Iv

B (Normal)

100% of normal activity

No hemolysis

Pathogenesis

1. Red cell G6PD activity falls rapidly and prematurely as red cells age

2. Decreased glucose metabolism

3. Diminished NADPH/NADP and GSH/GSSG ratios

4. Impaired elimination of oxidants (e.g., H2O2)

5. Oxidation of hemoglobin and of sulfhydryl groups in the membrane

6. Red cell integrity impaired, especially on exposure to oxidant drugs and chemicals.

Clinical Features

Episodes of hemolysis may be produced by:

• Fava bean (broad bean, Vicia fava): ingestion or exposure to pollen from the bean's flower (hence favism)

• Infection (in more susceptible subjects).

1. Drug-induced hemolysis a. Typically in African Americans but also in Mediterranean and Canton types b. List of drugs (see Table 7-7); occasionally need additional stress of infection or the neonatal state c. Acute self-limiting hemolytic anemia with hemoglobinuria d. Heinz bodies in circulating red cells e. Blister cells, fragmented cells, and spherocytes f. Reticulocytosis g. Hemoglobin normal between episodes

Table 7-7. Agents Capable of Inducing Hemolysis in G6PD-Deficient Subjects"

Clinically significant hemolysis

Usually not clinically significant hemolysis

Analgesics and antipyretics

Acetanilid

Antimalarial agents

Pentaquine Pamaquine Primaquine Quinocide

Sulfonamides

Sulfanilamide

N-Acetylsulfanilamide

Sulfapyridine

Sulfamethoxypyridazine (Kynex) Salicylazosulfapyridine (Azulfidine)

Nitrofurans

Nitrofurazone (Furacin) Nitrofurantoin (Furadantin) Furaltadone (Altafur) Furazolidone (Furoxone)

Sulfones

Thiazolsulfone (Promizole) Diaminodiphenylsulfone (DDS, dapsone)

Miscellaneous

Naphthalene

Phenylhydrazine

Acetylphenylhydrazine

Toluidine blue

Nalidixic acid (NegGram)

Neoarsphenamine (Neosalvarsan)

Infections

Diabetic acidosis

Acetophenetidin (phenacetin) Acetylsalicylic acid (large doses) Antipyrineab Aminopyrineb p-Aminosalicyclic acid

Quinacrine (Atabrine)

Quinineb

Chloroquinec

Pyrimethamine (Daraprim) Plasmoquine

Sulfadiazine Sulfamerazine Sulfisoxazole (Gantrisin)c Sulfathiazole Sulfacetamide

Sulfoxone sodium (Diasone)

Menadione Dimercaprol (BAL) Methylene blue Chloramphenicol6 Probenecid (Benemid) Quinidine6 Fava beans6

"Many other compounds have been tested but are free of hemolytic activity. Penicillin, the tetracyclines, and erythromycin, for example, will not cause hemolysis, and the incidence of allergic reactions in G6PD-deficient persons is not any greater than that observed in others. Any drug, therefore, not included in the list of those known to cause hemolysis may be given. bHemolysis in Caucasians only.

cMild hemolysis in African Americans, if given in large doses.

2. Favism a. Acute life-threatening hemolysis, often leading to acute renal failure caused by ingestion of fava beans b. Associated with Mediterranean and Canton varieties c. Blood transfusion required

3. Neonatal jaundice a. Usually associated with Mediterranean and Canton varieties b. Infants may present with pallor, jaundice (can be severe and produce ker-nicterus*), and dark urine.

Often no exposure to drugs; occasionally exposure to naphthalene (mothballs), aniline dye, marking ink, or a drug. In a majority of neonates, the jaundice is not hemolytic but hepatic in origin.

4. Chronic nonspherocytic hemolytic anemia a. Occurs mainly in people of northern European origin b. Hematologic picture

(1) Chronic nonspherocytic anemia

(2) Reticulocytosis

(3) Shortened red cell survival

(4) Increased autohemolysis with only partial correction by glucose

(5) Slight jaundice

(6) Mild splenomegaly.

Treatment

1. Avoidance of agents that are deleterious in G6PD deficiency

2. Indication for transfusion of packed red blood cell in children presenting with acute hemolytic anemia:

a. Hemoglobin (Hb) level below 7 g/dL

b. Persistent hemoglobinuria and Hb below 9 g/dL

3. Chronic nonspherocytic hemolytic anemia (NSHA):

a. In patients with severe chronic anemia: transfuse red blood cells to maintain Hb level 8-10 g/dL and iron chelation, when needed b. Indications for splenectomy

(1) Hypersplenism

(2) Severe chronic anemia

(3) Splenomegaly causing physical impediment c. Genetic counseling and prenatal diagnosis for severe CNSHA if the mother is a heterozygote.

Other Defects of Glutathione Metabolism

Glutathione Reductase

In this autosomal dominant disorder, hemolytic anemia is precipitated by drugs having an oxidant action. Thrombocytopenia has occasionally been reported. Neurologic symptoms occur in some patients.

Glutamyl Cysteine Synthetase

In this autosomal recessive disorder, there is a well-compensated hemolytic anemia. Glutathione Synthetase

In this autosomal recessive disorder, there is a well-compensated hemolytic anemia, exacerbated by drugs having an oxidant action.

*The excessive jaundice is not only due to hemolysis but may be due to reduced glucuronidation of bilirubin caused by defective G6PD activity in the hepatocytes.

Glutathione Peroxidase

In this autosomal recessive disorder, acute hemolytic episodes occur after exposure to drugs having an oxidant action.

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