Glucose 6 phosphate dehydrogenase deficiency

Synonyms

2

Overview

G6PD deficiency (favism after the fava bean, G6PD deficiency) is an X-linked recessive, therefore, symptomatic patients are almost exclusively male. Homozygous females have been described (double X deficiency) almost as sensitive as a male. This genetic condition predisposes to hemolysis (spontaneous destruction of red blood cells) and resultant jaundice in response to a number of triggers, such as certain foods, illness or medication.

Symptoms

The severity of symptoms varies greatly from case to case, depending upon the form of the disorder that is present, and some people are aysmptomatic.

Typical symptoms are:

  • Fatigue
  • Pale color
  • Shortness of breath
  • Rapid heart beat
  • Jaundice or yellow skin color
  • Dark urine and enlarged spleen (splenomegaly).

When exposed to fava beans, the affected individual will experience severe episodes of hemolytic anemia (Favism). 

Neonatal G6PDD is particularly dangerous:  it appears as prolonged neonatal jaundice, and leads to kernicterus  (arguably the most serious complication of G6PD deficiency). It is manageable if caught early and screening for the disorder is common.

Causes

Genetics

Two variants (G6PD A− and G6PD Mediterranean) are the most common in human populations. G6PD A− has an occurrence of 10% of African-Americans while G6PD Mediterranean is prevalent in the Middle East. The known distribution of the disease is largely limited to people of Mediterranean origins (Spaniards, Italians, Greeks, Armenians, and Jews). These variants are believed to stem from a protective effect against Plasmodium falciparum and Plasmodium vivax malaria.
All mutations that cause G6PD deficiency are found on the long arm of the X chromosome, on band Xq28. The G6PD gene spans some 18.5 kilobases.

Drugs

Many substances are potentially harmful to people with G6PD deficiency. Variation in response to these substances makes individual predictions difficult. Antimalarial drugs that can cause acute hemolysis in people with G6PD deficiency include primaquine, pamaquine, and chloroquine. There is evidence that other antimalarials may also exacerbate G6PD deficiency, but only at higher doses. Sulfonamides (such assulfanilamide, sulfamethoxazole, and mafenide), thiazolesulfone, methylene blue, and naphthalene should also be avoided by people with G6PD deficiency as they antagonize folate synthesis, as should certain analgesics (such as aspirin, phenazopyridine, and acetanilide) and a few non-sulfa antibiotics (nalidixic acid, nitrofurantoin, isoniazid, dapsone, and furazolidone). Henna has been known to cause hemolytic crisis in G6PD-deficient infants. Rasburicase is also contraindicated in G6PD deficiency.

Prevention

Genetic counseling or testing:

May be available to those who have a family history of G6PD deficiency.

People with G6PD deficiency must strictly avoid things that can trigger an episode.

Diagnosis

The diagnosis is generally suspected when patients from certain ethnic groups (see epidemiology) develop anemia, jaundice and symptoms of hemolysis after challenges from any of the above causes, especially when there is a positive family history.

Generally, tests will include:

  • Complete blood count and reticulocyte count; in active G6PD deficiency, Heinz bodies can be seen in red blood cells on ablood film;
  • Liver enzymes (to exclude other causes of jaundice);
  • Lactate dehydrogenase (elevated in hemolysis and a marker of hemolytic severity)
  • Haptoglobin (decreased in hemolysis);
  • A "direct antiglobulin test" (Coombs' test) – this should be negative, as hemolysis in G6PD is not immune-mediated;

When there are sufficient grounds to suspect G6PD, a direct test for G6PD is the "Beutler fluorescent spot test", which has largely replaced an older test (the Motulsky dye-decolouration test). Other possibilities are direct DNA testing and/or sequencing of the G6PD gene.

The Beutler fluorescent spot test is a rapid and inexpensive test that visually identifies NADPH produced by G6PD under ultraviolet light. When the blood spot does not fluoresce, the test is positive; it can be falsely negative in patients who are actively hemolysing. It can therefore only be done 2–3 weeks after a hemolytic episode.

When a macrophage in the spleen identifies a RBC with a Heinz body, it removes the precipitate and a small piece of the membrane, leading to characteristic "bite cells". However, if a large number of Heinz bodies are produced, as in the case of G6PD deficiency, some Heinz bodies will nonetheless be visible when viewing RBCs that have been stained with crystal violet. This easy and inexpensive test can lead to an initial presumption of G6PD deficiency, which can be confirmed with the other tests.

Classification

The World Health Organization classifies G6PD genetic variants into five classes, the first three of which are deficiency states.

  • Class I: Severe deficiency (<10% activity) with chronic (nonspherocytic) hemolytic anemia
  • Class II: Severe deficiency (<10% activity), with intermittent hemolysis
  • Class III: Mild deficiency (10-60% activity), hemolysis with stressors only
  • Class IV: Non-deficient variant, no clinical sequelae
  • Class V: Increased enzyme activity, no clinical sequelae

Prognosis

G6PD-deficient individuals do not appear to acquire any illnesses more frequently than other people, and may have less risk than other people for acquiring ischemic heart disease and cerebrovascular disease.

Treatment

There is no specific treatment, other than avoiding known triggers. Abnormal red blood cell breakdown (hemolysis) in G6PD deficiency can manifest in response to:

  • Illness (especially infections)
  • Drugs:  Antimalarial, Sulfonamides, thiazolesulfone, methylene blue, naphthalene, analgesics (such as aspirin , phenazopyridine , and acetanilide ) and a few antibiotics (nalidixic acid , nitrofurantoin , isoniazid , dapsone , and furazolidone ). Henna  has been known to cause hemolytic crisis in G6PD-deficient infants. Rasburicase  is also contraindicated in G6PD deficiency.
  • Foods, most notably broad beans
  • Certain chemicals (oxidants)

Vaccination against some common pathogens (e.g. hepatitis A  and hepatitis B) may prevent infection-induced attacks.

In the acute phase of hemolysis, blood transfusions  might be necessary or even dialysis  in acute kidney failure. Blood transfusion is an important symptomatic measure, as the transfused red cells are generally not G6PD deficient and will live a normal lifespan in the recipient’s circulation.