VITAMIN B12 DEFICIENCY: CORRELATION BETWEEN MTHFR POLYMORPHISMS AND CLINICAL AND LABORATORY FINDINGS

Background: Vitamin B12 deficiency is a common condition, particularly among\r\nthe elderly. The classical manifestations include megaloblastic anemia, due to\r\nineffective erythropoiesis, and neurological complication such as peripheral\r\nneuropathy, depression, cognitive disturbances and dementia, due to\r\ndemyelination of the cervical and thoracic dorsal and lateral columns of the spinal\r\ncord. Most common causes are pernicious anemia, gastrectomy, ileal resection,\r\natrophic gastritis, long-term vegetarian or vegan dietary. The interaction between\r\nfolate and B12 is responsible for the megaloblastic anemia seen in both vitamin\r\ndeficiency. Folate metabolism plays an essential role in DNA synthesis and\r\nmethylation processes. Methylfolate trap hypothesis is based on the assumption\r\nthat 5-methyltetrahydrofolate (5-MTHF) cannot be transformed back to its\r\nprecursor 5,10-methylenetetrahydrofolate (5,10-MTHF), because the reaction\r\ncatalyzed by MTHFR is irreversible. In cobalamin deficiency, methionine synthase\r\nis inactive, causing accumulation of 5-MTHF. So trapped 5-MTHF flows out of the\r\ncells, leading a progressive cellular loss of plyglutamated folates. The C677T and\r\nA1298C MTHFR gene polymorphisms are associated with a decreased enzyme\r\nactivity. So homozygous genotype may protect patients with reduced methionine\r\nsynthase activity from defective DNA synthesis because folate metabolism tends\r\nto be shifted to thymidylate synthesis.\r\nAims: Our aim is to examine cobalamin-deficient patients with reduced MTHFR\r\nactivity, according to the polymorphisms mentioned, in order to evaluate their\r\npredisposition to develop anemia, neurological symptom and atrophic gastritis.\r\nMethods:We studied 80 Caucasian patients with a diagnosis of megaloblastic\r\nanemia consecutively admitted to our Hematology Division from 2006 to\r\nDecember 2013. All patients were tested for C677T and A1298C SNPS by\r\npolymerase chain reaction. By univariate analysis we correlate hemoglobin,\r\nMCV, white blood count (WBC), neutrophil count, platelets count, folate and\r\nB12 levels, neurological symptoms and presence of atrophic gastritis and\r\npositivity of parietal cells antibody (PCA) at diagnosis with the distribution of\r\nC677T and A1298C genotypes (Table 1). Statistical analysis was performed\r\nusing Fisher’s exact test and x2 test.\r\nResults: We found a correlation statistically significant between patients\r\ncarrying MTHFR C677T homozygous genotype and lower hemoglobin value\r\n(P= 0.022), higher MCV value (P=0.05), lower WBC (P=0.03) and lower platelet\r\ncount (P=0.05). Forty of the 80 patients had a diagnosis of atrophic gastritis\r\ndocumented by istological examination; twentyseven patients were positive for\r\nPCA. We found a significant association between patients carrying MTHFR\r\nC677T homozygous genotype and patients with a diagnosis of atrophic gastritis\r\nand the absence of antiparietal cell anytibodies (P=0.03). MTHFR A1298C\r\npolymorphism showed no correlation with all the variables previously analyzed.\r\nMoreover the analysis of plasma levels of folate and vitamin B12 showed the\r\npresence of low folate levels in patients with gastric biopsy negative (p=0.02)\r\nand antibody negative (P= 0.04).Summary and Conclusions: On the basis of results it can be assumed that\r\nMTHFR C677T polymorphism, which shunt folate towards thymidylate synthesis and away from methionine synthesis, do not protect against\r\nmacrocytic anemia and it is associated with a lower WBC and a lower platelet\r\ncount. Moreover we can speculate that impaired MTHFR function could\r\nincrease susceptibility to atrophic gastritis in cobalamin deficient-patient with\r\nPCA negativity.