Anemia: Macrocytic Anemia.

Macrocytic anemia is divided into megaloblastic and nonmegaloblastic causes, with the former being more common. Megaloblastic anemia results from impaired DNA synthesis, leading to release of megaloblasts, which are large nucleated red blood cell precursors with chromatin that is not condensed. Vitamin B12 deficiency is the most common cause for megaloblastic anemia, although folate deficiency also can contribute. Nonmegaloblastic anemia entails normal DNA synthesis and typically is caused by chronic liver dysfunction, hypothyroidism, alcohol use disorder, or myelodysplastic disorders. Macrocytosis also can result from release of reticulocytes in the normal physiologic response to acute anemia. Management of macrocytic anemia is specific to the etiology identified through testing and patient evaluation.

Clonal cytopenia of undetermined significance and atypical Behçet's: the importance of zinc.

Atypical Behçet's is recognised in myelodysplastic syndrome (MDS) cases and is associated with trisomy 8. Clonal cytopenia of undetermined significance (CCUS) is recognised as a precursor to MDS. Our case describes the presentation of atypical Behçet's, in association with CCUS, post a Streptococcal infection. A mutation of a zinc finger RNA spliceosome, ZRSR2, is also described. Our patient initially presented with macrocytic anaemia, together with neutropenia and lymphocytopenia on routine monitoring. Later gastrointestinal symptoms together with oral and anal ulcerations developed. He was treated with oral zinc therapy and had resolution of recurrent oral ulcerations and significant reduction in severity of anal ulcerations. The functional impact of ZRSR2 mutation on spliceosome assembly is yet to be defined, but has been previously reported in CCUS with a clinical phenotype of macrocytic anaemia.

Profile of anemia in acute lymphoblastic leukemia patients on maintenance therapy and the effect of micronutrient supplementation.

BACKGROUND: Anemia is a common finding and important cause of morbidity in patients with acute lymphoblastic leukemia (ALL) at diagnosis or during the course of its protracted treatment. We studied profile of anemia in ALL patients on maintenance therapy and evaluated specific micronutrients as cause of this anemia. PATIENTS AND METHODS: ALL patients who were on maintenance therapy and had grade ≥ 2 anemia were recruited for the study. Serum iron studies, folate, and vitamin B12 were done to identify micronutrient deficiency and to initiate supplementation with specific components if found to be deficient. Toxicities, improvement of anemia, micronutrient levels, and disease outcome were studied after 3 months. RESULTS: From March 2015 to September 2016, 105 ALL patients were found to be on maintenance fulfilling the inclusion criteria. Overall, the proportion of anemia was 80%(N = 84). Majority had normocytic normochromic anemia (71%). Macrocytic anemia was seen in 18% and microcytic hypochromic in 9.5%. In patients with anemia of grade ≥ 2 (N = 84), 38 patients (45%) had biochemical deficiency of serum folate, and 7 (8%) had vitamin B12 deficiency. No biochemical evidence of iron deficiency was found. Supplementation of deficient micronutrients improved anemia: mean hemoglobin significantly increased from 8.06 ± 1.63 to 10.78 ± 1.53 (p < 0.001) at 3 months; and reduced treatment toxicities, mean number of febrile neutropenia episodes (p = 0.007), and treatment interruptions of > 2 weeks (p = 0.002) were lowered. Patients with anemia had significantly more relapses (N = 14,64%) compared to patients without anemia (N = 8,36%), (p = 0.040). CONCLUSION: Timely identification and correction of micronutrient deficiencies causing anemia in ALL patients on maintenance can enhance treatment outcomes.

TASP1 mutation in a female with craniofacial anomalies, anterior segment dysgenesis, congenital immunodeficiency and macrocytic anemia.

BACKGROUND: Threonine Aspartase 1 (Taspase 1) is a highly conserved site-specific protease whose substrates are broad-acting nuclear transcription factors that govern diverse biological programs, such as organogenesis, oncogenesis, and tumor progression. To date, no single base pair mutations in Taspase 1 have been implicated in human disease. METHODS: A female infant with a new pattern of diagnostic abnormalities was identified, including severe craniofacial anomalies, anterior and posterior segment dysgenesis, immunodeficiency, and macrocytic anemia. Trio-based whole exome sequencing was performed to identify disease-causing variants. RESULTS: Whole exome sequencing revealed a normal female karyotype (46,XX) without increased regions of homozygosity. The proband was heterozygous for a de novo missense variant, c.1027G>A predicting p.(Val343Met), in the TASP1 gene (NM_017714.2). This variant has not been observed in population databases and is predicted to be deleterious. CONCLUSION: One human patient has been reported previously with a large TASP1 deletion and substantial evidence exists regarding the role of several known Taspase 1 substrates in human craniofacial and hematopoietic disorders. Moreover, Taspase 1 deficiency in mice results in craniofacial, ophthalmological and structural brain defects. Taken together, there exists substantial evidence to conclude that the TASP1 variant, p.(Val343Met), is pathogenic in this patient.

MDS with 5q deletion and rare cKIT positive mastocytosis: a diagnostic and therapeutic challenge.

A patient with a diagnosis of myelodysplastic syndrome (MDS) with isolated 5q deletion underwent repeat bone marrow biopsy to assess haematological response after 6 months of initial lenalidomide therapy. Subsequent bone marrow biopsies revealed persistent MDS with del(5q) in addition to a small atypical mast cell population with >25% of mast cells with spindle-shaped morphology and immunohistochemistry characteristics consistent with mastocytosis. Molecular testing on the bone marrow was positive for cKIT D816V and the patient was diagnosed with systemic mastocytosis (SM) with an associated haematological neoplasm. MDS with SM is well known to be associated; however, to the best of our knowledge, only one prior case report identifies MDS with del(5q) and associated cKIT D816V positive mastocytosis. While the exact clonal origin of both chromosomal aberrations is unclear, this case illustrates the therapeutic efficacy of lenalidomide in a patient with MDS with del(5q) and rarely associated cKIT positive SM.

Identificación de &-talasemia en anemias microcíticas hipocrómicas refractarias al tratamiento con hierro en Nicaragua / Identification of &-thalassemia in hypochromic microcytic anemias refractory to iron treatment in Nicaragua

Resumen Justificación y objetivo: gran parte de los casos descritos de anemias microcíticas-hipocrómicas corresponden a anemias ferropénicas y síndromes talasémicos. El diagnóstico diferencial se complementa con pruebas de laboratorio como el hierro sérico, ferritina, entre otras; sin embargo, estas son de baja disponibilidad en países en vías de desarrollo. En Nicaragua, el diagnóstico de estas patologías se basa en el historial clínico y análisis hematológicos de rutina. El objetivo de este trabajo fue la implementación de la técnica de cuantificación de hemoglobina A2 en el diagnóstico clínico de β-talasemia. Métodos: se realizó un estudio transversal con 30 pacientes que mostraban microcitosis e hipocromía después de 3 meses de tratamiento con sales de hierro. Se realizó electroforesis de hemoglobina y se utilizó el kit de la casa comercial Beta-Thal HbA2 Quik Column para cuantificar la hemoglobina A2 en cada paciente. El análisis estadístico utilizado fue la prueba de t de student. Se consideraron significativas las diferencias a p<0,05. Esta investigación respetó los principios éticos que conciernen. Se contó con la aprobación del Comité de Ética Institucional, UNAN-Managua. Los participantes dieron su consentimiento informado. Resultados: al aplicar el método para cuantificación de hemoglobina A2, se obtuvo que el 67 % de las muestras presentaron una concentración de hemoglobina A2 mayor al valor de referencia establecido (3,3 %), siendo pacientes diagnosticados para β-talasemia menor. El 33 % restante presentó valores normales de hemoglobina A2 con microcitosis e hipocromía. Se encontraron diferencias estadísticamente significativas entre las medias de glóbulos rojos, volumen corpuscular medio, hemoglobina corpuscular media y hemoglobina A2, entre ambos grupos. Conclusión: el diagnóstico diferencial de anemias microcíticas hipocrómicas refractarias al tratamiento con hierro, se realiza inicialmente por el historial clínico del paciente, pero es necesario contar con pruebas diagnósticas como la cuantificación de hemoglobina A2 que permitan identificar las diversas patologías que cursan con microcitosis e hipocromía.

Abstract Justification and objective: much of the described cases of microcytic-hypochromic anemias are ferropenic anemias and Thalassemia syndromes. The differential diagnosis is complemented by laboratory tests as serum iron, ferritin, among others; However, these are of low availability in developing countries. In Nicaragua, the diagnosis of these diseases is based on clinical history and routine blood analysis. The objective of this work was to implement a technique for quantification of hemoglobin A2 in the clinical diagnosis of β-Thalassemia. Methods: We conducted a cross-sectional study with 30 patients showing hypochromia and microcytosis after 3 months of treatment with iron salts. Hemoglobin electrophoresis was performed, a kit from Beta-Thal HbA2 Quik Column was used to quantify the hemoglobin A2 in each patient. The statistical analysis used was the student's t test. The differences were considered significant at p < 0.05. This research respected ethical principles that concern. It had the approval of the committee of ethics institutional, UNAN-Managua and the participants gave their informed consent. Results: when applying the method for quantification of hemoglobin A2, 67% of samples presented a concentration of hemoglobin A2 greater than the reference value set at 3.3%, these patients were diagnosed with β-Thalassemia minor. The remaining 33% presented normal values of hemoglobin A2 with hypochromia and microcytosis. Statistically significant differences between the averages of red blood cells, mean corpuscular volume, mean corpuscular hemoglobin and hemoglobin A2 between the two groups was observed. Conclusion: The differential diagnosis of microcytic hypochromic anemias refractory to treatment with iron, is initially performed by the clinical history of the patient, but it is necessary to have diagnostic tests such as the quantification of hemoglobin A2, which allow the identification of patients with β-Thalassemia minor within this group. In our study 67% of the studied samples were identified as β-Thalassemia minor.

Pruebas bioquímicas para el diagnóstico de anemia megaloblástica / Biochemical tests for diagnosis of megaloblastic anemias / Testes bioquímicos para o diagnóstico de anemia megaloblástica

Es intención de este trabajo hacer un breve repaso sobre el metabolismo de la Vitamina B12 y del Folato o Vitamina B9. Estas dos vitaminas hidrosolubles juegan un papel importante en el metabolismo celular. Son cofactores de reacciones metabólicas de transferencia de grupos monocarbonados, esenciales para el mantenimiento de la vida. Además se describen las nuevas determinaciones de laboratorio, se evalúan cuáles son los estudios necesarios para arribar a un correcto diagnóstico del paciente con Anemia Macrocítica (AM), su etiología y cómo muchas drogas de uso frecuente en medicina producen AM. Se realiza también la evaluación del conjunto de metodologías que se pueden efectuar como rutina en el laboratorio especializado en hematología y se propone un algoritmo para el diagnóstico del paciente con AM.

The aim of this article is to make a little review on Vitamin B12 and Folate or Vitamin B9 metabolism. These hydrosoluble vitamins have a very important role in cell metabolism. They are cofactors in metabolic reactions of methyl group transfer, essential for life maintaining. Furthermore, new laboratory tests are described, and it is evaluated which the necessary studies are to arrive at a correct diagnosis for macrocytic anemia (MA) patients, their etiology, and how many drugs frequently used in medicine originate MA. Also, the set of methodologies that can be carried out routinely in the laboratory specialized in hematology is evaluated. Finally, a diagnosis algorithm to detect MA in patients is proposed.

Este trabalho visa a realizar uma breve revisão sobre o metabolismo da Vitamina B12 e do Folato ou Vitamina B9. Estas duas vitaminas hidrossolúveis têm um papel importante no metabolismo celular. São cofatores de reações metabólicas de transferência de grupos monocarbonados, essenciais para manter a vida. Também são descritas novas determinações de laboratório, avaliam-se quais são os estudos necessários para chegar a um diagnóstico correto do paciente com Anemia Macrocítica (AM), sua etiologia e de qué maneira muitas drogas de uso frequente em medicina produzem AM. Realiza-se também a avaliação do conjunto de metodologias que podem realizar-se como rotina no laboratório especializado em hematologia e se propõe um algoritmo para o diagnóstico do paciente com AM.

[Macrocytosis of red blood cells and early arthritis positive for rheumatoid factor such as initial manifestations of a neuroendocrine gastrin-secreting gastric tumor.] / Macrocitosi emaziale ed early arthritis positiva per fattore reumatoide quali manifestazioni di presentazione di un tumore neuroendocrino gastrico gastrina-secernente.

Neuroendocrine tumors (NETs) represent uncommon tumors arising from the excessive proliferation of enterochromaffin-like (ECL) cells (so-called Kulchitsky cell). Gastric NETs (GNET) represent less than 2% of all NETs and less than 1% of all stomach neoplasms. In particular, gastric NETs type 1 (associated to chronic atrophic gastritis and hypergastrinaemia) is the more frequent one, accounting for 70-80% of all GNET. A macrocytic anemia is a frequent manifestation of GNET type 1. The possibility that macrocytic anemia appear during therapy with methotrexate (MTX) is widely documented. Similarly, MTX can determine gastric atrophy. We describe the case of a patient with rheumatoid factor-positive early arthritis (EA) in which the appearance of macrocytic anemia during treatment with MTX led to the recognition of a GNET type 1, until then asymptomatic. The endoscopic eradication of polypoid formations forming the GNET, the immediate suspension of MTX and therapy with octreotide long-action determined the complete remission of arthritis. This remission is maintained until today. According to our knowledge, the possibility that an EA may represent a paraneoplastic manifestation of GNET has never been described.

Suspected myelodysplastic/myeloproliferative neoplasm in a feline leukemia virus-negative cat.

A 10-year-old castrated Domestic Short-Haired cat was presented to a primary care veterinarian for a wellness examination and laboratory examination for monitoring of diabetes mellitus. The CBC revealed marked thrombocytosis, leukopenia and macrocytic, normochromic anemia. The cat tested negative for FeLV and feline immunodeficiency virus, but was positive for Mycoplasma haemominutum by PCR. Hematologic abnormalities were not responsive to therapy, so a repeat CBC and a bone marrow aspiration for cytology were performed. Additional blood smear findings included anisocytosis with megaloblastic erythroid precursors, large platelets, eosinophilic myelocytes and metamyelocytes, and rare unidentified blasts. The bone marrow smear was highly cellular, and the cytologic pattern was consistent with myelodysplastic syndrome with an erythroid predominance. At that time, 15% blasts were present. The cat was treated with a vitamin K2 analog, doxycycline, and prednisolone, but without a clinical response. Within 3 months, euthanasia was elected due to declining quality of life, and a necropsy was performed. Postmortem bone marrow smears were highly cellular and dominated by monomorphic blasts of unknown line of origin (52%), persistent marked erythroid and megakaryocytic dysplasia, and ineffective erythropoiesis and granulopoiesis. Immunohistochemical, immunocytochemical, and cytochemical stains resulted in a diagnosis of acute myeloid leukemia of unclassified type. Additional histologic findings included mixed hepatitis with trematode infestation and lymphoplasmacytic interstitial nephritis with fibrosis. The marked thrombocytosis with myelodysplastic syndrome and the FeLV-negative status of this cat were unusual. The difficulty in classifying the myelodysplasia and subsequent leukemia highlights a need for further reporting and characterization of these types of disease.

Evaluation of Anemia.

Anemia is a common problem in primary care. Classification based on mean cell volume narrows the differential diagnosis and directs testing. A marked macrocytosis is characteristic of vitamin B12 and folate deficiencies, certain medications, and primary bone marrow disorders. The three most common causes of microcytic anemia are iron deficiency, thalassemia trait, and anemia of inflammation. Additional laboratory testing is required for diagnosis. Determination of the rate of development of anemia and examination of a blood smear may provide diagnostic clues to guide more specialized testing. Diagnosis of iron, vitamin B12, or folate deficiency mandates determination of the underlying cause.

A Japanese family with X-linked sideroblastic anemia affecting females and manifesting as macrocytic anemia.

X-linked sideroblastic anemia (XLSA) is a rare hereditary disorder that typically manifests in males as microcytic anemia. Here, we report a family with XLSA that affects females and manifests as macrocytic anemia. The proband was a Japanese woman harboring a heterozygous mutation c.679C>T in the ALAS2 gene. This mutation causes the amino acid substitution R227C, which disrupts the enzymatic activity of erythroid-specific δ-aminolevulinic acid synthase. The mutation was not detected in the ALAS2 complementary DNA from peripheral blood red blood cells of the proband, indicating that the cells were mostly derived from erythroblasts expressing wild-type ALAS2. The proband's mother, who had been diagnosed with myelodysplastic syndrome, also had XLSA with the same mutation. Clinicians should be aware that XLSA can occur not only in males but also in females, in whom it manifests as macrocytic anemia.