TT@MHA: A machine learning-based webpage tool for discriminating thalassemia trait from microcytic hypochromic anemia patients.

BACKGROUND: Iron deficiency anemia (IDA) and thalassemia trait (TT) are the most common causes of microcytic hypochromic anemia (MHA) and are endemic in lower resource settings and rural areas with poor medical infrastructure. Accurate discrimination between IDA and TT is an essential issue for MHA patients. Although various discriminant formulas have been reported, distinguishing between IDA and TT is still a challenging problem due to the diversity of anemic populations. METHODS: We retrospectively collected laboratory data from 798 MHA patients. High proportions of α-TT (43.33 %) and TT concomitant with IDA (TT&IDA) patients (14.04 %) were found among TT patients. Five machine learning (ML) approaches, including Liner SVC (L-SVC), support vector machine learning (SVM), Extreme gradient boosting (XGB), Logistic Regression (LR), and Random Forest (RF), were applied to develop a discriminant model. Performance was assessed and compared with six existing discriminant formulas. RESULTS: The RF model was chosen as the discriminant algorithm, namely TT@MHA. TT@MHA was tested in an interlaboratory cohort with a sensitivity, specificity, accuracy, and AUC of 91.91 %, 91.00 %, 91.53 %, and 0.942, respectively. A webpage tool of TT@MHA (https://dxonline.deepwise.com/prediction/index.html?baseUrl=%2Fapi%2F&id=26408&topicName=undefined&from=share&platformType=wisdom) was developed to facilitate the healthcare providers in rural areas. CONCLUSION: The ML-based TT@MHA algorithm, with high sensitivity and specificity, could help discriminate TT patients from MHA patients, especially in populations with high proportions of α-TT patients and TT&IDA patients. Moreover, a user-friendly webpage tool for TT@MHA could facilitate healthcare providers in rural areas where advanced technologies are not accessible.

Dilemma of identifying congenital hemolytic anemias in primary care.

ABSTRACT: Anemia, the overall reduction of red blood cell (RBC) mass in an individual, occurs as a result of an underlying condition. It is probably the most common pathological state worldwide and can be acute, chronic, congenital, or acquired. It can be placed in one of three broad categories: blood loss, hypoproliferative, and hemolytic. The most common and easiest to correct is hypoproliferative anemia caused by nutritional deficiencies. The most common genetic anemias are caused by mutations on the alpha- or beta-globin genes, but there are other mutations that alter red cell membrane function or decrease the bone marrow's ability to manufacture RBCs. Understanding the mechanisms of anemia can help providers interpret the symptom(s)/presentation and guide the clinical workup. Nurse practitioners, especially those in primary care, should be able to recognize when a microcytic anemia is not caused by iron deficiency because these anemias are not corrected by iron supplementation and will need additional workup and referral to hematology.

A novel ATRX splice variant causing acquired HbH disease in myelodysplastic syndrome with excess blasts-1.

A 60-year-old male with myelodysplastic syndrome with excess blasts-1 had unexplained microcytic hypochromic anemia. The cause of his anemia was revealed on supravital staining, hemoglobin studies and next-generation sequencing to be a novel hemizygous potentially pathogenic missense/splice site variant NM_000489.5:c.6848A>C, (p.Lys2283Thr) in exon 31 of the ATRX gene.

Associations between Serum Aflatoxin-B1 and Anemia in Pregnant Women: Evidence from Guangxi Zhuang Birth Cohort in China.

Aflatoxin B1 (AFB1) is a common toxic mycotoxin and is detectable in pregnant women. Animal studies have revealed that AFB1 caused the lysis of erythrocytes and a decrease in hemoglobin. We conducted a prospective cohort study in Guangxi, China, in order to evaluate the association between AFB1 exposure and anemia in pregnant women during the entire pregnancy. A total of 616 pregnant women from the Guangxi Zhuang Birth Cohort were included in the study. Serum AFB1-albumin (AFB1-ALB) adduct levels were measured. The effect of AFB1-ALB adducts on hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were analyzed by using multivariable linear regression. The risks of anemia from AFB1-ALB adduct exposure were assessed by multivariable logistic regression. We found that the AFB1-ALB adduct was significantly associated with a decrease in Hb (ß = -4.99, 95% CI: -8.42, -1.30), MCV (ß = -4.58, 95% CI: -7.23, -1.94), MCH (ß = -1.86, 95% CI: -2.87, -0.85), and MCHC (ß = -5.23, 95% CI: -8.28, -2.17) in the first trimester with the third tertile of AFB1-ALB adducts when compared with the first tertile. Furthermore, the third tertile of the AFB1-ALB adduct significantly increased the risk of anemia by 2.90 times than compared to the first tertile in the first trimester (OR = 3.90, 95% CI: 1.67, 9.14). A significant positive does-response relationship existed between AFB1-ALB adduct levels and anemia risk (Ptrend = 0.001). When dividing anemia types, we only found that the third tertile of AFB1-ALB adduct increased the risk of microcytic hypochromic anemia (MHA) in the first trimester (OR = 14.37, 95% CI: 3.08, 67.02) and second trimester (OR = 4.75, 95% CI: 1.96, 11.51). These findings demonstrate the correlation between maternal AFB1 exposure during early pregnancy and risk of anemia, especially MHA, and during different trimesters in Southern China. More efforts should be made to diminish AFB1 exposure for pregnant women.

From Microcytosis to Macrodiagnosis.

A 12-year-old Hispanic girl presented with fatigue, lightheadedness, and intermittent headaches. She was depressed and appeared pale to her mother. Her examination was unremarkable except for palpebral conjunctival pallor and was otherwise noncontributory. She had a profound hypoproliferative microcytic anemia with low iron level, low transferrin saturation, and a normal ferritin level. The patient experienced improvement in clinical symptoms following transfusion of packed red blood cells and oral iron therapy. At follow-up 2 months later, she presented with similar symptoms and persistent microcytic anemia with low iron levels. Her ferritin level was increased along with markedly elevated C-reactive protein and erythrocyte sedimentation rate. An oral iron challenge demonstrated lack of absorption, and hepcidin level was also significantly elevated. Thorough gastrointestinal and rheumatologic evaluations were performed to search for a source of inflammation. Key components of the patient's social history supplemented by serology, radiographic, and pathologic findings ultimately cinched an unexpected diagnosis.

Unexpected Cause of Persistent Microcytosis and Neurological Symptoms in a Child: Niemann-Pick Disease Type C.

Atypical microcytic anemias are rare diseases of iron/heme metabolism that can be diagnostically challenging. We report the case of a 2-year-old twin boy with neurodevelopmental delay and persistent microcytosis in whom atypical microcytic anemias was initially suspected. He had low blood iron and transferrin saturation with normal/high ferritin despite iron therapy. Hemoglobinopathies were excluded by conventional/DNA studies. Hepcidin was high but iron-refractory-iron-deficiency anemia was ruled out by a genetic panel. Bone marrow aspiration revealed foamy cells and iron depletion. A genetic study confirmed the diagnosis of Niemann-Pick disease type C which was finally considered the origin of microcytosis through anemia of chronic disease.

Heterozygosity for the Novel HBA2: c.*91_*92delTA Polyadenylation Site Variant on the α2-Globin Gene Expanding the Genetic Spectrum of α-Thalassemia in Iran.

There are four copy numbers of α-globin genes (16p13.3) in the human genome and the number of defective α-globin genes dictates the severity of α-thalassemia (α-thal). Mutations that occur in the 3' untranslated region (3'UTR), and especially at the polyadenylation (polyA) sites, affect the translation, stability and export of mRNA. A patient with hypochromic microcytic anemia was referred to the Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran by the health network. Molecular analysis of genomic DNA for the evaluation of mutations on the α- and ß-globin genes was performed. Direct sequencing of the hemoglobin (Hb) subunit α2 (HBA2) gene revealed a two nucleotide deletion between +816 and +817 in the 3'UTR, located at the polyA site, which seems to be a novel pathogenic variant. This novel variant expands the genetic spectrum of α-thal in the 3'UTR of the HBA2 gene.

Application of HbA2 levels and red cell indices-based new model in the differentiation of thalassemia traits from iron deficiency in hypochromic microcytic anemia Cases.

INTRODUCTION: Thalassemia traits and iron deficiency anemia are the most common types of hypochromic microcytic anemia with similar clinical and laboratory features. It is vital to establish a new screening model based on HbA2 levels and red cell indices for the differentiation of TT from IDA in hypochromic microcytic anemia cases. METHOD: The data comprised of the red blood cell indices and HbA2 prenatal diagnostic test results of 810 individuals who were identified to conform to the following criteria: MCV < 80 fl or MCH < 26 pg. We launched a new model consisting mainly of significative red cell indices and HbA2 levels, as well as proposing cutoff values by using decision trees and logistic regression analyses. Next, we evaluated our new method by comparing the sensitivity, specificity, positive, and negative predictive values with those of the previous formulas. RESULTS: We put forward a new model and compared it with 5 efficient formulas. The new model exhibited the highest accuracy (0.918), with its sensitivity and specificity calculated as 0.917 and 0.921, respectively. Our new model's Youden index was 0.838, which is higher than the other formulas' Youden indices. CONCLUSIONS: The new screening model, based on HbA2 levels and red cell indices, is suitable for the screening of thalassemia patients in the hypochromic microcytic anemia group and has the best efficiency in distinguishing TT and IDA.

Relative hypochromia and mortality in acute heart failure.

BACKGROUND: Relative hypochromia of erythrocytes defined as a reduced mean corpuscular hemoglobin concentration (MCHC) is a surrogate of iron deficiency. We aimed to evaluate the prevalence and prognostic impact of relative hypochromia in acute heart failure (AHF). METHODS: We prospectively characterized 1574 patients presenting with an adjudicated diagnosis of AHF to the emergency department. Relative hypochromia was defined as a MCHC ≤330 g/l and determined at presentation. The presence of AHF was adjudicated by two independent cardiologists. All-cause mortality and AHF-rehospitalization were the primary prognostic end-points. RESULTS: Overall, 455 (29%) AHF patients had relative hypochromia. Patients with relative hypochromia had higher hemodynamic cardiac stress as quantified by NT-proBNP concentrations (p < 0.001), more extensive cardiomyocyte injury as quantified by high-sensitive cardiac troponin T (hs-cTnT) concentrations (p < 0.001), and lower estimated glomerular filtration rate (eGFR; p < 0.001) as compared to AHF patients without hypochromia. Cumulative incidences for all-cause mortality and AHF-rehospitalization at 720-days were 50% and 55% in patients with relative hypochromia as compared to 33% and 39% in patients without hypochromia, respectively (both p < 0.0001). The association between relative hypochromia and increased mortality (HR 1.7, 95% CI 1.4-2-0) persisted after adjusting for anemia (HR 1.5, 95% CI 1.3-1.8), and after adjusting for hemodynamic cardiac stress (HR 1.46, 95% CI 1.21-1.76) and eGFR (HR 1.5, 95% CI 1.3-1.8, p < 0.001). CONCLUSIONS: Relative hypochromia is common and a strong and independent predictor of increased mortality in AHF. Given the direct link to diagnostic (endoscopy) and therapeutic interventions to treat functional iron deficiency, relative hypochromia deserves increased attention as an inexpensive and universally available biomarker.

Pattern of Anaemia in Chronic Kidney Disease.

The prevalence of chronic kidney disease (CKD) in Bangladesh is increasing. Chronic kidney disease refers to an irreversible deterioration in renal function which classically develops over a period of years. Initially, it manifest's only as a biochemical abnormality. Eventually loss of excretory, metabolic and endocrine functions of the kidneys leads to clinical symptoms and signs of renal failure, which are referred to as uraemia. In our country the number of CKD patient is increasing day by day, probably due to having uncontrolled DM, GN(Glumerulonephritis), uncontrolled hypertension, interstitial nephritis in addition to indiscriminate drugs & using of chemicals in fruits and foods. Objective of the study was to find out the morphological pattern of anaemia in patient with chronic kidney disease. This was a cross sectional observational study. This study was carried out at the Department of Medicine, Mymensingh Medical College Hospital, Mymensingh, Bangladesh from January 2011 to June 2011. Patients admitted in medicine ward male or female who satisfied the inclusion and exclusion criteria of the study were taken as study subjects. The socio demographic characteristics, presenting symptoms, risk factors, investigations and findings of diagnostic modalities and outcome were recorded. Mean age was 55.8 years of the patients who were included in this study, youngest patient is of 19 years old & older one is of 85 years. In this study 33 patients were male & 17 patients were female. Thirty three (33) patients were suffering from normocytic normochromic anaemia, 11 were suffering from microcytic hypochromic anaemia & rest 6 were suffering from combined deficiency. Female patient were suffering mainly from microcytic hypochromic anaemia (58.8%) & male patient suffered from normocytic normochromic anaemia (69.7%). CKD patients also suffered from microcytic hypochromic anaemia & also from combined deficiency.

Causes of Hypochromic Microcytic Anemia in Children and Evaluation of Laboratory Parameters in the Differentiation.

Most common causes of microcytic anemia in children are iron deficiency anemia (IDA) and thalassemia. Differentiation of these and detection of coexistence is essential for genetic counseling and to set a treatment plan. Aim is to characterize the frequency of IDA and thalassemia trait (TT) in children presenting with hypochromic, microcytic anemia and to define the significance of blood count parameters in differential diagnosis. Of the 200 enrolled, 107 were male (53.5%). In total 154 had IDA (77%), 27 had ß-TT (13.5%), and in 11 (5.5%) both conditions coexisted. Eight patients had α-thalassemia gene mutations, 3 of these also had IDA. RBC, MCV, Mentzer index, serum iron, TIBC, ferritin were significantly different between IDA and ß-TT patients (P<0.001); however, RDW was not different between the 2 groups (P>0.05). Sensitivity and specificity of Mentzer index for the detection of ß-TT were 100% and 69.4%, respectively. The positive and negative predictive values of Mentzer index in diagnosing ß-TT were 36.6% and 100%, respectively. Differential diagnosis of microcytic anemia is important in children, especially in regions where IDA and thalassemia are both prevalent. We found that 7% of children referred to our clinic for hypochromic, microcytic anemia had both TT and IDA. Our data showed that serum iron, ferritin, TIBC, MCV, and Mentzer index were all valuable markers in diagnosing IDA and were significantly different compared with ß-TT patients; RDW was not different between the 2 groups.

Effects of GlyT1 inhibition on erythropoiesis and iron homeostasis in rats.

Glycine is a key rate-limiting component of heme biosynthesis in erythropoietic cells, where the high intracellular glycine demand is primarily supplied by the glycine transporter 1 (GlyT1). The impact of intracellular glycine restriction after GlyT1 inhibition on hematopoiesis and iron regulation is not well established. We investigated the effects of a potent and selective inhibitor of GlyT1, bitopertin, on erythropoiesis and iron homeostasis in rats. GlyT1 inhibition significantly affected erythroid heme biosynthesis, manifesting as microcytic hypochromic regenerative anemia with a 20% steady-state reduction in hemoglobin. Reduced erythropoietic iron utilization was characterized by down-regulation of the transferrin receptor 1 (TfR1) on reticulocytes and modest increased iron storage in the spleen. Hepatic hepcidin expression was not affected. However, under the condition of reduced heme biosynthesis with reduced iron reutilization and increased storage iron, hepcidin at the lower and higher range of normal showed a striking role in tissue distribution of iron. Rapid formation of iron-positive inclusion bodies (IBs) was observed in circulating reticulocytes, with an ultrastructure of iron-containing polymorphic mitochondrial remnants. IB or mitochondrial iron accumulation was absent in bone marrow erythroblasts. In conclusion, GlyT1 inhibition in rats induced a steady-state microcytic hypochromic regenerative anemia and a species-specific accumulation of uncommitted mitochondrial iron in reticulocytes. Importantly, this glycine-restricted anemia provides no feedback signal for increased systemic iron acquisition and the effects reported are pathogenetically distinct from systemic iron-overload anemias and erythropoietic disorders such as acquired sideroblastic anemia.