Glucose-6-phosphate dehydrogenase deficiency is associated with improved survival in patients with acute myeloid leukemia treated with venetoclax and azacitidine.

G6PD-deficiency is associated with improved survival in patients with AML treated with venetoclax and azacitidine

Background and Objectives Sickle cell anemia (SCA) and glucose-6-phosphate dehydrogenase (G6PD) deficiency are both hereditary diseases of the red blood cells that cause hemolysis. The impact of the interaction of both conditions on the clinical and laboratory presentations of the affected persons is sparse. This study, therefore, correlated G6PD activity with disease severity in persons with SCA by comparing disease severity in G6PD-deficient SCA persons with those with normal G6PD activity. Methodology This cross-sectional study was conducted in the department of Haematology and Blood Transfusion of the Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria. G6PD activity, SCA disease severity, and hematological parameters including reticulocyte counts and Heinz body estimation, bilirubin, and aspartate transaminase were estimated in 67 SCA persons. The results were compared between SCA persons with G6PD deficiency and those with normal enzyme activity. Results The prevalence of G6PD deficiency was found to be 23.9%. The G6PD-deficient SCA patients included 4 (25.0%) males and 12 (75.0%) females. G6PD deficiency was significantly higher in females ( P = .047). There was no significant difference in disease severity scores between G6PD-deficient and G6PD-nondeficient SCA patients. However, G6PD-deficient persons reported significantly higher episodes of severe vasoocclusive crisis (VOC) per annum ( P = .048). The hematological and biochemical parameters were similar between G6PD-deficient and G6PD normal SCA persons except that the G6PD-deficient SCA persons have significantly higher reticulocyte response ( P = .001). There was no correlation between disease severity resulting from reduced G6PD activity and Heinz body formation in SCA persons in the steady state. Conclusion G6PD deficiency significantly contributes to recurrent painful vasoocclusive crisis in SCA persons in the steady state.

Neonatal screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency was established in a large general hospital in the Eastern Province of Saudi Arabia. During the first 2 years of ...

Glucose-6-Phosphate Dehydrogenase Deficiency and Borderline Deficiency: Association with Neonatal Hyperbilirubinemia

Glucose 6-phosphate dehydrogenase (G6PD) deficiency, the most common inherited enzymopathy, can affect HbA1c levels and the diagnosis of type 2 diabetes. This cross-sectional study aimed to investigate the association between G6PD deficiency, its common mutations (G6PD ViangchanG871A, G6PD MahidolG487A) and HbA1c levels in a Thai cohort. Blood samples from 1007 healthy hospital staff were collected during annual health checkups. Individuals with diabetes, diabetes medication use and conditions affecting erythrocyte turnover were excluded. HbA1c levels were measured by enzymatic assay and HPLC, while fasting plasma glucose (FPG) and haematological variables were obtained from checkup records. Fructosamine levels and G6PD activity (classified as deficiency, intermediate, normal) were measured by spectrophotometric assay. Genotyping was performed using TaqMan SNP, PCR-Restriction Fragment Length Polymorphism (RFLP) and Sanger sequencing. Prediabetes and diabetes were diagnosed based on two abnormal results from FPG and HbA1c at the same time, following the modified ADA criteria. Optimal HbA1c cutoffs were determined using receiver operating characteristic curve analysis with bootstrapping in RStudio, optimising Youden's index and the harmonic mean of sensitivity and specificity. HbA1c levels were significantly lower in individuals with G6PD deficiency (25.68 mmol/mol [4.50%] by enzymatic assay; 27.33 mmol/mol [4.65%] by HPLC; n=28; p<0.001) compared with those with normal G6PD levels (34.05 mmol/mol [5.27%] by enzymatic assay; 36.61 mmol/mol [5.50%] by HPLC; n=492). Similarly, individuals with G6PD ViangchanG871A (29.46 mmol/mol [4.85%] by enzymatic assay; 31.15 mmol/mol [5.00%] by HPLC; n=52; p<0.001) and G6PD MahidolG487A (28.63 mmol/mol [4.77%] by enzymatic assay; 31.15 mmol/mol [5.00%] by HPLC; n=15; p<0.001) had significantly lower HbA1c levels. HbA1c levels positively correlated with G6PD activity (r=0.208, p<0.001 by enzymatic assay; r=0.211, p<0.001 by HPLC). The optimal HbA1c cutoffs for predicting prediabetes in participants with G6PD mutation were 33 to <42 mmol/mol (5.2% to <6.0%) by enzymatic assay (sensitivity 70%; specificity 88.64%; accuracy 86.74%) and 34 to <43 mmol/mol (5.3% to <6.1%) measured by HPLC (sensitivity 72.73%; specificity 86.21%; accuracy 84.70%). For diabetes, the optimal cutoffs were ≥42 mmol/mol (≥6.0%) by enzymatic assay (sensitivity 100%; specificity 97.92%; accuracy 97.96%) and ≥43 mmol/mol (≥6.1%) by HPLC (sensitivity 100%; specificity 96.88%; accuracy 96.94%). Using the mutation-specific HbA1c cutoffs resulted in the proportion of individuals being diagnosed with diabetes remaining the same but the proportion diagnosed with prediabetes rose from 8.2% (ADA criteria) to 18.4% using enzymatic assay and from 9.2% to 21.4% using HPLC. HbA1c levels were positively correlated with G6PD activity, with individuals carrying G6PD ViangchanG871A and G6PD MahidolG487A exhibiting significantly lower HbA1c levels. Our findings highlight the need to consider G6PD deficiency and G6PD mutations when using HbA1c to diagnose type 2 diabetes in Southeast Asian populations.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common X-linked enzymopathies caused by G6PD gene mutation. We aimed to provide the characteristics of G6PD deficiency and G6PD gene mutation distribution in a large Chinese newborn screening (NBS) population. Methods: We collected screening information of all the NBS centers around China, from January 2013 to December 2017. G6PD activity fluorescence screenings and G6PD/6PGD tests were performed in 1,764,299 birth population from 29 centers in 12 representative provinces in 2016. We then performed multicolour melting curve analysis (MMCA) to classify G6PD gene mutations in 10,357 neonates with activity-confirmed G6PD deficiency, and DNA Sanger sequencing for G6PD coding exons if hot site mutations were not found. Finally, we investigated G6PD gene mutation with MMCA in 6,443 female and 7,358 male neonates with normal G6PD activity respectively. Findings: The screened population, organizations and provinces of G6PD deficiency were increased from 2013 to 2017 in China, high in South and low in North. The top 5 frequency of G6PD gene mutations were c.1376G>T, c.1388G>A, c.95A>G, c.1024C>T, and c.871G>A and varied in different provinces, with regional and ethnic features, and 4 pathogenic mutation sites (c.152C>T, c.290A>T, c.697G>C, and c.1285A>G ) were firstly reported. Three hundred and seventy-two (372/6,443, 5·77%) female neonates with normal G6PD activity were detected as G6PD gene heterozygotes and 50 (17·42%, 50/287) female G6PD heterozygotes showed G6PD deficiency symptom in two years, suggesting that a supplementary NBS strategy of G6PD gene first screening for female G6PD deficiency in high-incidence regions of South China. Interpretation: G6PD deficiency mainly occurs in South China, and the frequency of G6PD gene mutation varies in different regions and ethnicities. Our suggested NBS strategy for G6PD deficiency could enhance the detection rate of female G6PD heterozygotes. Funding Statement: This work is partially financial supported by Natural Scientific Foundation of China (81570142), and the Ministry of Science and Technology (2016YFA0101300, 2017YFC1001700). Declaration of Interests: All the authors have nothing to disclose. Ethics Approval Statement: This study was approved by the Research Ethics Committees of Children’s Hospital of Chongqing Medical University and registered on Chinese Clinical Trail Registry (ChiCTR-SOC-17014057).

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most significant enzyme defect in India with an incidence ranging from 2% to 27.9% in different communities. Prolonged neonatal jaundice and haemolytic crisis are known to occur in children with G6PD deficiency. Hence, screening of a population for G6PD deficiency is paramount. A Novel water soluble tetrazolium-8 (WST-8) Formazan Method has been used in this study for in-field mass-screening of G6PD in the region of Himachal Pradesh, India. Materials and Methods: In this prospective study, 5652 neonates were screened to assay G6PD activity using WST8/1-methoxy phenazine methosulphate method within the first 48 h of life. Orange colour at the end of the procedure indicated normal G6PD activity while pink or colourless appearance indicated G6PD deficiency. Results: After the screening of 5652 neonates, the prevalence of G6PD deficiency was 12.4%. 45 newborns (6%) had a severe G6PD deficiency. Males were more affected than females (70:30). Furthermore, males had higher prevalence of deficiency than females (64% [n = 29] and 16% [n = 16]). Conclusions: G6PD deficiency assessment by the method used for population screening in the study was easy to do and quite simple. Following this, the high prevalence of this deficiency was noted in Himachal Pradesh. This study highlights the need to do neonatal screening of G6PD deficiency in population so that untowards complications like haemolytic crisis, complications due to neonatal jaundice can be avoided.

Intermediate values of glucose-6-phosphate dehydrogenase

The aim of this study was to estimate the incremental budget impact (IBI) of a rapid diagnostic test to detect G6PDd in male patients infected with Plasmodium vivax in the Brazilian Amazon, as compared with the routine protocol recommended in Brazil which does not include G6PDd testing. The budget impact analysis was performed from the perspective of the Brazilian health system, in the Brazilian Amazon for the years 2013, 2014 and 2015. The analysis used a decision model to compare two scenarios: the first consisting of the routine recommended in Brazil which does not include prior diagnosis of dG6PD, and the second based on the use of RDT CareStart™ G6PD (CS-G6PD) in all male subjects diagnosed with vivax malaria. The expected implementation of the diagnostic test was 30% in the first year, 70% the second year and 100% in the third year. The analysis identified negative IBIs which were progressively smaller in the 3 years evaluated. The sensitivity analysis showed that the uncertainties associated with the analytical model did not significantly affect the results. A strategy based on the use of CS-G6PD would result in better use of public resources in the Brazilian Amazon.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, which is caused by pathogenic variants of G6PD that result in decreased G6PD activity, is an X-linked inherited inborn error of metabolism that occurs worldwide. Individuals with G6PD deficiency and heterozygous females with normal G6PD activity (i.e., all individuals with pathogenic G6PD variants) are at risk of developing hemolytic anemia under increased oxidative challenge. However, this risk can be minimized by timely diagnosis. Currently, two assays are used to diagnose G6PD deficiency in China: evaluation of enzymatic activity and targeted genotyping. In terms of identification of all individuals with pathogenic G6PD variants, the performance and cost of different diagnostic strategies (isolated or combined evaluation of G6PD activity and G6PD genotyping) can vary, and these factors should be comprehensively evaluated. In this study, we examined 555 infants (437 males and 118 females) who were positive for the newborn screening of G6PD deficiency. We first evaluated the diagnostic performances of enzymatic testing and targeted genotyping. Both assays attained 100% specificities and positive predictive values for both male and female infants. In contrast, the sensitivities and negative predictive values (NPVs) of the diagnostic tests were different for male and female infants. For male infants, the sensitivities were 99.8 and 98.3%, and the NPVs were 94.1% and 69.6%, for enzymatic testing and targeted genotyping, respectively. For female infants, the sensitivities were 62.5% and 97.9%, and the NPVs were 37.9% and 91.7%, for enzymatic testing and targeted genotyping, respectively. We also evaluated the cost of the five different diagnostic strategies. The combination of G6PD activity testing of all infants, followed by genotyping of female infants with normal G6PD activity, attained high diagnostic sensitivity (99.8%) at a low cost (8.60 USD per diagnosed case). In the future, simultaneous examination of G6PD activity and whole-exon or whole-gene G6PD sequencing could become a standard clinical practice. Our data provide references for clinical practice on the standardization of current and future interventions for G6PD deficiency in China.

Introduction: Pulmonary hypertension (PH) is a fatal disorder with inadequate therapeutic choices and diminished survival rate with later prognosis. We previously reported that several patients with idiopathic pulmonary arterial hypertension had different types of glucose-6 phosphate dehydrogenase (G6PD) deficiency. G6PD is the key regulator enzyme in the pentose phosphate pathway (PPP) and the only source of NADPH in erythrocytes. However, the pathogenic mechanism of how G6PD deficiency contributes to PH development remains elusive. Hypothesis: We hypothesize that G6PD deficiency-induced PH is mediated through a multifactorial mechanism by increased red blood cell fragility, oxidative stress, and a metabolic switch. Methods: To delineate the contribution of G6PD in PH pathogenesis, we utilized a G6PD knockdown mouse line (11-13 week old) with decreased expression of G6PD (10% from wild-type level). Results: Hemodynamic and histological studies confirmed that G6PD deficient mice developed PH phenotype by an increase in right ventricular systolic pressure (30.08±0.91mmHg; p≤0.001), Fulton index (0.358±0.03; p≤0.01) and pulmonary vascular remodeling. G6PD deficiency resulted in increased free hemoglobin and activation of the p38/MAPK pathway, which we recently reported, induces the development of PH in the sugen/hypoxia model via endothelial barrier dysfunction. Metabolomics analysis of G6PD-deficient mice indicates the switch to alternative metabolic fluxes that feed into PPP, resulting in the upregulation of oxidative stress, fatty acid pathway, and reduction in pyruvate production. Thus, G6PD deficiency did not reduce PPP flux that is important for proliferation but activated collateral pathways at the cost of increased oxidative stress. Indeed, we found upregulation of Myo-inositol oxidase (p≤0.05), reduction in GSH/GSSG ratio (p≤0.01), and increased nitration (p≤0.05) in the lungs of G6PD deficient mice. Increased oxidative stress also results in the activation of PI3K, ERK1/2 and AMPK that contributes to the proliferation of pulmonary vasculature. Conclusions: Based on these results we infer that G6PD deficiency has a multi-modal effect, including hemolysis, metabolic reprogramming, and oxidative stress leading to PH.

Glucose 6-phosphate dehydrogenase (G6PD) deficiency, known as favism, is classically manifested by hemolytic anemia in human. More recently, it has been shown that mild G6PD deficiency moderately affects cardiac function, whereas severe G6PD deficiency leads to embryonic lethality in mice. How G6PD deficiency affects organisms has not been fully elucidated due to the lack of a suitable animal model. In this study, G6PD-deficient Caenorhabditis elegans was established by RNA interference (RNAi) knockdown to delineate the role of G6PD in animal physiology. Upon G6PD RNAi knockdown, G6PD activity was significantly hampered in C. elegans in parallel with increased oxidative stress and DNA oxidative damage. Phenotypically, G6PD-knockdown enhanced germ cell apoptosis (2-fold increase), reduced egg production (65% of mock), and hatching (10% of mock). To determine whether oxidative stress is associated with G6PD knockdown-induced reproduction defects, C. elegans was challenged with a short-term hydrogen peroxide (H2O2). The early phase egg production of both mock and G6PD-knockdown C. elegans were significantly affected by H2O2. However, H2O2-induced germ cell apoptosis was more dramatic in mock than that in G6PD-deficient C. elegans. To investigate the signaling pathways involved in defective oogenesis and embryogenesis caused by G6PD knockdown, mutants of p53 and mitogen-activated protein kinase (MAPK) pathways were examined. Despite the upregulation of CEP-1 (p53), cep-1 mutation did not affect egg production and hatching in G6PD-deficient C. elegans. Neither pmk-1 nor mek-1 mutation significantly affected egg production, whereas sek-1 mutation further decreased egg production in G6PD-deficient C. elegans. Intriguingly, loss of function of sek-1 or mek-1 dramatically rescued defective hatching (8.3- and 9.6-fold increase, respectively) induced by G6PD knockdown. Taken together, these findings show that G6PD knockdown reduces egg production and hatching in C. elegans, which are possibly associated with enhanced oxidative stress and altered MAPK pathways, respectively.

In patients with sickle cell anaemia (SCA), concomitant glucose-6-phosphate dehydrogenase (G6PD) deficiency is usually described as having no effect and only occasionally as increasing severity. We analysed sequential clinical and biological data for the first 42months of life in SCA patients diagnosed by neonatal screening, including 27 G6PD-deficient patients, who were matched on sex, age and parents' geographic origin to 81 randomly selected patients with normal G6PD activity. In the G6PD-deficient group, steady-state haemoglobin was lower (-6·2g/l, 95% confidence interval (CI), [-10·1;-2·3]) and reticulocyte count higher (247×10(9) /l, 95%CI, [97; 397]). The acute anaemic event rate was 3 times higher in the G6PD-deficient group (P<10(-3) ). A higher proportion of G6PD-deficient patients required blood transfusion (20/27 [74%] vs. 37/81 [46%], P<10(-3) ), for acute anaemic events, and also vaso-occlusive and infectious events. No significant between-group differences were found regarding the rates of vaso-occlusive, infectious, or cerebrovascular events. G6PD deficiency in babies with SCA worsens anaemia and increases blood transfusion requirements in the first years of life. These effects decrease after 2years of age, presumably as the decline in fetal haemoglobin levels leads to increased sickle cell haemolysis and younger red blood cells with higher G6PD activity.

BackgroundScreening for G6PD deficiency in newborns can help prevent severe hemolysis, hyperbilirubinemia, and bilirubin encephalopathy, as recommended by the World Health Organization (WHO). It has been speculated that the presence of a high number of reticulocytes in newborns interferes with the diagnosis of G6PD deficiency since reticulocytes contain higher amounts of G6PD enzyme than mature erythrocytes. Therefore, the purposes of this study were to assess the effect of reticulocytosis in the determination of blood G6PD activity in Thai newborns by using a novel automated UV-based enzymatic assay and to validate the performance of this assay for the detection of G6PD deficiency in newborn samples.MethodsThe levels of reticulocytes and G6PD activity were measured in blood samples collected from 1,015 newborns. G6PD mutations were identified using TaqMan® SNP genotyping assay, PCR–restriction fragment length polymorphism (PCR–RFLP), and direct sequencing. The correlation between the levels of reticulocytes and G6PD activity was examined. The performance of the automated method was compared with that of the fluorescent spot test (FST) and the standard quantitative assay.ResultsThe automated assay detected G6PD deficiency in 6.5% of the total newborn subjects compared to 5.3% and 6.1% by the FST and the standard method, respectively. The minor allele frequencies (MAFs) of G6PD ViangchanG871A, G6PD MahidolG487A, and G6PD UnionC1360T were 0.066, 0.005, and 0.005, respectively. The reticulocyte counts in newborns with G6PD deficiency were significantly higher than those in normal male newborns (p < 0.001). Compared with normal newborns after controlling for thalassemias and hemoglobinopathies, G6PD-deficient patients with the G6PD ViangchanG871A mutation exhibited elevated reticulocyte counts (5.82 ± 1.73%, p < 0.001). In a group of G6PD normal newborns, the percentage of reticulocytes was positively correlated with G6PD activity (r = 0.327, p < 0.001). However, there was no correlation between G6PD activity and the levels of reticulocytes in subjects with G6PD deficiency (r = -0.019, p = 0.881). The level of agreement in the detection of G6PD deficiency was 0.999, while the area under the receiver operating characteristic (AUC) curve demonstrated that the automated method had 98.4% sensitivity, 99.5% specificity, 92.4% positive predictive value (PPV), 99.9% negative predictive value (NPV), and 99.4% accuracy.ConclusionsWe report that reticulocytosis does not have a statistically significant effect on the detection of G6PD deficiency in newborns by both qualitative and quantitative methods.

Identification of glucose 6-phosphate dehydrogenase deficiency in a population with a high frequency of thalassemia