1. Chanarin I, Metz J. Diagnosis of cobalamin deficiency: the old and new. Br J Haematol 1997;97:695–700. [PubMed]
2. Kasper DL, Braunwald E, Fauci A, Hauser S, Longo D, Jameson JL. Harrison’s principles of internal medicine. 16th ed. New York: McGraw-Hill Medical Publishing Division; 2005.
3. Davidson RJ, Hamilton PJ. High mean red cell volume: its incidence and significance in routine haematology. J Clin Pathol 1978;31:493–498. [PMC free article][PubMed]
4. Hattersley PG, Gerard PW, Caggiano V, Nash DR. Erroneous values on the Model S Coulter Counter due to high titer cold autoagglutinins. Am J Clin Pathol 1971;55:442–446. [PubMed]
5. Lindenbaum J. Status of laboratory testing in the diagnosis of megaloblastic anemia. Blood 1983;61:624–627. [PubMed]
6. Lawrence AC, Bevington JM, Young M. Storage of blood and the mean corpuscular volume. J Clin Pathol 1975;28:345–349. [PMC free article][PubMed]
7. Breedveld FC, Bieger R, van Wermeskerken RK. The clinical significance of macrocytosis. Acta Med Scand 1981;209:319–322. [PubMed]
8. Colon-Otero G, Menke D, Hook CC. A practical approach to the differential diagnosis and evaluation of the adult patient with macrocytic anemia. Med Clin North Am 1992;76:581–597. [PubMed]
9. Savage DG, Ogundipe A, Allen RH, Stabler SP, Lindenbaum J. Etiology and diagnostic evaluation of macrocytosis. Am J Med Sci 2000;319:343–352. [PubMed]
10. Hoffbrand AV, Pettit, JE. Clinical hematology: Sandoz atlas. London: Glower; 1988.
11. Nathan DG, Orkin SH, Look AT, Ginsburg D. Nathan and Oski’s hematology of infancy and childhood. 6th ed. Philadelphia: Saunders; 2003; 1841.
12. Hoffbrand V, Provan D. ABC of clinical haematology. Macrocytic anaemias. BMJ 1997;314:430–433. [PMC free article][PubMed]
13. Sechi LA, De Carli S, Catena C, Zingaro L, Bartoli E. Benign familial macrocytosis. Clin Lab Haematol 1996;18:41–43. [PubMed]
14. Thomas CW Jr, Lowry PW, Franklin CL, Weaver AL, Myhre GM, Mays DC, Tremaine WJ, Lipsky JJ, Sandborn WJ. Erythrocyte mean corpuscular volume as a surrogate marker for 6-thioguanine nucleotide concentration monitoring in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. Inflamm Bowel Dis 2003;9:237–245. [PubMed]
15. Papadakis KA. Mean corpuscular volume: a simple and inexpensive way to monitor azathioprine/6-mercaptopurine treatment in patients with inflammatory bowel disease? Evidence-Based Gastroenterology 2004;5:22–23.
16. Petersen K, Hale BR, Wallace MR. Macrocytosis after nucleoside-containing HIV treatment regimens. Infect Dis Clin Pract 2005;13:65–67.
17. Steele RH, Keogh GL, Quin J, Fernando SL, Stojkova V. Mean cell volume (MCV) changes in HIV-positive patients taking nucleoside reverse transcriptase inhibitors (NRTIs): a surrogate marker for adherence. Int J STD AIDS 2002;13:748–754. [PubMed]
18. Bain BJ. Diagnosis from the blood smear. N Engl J Med 2005;353:498–507. [PubMed]
19. Torres Gomez A, Casano J, Sanchez J, Madrigal E, Blanco F, Alvarez MA. Utility of reticulocyte maturation parameters in the differential diagnosis of macrocytic anemias. Clin Lab Haematol 2003;25:283–288. [PubMed]
20. Hoffman R, Benz EJ Jr, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P, eds. Hematology: basic principles and practice. 4th ed. New York, NY: Churchill Livingston; 2005.
21. Harris JW, Kellermeyer RW. The red cell. rev ed. Cambridge, MA: Harvard University Press; 1970. 387.
22. Hoffman R, Benz EJ Jr, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P, eds. Hematology: basic principles and practice. 2nd ed. New York, NY: Churchill Livingston; 1995. 562–563.
23. Ward PC. Modern approaches to the investigation of vitamin B12 deficiency. Clin Lab Med 2002;22:435–445. [PubMed]
24. Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Intern Med 1999;159:1289–1298. [PubMed]
25. Andres E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB, Perrin AE, Noblet-Dick M, Maloisel F, Schlienger JL, Blickle JF. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ 2004;3:251–259. [PMC free article][PubMed]
26. Oh RC, Brown DL. Vitamin B12 deficiency. Am Fam Physician 2003;67:979–986. [PubMed]
27. Ashraf MJ, Goyal M, Hinchey K, Cook JR. Clinical utility of folic acid testing for anemia and dementia screen. J Gen Intern Med 2004;19(s1):130.
28. Chanarin I. The megaloblastic anaemias. 2nd ed. Oxford, England: Blackwell Scientific Publishers; 1979.
29. Handin RI, Lux SE, Stossel TP. Blood: principles and practice of hematology. 1st ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1995; 1406.
30. Handin RI, Lux SE, Stossel TP. Blood: principles and practice of hematology. 1st ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1995; 1421.
31. Lindenbaum J, Allen RH. Clinical spectrum and diagnosis of folate deficiency. In: Bailey LB, ed. Folate in health and disease. New York, NY: Marcel Dekker; 1995. 43–73.
32. Antony AC. Megaloblastic anemias. In: Hoffman R, Benz EJ Jr, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P, eds. Hematology: basic principles and practice. 3rd ed. New York, NY: Churchill Livingston; 2000. 446–485.
33. Jaffe JP, Schilling RF. Erythrocyte folate levels: a clinical study. Am J Hematol 1991;36:116–121. [PubMed]
34. Barney-Stallings RA, Heslop D. What is the clinical utility of obtaining a folate level in patients with macrocytosis or anemia? J Fam Pract 2001;50:544. [PubMed]
35. Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers GM, eds. Wintrobe’s clinical hematology. 10th ed. Baltimore: Williams & Wilkins; 1999.
36. Tisman G, Herbert V. B12 dependence of cell uptake of serum folate: an explanation for high serum folate and cell folate depletion in B12 deficiency. Blood 1973;41:465–469. [PubMed]
37. Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaum J. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest 1988;81:466–474. [PMC free article][PubMed]
38. Allen RH, Stabler SP, Savage DG, Lindenbaum J. Diagnosis of cobalamin deficiency I: usefulness of serum methylmalonic acid and total homocysteine concentrations. Am J Hematol 1990;34:90–98. [PubMed]
39. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamine deficiency: II. Relative sensitivities of serum cobalamine, methylmalonic acid, and total homocysteine concentrations. Am J Hematol 1990;34:99–107. [PubMed]
40. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med 1994;96:239–246. [PubMed]
41. Alpers DH. What is new in vitamin B(12)? Curr Opin Gastroenterol 2005;21:183–186. [PubMed]
42. Lloyd-Wright Z, Hvas A, Moller J, Sanders TA, Nexo E. Holotranscobalamin as an indicator of dietary vitamin B12 deficiency. Clin Chem 2003;49:2076–2078. [PubMed]
43. Nilsson K, Isaksson A, Gustafson L, Hultberg B. Clinical utility of serum holotranscobalamin as a marker of cobalamin status in elderly patients with neuropsychiatric symptoms. Clin Chem Lab Med 2004;42:637–643. [PubMed]
44. Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Blood 2005;105:978–985. [PubMed]
45. Robinson AR, Mladenovic J. Lack of clinical utility of folate levels in the evaluation of macrocytosis or anemia. Am J Med 2001;110:88–90. [PubMed]
46. Shojania AM. Protein synthesis-megaloblastic disorders. In: Gross S, Roath S, eds. Hematology. A problem-oriented approach. Baltimore: Williams & Wilkins. 1996. 25–54.
47. Nyholm E, Turpin P, Swain D, Cunningham B, Daly S, Nightingale P, Fegan C. Oral vitamin B12 can change our practice. Postgrad Med J 2003;79:218–220. [PMC free article][PubMed]
48. Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Barutca S, Senturk T. Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study. Clin Ther 2003;25:3124–3134. [PubMed]
49. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998;92:1191–1198. [PubMed]
50. Sharabi A, Cohen E, Sulkes J, Garty M. Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route. Br J Clin Pharmacol 2003;56:635–638. [PMC free article][PubMed]
51. Latif T, Hsi ED, Rybicki LA, Adelstein DJ. Is there a role for folate determinations in current clinical practice in the USA? Clin Lab Haematol 2004;26:379–383. [PubMed]
52. Smellie WS, Wilson D, McNulty CA, Galloway MJ, Spickett GA, Finnigan DI, Bareford DA, Greig MA, Richards J. Best practice in primary care pathology: review 1. J Clin Pathol 2005;58:1016–1024. [PMC free article][PubMed]
Nausea, tiredness and mild jaundice can all indicate severe anaemia, with urgent care required Dr David Morris explains.
Suzanne was a 54-year-old librarian who I had not seen before in surgery. She reported feeling nauseous and tired and, curiously, she thought her skin had taken on a yellow colour.
When pressed for further symptoms she admitted to shortness of breath on exercise and possibly weight loss but denied abdominal pain, dysphagia, rectal bleeding, change in bowel habit or change in colour of stool or urine.
Suzanne thought her symptoms may have first appeared around six months previously but had become progressively more intrusive since then.
Although Suzanne's sclera looked clear her skin did appear to have a yellow tinge to it. She was not tachypnoeic at rest but was tachycardic, with a regular pulse of 108 beats per minute.
Her chest was clear, heart sounds were normal and there was no calf swelling or tenderness. Abdominal examination revealed no tenderness, masses or organomegaly.
Iron deficiency anaemia was listed in her medical history 20 years previously, but other than a few minor gynaecological procedures the remainder of the history was unremarkable.
Suzanne was a lifetime non-smoker, consumed alcohol in only small quantities, ate a well-balanced diet and did not take any regular medication.
My first thoughts were to exclude anaemia and thyroid disorder and to check for renal or hepatic dysfunction. Blood tests were arranged accordingly.
Suzanne was called back in urgently on receipt of the blood tests, which showed a severe macrocytic anaemia with a haemoglobin of 5.2g/dL and a mean cell volume (MCV) of 112fL.
Her white cell count was adequate, although platelets were on the low side at 131 x 109/L. Her bilirubin level was elevated to 59 micromol/L with other LFTs normal. U&Es, TFTs and fasting glucose levels were normal with an ESR of 19mm/hr.
Possible underlying diagnoses of a macrocytic anaemia are listed in the box. Given the blood test results, the most likely causes in Suzanne's case were B12 or folate deficiency, a haemolytic anaemia or myelodysplasia.
At this point I was considering hospital admission, but the advice following a phone call to the haematologist was that hospital admission and blood transfusion were probably unnecessary and that B12 and folate levels would be assessed urgently. If the latter were normal then analysis of bone marrow would be indicated.
The absence of a significant reticulocytosis argued against haemolytic anaemia as being a primary cause of the anaemia.
B12 levels were reported as being very low with repeat analysis to be performed on a separate analyser. Ferritin and folate levels were within normal range.
The diagnosis was pernicious anaemia. Suzanne started a series of six IM injections of 1mg hydroxocobalamin over of two weeks and also given supplementary folic acid and ferrous sulphate to support erythropoiesis.
Within a week of commencing treatment Suzanne was feeling much better, with resolution of nausea, increased energy and reduced shortness of breath. Repeat blood testing gave a haemoglobin level of 7.5g/dL, an MCV of 107fL and normal platelet and bilirubin levels.
After a month Suzanne's haemoglobin had climbed to 11.4g/dL and MCV had normalised. She was advised to have lifelong three-monthly hydroxocobalamin injections.
Vitamin B12 is an essential factor in the synthesis of thymidine and DNA, so deficiency will lead to impaired red blood cell production. Intrinsic factor produced in the stomach binds to B12 and this complex is subsequently absorbed in the terminal ileum.
Deficiency of B12 usually arises either from poor intake (notably a vegan diet, as B12 is not found in plants) or from malabsorption, either because of lack of intrinsic factor from the stomach (pernicious anaemia of post-gastrectomy), or because of dysfunction of the small intestine (Crohn's disease or ileal resection).
If malabsorption is the problem then B12 must be given intramuscularly.
Pernicious anaemia is an autoimmune atrophic gastritis in which parietal cell and intrinsic antibodies are produced. It is associated with other autoimmune conditions and has a female preponderance.
A mild jaundice can be seen in pernicious anaemia because relatively abnormal red cells produced by the compromised marrow are haemolysed, liberating bilirubin. There may be an accompanying leukopaenia and thrombocytopaenia, which are rapidly corrected on initiation of B12 supplements.
B12 deficiency can lead to a peripheral neuropathy, typically reported as a symmetrical paraesthesia of hands and feet, ataxia, weakness, glossitis, angular stomatitis and, in the elderly, a reversible dementia.
- Dr Morris is a GP in Shrewsbury, Shropshire
|Differential diagnoses of macrocytic anaemia|