Pathology > Basic Hematology > Red Cell Disorders > Enzyme Deficiences

Enzyme Deficiencies

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is the most common enzyme deficiency known to cause hemolysis. G-6-PD reduces NADP (nicotinamide-adenine-dinucleotide phosphate) to NADPH. NADPH reduces oxidized glutathione (GSSH) to its reduced form GSH. GSH prevents oxidation of RBC membranes and hemoglobin.

More than 200 million people, mainly Mediterranean, West African, Mid-East, and Southeast Asian populations, are estimated to be G-6-PD deficient.

The deficiency is sex-linked (M>F), but with varying degrees of deficiency - mild in blacks and severe in Mediterranean populations. Blacks often have an episodic variant in which oxidant compounds such as antimalarials, sulfonamides, or infections cause hemolysis. In Mediterranean populations G-6-PD deficiency may result in a chronic hemolysis. Women heterozygotes (half the normal amount of RBC) G6PD show increased resistance to P falciparum.

Stressors of the G6PD System

antimalarials
sulfonamides
nitrofurans
phenacetin
synthetic vitamin K
naphthalene (moth balls)
fava beans
infection
diabetic ketoacidosis

G6PD deficiency is usually asymptomatic.

During times of oxidant stress the PBS usually shows spherocytes, schistocytes, and "bite" cells and "blister" cells where denatured hemoglobin (Heinz bodies) were removed in the spleen.

G6PD enzyme assays reveal relatively high levels in reticulocytes and young erythrocytes, declining in older RBCs. In hemolysis it is the older cells which destroyed. Because of this hemolysis is usually self-limited.

Pyruvate kinase deficiency an autosomal recessive disorder causing polychromasia, anisocytosis, poikilocytosis with burr cells and acanthocytes, and NRBCs.

Reduced ATP formation causes RBC membrane rigidity, resulting in hemolysis. Symptoms are usually mild as increased 2,3-DPG causes a right shift of the 02-dissociation curve.

Persons homozygote for PK deficiency show severe anemia and are usually discovered in childhood. Splenomegaly, cholelithiasis and jaundice are frequent.

Methemoglobin is hemoglobin that has been oxidized from the ferrous (Fe++) to the ferric (Fe+++) state, thus unable to bind oxygen. The NADH- methemoglobin reductase enzyme reduces methemoglobin to hemoglobin. Methemoglobinemia results from either inadequate enzyme activity or too much methemoglobin production.

Hereditary autosomal recessive deficiency of NADH-methemoglobin reductase presents with cyanosis because methemoglobin cannot carry oxygen. The cyanosis is usually mild, but if severe can be treated with IV methylene blue, activating NADH- methemoglobin reductase.

Methemoglobin production may exceed the capacity of the normal NADH-

methemoglobin reductase pathway. This can be acquired due to drug or toxic oxidation of hemoglobin (analine dyes, anesthetics-benzocaine; prilocaine, naphthalene, nitrates, nitrites, nitroglycerin, paraquat, phenazopyridine, sulfamethoxazole, trimethadione, etc.).

Certain single amino acid substitutions within a hemoglobin globin chain can cause the iron to stabilize in the ferric state.

Related is the carboxyhemoglobin that results from carbon monoxide binding to hemoglobin. Hemoglobin binds CO more tightly than oxygen by a factor of 200. The tissues are deprived of oxygen.

Co poisoning produces massive amounts of carboxyhemoglobin causing a cherry pink discoloration of the brain.

 

HEMATOPATHOLOGY

If in an inherited M hemoglobin the amino acid substitution was in the ß-globin chain would you expect cyanosis:

A. To cause fetal death
B. At birth
C. At 6 months
D. As an adult only
E. Not to occur

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