Haematology - Rare anaemias

G6PD deficiency and lead poisoning are rare causes of anaemia. By Dr Anicee Danaee and Dr Deepti Radia

Neonatal jaundice can be treated with phototherapy (Photograph: SPL)
Neonatal jaundice can be treated with phototherapy (Photograph: SPL)

Glucose-6-phosphate dehydrogenase deficiency
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common red cell enzymatic disorder with X-linked inheritance. It affects 400 million people worldwide, and is most predominant in the Middle East, Africa, south east Asia and southern Europe.

G6PD deficiency is more common in males but females are also affected due to lyonisation. There is significant correlation between the distribution of G6PD deficiency and prevalence of Plasmodium falciparum malaria.

Pathophysiology
G6PD is an essential enzyme which catalyses the first step in the pentose phosphate pathway and leads to the generation of nicotinamide adenine dinucleotide phosphate (NADPH), which helps protect cells against oxidative damage.

As a result of G6PD deficiency oxidative damage can occur within red cells and cause secondary haemolysis.

Factors leading to oxidative stress include a number of drugs, such as quinine-based antimalarials, nitrofurantoin, ciprofloxacin and sulfonamides, infection, fava beans and various metabolic conditions including diabetic ketoacidosis.

Clinical features
The WHO has created a classification system for G6PD deficiency based on the degree of enzyme deficiency and clinical severity (see table below).

WHO classification of G6PD deficiency
Class Enzyme activity Clinical features
I <10% Chronic haemolytic anaemia, neonatal jaundice
II <10% Intermittent haemolysis, heonatal jaundice,favism
III 10-60% Drug-induced haemolytic anaemia
IV 60-150% None
V >150% None

The four main clinical presentations of G6PD deficiency are neonatal jaundice, favism, drug-induced haemolytic anaemia and chronic non-spherocytic haemolytic anaemia. These occur to varying degrees depending on the enzyme deficiency.

Neonatal jaundice is considered one of the most severe manifestations of G6PD deficiency and may require phototherapy or an exchange transfusion to prevent neurological complications such as fever, muscle hyper/hypotonia and encephalopathy.

Although jaundice starts in utero, the clinical manifestations are evident two to three days post delivery. G6PD level measurement in parents will be informative.

Favism occurs as a result of intravascular haemolysis following exposure to fava beans. The degree of haemolysis will be directly related to the dose.

In between the acute attacks, there will be normal blood count and no evidence of haemolysis.

Chronic non-spherocytic haemolytic anaemia which is often sporadic and associated with extravascular haemolysis can progress onto an intravascular haemolysis with additional oxidative stress.

Clinical implications and management
Recognising the signs of acute haemolysis is crucial as delay in diagnosis can lead to death or permanent neurological damage. In general, haemolysis occurs within 24-72 hours of exposure to the triggering factor.

The patient may present with headaches, dyspnoea, abdominal pain, lumbar/substernal discomfort, jaundice and darker urine.

The majority of cases of acute haemolysis are self-limiting but some will require transfusion. Anyone with a history of previous haemolysis or family history should be screened for G6PD deficiency.

Numerous screening tests exist for G6PD deficiency but the methaemoglobin reduction test and ultraviolet spot test are most commonly used. Although these tests can distinguish between a deficient and non-deficient patient they do not provide a reliable quantitative measure. Spectrophotometric assay allows definite diagnosis as it quantifies G6PD.

Drug-induced haemolysis is the result of accumulation of oxidants in red cells with subsequent loss of function and death. Certain drugs, such as antimalarials, may be unsafe in class I G6PD deficiency.

The most common precipitator of haemolysis in patients with G6PD deficiency is infection such as viral hepatitis, Escherichia coli and beta-haemolytic streptococci. The underlying mechanism for red cell destruction in infection is not known.

FBC will confirm a macrocytic anaemia reflecting reticulocytosis. The blood film will show spherocytes, polychromasia and blister/hemi-ghost red cells in acute haemolysis. Heinz bodies are demonstrated with staining and Coombs' test will be negative. There will be a raised bilirubin and LDH to reflect the red cell destruction.

The mainstay of treatment is supportive with removal of the offending agent and treatment of infections. The anaemia should improve within 10 days. Not all patients will need admission and the frequency of blood tests will depend on the clinical presentation.

Lead poisoning
Lead poisoning occurs as a result of accumulation of lead. The amount of lead and time of exposure determines toxicity. Diagnosis and treatment are based on the level of lead in the blood. A level >10 micrograms/dl or above for children and >25micrograms/dl for adults is concerning.

Exposure occurs through inhalation and skin contact.

Environmental exposure can be due to lead paints, lead-lined pipes or toys, contaminated herbal medicines/cosmetics and contaminated soil.

Lead has no known physiological role. Lead damages cell structures including DNA and cell membranes. It interferes with vitamin D synthesis and enzymes that maintain cell membrane integrity, resulting in haemolysis.

Bone metabolism is affected due to alterations of blood vessel permeability and collagen synthesis. Lead toxicity has been shown to decrease the activity of neutrophils and may impair the immune system.

Diagnosis and management
Symptoms vary in children and adults. Symptoms in children include irritability, weight loss, fatigue and vomiting.

Adults may experience pain, numbness in extremities, muscular weakness, abnormal sperm count, miscarriage or premature birth.

Diagnosis is based on clinical suspicion and blood levels. Lead lines in the gums and teeth were evident in the past but are now rare. Patients can present with hypochromic, microcytic anaemia and possibly concomitant iron deficiency, which can aggravate lead toxicity. Classically, course basophilic stippling is seen in the blood film.

Management is to remove the source of the contamination and minimise exposure. Chelation therapy and ethylenediaminetetraacetic acid (EDTA) therapy are used in severe cases.

Test your knowledge

Are the following statements true or false?

  1. G6PD Deficiency does not affect women.
  2. Polychromasia, blister cells and Heinz Bodies are a feature of G6PD deficiency.
  3. Lead toxicity is due to free radical damage to cell structures and interferes with DNA transcription.
  4. Blood film features of a microcytic anaemia with basophilic stippling are consistent with lead toxicity.
  5. There is a significant correlation between the distribution of G6OD deficiency and prevalence of Plasmodium falciparum malaria.
  6. Clinical manifestation/severity of G6PD deficiency will depend on the degree of enzyme deficiency.
  7. Pica syndrome is a recognised manifestation of lead toxicity.
  8. Neurological problems can be seen in G6PD deficiency and lead toxicity.
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    • Dr Danaee is a specialist registrar in haematology; Dr Radia is a consultant haematologist, Guy's and St Thomas' NHS Foundation Trust

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    • Find more articles about haematology and questions on rare anaemias at the haematology resource centre gponline.com/haematology

    References
    1. Elyassi AR, Rowshan HH. Anesth Prog 2009, 56: 86-91.

    2. Ho HY, Cheng ML, Chiu DT. Chang Gung Med J 2005; 28: 606-12.

    3. Tripathy V, Reddy BM. J Postgrad Med 2007;53: 193-202.

    4. Hoffbrand V, Catovsky D, Tuddenham E et al. Postgraduate Haematology (fifth edition). Chapter Nine; Disorders of Red cell metabolism. 141-46.

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