Favism or G6PD Deficiency: What You Need to Know

You’ve probably heard of or known someone who can’t eat fava beans or can’t take certain medications. This individual has a condition known as G6PD deficiency. What is G6PD and how does it influence your body, making you intolerant to certain foods and medications?

What is G6PD: Glucose 6-Phosphate Dehydrogenase

Glucose 6 phosphate dehydrogenase is an enzyme that accelerates biochemical reactions in the body. Normally it is active in all human cells. In the cells, G6PD is a part of the pentose phosphate pathway.

Pentose phosphate pathway: it is the series of reactions that leads to the synthesis of nucleotides (the units that form the RNA and DNA). This pathway also generates a molecule called NADPH. NADPH plays a role in many pathways in the cells, most importantly it restores the antioxidants molecules.(1)

Anti-oxidants are substances that delay or prevent cells damage, and destruction.

G6PD’s role: G6PD catalyzes the first reaction of the pentose phosphate pathway. Any defect in the enzyme will affect the NADPH generation and thus may lead to cell destruction by accumulation of oxidant molecules.

DEFINITION OF THE G6PD DEFICIENCY

G6PD deficiency is a genetic inherited disease:

• Genetic because, a defect in the gene of the enzyme G6PD, decreases the amount or affects the activity of the enzyme.
• Inherited because it could be carried from one generation to another.

G6PD deficiency is the most common enzyme deficiency in the world, and it is most prevalent in Africa, Asia, and among the Mediterranean Sea populations.

Manifestation of the disease:

• G6PD deficiency affects red blood cells the most. That is because Red Blood Cells rely only on the pentose phosphate pathway to fight the oxidative stress. When the G6PD is deficient red blood cells will lose the ability to fight the excessive oxidative stress (in case of exposure) and will be destructed. This destruction is called hemolysis and is responsible of the symptoms.(2)
• In new born: “ neonatal jaundice” occurs within 24 hours of life
• In adults:
  • The disease is mostly asymptomatic. However, the exposure to factors (fava beans, some medications and infections) that increase the oxidative stress, will trigger the symptoms.
  • Hemolysis begins 24-72hours after exposure to oxidative stress and symptoms include: fatigue, jaundice, dark urine, back pain, increased heart rate, and anemia. Anemia is actually caused by the destruction of red blood cells and the inability of body to replace the lost efficaciously. (3)
  • In rare cases the hemolysis is chronic and leads to a chronic hemolytic anemia.

NOTE: Jaundice or yellow color is due to a yellow pigment called bilirubin produced after the destruction of Red Blood cells. Normally bilirubin is eliminated by the body, but when its production is high (case of a massive hemolysis), it accumulates into the body causing skin and blood mucosa to look yellow.

Classification of the Disease

Class	Enzyme activity	Severity	Hemolysis
I	<10% of normal	Severe	Chronic hemolytic anemia
II	<10% of normal	Severe	Intermittent hemolysis
III	10%-60%	Moderate	Hemolysis in presence of stressors
IV	60%-150%	Mild to none	Not clinically significant
v	>150%	None	Not clinically significant

Medications to avoid:

The medications that increase oxidative stress can trigger the hemolytic anemia when G6PD is deficient. The data regarding the risk of each medication are variable. If you have a G6PD deficiency you should be careful when taking some antibiotics, antidiabetic agents, some diuretic, antimalarial agents and many other treatment…The list below represents the drugs that have a definite risk of hemolytic anemia.

• Dapsone
• Methylene Blue (methylthioninium chloride)
• Nitrofurantoin
• Pegloticase 
• Phenazopyridine
• Primaquine
• Rasburicase
• Tafenoquine 
• Toluidine Blue (tolonium chloride)(5)
• Niridazol(3)
• Pamaquine(3)
• Quinolones (including ciprofloxacin, moxifloxacin, nalidixic acid, norfloxacin, and ofloxacin) (3)
• Sulfonamides (including co-trimoxazole; some sulfonamides, e.g. sulfadiazine, have been tested and found not to be hemolytic in many G6PD-deficient individuals) (3)

Note that there are other drugs that may cause a hemolytic anemia but with less clear evidence therefore you should always refer to your doctor or pharmacist to assess the risk versus benefit of the treatment. See the table below.

Medication(5)	Evidence of hemolytic anemia	Type of evidence	Action
Dapsone-Methylene Blue (methylthioninium chloride)-Nitrofurantoin-Pegloticase -Phenazopyridine-Primaquine (avoid use in patients with severe G6PD deficiency; assess risk vs benefit in those with mild to moderate deficiency and monitor hematologic parameters closely) – Rasburicase-Tafenoquine -Toluidine Blue (tolonium chloride)	Well established	case reports, clinical studies, and laboratory evidence	Avoid use
Cotrimoxazole (sulfamethoxazole/trimethoprim)-Sulfadiazine-Nalidixic acid-Ciprofloxacin-Ofloxacin	Reported	At least 1 well documented case report;.	the potential for drug-induced hemolytic anemia should be considered
Acetaminophen-Aspirin (high doses)-Ascorbic acid-Chloramphenicol-Chloroquine-Glyburide-Isoniazid-Isosorbide Dinitrate-Phytonadione (Vitamin K)-Quinine-Sulfasalazine	possible	limited data	the potential for drug-induced hemolytic anemia should be considered depending on (dosage, other concomitant drugs, comorbidity and other factors)

References

1. Glucose-6-phosphate dehydrogenase, NADPH, and cell survival – PubMed [Internet]. [cited 2022 Aug 20]. Available from: https://pubmed.ncbi.nlm.nih.gov/22431005/

2. Antioxidant Defense Mechanisms in Erythrocytes and in the Central Nervous System – PubMed [Internet]. [cited 2022 Aug 20]. Available from: https://pubmed.ncbi.nlm.nih.gov/30781629/

3. Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Clinical Presentation: History, Physical Examination [Internet]. [cited 2022 Aug 20]. Available from: https://emedicine.medscape.com/article/200390-clinical#

4. Harcke SJ, Rizzolo D, Harcke HT. G6PD deficiency: An update. JAAPA. 2019 Nov;32(11):21–6.

5. Drug Consult – MICROMEDEX [Internet]. [cited 2022 Aug 21]. Available from: https://www.micromedexsolutions.com/micromedex2/librarian/CS/5DFADB/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/B318CB/ND_PG/evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/evidencexpert.IntermediateToDocumentLink?docId=1286&contentSetId=50&title=Drug-Induced+Hemolytic+Anemia+in+Patients+with+Glucose-6-Phosphate+Dehydrogenase+%28G6PD%29+Deficiency&servicesTitle=Drug-Induced+Hemolytic+Anemia+in+Patients+with+Glucose-6-Phosphate+Dehydrogenase+%28G6PD%29+Deficiency