Navy Medical Department Guide to Malaria Prevention and Control

Chapter 5: Glucose-6-Phosphate Dehydrogenase Deficiency

Department of the Navy
Bureau of Medicine and Surgery

Overview

The recognition of Glucose-6-Phosphate Dehydrogenase (G-6-PD) deficiency was the direct result of investigations of the hemolytic effect of the drug primaquine in the 1950s. G-6-PD is the first enzyme of the hexose monophosphate shunt, a biochemical pathway crucial in the protection of red blood cells. Damage done to hemoglobin molecules (See Table 5-1) by oxidizing drugs or chemicals is neutralized or reversed by substances that the hexose monophosphate shunt produces.

Primaquine is the only currently available drug able to destroy dormant hypnozoites in liver cells and prevent relapse of P. vivax or P. ovale malaria. Unfortunately, it is a strong oxidizing agent, and can cause severe hemolytic anemia in G-6-PD deficient personnel. In the U.S. military population, 2 types of G-6-PD deficiency are common. Understanding the difference between these types, and the primaquine treatment schedules available for each, can minimize or prevent complications from drug reactions, and allow treatment of the relapsing forms of malaria.

Physiology of G-6-PD Deficiency

Red blood cells are normally protected from oxidizing substances in a complex chemical pathway in which G-6-PD is an essential enzyme. In G-6-PD deficient red blood cells, this protective mechanism is compromised and oxidizing substances produced by infections or oxidant drugs damage hemoglobin molecules. In this harmful process, hemoglobin is denatured irreversibly and precipitates in clumps of protein called Heinz bodies. Heinz bodies attach to red blood cell membranes, deforming the cells, and are filtered from circulation by the spleen. Free hemoglobin is released into the blood

Table 5-1. Summary of Hemolysis in G-6-PD Deficiency

from the destroyed red blood cells. If a large number of red blood cells are destroyed, the human body's normal compensatory mechanisms are overwhelmed. The amount of hemoglobin released into the bloodstream may be too great to be absorbed and metabolized by the liver, resulting in hemoglobinuria and kidney damage. Anemia may also occur if the loss of red blood cells is too great to be compensated by an increase in the rate of reticulocytosis. The extent of hemolysis depends on the type and severity of G-6-PD deficiency, and the amount of exposure to oxidizing substances (see Table 5-2).

G-6-PD Types. The gene for G-6-PD is located on the X chromosome(s). Severe deficiency is fully expressed in males and rare in females. Over 200 variants have been identified. In the U.S. military, the two types that are often encountered are G-6-PD ^A-, found in 16% of Afro-American males, and the more rare G-6-PD^Med found in Greeks, Sardinians, Sephardic Jews, Arabs, and other males of Mediterranean descent.

Table 5-2. Drugs and Chemicals that Should be Avoided by G-6-PD Deficient Individuals

As normal red blood cells age, the activity of G-6-PD decays slowly, reaching 50% of its original level in 60 days. Despite this loss, normal red blood cells retain enough activity to sufficiently protect red blood cells from oxidants. G-6-PD decay is significantly pronounced in deficient individuals. G-6-PD^A- declines to 50% of baseline activity in 13 days, while G-6-PD^Med declines to 50% of baseline activity in 1-2 days. In G-6-PD ^A- deficiency, young red blood cells have normal enzyme activity, while older cells are grossly deficient. In G-6-PD^Med virtually all red blood cells are deficient. Thus, hemolysis is self limited in individuals with G-6-PD^A-, ending when older red blood cells are destroyed. In G-6-PD^Med hemolysis is much more severe, as all red blood cells are at risk (see Table 5-3).

Most cases of drug induced hemolytic reactions related to G-6-PD ^A- deficiency are probably sub-clinical. During the Vietnam War, only 20 persons were documented to have developed a severe drug reaction because of G-6-PD deficiency. At that time, chloroquine-primaquine tablets were given weekly to service members as malaria prophylactic therapy, and routine G-6-PD testing was not done. As thousands of service members were required to take the weekly prophylaxis, 20 cases were much less than expected. It is probable that the reactions that occurred were due to G-6-PD^Med, not G-6-PD^A-.

Table 5-3. Clinical Comparison: G-6-PD ^A- and G-6-PD^Med

Signs and Symptoms of Hemolysis. Signs and symptoms appear 1-3 days after initiation of drug therapy. Shortness of breath, rapid pulse, hemoglobinuria (brown or black urine), and fatigue are common clinical manifestations. In mild cases, shortness of breath, rapid pulse, and fatigue appear during or after physical exertion. A modest decline in hemoglobin (3-4 mg/dl) occurs without hemoglobinuria. Most of these cases are easily overlooked unless caregivers are alert.

If hemolysis is markedly severe, shortness of breath, rapid pulse, palpitations, and fatigue can present at rest. Some patients complain of abdominal or back pain. Signs include hemoglobinemia (pink to brown plasma), hemoglobinuria, and jaundice. Heinz bodies can be seen if red blood cells are stained using methyl violet.

Laboratory Analysis. Urine dipstick and hematocrit are simple and useful screening tools that can be done in the field. Hemoglobin (blood), bilirubin (urobilinogen), and protein should be monitored when using urine dipsticks to screen for hemolysis. It is important to differentiate the "blood" identified by urine dipstick as free hemoglobin or as red blood cells (hematuria). Hemoglobin in urine is present when red blood cells are destroyed in the hemolytic process, while intact red blood cells are present due to another pathologic process. Hematocrit testing, if performed, should be compared to baseline values. If facilities are available, other useful laboratory tests include blood and plasma hemoglobin levels, plasma haptoglobin level, reticulocyte count, lactose dehydrogenase level, and identification of Heinz bodies.

Primaquine Use in G-6-PD Deficient Personnel

G-6-PD Screening and Documentation. All Navy and Marine Corps personnel are tested for G-6-PD deficiency. Testing is qualitative, determining the presence of G-6-PD deficiency, but not the type or severity. Members who test positive must be informed of the deficiency, the signs and symptoms they may experience and why they may occur, and the risks of taking oxidant medications. They also should be advised to consult with their unit corpsman or medical officer if malaria medications are administered to them.

The results of G-6-PD screening must be recorded in individual medical records, along with an entry documenting individual counseling of their deficiency. Unit medical records should be checked periodically to ensure that G-6-PD and other important information such as immunization status, blood type, etc., are recorded. If the information is not available, testing should be repeated. Use of spreadsheet software and microcomputers is an excellent medium for maintenance of unit medical readiness data.

Current Navy policy prohibits primaquine prophylaxis of G-6-PD deficient service members. If, in the future, treatment of G-6-PD deficient personnel is authorized, testing for the specific type of deficiency is recommended. Once tested, such personnel should be informed of the type and details of their deficiency. If test information is not available as to an individual's specific type of deficiency when terminal primaquine prophylaxis is sanctioned, the dosage regimen should be given based on demographic data. These data support the assumptions that G-6-PD deficiency in Afro-American personnel is the G-6-PD^A- type, and personnel of European descent have the G-6-PD^Med type.

Terminal Primaquine Prophylaxis/Treatment. Primaquine remains the only drug available for treatment of the relapsing types of malaria. It can be used safely in G-6-PD deficient personnel under close medical supervision. Doses must be given less often and over a longer period of time to avoid a serious hemolytic reaction. Ensuring treatment compliance will be challenging, as the primaquine regimen consists of 24 doses over 8 weeks in G-6-PD^A- deficient personnel, and 60 doses over 30 weeks in G-6-PD^Med deficient personnel (see table 5-4).

Monitoring. If, in the future, primaquine prophylaxis of G-6-PD deficient personnel is authorized, monitoring of deficient members is recommended. G-6-PD deficient personnel taking primaquine should be advised to seek medical evaluation if any symptoms or change in urine color occur. A simple urine dipstick and/or hematocrit performed 3 to 4 days after the initial dose and checked periodically would identify severe cases of hemolysis.

Therapy of Drug Reaction. If hemolysis occurs, particularly in G-6-PDA- deficient persons, transfusion is usually not required. Hemolytic episodes are usually self-limited, even if drug administration is continued. This is not the case with the more severe G-6-PDMed deficiency and drug treatment should be stopped. If the rate of hemolysis is rapid, transfusion of whole blood or packed cells may be useful. Good urine flow should be maintained in patients with hemoglobinuria to prevent kidney damage. Folic acid may be beneficial as in other patients with increased bone marrow activity (an increase in bone marrow activity is caused by red blood cell formation).

Table 5-4. Primaquine Treatment Regimens

*1 tablet consists of 26.3 mg primaquine phosphate, 15 mg primaquine base.

Approved for public release; Distribution is unlimited.

The listing of any non-Federal product in this CD is not an endorsement of the product itself, but simply an acknowledgement of the source. 

Operational Medicine 2001

Health Care in Military Settings

This web version is provided by The Brookside Associates Medical Education Division.  It contains original contents from the official US Navy NAVMED P-5139, but has been reformatted for web access and includes advertising and links that were not present in the original version. This web version has not been approved by the Department of the Navy or the Department of Defense. The presence of any advertising on these pages does not constitute an endorsement of that product or service by either the US Department of Defense or the Brookside Associates. The Brookside Associates is a private organization, not affiliated with the United States Department of Defense.

Contact Us  ·  ·  Other Brookside Products