Factors affecting haemoglobin dynamics in African children with acute uncomplicated Plasmodium falciparum malaria treated with single low-dose primaquine or placebo.

BACKGROUND: Single low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in patients with glucose-6-phopshate dehydrogenase (G6PD) deficiency. We, therefore, examined the independent effects of several factors on haemoglobin (Hb) dynamics in falciparum-infected children with a particular interest in SLDPQ and G6PD status. METHODS: This randomised, double-blind, placebo-controlled, safety trial was conducted in Congolese and Ugandan children aged 6 months-11 years with acute uncomplicated P. falciparum and day (D) 0 Hbs ≥ 6 g/dL who were treated with age-dosed SLDPQ/placebo and weight-dosed artemether lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPP). Genotyping defined G6PD (G6PD c.202T allele), haemoglobin S (HbS), and α-thalassaemia status. Multivariable linear and logistic regression assessed factor independence for continuous Hb parameters and Hb recovery (D42 Hb > D0 Hb), respectively. RESULTS: One thousand one hundred thirty-seven children, whose median age was 5 years, were randomised to receive: AL + SLDPQ (n = 286), AL + placebo (286), DHAPP + SLDPQ (283), and DHAPP + placebo (282). By G6PD status, 284 were G6PD deficient (239 hemizygous males, 45 homozygous females), 119 were heterozygous females, 418 and 299 were normal males and females, respectively, and 17 were of unknown status. The mean D0 Hb was 10.6 (SD 1.6) g/dL and was lower in younger children with longer illnesses, lower mid-upper arm circumferences, splenomegaly, and α-thalassaemia trait, who were either G6PDd or heterozygous females. The initial fractional fall in Hb was greater in younger children with higher D0 Hbs and D0 parasitaemias and longer illnesses but less in sickle cell trait. Older G6PDd children with lower starting Hbs and greater factional falls were more likely to achieve Hb recovery, whilst lower D42 Hb concentrations were associated with younger G6PD normal children with lower fractional falls, sickle cell disease, α-thalassaemia silent carrier and trait, and late treatment failures. Ten blood transfusions were given in the first week (5 SLDPQ, 5 placebo). CONCLUSIONS: In these falciparum-infected African children, posttreatment Hb changes were unaffected by SLDPQ, and G6PDd patients had favourable posttreatment Hb changes and a higher probability of Hb recovery. These reassuring findings support SLDPQ deployment without G6PD screening in Africa. TRIAL REGISTRATION: The trial is registered at ISRCTN 11594437.

Comparison of severity and prognosis of jaundice due to Rh incompatibility and G6PD deficiency.

INTRODUCTION: Undiagnosed and untreated hyperbilirubinemia in infants may result in Kernicterus Spectrum Disorder and poor prognoses. Rhesus incompatibility and glucose-6-phosphate dehydrogenase (G6PD) deficiency are among the known causes of infantile jaundice. This study was designed to define the severity and prognosis in jaundiced infants with Rh incompatibility or G6PD deficiency. METHODS: A total of 144 term, 2- 14 days old jaundiced infants (bilirubin > 20 mg/dl) with Rh incompatibility(85 infant) or G6PD deficiency(59 infant) were included in this cohort study with 24-month follow-up through available sampling at Ghaem hospital between 2015 and 2022. Denver II test was used at 6, 12, 18, and 24-month ages after discharge. Infants with Rh incompatibility or G6PD deficiency were assigned into two groups of favorable and poor prognosis. Following that, the bilirubin levels of these infants were compared at the time of admission. RESULTS: The bilirubin level in G6PD deficient infants with poor prognoses (37.96 ± 9.25 mg/dl) and neonates with Rh incompatibility (36.23 ± 5.08 mg/dl) almost was the same (P = 0.232). 40 babies (47%) caused by Rh incompatibility and 33 (56%) babies caused by G6PD deficiency had a poor prognosis (P = 0.465). Average bilirubin in babies with RH incompatibility with favorable prognosis is 21.8 and poor prognosis is 36.2 mg/dl. In infants with G6PD deficiency, it was 24 mg/dl with favorable prognosis and 38 mg/dl with poor prognosis (P < 0.0001). The severity of hyperbilirubinemia had a significant role in the prognosis of infants in both groups (P < 0.0001). CONCLUSION: The two-year prognoses of hyperbilirubinemia caused by G6PD deficiency are as poor as that of Rh incompatibility. The severity of hyperbilirubinemia had a significant role in the prognosis of infants in both groups.Exchange transfusion in cases with bilirubin < 25 mg/dl can improve the prognosis in both groups, especially in infants with Rh incompatibility.

EPISODE OF ACUTE HEMOLYSIS DUE TO UNDIAGNOSED GLUCOSE-6-PHOSPHATE DEHIDROGENASE DEFICIENCY IN AN ADOLESCENT WITH NEWLY DIAGNOSED TYPE 1 DIABETES MELLITUS: CASE REPORT AND REVIEW OF LITERATURE.

Glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency is common in the community. The most important clinical manifestation of G6PD deficiency is acute hemolytic anemia due to oxidative stressors. Diabetes Mellitus (DM) can precipitate hemolysis in patients with G6PD deficiency. Here, we described a 15-year-old male with newly diagnosed type 1 DM (T1DM) and unknown G6PD deficiency who suffered from hemolytic anemia during normalization of blood glucose. On admission, the patient did not have ketoacidosis. After the patient's blood sugars were regulated with insulin therapy, he presented five days later with hemolytic anemia. The cause of hemolytic anemia was G6PD deficiency. The patient had no previous episodes of hemolysis and had no relevant family history. Hypoglycemia did not occur during blood glucose regulation. The return of blood sugar to normal after a long period of hyperglycemia was thought to be the possible cause of hemolysis. In conclusion, G6PD deficiency should be considered when there is an episode of hemolysis in newly diagnosed children and adolescents with T1DM, especially in the absence of ketoacidosis and hypoglycemia.

Mechanisms of 8-aminoquinoline induced haemolytic toxicity in a G6PDd humanized mouse model.

Primaquine (PQ) and Tafenoquine (TQ) are clinically important 8-aminoquinolines (8-AQ) used for radical cure treatment of P. vivax infection, known to target hepatic hypnozoites. 8-AQs can trigger haemolytic anaemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDd), yet the mechanisms of haemolytic toxicity remain unknown. To address this issue, we used a humanized mouse model known to predict haemolytic toxicity responses in G6PDd human red blood cells (huRBCs). To evaluate the markers of eryptosis, huRBCs were isolated from mice 24-48 h post-treatment and analysed for effects on phosphatidylserine (PS), intracellular reactive oxygen species (ROS) and autofluorescence. Urinalysis was performed to evaluate the occurrence of intravascular and extravascular haemolysis. Spleen and liver tissue harvested at 24 h and 5-7 days post-treatment were stained for the presence of CD169+ macrophages, F4/80+ macrophages, Ter119+ mouse RBCs, glycophorin A+ huRBCs and murine reticulocytes (muRetics). G6PDd-huRBCs from PQ/TQ treated mice showed increased markers for eryptosis as early as 24 h post-treatment. This coincided with an early rise in levels of muRetics. Urinalysis revealed concurrent intravascular and extravascular haemolysis in response to PQ/TQ. Splenic CD169+ macrophages, present in all groups at day 1 post-dosing were eliminated by days 5-7 in PQ/TQ treated mice only, while liver F4/80 macrophages and iron deposits increased. Collectively, our data suggest 8-AQ treated G6PDd-huRBCs have early physiological responses to treatment, including increased markers for eryptosis indicative of oxidative stress, resulting in extramedullary haematopoiesis and loss of splenic CD169+ macrophages, prompting the liver to act as the primary site of clearance.

Glucose-6-phosphate dehydrogenase deficiency is more prevalent in Duffy-null red blood cell transfusion in sickle cell disease.

BACKGROUND: Resistance to malaria infection may be conferred by erythrocyte genetic variations including glucose-6-phosphate dehydrogenase (G6PD) deficiency and lack of Duffy antigens. In red blood cell (RBC) transfusion, G6PD deficiency may shorten transfusion survival. Because Duffy-null units are commonly transfused in sickle cell disease (SCD) due to antigen matching protocols, we examined whether Duffy-null donor RBC units have a higher prevalence of G6PD deficiency. MATERIALS AND METHODS: Pediatric patients with SCD on chronic transfusion therapy were followed prospectively for multiple transfusions. RBC unit segments were collected to measure G6PD activity and RBC genotyping. The decline in donor hemoglobin (ΔHbA) following transfusion was assessed from immediate posttransfusion estimates and HbA measurements approximately 1 month later. RESULTS: Of 564 evaluable RBC units, 59 (10.5%) were G6PD deficient (23 severe, 36 moderate deficiency); 202 (37.6%) units were Duffy-null. G6PD deficiency occurred in 40 (19.8%) Duffy-null units versus 15 (4.5%) Duffy-positive units (p < .0001). In univariate analysis, the fraction of Duffy-null RBC units per transfusion was associated with greater decline in HbA (p = .038); however, in multivariate analysis, severe G6PD deficiency (p = .0238) but not Duffy-null RBC (p = .0139) were associated with ΔHbA. CONCLUSION: Selection of Duffy-null RBC units may result in shorter in vivo survival of transfused RBCs due to a higher likelihood of transfusing units from G6PD deficient donors.

Glucose-6-phosphate dehydrogenase deficiency and intracranial atherosclerotic stenosis in stroke patients.

BACKGROUND AND PURPOSE: Intracranial atherosclerotic stenosis (ICAS) is a major cause of stroke in Asian countries. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a hereditary enzyme defect prevalent in Asian countries, has been associated with atherosclerotic cardiovascular disease and worse poststroke outcomes. However, the impact of G6PD deficiency on ICAS remains unclear. We aimed to compare the risk of ICAS in stroke patients with and without G6PD deficiency in a Chinese cohort. METHODS: We prospectively and consecutively recruited stroke patients from four centers in China. All patients received intracranial artery assessment by magnetic resonance/computed tomography angiography or digital subtraction angiography, as well as G6PD enzyme evaluation. The prevalence, burden, and characteristics of ICAS were compared between patients with and without G6PD deficiency using multivariate regression analysis. RESULTS: Among 1593 patients, 116 (63.7%) of 182 patients with G6PD deficiency and 714 (50.6%) of 1411 patients with normal G6PD levels were identified as ICAS. Age, hypertension, diabetes, and G6PD deficiency were independent predictors of ICAS. Among patients with ICAS, G6PD-deficient individuals were more likely to have multiple (≥2 segments) intracranial stenosis (odds ratio [OR] = 1.87, 95% confidence interval [CI] = 1.25-2.81, p = 0.002). G6PD deficiency increased the risk of ICAS in patients who were male (OR = 1.82, 95% CI = 1.24-2.66, p = 0.002), aged ≥70 years (OR = 2.40, 95% CI = 1.33-4.31, p = 0.004), or hypertensive (OR = 1.88, 95% CI = 1.28-2.77, p = 0.001). CONCLUSIONS: Stroke patients with G6PD deficiency have a higher prevalence and ICAS burden than those with normal G6PD, particularly those who are male, older, and hypertensive.

Thirty-five males with severe (Class 1) G6PD deficiency (c.637G>T) in a North American family of European ancestry.

In North America, jaundiced neonates are not usually tested for G6PD deficiency if the family is of European ancestry. However, we describe such a family where ≥35 males have had severe (Class I) G6PD deficiency. Many of the jaundiced neonates did not have this diagnosis considered, at least three of whom developed bilirubin neurotoxicity. Over seven generations 35 affected males were identified. Three developed signs of kernicterus spectrum disorder; three had exchange transfusions for hyperbilirubinemia; and nine received one or more blood transfusions during childhood.

Co-inheritance of G6PD deficiency and 211 G to a variation of UGT1A1 in neonates with hyperbilirubinemia in eastern Guangdong.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, which may manifest as neonatal hyperbilirubinemia, is the most prevalent erythrocytic enzyme-related disease in the world. OBJECTIVE: To investigate the association between neonatal hyperbilirubinemia and co-inheritance of G6PD deficiency and 211 G to A variation of UGT1A1 in Chaozhou city of eastern Guangdong province, the effects of G6PD deficiency and UGT1A1 gene variant on the bilirubin level were determined in neonates with hyperbilirubinemia. METHOD: The activity of G6PD was assayed by an auto-bioanalyzer. PCR and flow-through hybridization were used to detect 14 common G6PD mutations in G6PD deficient neonates. 211 G to A variation of UGT1A1 was determined by PCR and sequencing. The data of neonatal bilirubin was collected and analyzed retrospectively. RESULTS: Seventy four cases of the 882 hyperbilirubinemia neonates were G6PD deficiency (8.39%) while 12 cases of the 585 non-hyperbilirubinemia neonates (control group) were G6PD deficiency (2.05%). The rate of G6PD deficiency in the hyperbilirubinemia group was higher than that of the control group. Moreover, the peak bilirubinin of the G6PD-deficient group of hyperbilirubinemia neonates was 334.43 ± 79.27 µmol/L, higher than that of the normal G6PD group of hyperbilirubinemia neonates (300.30 ± 68.62 µmol/L). The most common genotypes of G6PD deficiency were c.1376G > T and c.1388G > A, and the peak bilirubin of neonates with these two variants were 312.60 ± 71.81 µmol/L and 367.88 ± 75.79 µmol/L, respectively. The bilirubin level of c.1388G > A was significantly higher than that of c.1376G > T. Among the 74 hyperbilirubinemia neonates with G6PD deficiency, 6 cases were 211 G to A homozygous mutation (bilirubin levels 369.55 ± 84.51 µmol/L), 27 cases were 211 G to A heterozygous mutation (bilirubin levels 341.50 ± 63.21 µmol/L), and 41 cases were wild genotypes (bilirubin levels 324.63 ± 57.52 µmol/L). CONCLUSION: The rate of G6PD deficiency in hyperbilirubinemia neonates was significantly higher than that of the non-hyperbilirubinemia neonates in Chaozhou. For the hyperbilirubinemia group, neonates with G6PD deficiency had a higher bilirubin level compared to those with normal G6PD. For hyperbilirubinemia neonates with G6PD deficiency, there was a declining trend of bilirubin levels among 211 G to A homozygous mutation, heterozygous mutation, and wild genotype, but there was no significance statistically among the three groups.

Association of alpha-thalassemia and Glucose-6-Phosphate Dehydrogenase deficiency with transcranial Doppler ultrasonography in Nigerian children with sickle cell anemia.

BACKGROUND: Stroke is a devastating complication of sickle cell anemia (SCA) and can be predicted through abnormally high cerebral blood flow velocity using transcranial Doppler Ultrasonography (TCD). The evidence on the role of alpha-thalassemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency in the development of stroke in children with SCA is conflicting. Thus, this study investigated the association of alpha-thalassemia and G6PD(A- ) variant with abnormal TCD velocities among Nigerian children with SCA. METHODS: One hundred and forty-one children with SCA were recruited: 72 children presented with normal TCD (defined as the time-averaged mean of the maximum velocity: < 170 cm/s) and 69 children with abnormal TCD (TAMMV ≥ 200 cm/s). Alpha-thalassemia (the α-3.7 globin gene deletion) was determined by multiplex gap-PCR, while G6PD polymorphisms (202G > A and 376A > G) were genotyped using restriction fragment length polymorphism-polymerase chain reaction. RESULTS: The frequency of α-thalassemia trait in the children with normal TCD was higher than those with abnormal TCD: 38/72 (52.8%) [α-/ α α: 41.7%, α -/ α -: 11.1%] versus 21/69 (30.4%) [α-/ α α: 27.5%, α -/ α -: 2.9%], and the odds of abnormal TCD were reduced in the presence of the α-thalassemia trait [Odds Ratio: 0.39, 95% confidence interval: 0.20-0.78, p = 0.007]. However, the frequencies of G6PDA- variant in children with abnormal and normal TCD were similar (11.6% vs. 15.3%, p = 0.522). CONCLUSION: Our study reveals the protective role of α-thalassemia against the risk of abnormal TCD in Nigerian children with SCA.

A greater awareness of children with glucose-6-phosphate dehydrogenase deficiency is imperative in western countries.

AIM: This national retrospective Danish study described the characteristics of children diagnosed with glucose-6-phosphate dehydrogenase (G6PD) deficiency, an inherited X-linked recessive disorder that often affects children of Middle Eastern descent. METHODS: We studied children born between 1 January 2000 and 31 December 2017 and diagnosed with G6PD deficiency. They were identified from the Danish National Hospital Discharge Register and the Danish Database of Extreme Neonatal Hyperbilirubinaemia. RESULTS: There were 113 children diagnosed with G6PD deficiency, 67% were of Middle Eastern descent and they were frequently diagnosed before the onset of symptoms, based on known heredity. Of the 67 infants born in Denmark, 10% had extreme neonatal hyperbilirubinaemia and one developed kernicterus spectrum disorder, as did one child born in the Middle East. Most (61%) of the 33 children with jaundice received phototherapy, 12% had exchange transfusions and 18% received whole blood transfusions. After the neonatal period, 23% of the cohort had blood transfusions and 4% needed intensive care for acute haemolytic anaemia. The incidence of G6PD deficiency appeared to be severely underestimated. CONCLUSION: Many families from countries where G6PD deficiency is endemic move to Denmark and other Western countries. Greater awareness is essential to avoid chronic and potentially lethal, consequences.

Evaluating the effect of ursodeoxycholic acid on total bilirubin of neonates with glucose-6-phosphate dehydrogenase deficiency complicated by indirect hyperbilirubinaemia.

AIM: This study aimed to investigate the effect of adding ursodeoxycholic acid (UDCA) to phototherapy in neonates with glucose-6-phosphate dehydrogenase (G6PD) deficiency and hyperbilirubinaemia. G6PD deficiency is a common cause of severe hyperbilirubinaemia in neonates. METHODS: This study was a triple blind, clinical trial study of 40 neonates with G6PD deficiency and hyperbilirubinaemia who admitted for phototherapy in hospitals affiliated to the University of Medical Sciences. The treatment group (n = 20) received UDCA 10 mg/kg (2 cc/kg) daily divided into 2 doses every 12 h. The control group (n = 20) received the same volume of placebo syrup. The drug and placebo treatments were continued until the bilirubin level dropped below 171 µmol/L. Both the control and treatment group received continuous phototherapy. Independent sample t-test, survival analysis and logrank test were used to statistically analyse the results. RESULTS: The mean total bilirubin level was 231.9 ± 18.8 µmol/L and 184.3 ± 18.6 µmol/L in the control and intervention group respectively, 24 h after drug administration and 209.7 ± 19.3 µmol/L and 157.4 ± 16.4 µmol/L, respectively, 48 h after intervention (P < 0.05). The median length of hospitalisation in the treatment group was approximately 1 day lower than the control group (logrank test P value: <0.001). CONCLUSION: The study showed that the addition of UDCA to phototherapy accelerates the reduction of total bilirubin level in neonates with G6PD deficiency and can reduce the duration of hospitalisation.

Molecular Characterization of Glucose-6-Phosphate Dehydrogenase Deficiency in the Shenzhen Population.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is caused by one or more mutations in the G6PD gene on chromosome X. This study aimed to characterize the G6PD gene variant distribution in Shenzhen of Guangdong province. METHODS: A total of 33,562 individuals were selected at the hospital for retrospective analysis, of which 1,213 cases with enzymatic activity-confirmed G6PD deficiency were screened for G6PD gene variants. Amplification refractory mutation system PCR was first used to screen the 6 dominant mutants in the Chinese population (c.1376G>T, c.1388G>A, c.95A>G, c.1024C>T, c.392G>T, and c.871G>A). If the 6 hotspot variants were not found, next-generation sequencing was then performed. Finally, Sanger sequencing was used to verify all the mutations. RESULTS: The incidence of G6PD deficiency in this study was 3.54%. A total of 26 kinds of mutants were found in the coding region, except for c.-8-624T>C, which was in the noncoding region. c.1376G>T and c.1388G>A, both located in exon 12, were the top 2 mutants, accounting for 68.43% of all individuals. The 6 hotspot mutations had a cumulative proportion of 94.02%. CONCLUSIONS: This study provided detailed characteristics of G6PD gene variants in Shenzhen, and the results would be valuable to enrich the knowledge of G6PD deficiency.

Application of genetic screening processor in screening neonatal glucose-6-phosphate dehydrogenase deficiency.

To evaluate the performance of genetic screening processor (GSP analyzer) in neonatal screening for glucose-6-phosphate dehydrogenase (G6PD)deficiency. The accuracy and precision of GSP analyzer was evaluated with the control materials from National Center for Clinical Laboratories and the low and high quality G6PD control kit (fluorescence analysis). GSP analyzer and semi-automatic fluorescence immunoanalyzer (1420 analyzer) were simultaneously used to detect 2622 neonatal screening samples and 41 confirmed samples to analyze the correlation and consistency of the test results; 78 floating samples and 78 non-floating samples were detected to compare the result. A total of 1 100 384 neonatal screening samples from January 2017 to December 2018 and 855 856 neonatal screening samples from January 2019 to December 2020 were detected with 1420 analyzer and GSP analyzer, respectively. Referring to the percentile method and the expert consensus, the new cut-off value of GSP analyzer for G6PD deficiency in screening was established. The relative bias of GSP analyzer in detecting G6PD was 0.71%-4.23%; the intra assay precision was 4.34%-4.91%, the inter assay precision was 0.85%-2.12%, and the total coefficient of variation was 5.44%-5.72%. There was a significant positive correlation between G6PD activity detected by GSP analyzer and 1420 analyzer (=0.740, <0.01). Forty-one clinical confirmed patients were identified by both 1420 analyzer and GSP analyzer (=0.945). The G6PD activity in floating dry blood spots detected by 1420 analyzer was significantly lower than that in non-floating dry blood spots (<0.05), but there was no significant difference in G6PD activity between floating and non-floating dry blood spots detected by GSP analyzer (>0.05). The sensitivities of GSP analyzer and 1420 analyzer in screening G6PD deficiency were both 100.00%, and the specificities were both more than 99.80%. Compared with 1420 analyzer, the positive predictive value, positive rate and prevalence of G6PD deficiency detected by GSP analyzer were increased, and the false positive rate was decreased (all <0.01). The new cut-off value was 26.1 U/dL for male and 29.1 U/dL for female according to the 99.1% percentile of the population. GSP analyzer has better detection performance with high automation, efficiency and throughput, which can be used in large-scale screening for neonatal G6PD deficiency.

Investigation of glucose-6-phosphate dehydrogenase (G6PD) deficiency prevalence in a Plasmodium vivax-endemic area in the Republic of Korea (ROK).

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most prevalent inborn disorder. This X-chromosome-linked recessive disease affects more than 400 million people globally, and is associated with haemolytic anaemia after medication with the anti-latent malaria drug, primaquine. To prevent malaria, the Republic of Korea (ROK) Army administers malaria chemoprophylaxis. Due to the previously low G6PD deficiency prevalence in the ROK, prior to primaquine administration, testing for G6PD deficiency was not mandatory. In this study, to evaluate the risk from malaria chemoprophylaxis in the ROK, G6PD deficiency prevalence was investigated. METHODS: Blood specimens from 1632 soldiers entering training camp for the 3rd Infantry of the ROK Army were collected. CareStart™ Biosensor for G6PD and haemoglobin (Hb) was used to detect G6PD levels. G6PD variants using the DiaPlexC G6PD Genotyping kit (Asian type) and full-length sequencing were examined. RESULTS: Of 1632 blood specimens tested, none was observed to be G6PD deficient. The median value of all tested samples was 7.582 U/g Hb. An investigation of 170 G6PD DNA variants was analysed and categorized as partially low normal [n = 131, 30-80% (2.27-6.05 U/g Hb) of the median value], high [n = 3, > 150% (> 11.373 U/g Hb) of the median value], or normal [n = 36, 80-150% (6.05-11.373 U/g Hb) of the median value], and none was amplified by the DiaPlexC kit. Five silent mutations (C→T) in 131 partially low normal specimens were found at the 1311th nucleotide position by sequence analysis. Another 8 silent mutations (T93C) were also detected in 131 partially low normal specimens. Thus, it is inferred that these silent mutations could be related to G6PD activity. CONCLUSIONS: This G6PD deficiency prevalence study, conducted among participants from the 3rd Infantry of the ROK Army, provided crucial evidence for the safety of malaria chemoprophylaxis. This study showed that the prevalence of G6PD deficiency among 1632 young soldiers was wholly absent. Although G6PD phenotypic mutations were not detected, many silent mutations (C1311T and T93C) were observed. Thus, it is inferred that malaria chemoprophylaxis is relatively safe against G6PD deficiency-mediated haemolytic anaemia. However, given the number of individuals whose G6PD were at the partially low normal range and the frequent detection of G6PD deficiency-related mutations, consistent monitoring of G6PD deficiency is needed.

High dose vitamin C induced methemoglobinemia and hemolytic anemia in glucose-6-phosphate dehydrogenase deficiency.

Investigational use of intravenous vitamin C has been on the rise, but its side effects may be underreported. A 75-year-old woman presented with acute onset of jaundice, dark urine and shortness of breath after receiving 30 g of vitamin C infusion as an unconventional therapy for her hemifacial spasm. Diagnosis of methemoglobinemia and hemolytic anemia was made clinically and confirmed on laboratory tests. She recovered with supportive treatment and packed cell transfusion. Her previously unrecognised underlying condition of glucose-6-phosphate dehydrogenase (G6PD) deficiency was confirmed months after the initial presentation. This is the first reported case of methemoglobinemia and hemolytic anemia induced by high dose vitamin C in a female patient with G6PD deficiency. The dosage of vitamin C administered was also relatively low compared with previous adult reports. When administered at physiological dose, vitamin C can be used as an alternative to methylene blue in treatment of methemoglobinemia in patients with G6PD deficiency. However at supraphysiological dose vitamin C can paradoxically lead to hemolytic anemia in the same group of patients. Physicians should be alert of these potential complications of high dose vitamin C.

Use of trimethoprim-sulfamethoxazole in a patient with G6PD deficiency for treating Pneumocystis jirovecii pneumonia without haemolysis: Case report and literature review.

WHAT IS KNOWN AND OBJECTIVE: A fixed dose of trimethoprim-sulphamethoxazole (TMP/SMZ) is the first-line therapy for Pneumocystis jirovecii pneumonia (PJP). Other alternative regiments have shown a suboptimal cure rate. However, TMP/SMZ has been reported to cause haemolyses when administered to patients with G6DP deficiency. PJP might be fatal without treatment. To date, there is still insufficient evidence to manage PJP with TMP/SMZ in G6DP deficiency population. CASE DESCRIPTION: We report a G6PD-deficient patient with human immunodeficiency virus (HIV) and PJP infection treated successfully with 21 days of high dose TMP/SMZ without any signs and symptoms of haemolysis. WHAT IS NEW AND CONCLUSION: Based on our experience, it is worth to note that despite TMP/SMZ is consider unsafe in patient with pre-existing G6PD-deficiency, it could still be suggested as the initial drug of choice in Taiwanese or southeast Asian population for treating PJP infected HIV patient.

Epidemiological Study of Hereditary Hemolytic Anemia in the Korean Pediatric Population during 1997-2016: a Nationwide Retrospective Cohort Study.

BACKGROUND: Hereditary hemolytic anemia (HHA) is a rare disease characterized by premature red blood cell (RBC) destruction due to intrinsic RBC defects. The RBC Disorder Working Party of the Korean Society of Hematology established and updated the standard operating procedure for making an accurate diagnosis of HHA since 2007. The aim of this study was to investigate a nationwide epidemiology of Korean HHA. METHODS: We collected the data of a newly diagnosed pediatric HHA cohort (2007-2016) and compared this cohort's characteristics with those of a previously surveyed pediatric HHA cohort (1997-2006) in Korea. Each participant's information was retrospectively collected by a questionnaire survey. RESULTS: A total of 369 children with HHA from 38 hospitals distributed in 16 of 17 districts of Korea were investigated. RBC membranopathies, hemoglobinopathies, RBC enzymopathies, and unknown etiologies accounted for 263 (71.3%), 59 (16.0%), 23 (6.2%), and 24 (6.5%) of the cases, respectively. Compared to the cohort from the previous decade, the proportions of hemoglobinopathies and RBC enzymopathies significantly increased (P < 0.001 and P = 0.008, respectively). Twenty-three of the 59 hemoglobinopathy patients had immigrant mothers, mostly from South-East Asia. CONCLUSION: In Korea, thalassemia traits have increased over the past 10 years, reflecting both increased awareness of this disease and increased international marriages. The enhanced recognition of RBC enzymopathies is due to advances in diagnostic technique; however, 6.5% of HHA patients still do not have a clear diagnosis. It is necessary to improve accessibility of diagnosing HHA.

Glucose-6-Phosphate Dehydrogenase Deficiency Activates Endothelial Cell and Leukocyte Adhesion Mediated via the TGFß/NADPH Oxidases/ROS Signaling Pathway.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common genetic inherited trait among humans, affects ~7% of the global population, and is associated with excess risk of cardiovascular disease (CVD). Transforming growth factor-ß (TGF-ß) regulates immune function, proliferation, epithelial-mesenchymal transition, fibrosis, cancer, and vascular dysfunction. This study examined whether G6PD deficiencies can alter TGF-ß-mediated NADPH oxidases (NOX) and cell adhesion molecules (CAM) in human aortic endothelial cells (HAEC). Results show that treatment with high glucose and the saturated free fatty acid palmitate significantly downregulated G6PD; in contrast, mRNA levels of TGF-ß components, NOX and its activity, and reactive oxygen species (ROS) were significantly upregulated in HAEC. The expression levels of TGF-ß and its receptors, NOX and its activity, and ROS were significantly higher in HG-exposed G6PD-deficient cells (G6PD siRNA) compared to G6PD-normal cells. The protein levels of adhesion molecules (ICAM-1 and VCAM-1) and inflammatory cytokines (MCP-1 and TNF) were significantly increased in HG-exposed G6PD-deficient cells compared to G6PD-normal cells. The adherence of monocytes (SC cells) to HAEC was significantly elevated in HG-treated G6PD-deficient cells compared to control cells. Pharmacological inhibition of G6PD enhances ROS, NOX and its activity, and endothelial monocyte adhesion; these effects were impeded by NOX inhibitors. The inhibition of TGF-ß prevents NOX2 and NOX4 mRNA expression and activity, ROS, and adhesion of monocytes to HAEC. L-Cysteine ethyl ester (cell-permeable) suppresses the mRNA levels of TGF-ß and its receptors, along with NOX2 and NOX4, and decreases NOX activity, ROS, and adhesion of monocytes to HAEC. This suggests that G6PD deficiency promotes TGF-ß/NADPH oxidases/ROS signaling, the expression of ICAM-1 and VCAM-1, and the adhesion of leukocytes to the endothelial monolayer, which can contribute to a higher risk for CVD.

Glucose-6-Phosphate Dehydrogenase Deficiency and the Benefits of Early Screening.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzymopathy worldwide, is an insufficient amount of the G6PD enzyme, which is vital to the protection of the erythrocyte. Deficient enzyme levels lead to oxidative damage, hemolysis, and resultant severe hyperbilirubinemia. If not promptly recognized and treated, G6PD deficiency can potentially lead to bilirubin-induced neurologic dysfunction, acute bilirubin encephalopathy, and kernicterus. Glucose-6-phosphate dehydrogenase deficiency is one of the three most common causes for pathologic hyperbilirubinemia. A change in migration patterns and intercultural marriages have created an increased incidence of G6PD deficiency in the United States. Currently, there is no universally mandated metabolic screening or clinical risk assessment tool for G6PD deficiency in the United States. Mandatory universal screening for G6PD deficiency, which includes surveillance and hospital-based risk assessment tools, can identify the at-risk infant and foster early identification, diagnosis, and treatment to eliminate neurotoxicity.

Dubin-Johnson syndrome coexisting with glucose-6-phosphate dehydrogenase deficiency presenting after acute viral hepatitis.

Dubin-Johnson syndrome presents as asymptomatic recurrent hyperbilirubinemia, while Glucose-6-Phosphate-Dehydrgenase-deficiecy as acute haemolytic anaemia. We present a case with coexisting Dubin-Johnson syndrome and Glucose-6-Phosphate Dehydrogenase deficiency unmasked by acute viral hepatitis E.