Glucose6phosphate Dehydrogenase Deficiency

There are a limited number of inherited disorders of red cells related to biochemical deficiencies. Glucoses-phosphate dehydrogenase (G6PD) deficiency represents a fascinating and far-reaching disorder that has at its core a metabolic misstep. G6PD is the catalyst in the first stages of the oxidative portion of the red cell's metabolism and a key player is the phosphogluconate pathway, whose role it is to keep glutathione in the reduced state. Glutathione is the chief red cell antioxidant and serves to protect the red cell from oxidant stress due to peroxide buildup and other compounds or drugs. The pathway to reduced glutathione is initiated when NADP (nicotinamide adenine dinucleotide phosphate) is converted to NADPH by the action of G6PD, an essential enzyme in the hexose monophosphate shunt. Once this occurs, NADPH converts oxidized glutathione to reduced glu-tathione and the red cell is protected.

The Genetics of Glucose-6-Phosphate Dehydrogenase Deficiency

G6PD deficiency is the most common human enzyme deficiency in the world, present in over 400 million people.17 This is a staggering number of affected individuals, yet this disease has an extraordinarily low profile for reasons we will soon understand. G6PD was discovered in America in 1950, when healthy black soldiers developed hemolysis as a result of primaquine antimalarial drugs. The populations most affected are in West Africa, the Middle East, Southeast Asia, and other Mediterranean ethnicities. G6PD is inherited as an X-linked recessive disorder with mother-to-son transmission. Women are conductors of the aberrant genes, and if they pass this gene to their male children, the child will inherit the disease. In heterozygous females, two populations of cells have been observed: a normal cell population and a G6PD cell population. The expression of G6PD deficiency is highly variable among heterozygotes and may at times cause disease. Homozygous females will manifest the disease. The human purified G6PD gene has 531 amino acids and is located near the genes for factor 8 and color blindness. Over 400 variants have been named, and many of the variants are caused by amino acid substitutions.18 There are five known genotypes: two are normal and three are abnormal with varying amounts of hemolysis (Table 7.2). G6PD-deficient individuals are also afforded protection during malarial infections.19 For a Web-accessible database that details locus-specific mutations, see http:// www.bioinf.org.uk/g6pd/.

Clinical Manifestations of Glucose-6-Phosphate Dehydrogenase Deficiency

Acute Hemolytic Anemia

Four clinical conditions are associated with G6PD deficiency: drug-induced acute hemolytic anemia, favism, neonatal jaundice, and congenital nonspherocytic anemia. Classically, individuals with G6PD are hematologi-cally normal and totally unaware that they possess a variant G6PD genotype. For whatever reason, they become exposed to a drug or have an infection and develop a self-limited but frightening hemolytic episode. Eventually, their G6PD status is investigated, and if a diagnosis is made, it becomes part of their medical record. Affected individuals are then made aware of a growing list of drugs that may cause hemolysis if injected or ingested. In a drug-induced process or an infection-induced hemolytic process, the patient experiences nausea, abdominal pain, and rapidly decreasing hematocrit within a 24- to 48-hour period. The level of hemolysis is alarming as the hemoglobin and hemat-ocrit drop quickly and the intravascular lysis manifests as hemoglobinuria in which the urine has the color of Coca Cola, port wine, or strong tea.20 The LDH and reticulocytes are increased, while the anemia is nor-mochromic and normocytic with the bone marrow showing erythroid hyperplasia. The peripheral smear shows marked polychromasia and a few bite cells. Bite cells (Fig. 7.8) are formed as Heinz bodies and are pitted from the red cells by the spleen. Heinz body inclusions (Fig. 7.9) are large inclusions (0.2 to 3 pm) that are rigid, distort the cell, and hang on the cell periphery (see Chapter 3). These inclusions are formed from denatured or precipitated hemoglobin that occurs in the G6PD-deficient individual on exposure to the oxidizing agent, because the lack of the G6PD enzyme causes oxidative destruction of the red cell. Heinz bodies are not visible on Wright's stain but may be seen when blood cells are stained with supravital stains such as crystal violet. The formation of Heinz bodies may be induced experimentally with phenylhydrazine. As the inclusion-laden red cells pass through the spleen, the Heinz bodies are pitted from the cell surface and what remains are bite or helmet cells (Fig. 7.10). Heinz bodies and subsequently bite cells are a transitory finding in G6PD-deficient individuals. The absence of this particular morphology cannot be used as a definitive argument against this diagnosis. Fortunately, for individuals who have a drug-induced hemolytic event, the hemato-

Table 7.2 O Genotypes of G6PD

GdB+ Normal genotypes

GdA+ Normal genotype but mutated gene

GdA— Abnormal genotype in 11% of American black males

Gd Med Abnormal genotype seen in whites, those of Mediterranean origin, Kurdish Jews

Gd Canton Abnormal genotype seen in Thailand, Vietnam, other Asian populations

Nonspherocytic Hemolytic Anemia
Figure 7.8 Bite cells.

104 Part II • Red Cell Disorders

104 Part II • Red Cell Disorders

G6pd Heinz Body

Figure 7.9 Heinz bodies.

Table 7.3 O Modified List of Compounds That May Cause Hemolysis in G6PD-Deficient Individuals

Aspirin

Phenacetin

Chloroquine

Chloramphenicol

Sulfacetamide

Naphthalene

Vitamin K

Figure 7.9 Heinz bodies.

logical consequences are self-limiting; however, individuals with G6PD variants must be cautioned about their drugs or chemicals known to provoke a hemolytic episode in susceptible individuals (Table 7.3).

Favism

The second most severe clinical condition is favism. Favism is usually found in individuals of the G6PD Mediterranean or Canton type. Hours after ingesting young fava beans or broad beans, the individual usually becomes irritable and lethargic. Fever, nausea, and abdominal pain follow, and within 48 hours gross hemoglobinuria may be noted. Heinz bodies may or may not be observed. Patients present with a nor-mochromic, normocytic process with polychromasia, decreased haptoglobin, and increased bilirubin. There have been incidents of favism from individuals inhaling fava beans pollen or from babies nursed by a mother who unknowingly transmitted fava bean metabolites in their milk. Fava beans, however, trigger hemolytic episodes in only 25% of those deficient individuals.

Neonatal Jaundice

Neonatal jaundice (NNJ) related to G6PD deficiency occurs within 2 to 3 days after birth. In contrast to hemolytic disease of the newborn, patients with neonatal jaundice show more jaundice than anemia. Early recognition and management of the rising bilirubin are essential to prevent neurological complications (such as kernicterus) in these infants. Data on infants from Malaysia, the Mediterranean, Hong Kong, and Thailand have shown the incidence of NNJ to be quite frequent. Of note also is the increased sensitivity of these individuals to vitamin K substitutes, triple dye used to treat umbilical cords, and camphorated powder. These substances may cause a deterioration of the hematological

Splenic cord

Red cell with Heinz bodies

Basement membrane of spleen

Splenic cord

Basement membrane of spleen

Bite Cell Spleen

Red cell with Heinz bodies

Red cell squeezes through

Resealing of red cell membrane, leaving bite out deformity

Undeformable Heinz bodies torn away

Figure 7.10 Schematic representation of bite cell formation.

Red cell squeezes through

Resealing of red cell membrane, leaving bite out deformity

Undeformable Heinz bodies torn away

Figure 7.10 Schematic representation of bite cell formation.

state. Phototherapy (intense light therapy) and transfusion support are used to treat affected infants.

Congenital Nonspherocytic Hemolytic Anemia

The final clinical condition is congenital nonspherocytic hemolytic anemia (CNSHA). Patients who have this condition have a history of neonatal jaundice complicated by gallstones, enlarged spleen, or both and may be investigated for jaundice or gallstones in their adult life. The anemia varies in severity from minimum to transfusion dependent. Splenectomy may be considered provided the appropriate management is in place, that is, prophylactic therapy and management. The clinical picture suggests a chronic hemolysis that is mainly extravascular with hyperbilirubinemia, decreased hap-toglobin, and increased reticulocytes.

Diagnosis of Glucose-6-Phosphate Dehydrogenase Deficiency

The detection of G6PD deficiency in an individual is complicated by the many genetic variants, the heterozy-gosity of the disorder, and the fact that young red cells show an increased enzyme level just by virtue of age. Several technical considerations must be kept in mind when determining a person's enzyme status. Appropriate timing of the test is critical for accurate results. If G6PD deficiency is considered during an acute hemolytic episode, reticulocytes will be pouring from the bone marrow into the peripheral circulation. Therefore, testing should be performed once the hemolytic episode has resolved and the counts have returned to normal. Enzyme assay of older red cells are recommended. The entire picture, including clinical presentation, CBC, peripheral smear, and the enzyme status, must be analyzed before a diagnosis is made.

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Responses

  • egidio
    How are bite cells formed?
    4 years ago

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