HaematologyTier 2Disease (DEADMAN)

G6PD deficiency

Description

The commonest enzymopathy in the world - ~400 million people
X-linked recessive - males hemizygous and affected; females heterozygous with a variable phenotype from lyonisation
Episodic acute haemolysis triggered by oxidative stress, on a background of normal blood counts
- Between episodes the FBE, LDH and film are entirely normal - this is the diagnostic pitfall

Clinical variants (WHO classification)

Class	Activity	Phenotype
I	<1%	Chronic non-spherocytic haemolytic anaemia (rare, sporadic mutations)
II	<10%	Mediterranean, Asian - severe episodic haemolysis, favism
III	10-60%	African (A-) - milder, self-limiting episodes
IV	Normal	Non-deficient variant

*African A- variant is self-limiting because the enzyme is unstable rather than absent* - young red cells retain enough activity, so haemolysis stops even with continued exposure
*Mediterranean variant does not self-limit* - haemolysis continues while the trigger persists

Epidemiology

~4-5% of the world's population; highest prevalence in sub-Saharan Africa, the Mediterranean basin, the Middle East and South-East Asia (up to 20-30%)
Geographic distribution mirrors historical malaria endemicity - heterozygote advantage against P. falciparum
M >> F symptomatically; ~1-2% of Australian males of relevant ancestry
>400 described variants; G6PD A- and G6PD Mediterranean account for most clinical disease
Rising relevance in Australia through migration - and through rasburicase and dapsone prescribing

Aetiopathogenesis

The pathway

G6PD catalyses the first and rate-limiting step of the hexose monophosphate (pentose phosphate) shunt
- Glucose-6-phosphate -> 6-phosphogluconate, generating NADPH
NADPH is the red cell's only source of reducing power
- -> regenerates reduced glutathione (GSH)
- -> GSH detoxifies hydrogen peroxide and free radicals
*The mature red cell has no mitochondria and no nucleus - it cannot make more enzyme and has no alternative NADPH source*

The consequence of failure

Oxidative stress -> haemoglobin denatures and precipitates -> Heinz bodies
Heinz bodies bound to the membrane -> removed ("pitted") by splenic macrophages -> bite cells / blister cells
Membrane oxidation -> intravascular and extravascular haemolysis
Methaemoglobinaemia may coexist (loss of reducing capacity)

Triggers - the list she needs

Drugs

*Rasburicase (contraindicated* - generates hydrogen peroxide -> haemolysis + methaemoglobinaemia)
Primaquine, tafenoquine, chloroquine (high dose)
Dapsone
Nitrofurantoin
Sulfonamides - co-trimoxazole, sulfasalazine
Methylene blue (and therefore useless and dangerous for methaemoglobinaemia in G6PD deficiency)
Quinolones, chloramphenicol, high-dose aspirin, vitamin K analogues
Aspirin at usual doses and paracetamol are safe

Non-drug

*Infection is the commonest trigger of all* - especially pneumonia, hepatitis, typhoid, and any febrile illness
Fava beans (favism) - divicine and isouramil. Class II variants only; can occur via breast milk
Diabetic ketoacidosis, other metabolic acidosis
Naphthalene (mothballs), henna

Malaria protection

Oxidative environment within the parasitised cell is more damaging to G6PD-deficient red cells -> early clearance
Heterozygous females appear to be most protected

Diagnosis

Presentation

Acute: 1-3 days after exposure - jaundice, dark urine, back/abdominal pain, pallor, fatigue; haemoglobin can fall precipitously
Neonatal jaundice - often without overt anaemia; *a leading cause of severe neonatal hyperbilirubinaemia and kernicterus worldwide*
Chronic non-spherocytic haemolytic anaemia in class I variants

Blood film - the classic findings

*Bite cells and blister cells*
Heinz bodies on a supravital stain (methyl violet or brilliant cresyl blue) - not seen on a routine Romanowsky film
Polychromasia, spherocytes, nucleated red cells
"Hemi-ghost" cells in severe episodes

Laboratory

Haemolysis screen: Hb falling, reticulocytes rising, LDH high, unconjugated bilirubin high, haptoglobin low, haemoglobinuria
DAT negative (separates it from autoimmune haemolysis)

Enzyme assay - and its trap

Quantitative spectrophotometric G6PD activity is the diagnostic test
*Can be FALSELY NORMAL during and immediately after an acute haemolytic episode* - the deficient old cells have been destroyed and the surviving reticulocytes have high enzyme activity
- Repeat 2-3 months after the episode has resolved
Heterozygous females can have normal or intermediate activity despite significant clinical deficiency (lyonisation)
- Genotyping or cytochemical/flow cytometric assays clarify
Point-of-care qualitative tests are used before primaquine/tafenoquine in malaria-endemic settings

Management

A. Acute haemolytic episode

*Identify and remove the trigger* - stop the drug, treat the infection
Supportive care: hydration, monitor haemoglobin and renal function
Transfusion if symptomatic or Hb falling rapidly (usually only in class II variants or severe exposure)
Watch for AKI from haemoglobinuria - maintain urine output
Most African A- episodes are self-limiting within 4-7 days even without intervention

B. Neonatal jaundice

Phototherapy; exchange transfusion if bilirubin approaches exchange thresholds
*The risk is kernicterus, and it is preventable* - lower the threshold for intervention in known or suspected G6PD deficiency
Avoid naphthalene-treated clothing and maternal exposure to oxidant drugs while breastfeeding

C. Prevention - the actual management of the condition

*Give the patient a written list of drugs and foods to avoid* and record it prominently in the medical record and with the GP and pharmacist
Avoid fava beans (class II variants)
Prompt treatment of infections
Family screening - X-linked, so screen male relatives and counsel female carriers

D. Prescribing implications she will meet on the ward

*Rasburicase for tumour lysis syndrome - screen before use in at-risk ethnic groups; contraindicated if deficient*
- In a true emergency where screening is unavailable, discuss with haematology - allopurinol plus aggressive hydration is the alternative
*Primaquine or tafenoquine for P. vivax radical cure - G6PD testing is mandatory before prescribing*
- Quantitative testing required for tafenoquine
- Weekly higher-dose primaquine regimens under supervision in mild deficiency
Dapsone (PJP prophylaxis, dermatitis herpetiformis) - screen first
Methylene blue is contraindicated - use ascorbic acid or exchange transfusion for methaemoglobinaemia instead
Nitrofurantoin, co-trimoxazole, sulfasalazine - avoid or use with caution

E. Chronic (class I) disease

Folic acid supplementation
Transfusion support; splenectomy occasionally in severe chronic haemolysis
Iron overload monitoring if transfusion-dependent
Avoid all oxidant exposures lifelong

Associations

Malaria endemicity - heterozygote advantage against P. falciparum
Neonatal jaundice and kernicterus
Favism (class II Mediterranean and Asian variants)
Methaemoglobinaemia
Diabetic ketoacidosis (a metabolic trigger)
Co-inheritance with sickle cell trait/disease and thalassaemia in the same populations
Gilbert syndrome - co-inheritance markedly increases neonatal jaundice severity
Chronic granulomatous disease (the phagocyte counterpart - NADPH oxidase failure)
Cataracts in some chronic variants

Natural history & complications

*Normal life expectancy and normal blood counts between episodes*
Class III (African A-): self-limiting episodes, Hb falls ~30-40% then recovers as reticulocytes with higher enzyme activity replace the older cells
Class II (Mediterranean): severe, does not self-limit while the trigger continues - potentially fatal
Class I: lifelong chronic haemolysis, transfusion dependence in some

Complications

Acute severe anaemia and haemodynamic collapse with a large exposure
Acute kidney injury from haemoglobinuria
Kernicterus in the neonate - the most serious avoidable outcome
Gallstones (pigment) in chronic haemolysis
Iron overload if chronically transfused
*The commonest "complication" is iatrogenic* - an unrecognised diagnosis and a prescribed oxidant drug

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