Glucose-6-phosphate dehydrogenase deficiency D55.0

In 1920, the first drug (primaquine an antimalarial drug) was described to cause hemolytic anemia (Luzzatto et al. 2016).

The enzyme G-6-PD was discovered in 1932 by Otto Warburg and Walter Christian.

Glucose-6-phosphate dehydrogenase is an endogenous enzyme that occurs in all cells of the human body and plays an important role in pentose-phosphate metabolism. An X-linked recessive gene defect resulting in a functional deficiency of the enzyme predisposes to damage of erythrocytes by reactive oxygen species.

2 defect variants have been described:

• G6PD A- defect variant A (Africa, Mediterranean region, coloured people in USA and South America).
• G6PD Mediterranean defect variant (Mediterranean region, Middle East, India, Indonesia)

WHO classification: The World Health Organization (WHO) classifies G6PD deficiency into the following 5 classes based on enzyme activity:

• Class I (enzyme activity) < 1% or undetectable. Clinical symptoms: chronic haemolytic anaemia
• Class II (enzyme activity) < 10 %. Clinical signs: acute haemolytic anaemia on fava beans and appropriate drugs.
• Class III (enzyme activity) 10 - 60 %. Clinical signs: occasional haemolytic anaemia.
• Class IV (enzyme activity) 60 - 90 %. Clinical symptoms: asymptomatic
• Class V (enzyme activity) > 110 %. Clinical symptoms: asymptomatic

Remark: The more residual function of the enzyme is present, the less symptoms the patients show. Even hyperfunction of the enzyme is asymptomatic. Classes IV and V are not clinically relevant.

Glucose-6-phosphate dehydrogenase deficiency (G-6-PD deficiency) is the most common enzyme defect worldwide after diabetes mellitus. More than 400 million people worldwide are affected; in Africa the prevalence is estimated to be between 5 - 25 %, in Central Europe < 0.5 %" (Depta et al. 2006). G-6 PD deficiency is common in the tropics and is prevalent in Africa, the Middle East and the Indian subcontinent (Hofmann et al. 2016). There are certain populations that are at higher risk of suffering from G6PD deficiency. These include Kurdish Jews, South Africans, Brazilians, African Americans, Thais, Sardinians, Greeks, Southern Chinese, and Indians. In addition, men are more often affected than women due to genetics (Gautam K et al. 2016).

Glucose-6-phosphate dehydrogenase deficiency is due to an X-linked recessive (as in haemophilia) inherited defect in the gene coding for glucose-6-phosphate dehydrogenase (gene locus: long arm of the X chromosome, Xq28). There are >100 known mutations of the G-6-PD gene. The defect affects all cells, which are now unable to produce this enzyme.

Hemizygous males are mainly affected. Homozygous women (this constellation is rare) are also always affected. Heterozygous women are usually not or hardly affected.

Triggers that trigger oxidative stress in the body include:

• Drugs (see below)
• Pneumoperitoneum (Bhageria et al. 2016).
• Hypothermia
• reperfusion after ischemia (e.g., tourniquet/empty)
• perioperative stress
• Infections
• Metabolic ketoacidosis
• Fava beans (Depta A et al. 2006)
• Drugs: A number of drugs see below) induce oxidative stress in the body by interacting with hemoglobin and with oxygen in erythrocytes, producing hydrogen peroxide (H2O2) as a result. H2O2 is a very powerful oxidant (Glader 2017).
• Infections: Infections are among the most common triggers of hemolytic anemia in patients with G6PD deficiency (Gautam K 2016). Infections are the leading triggers of hemolytic anemia especially in patients who are already aware of this enzyme deficiency and consciously avoid the relevant medications and foods. However, why oxidative stress occurs in the body during infections is not yet fully understood. It is thought that leukocytes produce oxidative substances during phagocytosis. The most common causative agents of hemolytic anemias include:
• Salmonella
• Escherichia coli
• Streptococci (type β-hemolysis).
• Rickettsiae
• Hepatitis viruses
• Influenza A viruses (Gautam K 2016).

The peptide glutathione protects the erythrocyte membrane from oxidative stress by reactive oxygen species (free radicals) by being oxidized itself. GSH provides neutralization of these free radicals such as hydrogen peroxide (H2O2) in the glutathione cycle. H2O2 is reduced to water. In many cells, several enzymes are responsible for NADPH production. In erythrocytes, G-6-PD is exclusively responsible for this task.

In the case of glucose-6-phosphate dehydrogenase deficiency, increased oxidative stress (free oxygen radicals, e.g. due to drugs or other influences) can occur. Reactive oxygen species damage the erythrocyte membrane, resulting in hemolysis. Since there is often a residual activity of the enzyme and NADPH is also produced by other enzymes (e.g. 6-phosphogluconate dehydrogenase, in short: 6PGD), no symptoms are often apparent in the absence of oxidative stress. Only when external triggers increase the demand for NADPH and GSH can the erythrocytes no longer compensate for this and are damaged (Luzzatto L et al. 2016).

In the vast majority of cases, those affected are asymptomatic for life. Only in the case of increased oxidative stress, for example through the consumption of broad beans (the resulting clinical picture is then referred to as favism) or through the intake of various drugs (see below) do the affected individuals become conspicuous through the appearance of the clinical symptoms of haemolysis. These signs often appear 1 - 3 days after the stressful exposure. The following clinical symptoms present themselves:

• Headache, backache, abdominal pain
• Tachycardia
• Dyspnoea
• Lethargy
• Cyanosis
• Reddish-brown discolored urine (hemoglobinuria)
• scleral and/or generalized jaundice
• acute renal failure
• splenomegaly (Depta A et al. 2006).
• The hemoglobin level may drop to 4 mg/dl. Hyperbilirubinemia occurs due to hemolysis (Depta A et al. 2006).

The anamnesis (positive family history, family background in risk areas, known G6PD deficiency or the occurrence of icterus or splenomegaly of unknown cause) is indicative for the diagnosis.

Diagnosis of anaemia: CBC: Usually normochromic and normocytic anaemia, possibly reticulocytosis (in the course). Blood smear: Heinz's internal body

In haemolytic crisis: haemolysis signs possible (LDH, indirect bilirubin increased, haptoglobin decreased), polychromasia possible.

For confirmation, the reduced enzyme activity is detected spectrophotometrically (pathological: reduced activity <60 % - confirmation of diagnosis).

A deficiency exists when the blood level of G-6 PD falls below the normal values (men: 2.70 - 6.62 U/g Hb; women: 3.25 - 7.87 U/g Hb) (Depta et al. 2006).

There is no specific therapy for hemolytic anemia. If hemolysis is diagnosed, the potential trigger should be found. It is important to maintain renal perfusion (Valiaveedan et al. 2011). Depta et al. (2006) also recommend urinary alkalinization with intravenous sodium bicarbonate to prevent precipitation of hemoglobin in the renal tubules with subsequent renal failure (Depta A et al. 2006).

The course of haemolysis varies greatly. In mild cases it is self-limiting; in severe cases it can be life-threatening. The anemia stimulates erythropoiesis in the bone marrow (reticulocytosis with a peak seven to ten days after the onset of hemolysis). The further course depends on the mutation type and the residual activity of the enzyme (WHO classification). Patients of the activity levels "class I and II" show more severe courses of their anemias with worse prognoses. Those from class III will recover more quickly (Glader et al. 2017).

Carry an emergency identification card in case of known enzyme deficiency; avoid triggering factors.

Trigger: Generally, in glucose-6-phosphate dehydrogenase deficiency, hemolysis occurs only when patients ingest triggering substances such as:

• Beans, especially broad beans (Vicia faba, hence the name "favism").
• Peas
• Currants

Triggering drugs are:

• Acetazolamide (sulfonamide)
• Acetylsalicylic acid
• Aminophenazone
• quinine (Limpar®,Quinine® )
• Chloroquine (Resochin®⁾
• Cotrimoxazole (trimethoprim/sulfamethoxazole) (Cotrim®)
• Quinolones (ciprofloxacin, moxifloxacin, norfloxacin, ofloxacin)
• Dapsone (Dapsone-Fatol®)
• Furazolidone
• hydroxychloroquine sulfate (Quensyl®)
• Isoniazid
• Meloquine (Lariam®)
• Metamizole
• Nitrofurantoin
• Phenazone (Eu-Med®)
• Primaquine
• probenecid (Probenecid®)
• Propyphenazone (Optalidon®)
• Sulfonamides
• sulfadiazine (Sulfadiazine®)
• Sulfasalazine (Azulfidine®)
• Sultiam
• Nitrofurans
• Vitamin C
• Nalidixic acid
• Naphthalene (used as moth powder in southern countries. Symptoms can occur when inhaled)

Other

• Rasburicase
• Methylthioninium chloride (methylene blue)
• Tolonium chloride (toluidine blue)
• Dimercaptosuccinic acid (succimer)
• Glibenclamide
• Isosorbide dinitrate (ISDN)
• vitamin C

The following antimalarials are available for 6G-6 PD deficiency:

• Malarone
• Paludrine
• Riamet

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2. Depta A et al. (2006) Anesthesia in patients with glucose-6-phosphate dehydrogenase deficiency: case report and perioperative anesthesiologic management (Electronic version). The Anaesthesiologist 5: 550-554
3. Elyassi AR et al (2009). Perioperative Management of the Glucose-6- Phosphate Dehydrogenase Deficient Patient: A Review of Literature (Electronic version). Anesthesia Progress 56: 86-91
4. Gautam, K. (2016). Glucose-6-phosphate dehydrogenase: History and diagnosis (Electronic version). Journal of Pathology of Nepal 6: 1034-1039.
5. Hofmann S et al (2016) Glucose-6-phosphate dehydrogenase deficiency (Electronic version). SWISS MEDICAL FORUM 16: 241-244
6. Inglin T (2017) Glucose-6-phosphate dehydrogenase deficiency. NDS HF Anesthesia Nursing Course F16.
7. Luzzatto L et al (2016) Glucose-6-phosphate dehydrogenase deficiency (Electronic version). Hematology/oncology Clinics of North America 30: 373-393.
8. Reading NS et al (2016). Favism, the commonest form of severe hemolytic anemia in Palestinian children, varies in severity with three different variants of G6PD deficiency within the same community (Electronic version). Blood Cells, Molecules and Diseases 60: 58-64
9. Valiaveedan S et al. (2011) Anaesthetic management in patients with glucose-6-phosphate dehydrogenase deficiency undergoing neurosurgical procedures (Electronic version). Indian Journal of Anaesthesia 55: 68-70