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ORIGINAL / RESEARCH

A Study of Vitamin B12 Deficiency in Different Diseases
SR Kankonkar*, SV Joshi**, SJ Tijoriwala*, RV Prabhu*, SC Raikar*, RC Kankonkar*, HL Dhar**

Objective : To see if any correlation existed in the serum vitamin B12 deficiency amongst patients manifesting many folded symptoms of neurological, neuromuscular, dietary, thyroidic disorders and to see if such a correlation could be of therapeutic value.

Methods : The vitamin B12 in serum of patients was estimated using Abbot’s IMX system.

Results : Serum vitamin B12 deficiency (percentage wise) was 3.35 times more in vegetarian patients as compared to that in non-vegetarians. It may be because of the dietary habit that the serum vitamin B12 deficiency was on higher side amongst Hindus of Rajasthan, Gujarat and Maharashtra and it descended in that order. Muslims, being mostly non-vegetarians, had the lowest number of serum vitamin B12 deficient patients. Disorderwise, more deficient patients were found in thyroid disorder and the number decreased in the following order of disorders - gastrointestinal, anaemia, general debility, neurological and it was the lowest in diabetic patients.

Conclusion : It is of advantage to initially estimate serum B12 levels to rule out vitamin B12 deficiency in patients with history of neurological, gastro-intestinal, anaemia, diabetes, general debility and thyroidism. Disorders in deficient patients, could be in the first instance, corrected by vitamin B12 therapy, failing which the clinician may treat the patient accordingly.


Introduction

Attempts to unravel the mystery of anaemia dates back to almost to two centuries. During this period, Combe1, Thomas Addison2, Austin Flint3 and William Castle4 made important contributions in the field. Their work ultimately revealed that the pernicious anaemia is a foetal disease and that a protein substance present in the normal gastric juice is essential for the absorption of the particular factor/s from the food. This protein substance was then called the “Intrinsic factor”. The “Extrinsic factor” (in the food outside the body) contained in the animal protein resulted in the absorption of “antipenicious anaemic principle”. Vitamins were not known till 1921. The scientists came to know about vitamin B12 only in the year 1948 and then they realised that the “antipernicious anaemia principle” was nothing other than the vitamin B12.

The purpose of the present study is to correlate
the serum vitamin B-12 level in patients manifesting many folded symptoms or disorders such as neurological, neuromuscular, dietary, thyroidism, etc. and see whether such a study could be potentially useful in identifying clinical, subclinical or tissue disorders. If such a relation existed between the disorder and serum vitamin B-12 deficiency, then the estimation of vitamin B12 in patient’s serum could be of help to the clinicians either to ascertain or to evaluate the risk of such a deficiency in patients with history of anaemia of different types and peripheral disorders.

Patients and Methods

Five hundred patients referred to the Tissue Typing Laboratory between the period of 1994 to 1997 for the estimation of serum vitamin B12 level were included in the study. Following symptoms and disorders viz. loss of memory, thyroidism, ulcer, abdominal pain, loss or diminution of vision, general debility, peripheral neuropathy (numbness, tingling sensation), loss of sensation in lower extremities, etc. were noted from patient’s detailed history. Out of 500 patients, 270 patients were vegetarian while 230 were non-vegetarian. The patients were further subdivided on the basis of the community and the disorder they suffered from. Five ml of venous blood was collected in a plain sterile bulb and serum was aseptically separated. The vitamin B12 in serum was estimated using Abbot’s IMX system (Macroparticle Immunoabsorbent Assay). This test is known as the “The IMX B12 microparticle enzyme intrinsic factor assay for quantitative measurement of vitamin B12 in human serum or plasma.”

Human serum vitamin B12 (also called as cyanocobalamin) levels were measured in picograms (pg = 10-12µg/ml). Picogram is also called micro-microgram and is denoted as µ µ g. The normal value range of serum vitamin B12 level is between 200 and 900 pg/ml. According to WHO Scientific Group on Nutritional anaemia, the value below 80 pg/ml indicates unequivocal vitamin B12 deficiency.

The IMX vitamin B12 kit provides vitamin B12 level ranges along with the category. They are

1. Deficient - < 179 pg/ml

2. Interminate - 179-223 pg/ml

3. Normal - 223-1132 pg/ml

4. More than normal - > 2000 pg/ml

and the same have been used in the present study. Here interminate range means the values which lie between deficient and normal values.

Results

Out of 500 patients studied for their serum vitamin B12 levels, it was found that 148 patients (29.6%) were deficient, 22 patients (4.4%) belonged to the interminate group, 271 patients (54.2%) were normal, while 59 (11.8%) showed values exceeding 2000 pg/ ml (Fig. 1).


Amongst the 500 patients studied, 270 (54%) were vegetarian and 230 (46%) were non-vegetarian. Out of the vegetarian patients 118 (43.70%) were found to be deficient in serum vitamin B12 level while out of the non-vegetarian patients only 30 (13.04%) were deficient in vitamin B12. Thus majority of deficient patients belonged to the vegetarian group. The results reveal that the percentage wise number of vitamin B12 deficient patients in the vegetarian group was nearly 3.35 times the number that in non-vegetarian group. The patients were further subdivided on the basis of the community of different states and disorders they suffered from as shown below in Table 1. Findings of serum vitamin B12 levels amongst patients of different types of disorders are tabulated in Table 2.



Vitamin B12 deficiency was of higher amongst thyroid patients (Hypothyroid 9 and hyperthyroid 1), followed by gastrointestinal (GI), anaemia, general debility, neurological disorders and the lowest in diabetic (Type II) patients (Fig. 2).
Further analysis of patients with different types of neurological disorders on the basis of vitamin B12 deficiency in their serum gave results shown in Table 3.

Amongst neurological disorders with vitamin B12 deficiency - loss of memory (n=7), dementia (n=3), peripheral neuropathy (n=5) were the main complaints. However, majority of the patients (n=24) complained of weakness of the lower limbs, tingling and numbness. Important gastro-intestinal symptoms were abdominal pain, loss of appetite and loose motions. Out of 49 patients with gastrointestinal disorders, 17 were deficient in serum vitamin B12. Out of 47 anaemic patients including megaloblastic and nutritional anaemia, 20 were found to be deficient in serum vitamin B12. Megaloblastic and nutritional anaemia was observed in nine patients (Table 2).

Discussion

From the results it was evident that vitamin B12 deficiency was higher with vegetarian diet and the incidence was more in
women than in men. The percentage of vitamin B-12 deficient patients was nearly 3.35 times more amongst the vegetarian group as compared to that in the nonvegetarian group. This could be attributed to the vegetarian diet and the findings are in agreement with those of Cooper et al.5 and Gopalan.6 This is also the reason for higher deficiency in the Hindu community of Rajasthan, Gujarat, Maharashtra States in that descending order.

Muslims, mostly nonvegetarians, had a small number of serum vitamin B12 deficient patients.

From the results shown in Table 1, it seems that the deficiency of vitamin B12 to be most in the Hindu community of Rajasthan and Gujarat. This could be due to vegetarian diet. The Hindu community of Maharashtra and Hindu community of rest of the states showed around 20% deficiency. The comparative percentage was lower in Hindus of Maharashtra and other states because the number of people taking nonvegetarian diet was more as compared to people taking vegetarian diet amongst these Hindus. The deficiency was found to be the lowest amongst Muslims as almost all of them were non-vegetarians.

Katsuoka et al7 reported a case of 48 years old lady with the history of gastrointestinal disturbances, motor weakness, sensory disturbances in limbs and loss of hair. They corrected the disorders by administering her enough methyl vitamin B12, thereby showing that neurological disorders could be due to deficiency of vitamin B12.

In the present study, 22.8% neurological patients were deficient in vitamin B12. Amongst the patients with different neurological disorders viz. peripheral neuropathy, dementia, loss of memory, etc. it has been observed that the vitamin B12 deficiency range is from 20 to 28%. Similar observations have been made by Roach and McLean.8 Further, these workers stated that if the treatment is started early, most of the neurological disorders resolve. Delayed therapy usually halts the progression of the disease, but permanent sequelae might remain. Hence it may be necessary to rule out vitamin B12 deficiency in patients with neurological disorders. In our series, patients with dementia were in the age group of 20 to 70 years, out of which three patients (20%) were deficient in vitamin B12. Such deficiency could be attributed to higher age group as observed by Martin.9

In this study, 23 patients (22.8%) with peripheral neuropathy were vitamin B12 deficient. According to Martin,9 the underlying cause may be megaloblastosis.

Our study showed that 87.72% of neurological cases had normal haemoglobin concentration while 12.28% had lower values. Similar findings were reported by Mouallem et al.10

In this study, 39 patients had GI symptoms leading to inadequate digestion, absorption, utilization, increased dietary requirement, excretion and metabolism resulting in vitamin B12 deficiency in 17 patients (43.60%). Six patients (15.38%) had elevated vitamin B12 levels and remaining 16 patients (41.02%) showed normal levels. Since GI disorders such as amoebiasis, parasitic infestation are more common in a developing country like India, it is possible that deficiency in our patients could be due to poor absorption of vitamins. Moreover, poor vegetarian diet, deficient in vitamin B12, may lead to vitamin B12 deficiency contributing to low serum level.

Chanarin11 and Beuerlein12 have shown that anaemia is the major disorder related to low serum vitamin B12 levels. In this study, we found that out of 47 anaemic patients, 20 patients (42.55%) were deficient in serum vitamin B12 level. Of these patients, 13 patients had general anaemia, 5 patients had megaloblastic anaemia, 1 suffered from pernicious anaemia and one from macrocytic anaemia. However 5 patients (10.64%) showed higher values of vitamin B12 (> 2000 pg/ml) while in 22 patients (46.81%) the values were within normal limits. The anaemic patients complained of neuropsychiatric disorders including chest pain, numbness, pain in legs, backache, breathlessness and testicular enlargement. Kalayci et al.13 have shown that the deficiency of vitamin B12 returned to normal after vitamin B12 replacement. Deficiency in these cases could be due to specific cobalamine malabsorption or inadequate dietary intake. However, Lindenbaum et al.14 have reported neuropsychiatric disorders caused by vitamin B12 deficiency in the absence of anaemia.

In our studies, 330 (66%) cases between the age group of 10 and 79 years showed low MCV (microcapsular volume), of these 212 (64%) showed correlation between vitamin B12 deficiency and low MCV. This correlation agrees with the findings of Vant et al.15 However Craig et al.16 did not find such a correlation between vitamin serum B12 deficiency and MCV in elderly subjects. Correlation between vitamin B12 and MCV in our series could be attributed to the vegetarian diet. Out of 5 cases of megaloblastic anaemia with serum vitamin B12 deficiency, two patients showed elevated MCV and three low MCV. This discrepancy can be explained by the fact that amongst three patients who had low MCV, two were alcoholics while the third patient had a history of thyroidism. Our findings that two megaloblastic patients had elevated MCV agree with those of Chanarin11 and Beuerlein.12 Ten patients of general anaemia showing low MCV, could be categorised as microcytic anaemia.17 The remaining 44 patients showing low MCV had other disorders such as neurological, GI etc. We observed that the vulnerable age group for vitamin B12 deficiency is 40 to 49 years in both vegetarians and nonvegetarians.

In the present study, thyroid disorders associated with vitamin B12 deficiency were found in 55.55% cases. It has been reported that thyroid disease is a kind of auto-immune disorder. Autoimmune patients have a tendency to developing pernicious anaemia. In case of hyperthyroid patients, their requirement of vitamin B12 increases. Hypothyroid cases in our study could be explained on the basis of association of autoimmunity with gastric atrophy resulting in vitamin B12 deficiency. Hence it becomes necessary to rule out vitamin B12 deficiency in hypothyroid patients before treating them.

In this study, elevated levels of vitamin B12 (> 2000 pg/ml) were observed in 23 patients with neurological disorders (13.45%), 20 patients (10%) with general debility, 6 patients with gastrointestinal disorders (15.38%), and 5 patients (10.64%) with anaemia. Beck,18 too, has reported similar findings.

From the results and discussion thereon, it appears that estimation of vitamin B12 level, to start with, may be necessary to rule out vitamin B12 deficiency in neurological, gastrointestinal, anaemia, diabetes, general debility and thyroid patients. Vitamin B12 deficiency could be first corrected by administering methyl vitamin B12 or plain vitamin B12 to see if the disorders resolve, failing which the clinician may treat the patients accordingly.

References

1. Combe JS. Trans R Med Chir Soc Edinb 1824; 7 : 194. 1961.

2. Addison T. On the constitutional and local effects of disease of the suprarenal capsule. In : Modern Nutrition in Health and Disease. Ed. Goodhart RS and Shils ME. 6th edition, 1980; 229-59.

3. Flint A. Am Med Times 1960; 7 : 181.

4. Castle WB. Am J Med Sci 1929; 178 : 748.

5. Cooper BA, Fehedy V, Blashay P. Recognition of deficiency of Vit B12 using measurement of serum concentration. J Lab Clin Med 1986; 107 (5) : 447-52.

6. Gopalan C, Ramasastri BV, Balasubramanian SC. Nutritive value of Indian foods, National Institute of Nutrition. ICMR 1993; 2nd Ed : 87-93.

7. Katsuoka H, Watanabe C, Mimori Y, Nakamura S. A case of vitamin B-12 deficiency with baroad neurologic disorders and canities. No To Shinkei. 1997; 49 (3) : 283-86.

8. Roach ES, McLean WT. Neurologic disorders of Vitamin B12 deficiency. Am Fam Physician 1982; 25 (1) : 111-15.

9. Martin DC. B12 and folate deficiency dementia. Clin Geratri Med 1988; 4 (4) : 841-52.

10. Mouallem M, Pauzner R, Maayan H, Farfel Z. Vitamin B12 deficiency ; neurological disease with minimal or no anaemia. 1990; 118 (7) : 385-86.

11. Chanarin I. Megaloblastic anemia, cobalamin and folate. J Clin Pathol 1987; 40 : 978-84.

12. Beuerlein FJ. Testing strategies for anemias. Lab Mgmnt 1988; 23-29.

13. Kalayci O, Cetin M, Kirel B, et al. Neurologic findings of vitamin B12 deficiency : presentation of 7 cases. Turk J Pediatr 1996; 38 (1) : 67-72.

14. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anaemia or macrocytosis. N Engl J Med 1988; 318 : 1720-28.

15. Vant Sant P, Kusters PF, Harthoom-Lasthuizen EJ. Dependency of MCV and haemoglobin concentration on plasma vitamin B12 levels in relation to sex and age. Clin Lab Haematol 1997; 19 (1) : 27-31.

16. Craig GM, Elliot C, Hughes KR. Masked vitamin B12 and folate deficiency in elderly. Br J Nutr 1985; 54 (3) : 613-19.

17. Wintrobe MM, Lee GR, Boggs DR, et al. Clinica Haematology. Ed Vintro MM et al. 8th Ed. KM Varghese and Co., Bombay 1981; 22 : 605-16.

18. Beck WS. Biological and Medical Aspects of Vitamin B12. In : Dolphin D, editor. B12, Biochemistry and Medicine. New York; Wiley-Interscience. 1982; 2.


INTERVENTIONAL RHEUMATOLOGY : AN EMERGING NEW CONCEPT

The spectrum of Intervantional Rheumatology encompasses: I. Joint and soft tissue injections A) Diagnostic B) Therapeutic - Arthritis, Bursitis, Tenosynovitis, Enthesitis, Nerve entrapment, Fascitis. II. Arthroscopy-Diagnostic, Therapeutic, Research. III. Minimally invasive procedures - Skin and subcutaneous biopsy, Muscle biopsy (open; percutaneous), Sural nerve biopsy, Minor salivary gland biopsy. Needle biopsy of synovium (blind, fluoroscopic). IV. Others-Vertebral balloon kyphoplasty.

Joint injections and arthroscopy are two procedures that are firmly entrenched in Rheumatology. Rheumatologists usually administer joint injections in the clinic/office setting. While aseptic techniques should not be used, injection in operation theatre is not required. In general, the same joint should not be injected more than 3 times/year. Sonographic guidance is particularly useful when fluid collections are small (less than 5 mm) and deep. There are few rheumatologists who use the technique of arthroscopy, in most centres referral is made to orthopaedic who specializes in this procedure. The Arthroscopy association of North America (AANA) has issued guidelines for practice of arthroscopy that could apply either to a rheumatologist or an orthopaedic surgeon. Office arthroscopy is being developed with the help of smaller needle flexible scope that can be used on patients under local anaesthesia. A new term Medical Arthroscopy may be coined for arthroscopy used exclusively for diagnosis of arthritis and synovial research.

R Handa, JAPI, 2004; 52 : 275-77.




*Department of Tissue Typing; **Department of Medical Research, Bombay Hospital Institute of Medical Sciences, Mumbai 400 020.

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