G6PDH deficiency

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Glucose-6-phosphate dehydrogenase deficiency

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. 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 react to consumption of broad beans.

G6PD deficiency is the most common human enzyme defect.

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 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. Abnormal red blood cell breakdown (hemolysis) in G6PD deficiency can manifest in a number of ways:

Prolonged neonatal jaundice, possibly leading to kernicterus (arguably the most serious complication of G6PD deficiency)
Hemolytic crises in response to:

Illness (especially severe 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 G6PD deficiency, but none reported symptoms of favism, despite fava in the diet. Favism is known to be more prevalent in infants and children, and G6PD genetic variant can influence chemical sensitivity. Other than this, the specifics of the chemical relationship between favism and G6PD are not well understood.

Potentially harmful substances

Many substances are potentially harmful to people with G6PD deficiency, although many will not produce symptoms unless taken in high doses. Antimalarial drugs that can cause acute haemolysis 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 as sulfanilamide, sulfamethoxazole and mafenide), thiazolesulfone, methylene blue and naphthalene should also be avoided by people with G6PD deficiency, as should certain analgesics (such as aspirin, phenazopyridine and acetanilide) and a few non-sulfa antibiotics (nalidixic acid, nitrofurantoin, and furazolidone). Henna has been known to cause haemolytic crisis in G6PD-deficient infants.

Mutations

All mutations that cause G6PD deficiency are found on the long arm of the X chromosome, on band Xq26. The G6PD gene spans some 18.5 kilobases. The following variants and mutations are well-known and described:

305900.0001
Table 1. Descriptive mutations and variants
Variants or mutations				Gene			Protein
Designation	Short name	Isoform G6PD-Protein	OMIM-Code	Type	Subtype	Position	Position	Structure change	Function change
G6PD-A(+)	Gd-A(+)	G6PD A	valign="top"
Polymorphism nucleotide	A→G	376 (Exon 5)	126	Asparagine→Aspartic acid (ASN126ASP)	No enzyme defect (variant)
G6PD-A(-)	Gd-A(-)	G6PD A	valign="top"
Substitution nucleotide	G→A	376 (Exon 5) and 202	68 and 126	Valine→Methionine (VAL68MET) Asparagine→Aspartic acid (ASN126ASP)
G6PD-Mediterran	Gd-Med	G6PD B	valign="top"
Substitution nucleotide	C→T	563 (Exon 6)	188	Serine→Phenylalanine (SER188PHE)	Class II
G6PD-Canton	Gd-Canton	G6PD A	valign="top"
Substitution nucleotide	G→T	1376	459	Arginine→Leucine (ARG459LEU)	Class II
G6PD-Chatham	Gd-Chatham	G6PD	valign="top"
Substitution nucleotide	G→A	1003	335	Alanine→Threonine (ALA335THR)	Class II
G6PD-Cosenza	Gd-Cosenza	G6PD B	valign="top"
Substitution nucleotide	G→A	1376	459	Arginine→Proline (ARG459PRO)	G6PD-activity <10%, thus high portion of patients.
G6PD-Mahidol	Gd-Mahidol	G6PD	valign="top"
Substitution nucleotide	G→A	487 (Exon 6)	163	Glycine→Serine (GLY163SER)	Class II
G6PD-Orissa	Gd-Orissa	G6PD	valign="top"
Substitution nucleotide			44	Alanine→Glycine (ALA44GLY)	NADP-binding place affected. Higher stability than other variants.
G6PD-Asahi	Gd-Asahi	G6PD A-	valign="top"
Substitution nucleotide (several)	A→G ± G→A	376 (Exon 5) 202	126 68	Asparagine→Aspartic acid (ASN126ASP) Valine→Methionine (VAL68MET)	Class III.

Diagnosis

The diagnosis is generally suspected when patients from certain ethnic groups (see below) develop anemia, jaundice and symptoms of hemolysis after challenge to 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 an 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 Organisation classifies G6PD genetic variants into five classes, 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

Pathophysiology

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the pentose phosphate pathway (see image). G6PD converts glucose-6-phosphate into 6-phosphoglucono-δ-lactone and is the rate-limiting enzyme of this metabolic pathway that supplies reducing energy to cells by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). The NADPH in turn maintains the supply of reduced glutathione in the cells that is used to mop up free radicals that cause oxidative damage.

The G6PD / NADPH pathway is the only source of reduced glutathione in red blood cells (erythrocytes). The role of red cells as oxygen carriers puts them at substantial risk of damage from oxidizing free radicals except for the protective effect of G6PD/NAPDH/glutathione.

People with G6PD deficiency are therefore at risk of hemolytic anemia in states of oxidative stress. Oxidative stress can result from severe infection and from chemical exposure to medication and certain foods. Broad beans contain high levels of vicine, divicine, convicine and isouramil, all of which are oxidants.

When all remaining reduced glutathione is consumed, enzymes and other proteins (including hemoglobin) are subsequently damaged by the oxidants, leading to electrolyte imbalance, cross-bonding and protein deposition in the red cell membranes. Damaged red cells are phagocytosed and sequestered (taken out of circulation) in the spleen. The hemoglobin is metabolized to bilirubin (causing jaundice at high concentrations). The red cells rarely disintegrate in the circulation, so hemoglobin is rarely excreted directly by the kidney, but this can occur in severe cases, causing acute renal failure .

Deficiency of G6PD in the alternative pathway causes the build up of glucose and thus there is an increase of advanced glycation endproducts (AGE). The deficiency also causes a reduction of NADPH which is necessary for the formation of Nitric Oxide (NO). The high prevalence of diabetes mellitus type 2 and hypertension in Afro-Caribbeans in the West could be directly related to G6PD deficiency.

Although female carriers can have a mild form of G6PD deficiency (dependent on the degree of inactivation of the unaffected X chromosome—see lyonization), homozygous females have been described; in these females there is co-incidence of a rare immune disorder termed chronic granulomatous disease (CGD).

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. An explanation 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.

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.

Some patients 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.

History

Favism is a disorder characterized by hemolytic anemia in response to ingestion of fava beans. Favism as a diagnosis has been known since antiquity. One theory for the Pythagoreans' avoidance of beans is avoidance of favism, but more likely, this was a philosophical matter, such as the belief that beans and humans were created from the same material.

The modern understanding of the condition began with the analysis of patients who exhibited sensitivity to primaquine. The discovery of G6PD deficiency relieved heavily upon the testing of prisoner volunteers at Illinois State Penitentiary, although today such studies cannot be performed. When some prisoners were given the drug primaquine, some developed hemolytic anemia but others did not. After studying the mechanism through Cr⁵¹ testing, it was conclusively shown that the hemolytic effect of primaquine was due to an internal defect of erythrocytes.