Severe Hyperuricemia as a Presenting Feature of Megaloblastic Anemia

The history of folic acid.

Background: Macrocytic anemia is common and is characterized by decreased hemoglobin levels with elevated Mean Corpuscular Volume (MCV), due to a range of diseases and divided into Megaloblastic and Non-megaloblastic anemia. Serum vitamin B12 and folic acid tests are usually performed but they are limited by their low sensitivity and specificity. To confirm diagnosis of macrocytic anemia bone marrow examination is required but it is invasive procedure. Vitamin B12 and/or B9 deficiency leads to a defect in DNA synthesis leading to ineffective erythropoiesis and intramedullary hemolysis in patients of megaloblastic anemia, this leads to increased serum LDH (Lactate Dehydrogenase) and unconjugated bilirubin. Aims of study: This study was carried out to evaluate the role of serum LDH in the distinction between megaloblastic and non-megaloblastic anemia, and to study the correlation between serum LDH and MCV Patient and Methods: The study included 60 patients with non-regenerative macrocytic anemia (We exclude patients with regenerative macrocytic anemia because elevated reticulocytes leads us to hymolysis anemia or bleeding and it’s not a diagnostic problem(. Complete blood count, biochemical investigation, peripheral blood examination, reticulocyte count, bone marrow examination was performed in all cases Results: The most common cause of macrocytic anemia was Megaloblastic anemia (65%). The other causes were primary bone marrow disorders (35%). There was a significant difference in the mean values of serum LDH and MCV between two groups ( megaloblastic and non-megaloblastic anemia). When LDH>2076.5 IU/L, there is more probability of having megaloblastic anemia than non-megaloblastic anemia but when LDH>2076.5 and MCV>109.45 with bilirubin> 1.2mg/dl will must more probably not have non-megaloblastic anemia (the specificity was 100%), all three parameters combined together can be used as screening test to distinguish between the 2 groups of macrocytic anemia (megaloblastic and non-megaloblastic) without necessity of bone marrow aspiration in patients of non- regenerative macrocytic anemia. Present study had also shown that there were a positive relationship between serum LDH and MCV (r=+0.613).

CA 15-3 is a tumor-associated antigen and is overexpressed in breast tumors, and may also be high in some other non-cancerous conditions. The aim of this study was to investigate the effect of megaloblastic anemia due to vitamin B12 or folic acid deficiency on the levels of tumor markers. Five-year patient data were retrospectively analyzed. The associations between megaloblastic anemia due to vitamin B12 deficiency and CA 15-3, CA 125, CA 19-9, CEA, and AFP levels were analyzed. Furthermore, association between CA 15-3 level and megaloblastic anemia due to folic acid deficiency was evaluated. Median CA 15-3 level was 38.1U/mL in the group with megaloblastic anemia due to vitamin B12 deficiency(n=15), 46.7U/mL in the group with megaloblastic anemia related to folic acid deficiency (n=3), and 17.8U/mL in the normal group(n=1724). CA 15-3 levels were significantly higher among patients with vitamin B12- and folic acid-associated megaloblastic anemia compared to the normal group (p=0.001 and p=0.005, respectively). Megaloblastic anemia due to vitamin B12 deficiency was not associated with any significant differences in CA 125, CA 19-9, CEA, or AFP levels compared to the normal group (p=0.777, p=0.327, p=0.577, and p=0.197, respectively). The numbers of anemic and normal subjects compared in these tests were 12 vs. 1501, 17 vs. 1827, 4 vs. 897, and 8 vs. 1041, respectively. In conclusion, megaloblastic anemia results in ineffective erythropoiesis, and increased levels of CA 15-3 may be associated with this issue. Clinicians should take this into account when evaluating for a pre-diagnosis of breast cancer.

Flow cytometric analysis enables evaluating maturation of reticulocytes by quantitating the fraction of reticulocytes within low-, middle-, and high-fluorescence intensity regions (LFR, MFR, and HFR, respectively) [1]. The immature reticulocyte fraction (IRF), the sum of MFR and HFR, which corresponds to young reticulocytes released prematurely, is a useful parameter to evaluate the erythropoietic activity in anemia. The reticulocyte maturity index (RMI) is calculated from the proportion of reticulocyte subpopulations and can be used as the earliest and most sensitive predictor of erythropoiesis [2]. The premature destruction of erythroid precursors in the medullary cavity is termed ineffective erythropoiesis and occurs normally in less than 10% of the developing cells [3]. However, loss of much larger numbers of cells is seen in myelodysplastic syndromes (MDS), megaloblastic anemia, hemoglobinopathies, and several rare congenital anemias such as congenital dyserythropoietic anemias. MDS are bone marrow stem cell disorders characterized by ineffective hematopoiesis leading to blood cytopenias despite the presence of a cellular marrow and a propensity towards leukemic transformation [4]. There have been few studies, which have closely examined the production of reticulocytes in the bone marrow from patients with MDS and the significance of the ratio of reticulocyte subpopulations. Hence, in this study we assessed the immature reticulocytes and RMI using flow cytometry in both bone marrow and peripheral blood from MDS patients and compared the values to those of non-MDS patients as well as healthy controls. The number of mature reticulocytes and immature reticulocyte subpopulations were measured with flow cytometry in bone marrow and venous blood samples from 72 MDS patients and 65 controls (70 males, 67 females, age range: 51–76 years). The MDS patients included 31 with refractory anemia (RA), 12 RA with ringed sideroblasts, and 29 RA with excess of blasts. We studied 34 ageand gender-matched nonanemic individuals as controls, who had no hematologic disorders. As additional controls, we also assessed the reticulocytes in the bone marrow from non-MDS patients (n=31) with anemia but with no evidence of ineffective erythropoiesis such as carcinoma (n=12) and lymphoma (n=19) not involving the bone marrow. Because reticulocyte production is affected by the degree of anemia, we compared MDS patients not only to the healthy controls but also to non-MDS patients who showed similar hemoglobin levels to MDS patients. Bone marrow and peripheral blood specimens were obtained at initial presentation from patients, and none of the patients had received any specific therapy prior to the study. Complete blood cell count was determined using an electronic counter (SE 9000, Sysmex, Kobe, Japan). Reticulocytes and their subpopulations were automatically analyzed by flow cytometry (R-3000, Sysmex, Kobe, Japan). The corrected reticulocyte count was calculated, based on a normal hematocrit of 45%, using the following formula: corrected reticulocyte (%) = (subject’s hematocrit/45) reticulocyte count (%). RMI was calculated using the equation: RMI = (MFR + HFR) 100/LFR and expressed as the percentage [5]. We compared the values of reticulocytes, corrected reticulocytes, IRF, and RMI of bone marrow (BM) to those of peripheral blood (PB). The Mann-Whitney U test was used to compare differences of mean values. P<0.01 was considered statistically significant (Table 1). There were no significant differences in the mean values of total reticulocytes between MDS patients and control group, nor between MDS patients and non-MDS patients in bone marrow. However, immature reticulocyte subpopulations in bone marrow from patients with MDS J. W. Choi ()) · S. H. Pai Department of Laboratory Medicine, College of Medicine, Inha University, 400-711 Inchon, South Korea e-mail: jwchoi@inha.ac.kr Tel.: +82-32-8902503 Fax: +82-32-8902529

Combined B12 and folate deficiency presenting as an aggressive hematologic malignancy.

Megaloblastic anemia as a differential diagnosis in pancytopenia

BackgroundMegaloblastic anemia (MBA), also known as macrocytic anemia, is a type of anemia characterized by decreased number of RBCs as well as the presence of unusually large, abnormal and poorly developed erythrocytes (megaloblasts), which fail to enter blood circulation due to their larger size. Lack of vitamin-B12 (VB12) and / or folate (Vitamin-B9, VB9) with elevated homocysteine is the key factor responsible for megaloblastic anemia. Prior studies have demonstrated the induction of apoptosis in these abnormal under-developed erythrocytes. However, it is not clear whether this apoptosis induction is due to elevated p53 level or due to any other mechanism. Furthermore, it is also not fully known whether decreased vitamin-B12 and / or folate are responsible for apoptosis induction mediated by p53 in pre-erythroblasts.MethodsLevels of serum VB9, VB12 and homocysteine in 50 patients suffering from MBA were compared with 50 non-megaloblastic anemia control subjects, who were referred by the clinicians for bone marrow examination for medical conditions other than MBA. Next, we have measured the p53 expression in the paraffin embedded blocks prepared from bone marrow biopsy, using immunohistochemistry, and the expression levels correlated with VB9 and VB12 levels.ResultsOut of 50 MBA patients 40 (80%) and 44 (88%) subjects had very low VB12 and VB9 levels respectively. In contrast, only 2 (4%) and 12 (24%) non-megaloblastic anemia controls, out of 50 subjects, had low VB12 and VB9 respectively. Correlating with low vitamin B9 and B12, the homocysteine levels were high in 80% cases. But, only 20% non-megaloblastic controls exhibited high homocysteine in plasma. Immunohistochemical analysis for p53 expression showed a significantly high level of expression in MBA cases and no—or very low—expression in control subjects. Our correlation studies comparing the VB12 and VB9 levels with p53 expression concludes unusually high p53 levels in patients suffering from VB12 and VB9 deficiency induced MBA compared to control subjects not suffering from MBA.ConclusionTumor protein p53 is the key protein expressed heavily in the bone marrow biopsies of patients suffering from VB12 and VB9 deficiency induced MBA but not in control subjects. Hence, p53 expression could be used as a surrogate marker for confirming the VB9 and VB12 induced MBA.

A direct method for measuring red cell lifespan in vivo using the radioiron occupancy method (Dagg et al, 1972) has been applied to eight normal subjects. The mean red cell lifespan was 116 d with a range of 104-124 d. To establish the method clinically in the presence of haemolysis and ineffective erythropoiesis, 22 patients with haemolytic disease and six patients with megaloblastic and sideroblastic anaemia were studied. All 22 patients with haemolytic anaemia had shortening of the red cell lifespan, with a range from 62 to 10 d; the results were compared with red cell lifespan derived from simultaneous radiochromium studies (Bentley et al, 1974). A close agreement between the two methods was obtained (r = 0.87; P less than 0.001). To assess the validity of the method in the presence of ineffective erythropoiesis, double isotope studies were also carried out in three patients with megaloblastic anaemia and three with sideroblastic anaemia. Close agreement was again obtained between lifespan measurements obtained from radioiron occupancy data and those derived from radiochromium studies, suggesting that the presence of significant ineffective erythropoiesis does not invalidate the method. The theoretical considerations involved in the application of the radioiron occupancy method to haemolytic states are discussed.

BackgroundIn ineffective erythropoiesis, hepcidin synthesis is suppressed by erythroid regulators, namely erythroferrone and growth differentiation factor-15. For the first time, the hypothesis that iron overload in megaloblastic anemia may be related to ineffective erythropoiesis is explored by describing the kinetics of hepcidin, erythroferrone, and growth differentiation factor-15 levels in a patient diagnosed with megaloblastic anemia associated with iron overload.Case presentationAn 81-year-old Caucasian male was admitted for fatigue. He had type-2 diabetes previously treated with metformin, ischemic cardiac insufficiency, and stage-3 chronic kidney disease. Vitiligo was observed on both hands. Biological tests revealed normocytic non-regenerative anemia associated with hemolysis, thrombocytopenia, and elevated sideremia, ferritin, and transferrin saturation levels. Megaloblastic anemia was confirmed with undetectable blood vitamin B12 and typical cytological findings like hyper-segmented neutrophils in blood and megaloblasts in bone marrow. The patient received vitamin B12 supplementation. At 3 months, biological parameters reached normal values. Hepcidin kinetics from diagnosis to 3 months inversely correlated with those of erythroferrone and growth differentiation factor-15.ConclusionsThis case suggests that iron-overload mechanisms of dyserythropoietic anemias may apply to megaloblastic anemias.

Introduction: Megaloblastic anaemia is one of the important causes of anaemias. It is a macrocytic anaemia resulting from abnormal maturation of hematopoietic cells due to faulty DNA synthesis. Two vitamins, cyanocobalamin (vitaminB12) and folic acid are essential for DNA biosynthesis. Deficiency of either vitamin results in abnormal nuclear maturation with normal cytoplasmic maturation, apoptosis, ineffective erythropoiesis, intramedullary haemolysis, pancytopenia and typical morphological abnormalities in blood and marrow cells. Methods: This descriptive study was carried out for two and a half years (July 2011 to December 2013) in the department of Pathology, Star hospital, Kathmandu, Nepal. Out of 885 anaemic patients 55 diagnosed as megaloblastic anaemia were included in the study. Complete blood count, reticulocyte count, peripheral smear and bone marrow examination were performed. Serum vitamin B12 and folic acid estimation was done in 32 cases. Results: Out of 55 cases of megaloblastic anaemia, 31 were female and 24 were male with a female to male ratio of 1.3:1. Age range was 18 to 80 years. Pallor was the predominant clinical finding in these cases. Twenty cases (36.36%) presented with only anaemia while others presented with pancytopenia or bicytopenia. Of the 55 cases of megaloblastic anaemia,32 had assays done for cobalamin and folate, of which 15 (46.88%) had cobalamin deficiency, 4 (12.5%) had folate deficiency and 13 (40.62%) had combined deficiency. Conclusion: Megaloblastic anaemia can present with varied clinical manifestations. Strong suspicion of megaloblastic anaemia should be entertained by clinicians to improve clinical outcome. Prompt diagnosis is important as it is a completely curable condition.

Objective To analyze the clinical features of patients with megaloblastic anemia diagnosed as diseases of unknown origin at admission. Methods Seventeen patients admitted during the period of January 2001 to September 2015, who were diagnosed as disease of unknown origin at admission and finally diagnosed as megaloblastic cell anemia, were included in the analysis. The clinical data of patients including age, gender, disease duration, clinical manifestations, laboratory testing, misdiagnosis and treatments were retrospectively analyzed. Results Of the 17 patients, 14 were males and 3 were females, the median age is 63 years. The interval from disease onset to consultation was 22 days-60 months with a median time of 7 months. Nine cases had the history of repeated consultations without confirmed diagnoses, 13 cases were misdiagnosed in the first visit or at the admission. Symptoms of neurological(12 cases), digestive(10 cases)and cardiovascular(8 cases)systems were predominant clinical manifestations. The average hemoglobin concentration at admission was (64.9±18.7) g/L, the mean corpuscular volume (MCV) was(112.2±10.5) fl, and 12 cases had pancytopenia. Two cases were diagnosed based on the elevated MCV and hyper-segmented nucleus of neutrophils, respectively. Fifteen patients underwent serum vitamin B12 and folate examination; vitamin B12 levels decreased in all cases, while only 1 had folate under normal range. All 17 patients recovered successfully by vitamin B12 and folate supplement and were doing well during follow-ups. Conclusions Megaloblastic anemia is likely to be misdiagnosed, because the clinical manifestations are usually not specific. It is necessary to raise the awareness of the disease for early diagnosis and treatment. Key words: Anemia, megaloblastic; Diagnosis; Vitamin B12

Case Reports1 January 1961MEGALOBLASTIC ANEMIA DUE TO DILANTIN THERAPYALFRED LUSTBERG, M.D., DOUGLAS GOLDMAN, M.D., O. HERMAN DRESKIN, M.D.ALFRED LUSTBERG, M.D.Search for more papers by this author, DOUGLAS GOLDMAN, M.D.Search for more papers by this author, O. HERMAN DRESKIN, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-54-1-153 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThe occurrence of megaloblastic anemia following the use of anticonvulsant drugs has been reported in the British and Scandinavian literature. We believe the following case is among the first in the American literature.CASE REPORTSince age 19, a 42-year-old white female had been admitted intermittently to state hospitals for treatment of a convulsive disorder, at times associated with psychotic manifestations. From December, 1951, to November 6, 1958, treatment had consisted of Dilantin, gr. 1½, three times a day, and phenobarbital, gr. ½, three times a day. This was reduced to twice a day from November 6, 1958, until December...Bibliography1. Badenoch J: Use of labelled vitamin B12 and gastric biopsy in the investigation of anemia. Proc. Roy. Soc. Med. 47: 426-427 (June) 1954. MedlineGoogle Scholar2. HawkinsMeynell CFMJ: Megaloblastic anemia due to phenytoin sodium. Lancet 2: 737 (Oct. 9) 1954. CrossrefGoogle Scholar3. ChalmersBoheimer JNK: Megaloblastic anemia and anticonvulsant therapy. Lancet 2: 920, 1954. CrossrefGoogle Scholar4. Fuld H: Megaloblastic anemia following anticonvulsants. Brit. Med. J. 1: 1475, 1955. CrossrefGoogle Scholar5. NewmanSummer MJDW: Megaloblastic anemia following use of primidone. Blood 12: 183, 1957. CrossrefMedlineGoogle Scholar6. ChanarinElmerMollin IPCDL: Folic acid studies in megaloblastic anemia due to primidone. Brit. M. J. 2: 80-82, 1958. CrossrefMedlineGoogle Scholar7. CalvertHurworthBean RJEAL: Megaloblastic anemia from methophenobarbital. Blood 13: 894, 1958. CrossrefMedlineGoogle Scholar8. ChristensonUltmannRoseman WWJEDM: Megaloblastic anemia during primidone (Mysoline) therapy. J. A. M. A. 163: 940 (Mar. 16) 1957. CrossrefMedlineGoogle Scholar9. HawkinsMeynell CFMJ: Macrocytosis and macrocytic anemia caused by anticonvulsant drugs. Quart. J. Med. 27: 45-64, 1958. MedlineGoogle Scholar10. RhendVaradi EGS: Megaloblastic anemia due to phenytoin. Lancet 2: 920-921, 1954. Google Scholar11. BerlgneMcCloshan LMA: Megaloblastic anemia following anticonvulsants. Brit. Med. J. 1: 1247, 1957. CrossrefGoogle Scholar12. Girdwood RH: The megaloblastic anemias. Quart. J. Med. 25: 87-119, 1956. MedlineGoogle Scholar13. KeddMollin PDL: Megaloblastic anemia and vitamin B12 deficiency after anticonvulsant therapy. Brit. Med. J. 2: 974-976 (Oct. 26) 1957. CrossrefMedlineGoogle Scholar14. BeniansHunter RCRA: Megaloblastic anemia occurring during treatment of epilepsy with sodium phenytoin, primidone and phenobarbitone. J. Ment. Sci. 103: 606, 1957. CrossrefMedlineGoogle Scholar15. RyanForshaw GMJW: Megaloblastic anemia due to sodium phenytoin. Brit. Med. J. 2: 242, 1955. CrossrefMedlineGoogle Scholar16. Gydell K: Megaloblastic anemia in patients treated with diphenylhydantoin and primidone. Acta haemat. 17: 1, 1957. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Cincinnati, Ohio*Received for publication August 28, 1959.From the Medical Services of Longview State Hospital, Cincinnati, Ohio.Requests for reprints should be addressed to Alfred Lustberg, M.D., 511 Doctors Building, 19 Garfield Place, Cincinnati 2, Ohio. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byUse of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and LamotrigineGingival EnlargementGingival hyperplasia and folic acid deficiency from anticonvulsive drug therapy A theoretical relationshipMyeloidOral Changes in a Folic Acid Deficient Patient Precipitated by Anticonvulsant Drug TherapyDie megaloblastischen AnämienHaematological Aspects during Treatment with Anticonvulsant DrugsDiphenylhydantoin-induced hypersensitivity reactionDiagnostically Confusing Complications of Diphenylhydantoin Therapy A ReviewMARSHALL SPARBERG, M.D.Anticonvulsant-Associated Megaloblastic Anemia 1 January 1961Volume 54, Issue 1Page: 153-158KeywordsAnticonvulsantsFolic acidMedical servicesMegaloblastic anemia ePublished: 1 December 2008 Issue Published: 1 January 1961 PDF downloadLoading ...

The presence of megaloblasts and macrocytes in the bone marrow characterizes megaloblastic anaemia. Megaloblastic anaemia is the result of folate and vitamin B12 deficiency in more than 95% of cases. We hereby report a case of megaloblastic anaemia in a 23-year old female having glossitis and a burning sensation on the tongue. The blood picture showed megaloblastic anaemia and haematological tests confirmed the diagnosis. The patient positively responded to vitamin B12 and folic acid supplementation. The presence of oral signs and symptoms offer the dentist an opportunity to participate in the diagnosis of this condition. Early diagnosis is important to prevent deficiency. This paper explains the oral changes induced by dietary deficiency of cobalamin or folate in a patient with megaloblastic anaemia.&#x0D; Update Dent. Coll. j: 2021; 11 (1): 26-28

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