Mechanism of megaloblastic anemia combined with hemolysis.

Megaloblastic anemia (MA) patients often exhibit hemolysis, but it is not clear whether there are other hemolytic mechanisms in addition to intramedullary hemolysis. We retrospectively analyzed the clinical characteristics of 124 MA patients, measured erythrocyte physical parameters in two patients with hemolysis and one healthy volunteer by atomic force microscopy, and measured 18F-FDG uptake in one MA patient with hemolysis. In multivariate analysis, hemolysis was associated with mean corpuscular volume (MCV) and indirect bilirubin. A receiver operating characteristic curve analysis, with sensitivity of 83.1% and specificity of 68.7%, suggested that the MCV cutoff value that predicts hemolysis is 116.4 fL. Hb was negatively correlated with MCV in the hemolysis group (r = -0.317, P = 0.007) but not in the nonhemolysis group. The erythrocyte peak-valley value, average cell surface roughness and surface area in the MA patients with hemolysis were significantly lower than those in controls (P < 0.05). 18F-FDG uptake by the liver and spleen was diffuse and increased in MA patients undergoing hemolysis. MA combined with extramedullary hemolysis could be caused by macrophages removing mechanically damaged erythrocytes and the retention of erythrocytes with decreased deformability when blood circulates through narrow spaces in the liver and spleen.

Relapse of rare diseases during COVID-19 pandemic: bicytopenia in an adult patient with thiamine-responsive megaloblastic anaemia.

Thiamine-responsive megaloblastic anaemia (TRMA) is a syndrome associated with megaloblastic anaemia, diabetes mellitus and sensorineural deafness, due to mutations in the SLC19A2gene, which codes for a thiamine carrier protein. Oral thiamine supplementation is the main treatment. We report the case of a 19-year-old man known for TRMA, who presented in the emergency department with bicytopenia (haemoglobin 5,4 g/dL, thrombocytes 38×109/L) revealed by dyspnea and chest pain. Investigations excluded bleeding, hemolysis, coagulopathy and iron deficiencies. A recent infection and an acute coronary syndrome have also been eliminated. We later found out that thiamine treatment had been discontinued three months before, due to general confinement in Tunisia during the COVID-19 pandemic. Parenteral administration of 100 mg of thiamine daily resulted in the recovery of haematopoiesis within three weeks.

[Thiamine-responsive megaloblastic anemia or Rogers syndrome: A literature review]. / L'anémie mégaloblastique thiamine dépendante ou syndrome de Rogers : une revue de la littérature.

Thiamine-responsive megaloblastic anemia (TRMA), also known as Rogers syndrome, is a rare autosomal recessive disease characterized by three main components: megaloblastic anemia, diabetes mellitus and sensorineural deafness. Those features occur in infancy but may arise during adolescence. Diagnosis relies on uncovering genetic variations (alleles) in the SLC19A2 gene, encoding for a high affinity thiamine transporter. This transporter is essentially present in hematopoietic stem cells, pancreatic beta cells and inner ear cells, explaining the clinical manifestations of the disease. Based on a multidisciplinary approach, treatment resides on lifelong thiamine oral supplementation at pharmacological doses, which reverses anemia and may delay development of diabetes. However, thiamine supplementation does not alleviate already existing hearing defects.

Ileocaecal tuberculosis: an under-recognised cause of vitamin B12 deficiency.

A combination of anaemia and knuckle pigmentation should always raise concern for megaloblastic anaemia. As the terminal ileum is the site of vitamin B12 absorption and also the commonest site of abdominal tuberculosis, a clinical triad of prolonged fever, knuckle pigmentation and right lower quadrant abdominal tenderness should suggest ileocaecal tuberculosis in endemic areas.

Hiperpigmentación cutánea en el déficit de vitamina B12 / Cutaneous hyperpigmentation in vitamine B12 deficiency

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Vitamin B12 deficiency: unusual cause of jaundice in an adolescent.

Vitamin B12 deficiency in vegans is a known cause of megaloblastic anaemia. We report an adolescent girl who presented with jaundice and weight loss for 6 months secondary to vitamin B12 deficiency, leading to megaloblastic anaemia. Replacement with vitamin B12 reversed her symptoms, resulting in weight gain, and normalised her haemoglobin, red blood cell morphology, bilirubin levels and serum vitamin B12 levels.

Clinicohematological Study of Pancytopenia in a Tertiary Care Hospital of Western Region of Nepal.

INTRODUCTION: Pancytopenia is a relatively common hematological entity and is a manifestation of many illnesses which can be life threatening at times. The severity of pancytopenia and the underlying pathology determine the management and prognosis. This study was conducted to evaluate hematological and bone marrow findings in patients presenting with pancytopenia. METHODS: A prospective observational study was conducted in Department of Pathology, Manipal College of Medical Sciences, Pokhara from January 2011 to December 2016. Clinical and hematological parameters including bone marrow aspiration and biopsy were evaluated in all patients who presented with pancytopenia. RESULTS: Among 138 cases studied, patients' age ranged from 2 to 82 years with a mean age of 43.95 years, and there was male predominance. Most of the patients presented with generalized weakness, pallor, dypnoea and fever. Hypoplastic marrow was seen in 38 (27.5%) cases, followed by 26 (18.8%) cases of megaloblastic anemia and 19 (13.76%) cases of acute leukemia. Other findings included one case each of hemophagocyosis, leishmaniasis, plasmodium vivex malaria and metastatic carcinoma. CONCLUSIONS: This study highlights that pancytopenia is a common hematological problem and that the study of detailed primary hematological investigations along with bone marrow study in patients with pancytopenia will help to identify the cause for further planning and management.

Megaloblastic Anemias: Nutritional and Other Causes.

Vitamin B12 and folate deficiencies are major causes of megaloblastic anemia. Causes of B12 deficiency include pernicious anemia, gastric surgery, intestinal disorders, dietary deficiency, and inherited disorders of B12 transport or absorption. The prevalence of folate deficiency has decreased because of folate fortification, but deficiency still occurs from malabsorption and increased demand. Other causes include drugs and inborn metabolic errors. Clinical features of megaloblastic anemia include anemia, cytopenias, jaundice, and megaloblastic marrow morphology. Neurologic symptoms occur in B12 deficiency, but not in folate deficiency. Management includes identifying any deficiency, establishing its cause, and replenishing B12 or folate parenterally or orally.

Thiamine-responsive megaloblastic anemia syndrome with atrial standstill: a case report.

Thiamine-responsive megaloblastic anemia (TRMA) syndrome is an uncommon autosomal recessive disorder. The disease is caused by mutations in the gene, SLC19A2, encoding a high-affinity thiamine transporter, which disturbs the active thiamine uptake into cells. Major features include megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Cardiac malformations with conduction defects and/or dysrhythmias, have also been described in some patients. To our knowledge, only 13 TRMA patients with cardiac defects have been reported. Here, we describe the first case of TRMA syndrome with atrial standstill, probably caused by a 2 base-pair deletion in exon 4 (1147delGT) of the gene SLC19A2.

Clinical manifestations of infants with nutritional vitamin B deficiency due to maternal dietary deficiency.

AIM: In developing countries, nutritional vitamin B(12) deficiency in infants due to maternal diet without adequate protein of animal origin has some characteristic clinical features. In this study, haematological, neurological and gastrointestinal characteristics of nutritional vitamin B(12) deficiency are presented. METHODS: Hospital records of 27 infants diagnosed in a paediatric haematology unit between 2000 and 2008 were evaluated retrospectively. RESULTS: The median age at diagnosis was 10.5 months (3-24 months). All the infants were exclusively breast fed and they presented with severe nonspecific manifestations, such as weakness, failure to thrive, refusal to wean, vomiting, developmental delay, irritability and tremor in addition to megaloblastic anaemia. The diagnosis was confirmed by complete blood counts, blood and marrow smears and serum vitamin B(12) and folic acid levels. The median haemoglobin level was 6.4 g/dL (3.1-10.6) and mean corpuscular volume (MCV) was 96.8 fL (73-112.3). Some patients also had thrombocytopaenia and neutropaenia. All the infants showed clinical and haematological improvement with vitamin B(12) administration. Patients with severe anaemia causing heart failure received packed red blood cell transfusions as the initial therapy. CONCLUSION: Paediatricians must consider nutritional vitamin B(12) deficiency due to maternal dietary deficiency in the differential diagnosis of some gastrointestinal, haematological, developmental and neurological disorders of infants with poor socioeconomic status. Delay in diagnosis may cause irreversible neurological damage.

Anemias megaloblásticas / Megaloblastic anemias

Las anemias megaloblásticas son producidas por una alteración en la síntesis del DNA con una síntesis normal de ARN. Se origina por un déficit de vitamina b12 ó de folatos. Las alteraciones afectan no solamente a la médula ósea sino también a las células epiteliales, sobre toda las del tracto digestivo. Se acompañan de alteraciones neurológicas específicas. El déficit se corrige mediante la corrección de la dieta (AU)

Megaloblastic anemias are produced by an alteration in the synthesis of DNA with a normal synthesis of RNA. It arises due to a vitamin B12 of folate deficit. The alterations not only affect the bone marrow but also the epithelial cells, above all those of the digestive tract. They are accompanied by specific neurologic alterations. The deficit is corrected by correcting the diet (AU)

Masked deficit of vitamin B12 in the patient with heterozygous beta-thalassemia and spastic paraparesis.

The spinal cord, brain, optic nerves and peripheral nerves may be affected by vitamin B12 (cobalamin) deficiency. Deficiency of vitamin B12 also causes megaloblastic anaemia, meaning that the red blood cells are usually larger than normal. In this paper we report a 16-year old girl who was referred to us for the evaluation of mild paraparesis and paresthesias marked by tingling "pins and needles" feelings and general weakness. The patient, her parents and sisters were on a strict vegan diet, which made us believe that vitamin B12 deficiency may be the possible cause of the neurologic clinical manifestations. The serum level of vitamin B12 was low, but there was no macrocytosis in the routine blood examination. The electrophoresis of haemoglobin was pathologic, there was 3.7% of HbA2 and 11.6% of HbF (heterozygous form of beta-thalassaemia). When megaloblastic anaemia occurs in combination with a condition that gives rise to microcytic anaemia, many megaloblastic features may be masked. Instead of being macrocytic, the anaemia could be normocytic or even microcytic. Vitamin B12 deficiency is a diagnosis that must not be overlooked. This case report turns the light on the fact that increased MCV is a hallmark in vitamin B12 deficiency, but it is not an obligatory sign.

Mitochondrial diabetes, diabetes and the thiamine-responsive megaloblastic anaemia syndrome and MODY-2. Diseases with common pathophysiology?

Diabetes represents a conglomerate of diseases with chronic hyperglycaemia as hallmark. The present review discusses those diabetic cases that associate with variants in genes that affect the magnitude of the glycolytic flux and oxidative disposal of glucose by mitochondria in pancreatic beta-cells. These genetic variants result in an attenuated secretion of insulin in response to glucose stimulation. The diabetic states that associate with these genetic variants are MODY 2, thiamine responsive anaemia syndrome (TRAS) and mitochondrial diabetes. These disease states highlight the critical contribution of the carbohydrate flux through glycolysis and mitochondria and its coupling to ATP production in determining insulin secretion.

Functional role of specific amino acid residues in human thiamine transporter SLC19A2: mutational analysis.

SLC19A2 is a membrane thiamine transporter expressed in a variety of human tissues, including the gastrointestinal tract. Little is currently known about the structure/function relationship of SLC19A2. We examined the effect of introducing mutations in SLC19A2 identical to those found in thiamine-responsive megaloblastic anemia syndrome (TRMA), on functional activity and membrane expression of the transporter. We also examined the effect of mutating the only conserved anionic residue (E138) in the transmembrane (TM) domains of the SLC19A2 and that of the putative glycosylation sites (N63, N314). Northern blot analysis showed SLC19A2 mRNA was expressed at the same level in HeLa cells transfected with wild-type or mutated SLC19A2. Introducing the clinically relevant mutations (D93H, S143F, G172D) or mutation at the conserved anionic residue (E138A) of SLC19A2 led to a significant (P < 0.01) inhibition of thiamine uptake. Mutations of the two potential N-linked glycosylation sites (N63Q, N314Q) of SLC19A2 did not affect functional activity; they did, however, lead to a noticeable reduction in apparent molecular weight of protein. Western blot analysis showed all proteins (except D93H) were expressed in the membrane (not the cytoplasmic) fraction of HeLa cells. These results provide direct confirmation that clinically relevant mutations in SLC19A2 observed in TRMA cause malfunctioning of the transporter and/or a defect in its translation/stability. Results also show conserved TM anionic residue of the SLC19A2 protein is critical for its function. Furthermore, native SLC19A2 is glycosylated, but this is not important for its function.

Benefits and risks of folic acid to the nervous system.

During three decades of neurological practice I have witnessed a remarkable change in attitudes to the benefits and risks of folic acid therapy in nervous system disorders. In the 1960s all that was known and taught was that folic acid was harmful to the nervous system, especially in precipitating or exacerbating the neurological complications of vitamin B12 deficiency. So deeply held was this view that the possibility of neuropsychological benefits from this vitamin was initially viewed with considerable scepticism.

Apoptosis in megaloblastic anemia occurs during DNA synthesis by a p53-independent, nucleoside-reversible mechanism.

Deficiency of folate or vitamin B(12) (cobalamin) causes megaloblastic anemia, a disease characterized by pancytopenia due to the excessive apoptosis of hematopoietic progenitor cells. Clinical and experimental studies of megaloblastic anemia have demonstrated an impairment of DNA synthesis and repair in hematopoietic cells that is manifested by an increased percentage of cells in the DNA synthesis phase (S phase) of the cell cycle, compared with normal hematopoietic cells. Both folate and cobalamin are required for normal de novo synthesis of thymidylate and purines. However, previous studies of impaired DNA synthesis and repair in megaloblastic anemia have concerned mainly the decreased intracellular levels of thymidylate and its effects on nucleotide pools and misincorporation of uracil into DNA. An in vitro model of folate-deficient erythropoiesis was used to study the relationship between the S-phase accumulation and apoptosis in megaloblastic anemia. The results indicate that folate-deficient erythroblasts accumulate in and undergo apoptosis in the S phase when compared with control erythroblasts. Both the S-phase accumulation and the apoptosis were induced by folate deficiency in erythroblasts from p53 null mice. The complete reversal of the S-phase accumulation and apoptosis in folate-deficient erythroblasts required the exogenous provision of specific purines or purine nucleosides as well as thymidine. These results indicate that decreased de novo synthesis of purines plays as important a role as decreased de novo synthesis of thymidylate in the pathogenesis of megaloblastic anemia.