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Glucose-6-phosphate dehydrogenase (G6PD) deficiency

Inborn error of metabolism that predisposes to hemolysis and resultant jaundice in response to a number of triggers, such as certain foods, illness, or medication.

Inborn error of metabolism that predisposes to hemolysis and resultant jaundice in response to a number of triggers, such as certain foods, illness, or medication.

  • X-linked recessive inheritacne

Epidemiology

  • M/C human enzymopathy (affects 10% population worldwide)
  • Higher prevalence in malaria endemic area: Protective against malaria
(A) Worldwide prevalence of G6PD deficiency according to WHO (1989). (B) Worldwide prevalence of G6PD deficiency according to Nkhoma et al. (2009)
(A) Worldwide prevalence of G6PD deficiency according to WHO (1989). (B) Worldwide prevalence of G6PD deficiency according to Nkhoma et al. (2009). | (C) Worldwide prevalence of malaria, expressed as numbers of infections per 100,000 inhabitants, according to the WHO (2009). | (A) World Health Organization. Bull World Health Organ 67:601–611, 1989. | (B) Nkhoma et al. Blood Cells Mol Dis 42:267–278, 2009. | (C) World Health Organization. http://gamapserver.who.int/maplibrary/Files/Maps/Global_Malaria_ITHRiskMap.jpg

Biochemistry

Glucose-6-phosphate dehydrogenase (G6PD):

Key regulatory enzyme in the pentose phosphate pathway (PPP) which produces nicotinamide adenine dinucleotide phosphate (NADPH) to maintain an adequate reducing environment in the cells and is especially important in red blood cells (RBC).
  • Rate-limiting enzyme of the pentose phosphate pathway (PPP) that breaks down glucose, promotes the oxidation of β-D-glucose-6-phosphate to D-glucono-1,5-lactone-6-phosphate, and produces a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) as a byproduct in oxidative phase
  • NADPH is necessary to keep glutathione reduced, which in turn detoxifies free radicals and peroxides
Schematic representation of the involvement of G6PD in energy harnessing and as an antioxidant
Schematic representation of the involvement of G6PD in energy harnessing and as an antioxidant: The enzyme acts differently in oxidative and nonoxidative phase with different outputs. | Tiwari M. (2017). Glucose 6 phosphatase dehydrogenase (G6PD) and neurodegenerative disorders: Mapping diagnostic and therapeutic opportunities. Genes & diseases, 4(4), 196–203. https://doi.org/10.1016/j.gendis.2017.09.001

RBC:

Unlike other cells types, RBCs do not contain mitochondria and therefore the PPP pathway is the only source of NADPH, which plays a key role in the protecting cells against oxidative damage due to reactive oxygen species (ROS)
  • ↓ NADPH in RBCs leads to hemolytic anemia due to poor RBC defense against oxidizing agents
Function of G6PD enzyme in the PPP from red blood cells
Function of G6PD enzyme in the PPP from red blood cells: In G6PD-normal red cells, the NADPH is produced by the action of glucose 6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) enzymes. The NADPH serves as proton donor to regenerates the GSSG oxidized. | Cat = Catalase; GPx = Glutathione peroxidase; GR = Glutathione reductase; G6PD = glucose 6-phosphate dehydrogenase; 6PGL = 6-phosphogluconolactonase; 6GPD = 6-phosphogluconate dehydrogenase; SOD = Superoxide dismutase; GSH = Reduced glutathione; GSSG = Oxidized glutathione; H2O2 = Peroxide; O2− = Superoxide. | Gómez-Manzo, S., Marcial-Quino, J., Vanoye-Carlo, A., Serrano-Posada, H., Ortega-Cuellar, D., González-Valdez, A., Castillo-Rodríguez, R. A., Hernández-Ochoa, B., Sierra-Palacios, E., Rodríguez-Bustamante, E., & Arreguin-Espinosa, R. (2016). Glucose-6-Phosphate Dehydrogenase: Update and Analysis of New Mutations around the World. International journal of molecular sciences, 17(12), 2069. https://doi.org/10.3390/ijms17122069

Hemolytic triggers:

  • Diet: Fava beans (hallmark trigger), soy products, red wine
  • Infection (M/C cause):
    • Viral hepatitis
    • Pneumonia
  • Oxidant drugs:
    • Analgesics: Aspirin, phenacetin
    • Antimalarials: Primaquine, Quinine, Chloroquine, Pyrimethamine
    • Antibiotics: Sulphonamides, Nitrofurantoin, Ciprofloxacin
    • Miscellaneous: Quinidine, Probenecid, Vitamin K, Dapsone

Associated conditions:

Unrelated events to triggering agents which can trigger hemolysis
Schematic representation of the role of G6PD in various inflammatory and neurodegenerative disorders
Schematic representation of the role of G6PD in various inflammatory and neurodegenerative disorders: The enzyme G6PD is associated with several neurodegenerative disorders directly and indirectly as well. | Tiwari M. (2017). Glucose 6 phosphatase dehydrogenase (G6PD) and neurodegenerative disorders: Mapping diagnostic and therapeutic opportunities. Genes & diseases, 4(4), 196–203. https://doi.org/10.1016/j.gendis.2017.09.001

Classification

World Health Organization (WHO) classification

Classified according to the severity of the G6PD deficiency that accompanies the enzyme activity and hematological parameter of the patients
  • Deficiency states:
    • Class I: Severe deficiency (<10% activity) + chronic (nonspherocytic) hemolytic anaemia
    • Class II: Severe deficiency (<10% activity) + intermittent hemolysis
    • Class III: Mild deficiency (10-60% activity) hemolysis + stressors only
  • Non-deficiency states:
    • Class IV: Non-deficient variant, no clinical sequelae
    • Class V: Increased enzyme activity, no clinical sequelae

Presentation

Clinical manifestation of G6PD deficiency in humans has a broad clinical spectrum ranging from almost asymptomatic individuals to those with severe neonatal jaundice, acute hemolytic episodes, and chronic non-spherocytic hemolytic anemia suggesting that gene-environment interactions may influence the clinical outcome of G6PD deficiency.

Asymptomatic presentation

A large majority of G6PD deficiencies are asymptomatic most of the time, until they are exposed to a hemolytic trigger.

Neonatal jaundice (NNJ)

M/C severe clinical symptom of G6PD deficiency , which peaks 2-3 days after birth
  • Class I G6PD deficient variants:
    • Severe jaundice
    • Kernicterus and permanent neurological damage which in many cases provokes the death of the patient

Acute hemolytic anemia (AHA):

M/C manifestation of the deficiency, which is originated when the RBCs are under oxidative stress and may be triggered by a range of exogenous agents as fava beans, drugs, or infections, causing intravascular hemolysis and jaundice
  • Intravascular hemolysis → Hemolytic crises:
    • Jaundice
    • Scleral icterus
    • RUQ pain
    • Fatigue
    • Recurrent infections (rare)
    • Acute renal failure (M/severe outcome)

Chronic nonspherocytic hemolytic anemia (CNSHA):

M/severely affected variants of Class I G6PD (Zacatecas, Hamburg, Quilmes, Veracruz, Merlo, Yucatan, Tennessee, unnamed A1088T & unnamed C1187G mutants) presented acute hemolytic anemia and jaundice. Low residual levels of enzyme activity found in these mutants cannot maintain a sufficient concentration of NADPH, meaning that cells cannot even protect themselves against oxygen radicals continuously generated by the normal metabolism in the RBCs.
  • Chronic hemolytic anemia:
    • Neonatal jaundice
    • Chronic anemia (transfusion dependent)
G6PD deficiency
The Calgary Guide | http://calgaryguide.ucalgary.ca/

Diagnosis

Newborn screening:

  • Skin examination: Yellow appearance in a well lit room
  • Total serum bilirubin (TSB)
  • Transcutaneous bilirubin (TcB) in newborns
  • Rapid fluorescent spot test (to detect the generation of NADPH from NADP)
  • Quantitative spectrophotometric analysis

Lab studies:

  • Complete blood count (CBC)
  • Bilirubin levels
  • Reticulocyte count
  • Serum aminotransferases
  • Lactate dehydrogenase

Hemolytic anaemia workup:

  • Coomb’s test (-): Autoimmune hemolytic anaemia
  • Pi-linked antigen (PLINK) (-): PNH
  • Osmotic fragility test (-): Spherocytosis
  • Haptoglobin (↑)
  • Quantitative G6PD (CONFIRMATORY)

Peripheral blood smear (PBS):

  • Bite cells: Result from the phagocytic removal of Heinz bodies by splenic macrophages
  • Blister cells: Red cells with surface blistering
  • Irregularly shaped cells
  • Polychromasia:Reflects reticulocytosis
  • Heinz bodies: Denatured globin chainsprecipitate within RBCs due to oxidative stress
Glucose-6-phosphate dehydrogenase (G6PD) deficiency: Peripheral blood smear, 100 ×.)
Glucose-6-phosphate dehydrogenase (G6PD) deficiency: Peripheral blood smear, 100 ×.) Several features of G6PD deficiency in the setting of an oxidative challenge are shown. The polychromatophils (large, bluish young red blood cells) and nucleated red blood cells indicate the current hemolytic state. Also shown are “bite” cells, which are red blood cell morphologic changes that are the consequence of macrophage action on the Heinz bodies, which have precipitated in the inner leaflet of the red blood cell membranes. (L Damon.)

USG

If RUQ pain present

Differential diagnosis:

  • Autoimmune hemolytic anemia
  • Bilirubin conjugation disorders (e.g., Gilbert syndrome)
  • Hemolytic disease of the newborn
  • Hereditary spherocytosis
  • Sickle cell anemia
  • Thalassemia

Management

  • Avoid oxidative triggers
  • Folic acid supplementation
  • (Neonates) Phototherapy

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