Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive hereditary disease characterised by abnormally low levels of glucose-6-phosphate dehydrogenase (abbreviated G6PD or G6PDH), a metabolic enzyme involved in the pentose phosphate pathway, especially important in red blood cell metabolism. G6PD deficiency is the most common human enzyme defect. Individuals with the disease may exhibit nonimmune hemolytic anemia in response to a number of causes, most commonly infection or exposure to certain medications or chemicals. G6PD deficiency is closely linked to favism, a disorder characterized by a hemolytic reaction to consumption of broad beans, with a name derived from the Italian name of the broad bean (fava). The name favism is sometimes used to refer to the enzyme deficiency as a whole, although this is misleading as not all people with G6PD deficiency will manifest a physically observable reaction to consumption of broad beans.
CLASSIFICATIONS
The World Health Organization classifies G6PD genetic variants into five classes, the first three of which are deficiency states.
-Severe deficiency (<10% activity) with chronic (nonspherocytic) hemolytic anemia
-Severe deficiency (<10% activity), with intermittent hemolysis
-Mild deficiency (10-60% activity), hemolysis with stressors only
-Non-deficient variant, no clinical sequelae
-Increased enzyme activity, no clinical sequelae
CAUSES
G6PD deficiency is passed along in genes from one or both parents to a child. The gene responsible for this deficiency is on the X chromosome.
G6PD deficiency is most common in African-American males. Many African-American females are carriers of G6PD deficiency, meaning they can pass the gene for the deficiency to their children but do not have symptoms; only a few are actually affected by G6PD deficiency.
People of Mediterranean heritage, including Italians, Greeks, Arabs, and Sephardic Jews, also are commonly affected. The severity of G6PD deficiency varies among these groups — it tends to be milder in African-Americans and more severe in people of Mediterranean descent.
Why does G6PD deficiency occur more often in certain groups of people? It is known that Africa and the Mediterranean basin are high-risk areas for the infectious disease malaria. Researchers have found evidence that the parasite that causes this disease does not survive well in G6PD-deficient cells. So they believe that the deficiency may have developed as a protection against malaria.
PATHOPHYSIOLOGY
G6PD catalyzes nicotinamide adenine dinucleotide phosphate (NADP) to its reduced form, NADPH, in the pentose phosphate pathway.NADPH protects cells from oxidative damage. Because erythrocytes do not generate NADPH in any other way, they are more susceptible than other cells to destruction from oxidative stress. The level of G6PD activity in affected erythrocytes generally is lower than in other cells.Normal red blood cells that are not under oxidative stress generally exhibit G6PD activity at approximately 2 percent of total capacity.Even with enzyme activity that is substantially reduced, there may be few or no clinical symptoms. A total deficiency of G6PD is incompatible with life.The G6PD-deficient variants are grouped into different classes corresponding with disease severity.
SIGNS AND SYMPTOMS
Most individuals with G6PD deficiency are asymptomatic.
Symptomatic patients are almost exclusively male, due to the X-linked pattern of inheritance, but female carriers can be clinically affected due to unfavorable lyonization, where random inactivation of an X-chromosome in certain cells creates a population of G6PD-deficient red blood cells coexisting with normal red cells. A typical female with one affected X chromosome will show the deficiency in approximately half of her red blood cells. However, in rare cases, including double X deficiency, the ratio can be much more than half, making the individual almost as sensitive as a male.Abnormal red blood cell breakdown (hemolysis) in G6PD deficiency can manifest in a number of ways, including the following:
-Prolonged neonatal jaundice, possibly leading to kernicterus (arguably the most serious complication of G6PD deficiency)
-Hemolytic crises in response to:Illness (especially infections)
Certain drugs (see below)
Certain foods, most notably broad beans
Certain chemicals
-Diabetic ketoacidosis
-Very severe crises can cause acute renal failure
-Favism may be formally defined as a haemolytic response to the consumption of broad beans. All individuals with favism show G6PD deficiency. However, not all individuals with G6PD deficiency show favism. For example, in a small study of 757 Saudi men, more than 42% showed a variant of G6PD deficiency, but none displayed symptoms of favism. Favism is known to be more prevalent in infants and children, and G6PD genetic variant can influence chemical sensitivity.[citation needed] Other than this, the specifics of the chemical relationship between favism and G6PD are not well understood.
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, Heinz bodies can be seen in red blood cells on a blood 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.
G6PD DEFICIENCY SYMPTOMS TRIGGERS
Kids with G6PD deficiency typically do not show any symptoms of the disorder until their red blood cells are exposed to certain triggers, which can be:
illness, such as bacterial and viral infections
certain painkillers and fever-reducing drugs
certain antibiotics (especially those that have "sulf" in their names)
certain antimalarial drugs (especially those that have "quine" in their names)
Some kids with G6PD deficiency can tolerate the medications in small amounts; others cannot take them at all. Check with your doctor for more specific instructions, as well as a complete list of medications that could pose a problem for a child with G6PD deficiency.
Other substances can be harmful to kids with this condition when consumed — or even touched — such as fava beans and naphthalene (a chemical found in mothballs and moth crystals). Mothballs can be particularly harmful if a child accidentally swallows one, so ANY contact should be avoided.
Medications That Should Be Avoided By Persons with G6PD Deficiency*
Drug name Use
Dapsone Antimicrobial for treatment of leprosy
Flutamide (Eulexin) Antiandrogen for treatment of prostate cancer
Mafenide cream (Sulfamylon) Topical antimicrobial
Methylene blue (Urolene Blue) Antidote for druginduced methemoglobinemia
Nalidixic acid (NegGram) Antibiotic used primarily for urinary tract infections
Nitrofurantoin (Macrodantin) Antibiotic used primarily for urinary tract infections
Phenazopyridine (Pyridium) Antibiotic used primarily for urinary tract infections
Primaquine Antimalaria agent Rasburicase (Elitek)
Sulfamethoxazole (Gantanol) Antibiotic (ophthalmic and topical preparations)
Antibiotic used in combination preparations (i.e., trimethoprim-sulfamethoxazole [TMP-SMX; Bactrim, Septra])
Sulfanilamide (AVC) Antifungal agent for treatment of vulvovaginalCandida albicans infection
TREATMENT
The most important measure is prevention - avoidance of the drugs and foods that cause hemolysis. 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 renal 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.
Some patients may benefit from removal of the spleen (splenectomy), as this is an important site of red cell destruction. Folic acid should be used in any disorder featuring a high red cell turnover. Although vitamin E and selenium have antioxidant properties, their use does not decrease the severity of G6PD deficiency.
EPIDEMIOLOGY
G6PDH is the most common human enzyme defect, being present in more than 400 million people worldwide.African, Middle Eastern and South Asian people are affected the most along with those who are mixed with any of the above.A side effect of this disease is that it confers protection against malaria, in particular the form of malaria caused by Plasmodium falciparum, the most deadly form of malaria. A similar relationship exists between malaria and sickle-cell disease. One theory to explain this, is that cells infected with the Plasmodium parasite are cleared more rapidly by the spleen. This phenomenon might give G6PDH deficiency carriers an evolutionary advantage by increasing their fitness in malarial endemic environments.
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 diseases
