is the site for active absorption of B12. Ileocecal tuberculosis, which is very common in India, is the most common cause; it could persist even after treatment for tuberculosis, due to the fact that the damage that has occurred to the ileal region might produce a permanent defect in B12 absorption. More often with prompt diagnosis and treatment, there is recovery of these absorption problems. In addition, ileal resection, due to involvement of the ileum in tuberculosis or ileal perforation as in enteric fever, all can finally come with B12 deficiency. Since all these diseases are very common in India, the number of people with B12 malabsorption in the Indian subcontinent must be very high. Tropical sprue can rarely be a cause; fish tapeworm infestation can utilize all the B12 in the intestine, but it is not known to exist here. Gluten-induced enteropathy is rare; severe chronic pancreatitis will interfere with digestion of the R-protein in the duodenum. HIV infection and Radiotherapy are rarely the cause for B12 deficiency due to malabsorption.

Drugs causing B12 deficiency [10]

Metformin and proton pump inhibitors (PPIs) are most important now. Both can interfere with absorption of B12. If possible, PPI should be avoided as such considering lack of safety as compared to H2 receptor blockers, besides PPIs can cause refractory iron deficiency as well. Patients on metformin need B12 supplements. Other drugs known to cause deficiency are anti-consultants, cytotoxic drugs, alcohol, colchicine, and potassium chloride.

Very rarely, deficiency of B12 could be due to abnormalities of B12 metabolism.

Facts about sources of B12 in diet

Western scenario

Daily requirement of B12 is considered to be 1–3 mcg/day. Western diet routinely contains the following items. The usual source of calories is potatoes or wheat. They regularly consume meat or egg as source of protein. In addition, majority do consume raw vegetables and fresh fruits. Thus, they happen to get B12 regularly, and if they consume fresh fruits and vegetables, they get enough FA too. Hence, an average western diet gives 5–30 mcg of cobalamin daily. On a western diet, if B12 is absorbed properly, they would have body stores to the tune of 2000–3000 mcg (but only on western diet) which is sufficient for 3–4 years, even if fully cut off from B12 intake or absorption. In addition to that, some western countries fortify food with FA to ensure regular availability of it as B12 cannot function without FA. Due to these reasons, on a western diet, it is impossible to have B12 deficiency unless complicated by malabsorption due to autoimmunity or other reasons.

Indian scenario

As compared to a western diet, there is no B12 in the average Indian diet, which is mostly vegetarian. There are several other factors, which could potentially cause malabsorption of B12. Many have malabsorption due to subclinical, clinical, or treated ileocecal tuberculosis, hepatobiliary dysfunction, or chronic pancreatitis. Majority of our ailing population is now on PPI, metformin, or other drugs, due to increasing morbidities and the body stores of B12 are invariably very poor. Even those apparently healthy or those who consume meat and happen to get B12 do not get FA through diet because majority do not take fresh fruits or raw vegetables. To top it all, almost all in India destroy FA by cooking. We have a situation where no one gets B12 and FA in diet by plan, and if someone gets any of them, it is by chance only. In addition, those who get B12 do not get FA regularly.

Facts about B12/folic acid

Both vitamins act together, their deficiencies will always coexist and both have similar manifestations too. Deficiencies of both are extremely common in India. FA deficiency is universally more common. Another compounding issue is that manifestations are often subclinical, specific investigations are unavailable and if available are not reliable and diagnosis is possible only by a good dietary history, which is not done properly nowadays. Sometimes, subtle and vague symptoms and physical signs also help us in diagnosis, but most practicing doctors are unfamiliar with them too. In addition, in our scenario, since B12 deficiency is due to issues of nutrition, unlike in western situations, if there was one deficiency, other deficiencies also would coexist. Therefore, it is very important to have a high index of suspicion and be familiar with eliciting a good dietary history and of the symptoms and signs of deficiency.


  How Do Our Patients Present? Top


Clinical presentations of B12 deficiency

Hematological manifestations [11],[12]

They may come for anemic symptoms, or pallor is clinically detected, or anemia is picked up on a routine hemogram, or they are asymptomatic with high mean corpuscular volume (MCV) or cytopenia is noted on a routine checkup. Sometimes, they may be behaving as a refractory iron deficiency anemia, pancytopenia, myelodysplastic syndrome-like picture with bone marrow failure with cellular marrow. Bone marrow is unnecessary to diagnose B12 deficiency; in fact, bone marrow is needed only when the cause of cytopenia is not certain or when a bone marrow infiltrating disorder is suspected. Some who are unaware of the clinical presentations diagnose megaloblastic anemia only after bone marrow study. Anemia in B12 deficiency can be very severe, and often, it is a mixed deficiency anemia of B12, iron, FA, and even, thyroxin deficiency. Sometimes, they come with pallor, jaundice with unconjugated hyperbilirubinemia, and even splenomegaly leading to a wrong diagnosis of hemolytic anemia – it is due to dyserythropoiesis. Dyserythropoiesis behaves exactly like hemolysis, there is intramedullary destruction of immature red blood cells, and the reticulocyte count is low. Pancytopenia is a relatively common presentation, but thrombocytopenia is not severe enough to cause bruising, bruising would occur only if another coexisting disorder of platelet dysfunction, vascular insult – due to vasculitis or Vitamin C deficiency or infections. The anemia and low leukocyte count predispose to infections due to impaired bactericidal function of phagocytes.

Pancytopenia and B12 deficiency

One of the rare major hematological manifestations of B12 deficiency is pancytopenia, which we had evaluated by a planned study. It is seen that increasing number of patients present nowadays with pancytopenia due to B12 deficiency and due to other causes. Therefore, it is important to have a clinical diagnosis at presentation itself, in order to identify and treat the potentially correctable causes of pancytopenia like Vitamin B12 deficiency. Our study was to look into the correlation between clinical diagnosis and final diagnosis, to study the clinical profile, etiological factors, and treatment response in the subgroup of patients diagnosed to have B12 deficiency. There was a statistically significant correlation between clinical and final diagnosis. Sensitivity of clinical diagnosis was highest (93%) for pancytopenia due to B12 deficiency. Diet history, knuckle pigmentation, glossitis, and MCV >100 fl had a statistically significant association with B12 deficiency. Sensitivity of clinical and pathological diagnoses of B12 deficiency was 93% and 73%, respectively. Hence, the study has established that high clinical suspicion is mandatory for diagnosis of Vitamin B12 deficiency. In cases of pancytopenia, the diagnosis of Vitamin B12 deficiency can thus be predicted using the dietary history, knuckle pigmentation, glossitis, and MCV >100 fl.[11],[12]

Manifestations on epithelial surfaces

The second most affected after bone marrow is epithelial surfaces which also have rapidly multiplying cells; as in the bone marrow, there are macrocytosis and increased number of dying cells in all these rapidly multiplying cells of the mouth, stomach, intestine, and ano-genital areas – the patient could be presenting with glossitis, soreness of mouth, proctalgia, and urinary and genital mucosal symptoms. Thus, burning sensation over skin and mucous membrane anywhere in the body could be due to B12 and FA deficiency. Deficiency may even produce dysplastic cervical smear abnormalities.[1],[2]

Neuropsychiatric disturbances

Mood changes, depression, memory loss, and frank dementia could be the presentation. It could coexist with other causes of dementia or even wrongly diagnosed as Alzheimer's disease. They may be brought for abnormal behavior, personality changes, and hallucinations – these manifestations are even more likely if iron/B6/thiamine deficiency coexists.[13]

Neurologic manifestations

B12 deficiency is known to cause slow demyelination resulting in peripheral neuropathy, paresthesia of extremities, sensory loss, motor neuropathy causing manifestations such as weakness of lower limbs, ataxia, positive Romberg's sign, impaired vibration sense, degeneration of the posterior column, degeneration of pyramidal tracts of spinal cord, or subacute combined degeneration. – It could coexist with cervical myelopathy due to spondylotic changes. Other neurologic manifestations could be defective hearing (sensorineural deafness) loss of smell/loss of taste, cerebral degeneration, cerebellar degeneration, spinocerebellar ataxia, defective vision/optic atrophy, or erectile dysfunction. Other presentations such as anorexia, weight loss, unexplained fatigue, diarrhea, and constipation, incontinence of feces, incontinence of urine, or retention of urine could be the result of B12/folate deficiency.[1],[2],[13],[14]

Pregnancy related

Infertility in men and women, hyperemesis gravidarum, complications of pregnancy, prematurity, recurrent fetal loss and neural tube defects are known to occur with B12 or folic acid deficiency. Neural tube defects are well known to occur with folic acid deficiency, but the literature on this comes from west, where they have only folic acid deficiency as a nutritional disorder and rarely only B12 deficiency, that too due to reasons other than nutritional. Since all the manifestations are common to both B12 and folic acid, and since they always act together, our situation must be different, and when we get such manifestations it would be due to both deficiencies. Therefore prevention of pregnancy related problems including neural tube defects in India needs supplementation of both.[15]

Cardiovascular manifestations and thrombotic tendency

The most common cause for hyperhomocysteinemia in India is B12 and FA deficiency, which is probably the most important and easily preventable risk factor for cardiovascular and cerebrovascular thrombosis in India too. The patients could be presenting as ischemic heart disease, peripheral vascular disease, cerebrovascular accidents, including cerebral venous thrombosis, deep vein thrombosis, and pulmonary thromboembolism. Believing the western literature, we still consider hyperhomocysteinemia only as an emerging risk factor – in reality, we are literally drowning in it. Meta-analysis in western studies had even suggested that FA supplementation reduces the risk of stroke by 18%.[1],[2],[16] In our case, it must be even more beneficial, but we need to supplement FA and B12 together to get the benefit, more importantly the people should be empowered to consume a balanced diet.[17],[18]

Hair and skin changes

Premature graying of hair, lanugo hair (copper-brown hair), hair loss, reversible hyperpigmentation of skin, especially over the knuckles or anywhere else, dark circle around eyes, or hyperpigmentation of the whole body could be due to B12/folate deficiency.[19],[20],[21]

Case history

A 35-year-old female came with progressive pallor and pica; she had all the features of iron deficiency and had hyperpigmentation of knuckles suggesting B12 deficiency. She used to consume meat very often, but her diet was poor in vegetables and fruits. She however used to take excess of junk foods and fast foods. On examination, she had mild jaundice, spleen tip was palpable – hemolysis was confirmed by unconjugated hyperbilirubinemia and elevated reticulocyte count of 12%, and the direct Coombs test was positive; a diagnosis of autoimmune hemolysis was made. The MCV was 116 fl; low ferritin was documented for completion sake. Clinically itself, she had features of hypothyroidism, thyroid was prominent, and the thyroid-stimulating hormone was 18.[4],[5] Fine-needle aspiration cytology showed Hashimoto's thyroiditis. An autoimmune etiology for all the above problems was considered, and since she had a very high erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA) and anti-ds DNA were asked for, both came very highly positive confirming SLE as the cause for all her problems. The iron deficiency was due to low-grade intravascular hemolysis and consequent chronic iron loss in urine. B12 deficiency in this situation is consistent with the originally described variety of autoimmune pernicious anemia.[22]

Case history

A 25-year-old male came with anemia unresponsive to iron – the alopecia totalis gave the clue to his diagnosis as an autoimmune disorder and it turned out to be a male SLE with B12 deficiency. B12 deficiency in a patient with one autoimmune disorder could have an autoimmune etiology such as antibodies against gastric parietal cells or against IF or the receptors at various sites.[22]

Malignancies

Prophylactic FA in pregnancy is reported to reduce the subsequent incidence of acute lymphoblastic leukemia in childhood.[1],[2],[7],[8] FA deficiency due to MTHFR mutation is associated with carcinoma colon and colonic polyps, follicular lymphoma, breast cancer, and gastric cancer. It is also observed that dysplastic changes could occur in the marrow, cervical mucosa, and gastric mucosa due to B12 or folic acid deficiency. As an extension of these observations, we can hypothesize that B12/folic acid duo could be involved in the development or progression of other malignancies as well. If folic acid is implicated, B12 naturally is involved too because they always act together.

Nitrous oxide inhalation

N2O oxidizes methylcobalamin to inactive precursor; prolonged N2O anesthesia may thus cause megaloblastic anemia, besides this neuropathy is described in dentists and anesthetists.

Case history

A 35-year-old, electricity board (KSEB) employee had sustained high-voltage electric shock injury, while working on a high-voltage electric line, which he was repairing; someone had accidentally switched on the line and had irreparable electric burns on all the extremities. He was admitted to the plastic surgery ward of our medical college and the professor in-charge consulted me for solving the problem of fever and pancytopenia. The story was that he had to undergo a prolonged surgery (>6 h) to reconstruct the injured areas and amputate irreparable extremities. One upper limb and both lower limbs had to be amputated too. One week later, he had high fever and septicemia and the hemogram showed pancytopenia. The clinical suspicion of the possibility of B12 deficiency alone helped us to save this patient as it was not possible to confirm it by any means; a bone marrow examination was out of question, the MCV was >90 fl. He responded promptly to B12 injections, FA, and antibiotic cover.

Summary of clinical features

Features of B12 deficiency + features of the underlying disorder are as follows.

  1. It is not an uncommon scenario to see B12 deficiency along with all deficiencies in a grossly and visibly malnourished emaciated patient
  2. It could be an overweight person who apparently looks well nourished but has B12 and FA deficiency along with Vitamin D and even iron deficiency, because all these are common problems and they tend to go together in majority due to lack of a balanced diet
  3. Alcoholic or smoker who is overweight has a combination of B12 deficiency, NAFLD or B12, FA deficiency, and alcoholic liver disease with or without COPD
  4. Patient with infections such as tuberculosis and having Vitamin D deficiency and all other deficiencies
  5. Diabetic, hypertensive with peripheral neuropathy, which is attributed to diabetes but in fact, has got B12, folate, and Vitamin D deficiencies
  6. Hypothyroidism or hypoadrenalism with B12, folate, and Vitamin D deficiency also is a common picture now.



  How to Diagnose B12 and Folic Acid Deficiency Cost-Effectively? Top


Maintain a high index of suspicion while evaluating any clinical scenario, as it is a common problem. Eliciting a proper dietary history is the most important step in diagnosis. Strict vegetarians always have clinical or subclinical B12 deficiency unless they regularly consume green leafy vegetables. Always get a detailed drug history, and get details on GI surgeries if any, enquire whether they consume fresh fruits regularly or not and regarding adequacy of protein intake (Dietary history given as mixed diet is not enough). It should be followed by good physical examination (but need to condition the mind by becoming aware of the subtle signs); take clues from complete haemogram, design a plan to observe the therapeutic response, labs can helps us- not always confirm the diagnosis, If clinical indications are strong normal values do not even rule out that possibility; Clinical skill and Clinical judgment are needed for diagnosis.

Supportive findings in complete hemogram [11],[27]

Red blood cell

Hb can be normal, low normal or very low- it could be as low as 4gm/dL, MCV on higher side >90 in majority. But if it is more than 100 fl, in an appropriate setting it is almost diagnostic. If clinical indications are very strong, even normal MCV or low MCV does not exclude B12/folic acid deficiency, due to the commonly coexisting Iron deficiency or Thalassemia trait.[11],[27] If the dietary history is suggestive of B12/FA deficiency, or if there are symptoms and signs of it, a normal red cell distribution width (RDW), or low RDW can favor isolated B12/folic acid deficiency.

White blood cells

Leukopenia/low normal total leukocyte count/absence of leukocytosis could be seen – usually, it is >1500/cmm.

Platelet

Low normal or it may be reduced, but usually, the counts are >40,000/cmm. Iron deficiency state without thrombocytosis should make one suspect coexisting B12 or FA deficiency. In reality, dietary history is most important and is the most useful diagnostic step.

Textbooks say that in a nonanemic patient, the presence of a few macrocytes and hypersegmented neutrophils (>5 lobes) in the peripheral blood may be the only indication of B12 deficiency – it is not true in clinical practice.

Bone marrow, if at all, is done only when there is a need to exclude other causes of pancytopenia that too only if there is no response after adequate B12 supplementation, especially when the clinical indications for B12 deficiency are strong. In B12 deficiency, the bone marrow is hypercellular with accumulation of primitive cells due to selective death by apoptosis of more mature forms (ineffective hematopoiesis). There could be jaundice/splenomegaly, unconjugated hyperbilirubinemia, increased urine urobilinogen, due to the death of red cells in the marrow, and elevated lactic dehydrogenase as in hemolysis; reticulocyte count is normal or low – unless B12/FA was given and the marrow is responding to treatment.

Laboratory diagnosis of B12 deficiency

It is impossible to make laboratory diagnosis always because the B12 levels, even from standard laboratories, are not reliable due to several reasons. B12 levels between 160 and 200 ng/L but up to 1000 ng/L can be normal but is false normal in 50%; especially if it is an autoimmune etiology, serum methyl malonic acid (MMA) is elevated (950 nmol/L) most often and is said to be more specific.[16],[23],[24],[25],[26] Serum MMA could be used for early diagnosis, even in the absence of hematological abnormalities. However, it is also not reliable in renal failure and is false positive in 30% of normal individuals and in 15% of elderly. Homocysteine levels are elevated (>28) in both B12 and FA deficiencies: However, it is also elevated in pyridoxine deficiency, CKD, alcoholism, smoking, hypothyroidism, steroid therapy, cyclosporine and hence not useful for diagnosis. Serum gastrin is increased in pernicious anemia, but even while on PPI, it is elevated.

Tests for the causes of B12 deficiency [22],[27]

Schilling test has become obsolete. Sometimes, a weakly positive DCT is got but suspects collagen vascular disorder with coexisting AIHA in such a situation. If ESR is very high in a patient with B12 deficiency, think of underlying tuberculosis or SLE. ANA/Anti-dsDNA is to be done in cases of suspected autoimmune B12 deficiency, and Mantoux test, when tuberculosis is suspected.[22],[27] However, as gastric biopsy should never be done to diagnose B12 deficiency as it will amount it amount to an autopsy. In case, if it is done, the histopathology would reveal atrophy of all layers of the body and fundus, with loss of glandular elements, and absence of parietal and chief cells and replacement by mucous cells, a mixed inflammatory cell infiltrate, and perhaps intestinal metaplasia. However, all these changes could be the consequences of deficiency rather than the cause of B12 deficiency.

Guidelines/tips for diagnosis and for research

All features need not be present simultaneously, hematological findings can be minimal or absent. Anemia alone, thrombocytopenia, leukopenia, or pancytopenia can occur. Neuropsychiatric manifestation alone is extremely common. Even normal MCV is possible when there is definite deficiency. With a high index of suspicion, identify a clinical problem consistent with B12 deficiency; in that patient, if dietary history is supportive and if no other cause is identified for the clinical problem –look for supportive findings in haemogram. Finally, if there is improvement of the problem with treatment – it confirms B12 deficiency. Elevated MMA/homocysteine/low B12, all done together and all these normalizing after treatment can be used for diagnosis but not for routine diagnosis can be done only as a research tool.

A Study on pancytopenia [11] concluded that 65 consecutive patients with pancytopenia without lymphadenopathy or hepatosplenomegaly, during 1 year, were studied in our department. B12/FA deficiency and acute leukemia constituted maximum number. Thirty patients (46%) had B12 + FA deficiency. In most of them, history and physical examination were enough to arrive at the cause of pancytopenia. Sensitivity of clinical diagnosis was highest for Vitamin B12/folate deficiency (93%). Dietary history, presence of knuckle pigmentation, and MCV more than 100 fl were diagnostic of B12/folate deficiency. Bone marrow study is not necessary even if there is pancytopenia unless we suspect leukemia or other infiltrating disorders.[11]

How to manage B12 deficiency?

Guidelines for treatment

Replenish body stores with six intramuscular (IM) injections of hydroxocobalamin (1000 mcg/dose) daily or at 3–7-day intervals. Maintenance is with 1000 mcg IM every month or at least once in 3 months. Always give FA, give iron when needed. Prescribe a balanced diet without which they will not respond to treatment. Treat the underlying disorder causing B12 deficiency. Methyl cobalamin is not a good choice as it is unlikely to provide the other active ingredient adenosylcobalamin. Oral forms are not ideal, this is because during deficiency state, there could be malabsorption due to the mucosal changes arising from deficiency of B12, besides there are several other factors such as certain drugs such as metformin interfering with absorption.[10] Most people with B12 deficiency have problem with its absorption due to multiple reasons; hence, it is better to give the parenteral form at least in correcting deficiency.[28]

The problem of B12 deficiency

The Problem of B12 deficiency is often overlooked or grossly under diagnosed. It coexists with other nutritional deficiencies or medical disorders. Symptoms and signs due to deficiency could occur anywhere in the body. Therefore we need to look for B12 deficiency along with all the other disorders and in anyone with undiagnosed and unexplained symptoms. We also have to give up the wrong mindset of acting only after getting proof from laboratories. In clinical practice proof often comes indirectly only, it is the final outcome of clinical evaluation/clinical judgment and careful action and studying the response to the action. Laboratory proof is like autopsy, which, as we know, is not essential always. Unfortunate situation now in clinical practice is that all the manifestations are often attributed to other illnesses an individual has got already. Sometimes an entirely wrong diagnosis is made, due to lack of awareness of nutritional deficiency disorders.


  Summary Top


B12 deficiency is extremely common; majority does not take a balanced diet, and many have improper absorption. Strict vegetarians almost always have deficiency and B12 deficiency of autoimmune nature is increasing in prevalence. Megaloblastic anemia is a rare manifestation of B12 deficiency. Diagnosis is possible by dietary history, careful physical examination, and supportive evidences in hemogram. We should not rely on B12 estimations. Clinical skill and clinical judgment are most important. Deficiency coexists with several other diseases. Look for B12 deficiency in all individuals/undiagnosed issues. Always give FA ± iron + balanced diet; prompt therapeutic response with B12 is the best proof.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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