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.

• X-linked recessive inheritacne

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Epidemiology

• M/C human enzymopathy (affects 10% population worldwide)
• Higher prevalence in malaria endemic area: Protective against malaria

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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

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

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

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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

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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)

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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

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

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Management

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

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