Coexistence of Pernicious Anaemia and Chronic Myeloid Leukaemia: An Experiment of Nature Involving Vitamin B₁₂ Metabolism

Abstract

Summary. Chronic myeloid leukaemia (CML) and pernicious anaemia (PA) coexisted in a 51‐yr‐old man (who also had myasthenia gravis). His serum vitamin B12 level was normal instead of the high value expected in CML, or the low value expected in PA. Short‐term culture of his peripheral blood cells showed deranged DNA synthesis of the type observed in vitamin B12 deficiency, indicating that his ‘normal’ serum vitamin B12 level was not associated with normal amounts of vitamin B12 available to his CML cells. A tracer dose of 0.45 μg of[57 Co]vitamin B12 disappeared abnormally slowly from his serum over 24 hr (as previously observed by others in patients with either CML or PA). A therapeutic injection of vitamin B12 appeared to disappear abnormally slowly from his serum over a period of 2 yr. His serum showed a markedly elevated unsaturated vitamin B12 binding capacity, with a less sharp increase in percentage of vitamin B12 binding α as compared to β globulin than usually expected in CML. Withholding therapeutic vitamin B12 for 2 yr has been associated with stabilization of his WBC at the 40 000‐50 ooo/μl range. Although this association could be chance rather than cause and effect, the patient does represent an ‘experiment of nature’ involving vitamin B12 metabolism and does raise the question as to whether his leukaemia is retarded by his deficiency of vitamin B12, which results from inadequate absorption of vitamin B12 and possibly from elevated serum vitamin B12 binding a globulin rendering his circulating vitamin B12 metabolically inert.

Cancer risk following pernicious anaemia

“…Haematopoietic malignancies have been repeatedly observed in case reports of pernicious anaemia, including myeloid leukaemia (Blackburn et al, 1968;Corcino et al, 1971;Nielsen & Jensen, 1970;Zarafonetis et al, 1975), polycythaemia vera (Zarafonetis et al, 1975;Mitchell et al, 1986;Engel & Stickney, 1962;Riddle & Davidson, 1968), and multiple myeloma (Fraser, 1969;Larsson, 1962). Thus, it is noteworthy that we observed significant excesses of multiple myeloma (SIR=2.1), myeloid leukaemia (3.7), and other unspecified leukaemia (4.0).…”

“…The large size of the study population allowed assessment of stomach cancer risk according to several variables, including interval since diagnosis of pernicious anaemia. In addition, the study enabled evaluation of the risk of other cancers, notably leukaemia, which may be linked to pernicious anaemia (Corcino et al, 1971;Nielsen & Jensen, 1970;Zarafonetis et al, 1975).…”

Assay of methylmalonic acid in the serum of patients with cobalamin deficiency using capillary gas chromatography-mass spectrometry.

“…Low serum Cbl values in patients without hematologic abnormalities are frequently encountered in screening studies (16)(17)(18)(19), in the elderly (20,21), and in patients with certain neuropsychiatric abnormalities (22,23), but their significance has been difficult, if not impossible, to determine. More rarely, diagnostic problems can also develop in patients with hematologic abnormalities, since serum Cbl levels may be normal in Cbl-deficient patients who have elevated levels ofCblbinding proteins (24). Additional diagnostic tests like urinary methylmalonic acid (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) and the deoxyuridine suppression test (25,26) have not been widely used and, thus, a definite need exists for additional tests that could be used to evaluate patients for Cbl deficiency and to evaluate the sensitivity and specificity of the serum Cbl assay.…”

Unusual Presentation of Vitamin B12Deficiency

“…Raised gastric pH (achlorhydria) for any reason may present with combined vitamin B 12 and iron deficiency (due to reduced acidity which is needed for iron absorption and reduced intrinsic factor which is necessary for vitamin B 12 absorption). The cause of achlorhydria was not obvious except in the single case with pernicious anemia [1,2].Although pernicious anemia is not common in this part of the world, vitamin B 12 deficiency due to other causes may not be so uncommon [31].Cobalamin deficiency may be present without anemia and macrocytosis and even with normal or elevated serum vitamin B 12 in conditions with (a) increased cobalamin binders in such conditions as polycythemia vera, chronic myelogenous leukemia; (b) increased cobalamin analogues which are indistinguishable from vitamin B 12 by the current radioimmunoassay; and (c) exposure to nitrous oxide which abolishes vitamin B 12 function [25][26][27][28][29].Vitamin B 12 deficiency should be suspected in conditions with unexplained neuropsychiatric symptoms and signs even in the absence of hematological abnormalities; in such conditions, vitamin B 12 deficiency should be suspected even if serum B 12 levels are normal and ancillary tests need to be performed. These include: (1) leukocyte…”

“…Patients with achlorhydria, for instance, commonly present with unresponsive iron deficiency anemia due to masked vitamin B 12 deficiency [3][4][5][6][7][8][9][10][11]. Vitamin B 12 deficiency may present with neuropsychiatric manifestations in the absence of hematological abnormalities [12][13][14][15][16][17][18][19][20][21][22][23][24].Vitamin B 12 deficiency may even present with normal or elevated serum B 12 when associated with myeloproliferative disorders, leukocytosis, exposure to nitrous oxide, or conditions with increased cobalamin binders and/or analogues [25][26][27][28][29].In this paper we report nine cases (Table) with cobalamin deficiency in whom the diagnosis was delayed because of unusual presentation. Vitamin B 12 was measured when cobalamin deficiency was suspected because of unexplained neuropsychiatric symptoms or unresponsive iron deficiency anemia.…”