Favism (G6PD Deficiency): Symptoms, Diagnosis, and Drugs to Avoid

What is Favism (G6PD Deficiency)?

“Favism” is the common term used to describe a genetic disease linked to the X chromosome, characterized by a deficiency of a specific enzyme: glucose-6-phosphate dehydrogenase (G6PD). This enzyme is found primarily in red blood cells (erythrocytes), where it plays a critical role in protecting them from oxidative damage and ensuring their survival.

When G6PD is deficient or absent, red blood cells become vulnerable to oxidative stress. Exposure to certain triggers causes premature destruction of red blood cells. This process, known as hemolysis, leads to acute hemolytic crises that present with the following symptoms:

• Jaundice (yellowish discoloration of the skin and mucous membranes),
• Abdominal pain,
• Anemia (reduced number of circulating red blood cells),
• Dark-colored urine (due to hemoglobin released from destroyed red blood cells),
• Splenomegaly (enlargement of the spleen, the organ responsible for removing damaged red blood cells from circulation).

These crises are triggered by exposure to specific substances or situations, including:

• Foods (most notably fava beans and peas),
• Infections,
• Medications (a wide range of commonly used drugs),
• Inhalation of naphthalene (found in mothballs) or other toxic substances.

A note on terminology: The term “favism” is widely used, but it is technically imprecise. Not all individuals with G6PD deficiency experience a hemolytic crisis after eating fava beans, and many triggers are entirely unrelated to food.

G6PD deficiency is diagnosed based on the clinical picture (correlating symptom onset with exposure to trigger substances) and confirmed through blood tests.

There is currently no cure that corrects the underlying enzyme deficiency. Management is based entirely on prevention (avoiding all known triggers). In severe cases, additional medical interventions may be required, including:

• Blood transfusion to restore hemodynamic stability,
• Splenectomy (surgical removal of the spleen, where the majority of damaged red blood cells are destroyed).

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Causes

G6PD deficiency is the most common enzyme deficiency in the world, affecting over 400 million people globally. It is particularly prevalent in:

• Sub-Saharan Africa,
• The Middle East,
• The Mediterranean basin (Greece, Italy, Spain, and surrounding regions),
• Southeast Asia.

Why Is It So Common in These Regions?

This remarkably high prevalence is not coincidental. Carriers of the G6PD mutation have been shown to have a natural selective advantage against malaria (caused by Plasmodium falciparum). The parasite is less able to survive and replicate inside G6PD-deficient red blood cells, which tend to be destroyed more rapidly. This evolutionary pressure has maintained the mutation at high frequencies in malaria-endemic regions.

How Does G6PD Deficiency Cause Hemolysis?

G6PD’s primary function in red blood cells is to protect them from oxidative damage by generating NADPH. This molecule is essential for neutralizing reactive oxygen species, also known as free radicals. When G6PD is deficient:

• The red blood cell’s antioxidant defenses are impaired,
• Oxidative stress accumulates inside the cell,
• The red blood cell membrane and hemoglobin are damaged,
• The structurally compromised cell is recognized and destroyed (phagocytized) by the spleen.

This process of premature red blood cell destruction, known as hemolysis, is significantly accelerated when the individual is exposed to oxidizing agents, such as:

• Foods: primarily fava beans (Vicia faba), peas, and other legumes,
• Medications: analgesics, antipyretics, antimalarials, sulfonamides, and many others (see full list in the Prevention section),
• Infections: particularly pneumonia and hepatitis, which generate systemic oxidative stress.

Genetics: An X-Linked Disorder

Favism is caused by mutations in the G6PD gene, located on the X chromosome. Because males have only one X chromosome (inherited from their mother), they are more frequently and severely affected:

• A male carrying the mutation on his single X chromosome will develop the disease.
• A female has two X chromosomes. If only one carries the mutation, she is typically a healthy carrier. She does not develop symptoms but can transmit the mutation to her sons, who will be affected.

Females can only develop clinical disease if they are homozygous, meaning they have a mutation on both X chromosomes. This scenario is much rarer.

Classification

The World Health Organization (WHO) classifies G6PD deficiency into five classes based on residual enzyme activity and clinical severity:

• Class I is the most severe, presenting as a chronic hemolytic anemia that is present even without known triggers.
• Classes II and III manifest as intermittent, self-limiting hemolytic crises, predominantly triggered by oxidizing substances.
• Classes IV and V produce no symptoms and require no treatment.

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Symptoms

The majority of individuals with G6PD deficiency are completely asymptomatic throughout their lives and may be entirely unaware of their condition.

When exposed to a specific trigger, susceptible individuals may develop an acute hemolytic crisis. This reaction is usually self-limiting and resolves spontaneously within a few days after removing the offending agent.

Timing of Symptoms

Symptoms typically appear 12 to 48 hours after:

• Ingestion of fava beans, peas, or other triggering foods,
• Starting a medication known to trigger hemolysis,
• The onset of an infectious episode.

Mechanism of Jaundice and Dark Urine

As red blood cells are destroyed, large quantities of hemoglobin are released into the bloodstream. This hemoglobin is metabolized into bilirubin, whose accumulation causes:

• Jaundice: yellowish discoloration of the skin and mucous membranes, most visibly in the whites of the eyes (sclera),
• Dark or brown urine (hemoglobinuria): hemoglobin is filtered by the kidneys and appears in the urine.

In newborns, elevated bilirubin during a hemolytic crisis can cross the blood-brain barrier and deposit in the brain. This life-threatening condition, called kernicterus, can cause permanent neurological damage. Neonatal jaundice in G6PD-deficient infants must be treated urgently with phototherapy or, in severe cases, exchange transfusion.

Full Spectrum of Symptoms During a Hemolytic Crisis

• Anemia (pallor, fatigue),
• Nausea and vomiting,
• General weakness and malaise,
• Abdominal pain,
• Hemoglobinuria (hemoglobin in the urine, giving it a dark, cola-like color),
• Fever with chills,
• Dyspnea (difficulty breathing),
• Cardiovascular collapse / shock in severe cases,
• Splenomegaly (enlargement of the spleen due to increased red blood cell destruction).

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Diagnosis

Clinical History (Anamnesis)

The diagnostic process begins with a detailed medical history. The physician will investigate:

• The exact nature and timing of symptoms,
• Whether there is a clear temporal correlation between symptom onset and exposure to oxidizing foods, medications, or an infectious illness,
• Family history of favism or unexplained hemolytic anemia.

Physical Examination

The physical exam focuses on identifying the hallmark signs of hemolysis:

• Jaundice (yellowing of skin and sclera),
• Abdominal tenderness,
• Dark urine,
• Splenomegaly (detectable on abdominal palpation or ultrasound).

Laboratory Tests

Blood and urine tests typically reveal:

Specific Enzyme Assay

The G6PD enzyme activity test (fluorescent spot test or spectrophotometric assay) directly measures the residual enzymatic activity in red blood cells. This is the definitive biochemical diagnostic test.

Important caveat: Testing immediately after an acute crisis may yield falsely normal results, because the most severely G6PD-deficient cells have already been destroyed, leaving behind a population of less-affected, younger red blood cells (reticulocytes) with relatively preserved enzyme activity. Testing should ideally be performed 3–4 months after the acute episode to obtain a reliable baseline result.

Genetic Testing

Molecular genetic analysis can identify specific mutations in the G6PD gene, confirm the diagnosis in ambiguous cases, and is useful for family screening and carrier detection in females.

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Treatment

There is currently no pharmacological treatment that corrects or restores G6PD enzyme function. Management is therefore focused on:

1. Removing the Triggering Agent

The most important immediate action during an acute crisis is to identify and eliminate the offending substance. This means stopping the medication, treating the underlying infection, or removing the dietary trigger.

2. Supportive Care

Most acute hemolytic crises are self-limiting and resolve spontaneously within 7–10 days once the trigger is removed. Supportive care includes:

• Adequate hydration to protect the kidneys from hemoglobin-induced damage (hemoglobin precipitation in renal tubules can cause acute kidney injury),
• Monitoring of hemoglobin levels, renal function, and bilirubin.

3. Blood Transfusion

In severe cases with profound anemia or hemodynamic instability, blood transfusion of packed red blood cells may be necessary to restore adequate oxygen-carrying capacity.

4. Dialysis

Patients who develop acute kidney injury as a complication of massive hemoglobinuria may require dialysis until renal function recovers.

5. Splenectomy

In extreme cases, especially in Class I chronic hemolytic anemia, surgical removal of the spleen (splenectomy) may offer benefits. This procedure eliminates the primary site of red blood cell destruction. This is reserved for patients with severe, refractory disease.

6. Neonatal Jaundice Management

Newborns with G6PD deficiency and significant jaundice require:

• Phototherapy (light therapy to break down bilirubin in the skin),
• Exchange transfusion in severe hyperbilirubinemia to prevent kernicterus.

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Prevention

Prevention is the cornerstone of managing G6PD deficiency. Since there is no cure for the underlying enzyme defect, avoiding all known triggers is the only strategy to prevent hemolytic crises and their long-term consequences.

Medications to Avoid

The following is a non-exhaustive list of medications known to trigger hemolysis in individuals with G6PD deficiency, based on established clinical guidance and available evidence:

Always inform every healthcare provider, including dentists, emergency physicians, and pharmacists, about your G6PD deficiency before starting any new medication.

• Ascorbic acid (Vitamin C) at high doses,
• Acetylphenylhydrazine,
• Acetylsalicylic acid (Aspirin®, Vivin C®, and similar products),
• Bupivacaine (local anesthetic),
• Quinidine (antiarrhythmic),
• Ciprofloxacin (antibiotic),
• Chloramphenicol (antibiotic),
• Diethylamine,
• Dorzolamide (antiglaucoma agent),
• Hydroxychloroquine (antimalarial / autoimmune disease treatment),
• Gliclazide, glimepiride, glipizide (oral antidiabetic sulfonylureas),
• Mesalazine (anti-inflammatory for IBD),
• Metamizole (analgesic),
• Naphthalene (found in mothballs, a toxic agent),
• Primaquine (antimalarial),
• Sulfamethoxazole (antibiotic),
• Vitamin K (in high doses).

Foods to Avoid

The following foods are known to contain significant amounts of oxidizing compounds (particularly vicine and convicine in legumes) that can trigger hemolysis in susceptible individuals:

This list is non-exhaustive and individual tolerance may vary.

• Fava beans (the primary namesake trigger, whether raw, cooked, or dried),
• Peas,
• Other soy-containing legumes,
• Verbena (ornamental plant; contact or ingestion)
• Peanuts,
• Lupins,
• Blueberries,
• Red wine with high alcohol content (low risk),
• Tonic water (contains quinine, which poses low risk),
• Various plant extracts typical of Asian cuisine,
• Mint and mint-derived products.

Additional Preventive Measures

• Carry a medical alert card or wear a medical bracelet stating your G6PD deficiency diagnosis.
• Avoid exposure to naphthalene (traditional mothballs) and other chemical oxidants.
• Treat infections promptly: infections can trigger hemolytic crises in G6PD-deficient individuals.
• Screen newborns: in many countries with high G6PD deficiency prevalence, neonatal screening is included in standard newborn blood spot programs.
• Family screening: first-degree relatives (especially maternal brothers and sons of female carriers) should be tested.

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Sources and Bibliography

• Harrison’s Principles of Internal Medicine, Vol. 1 (17th Ed., McGraw-Hill, 2009)
• Core Curriculum – Ematologia. G. Castoldi, V. Liso (McGraw-Hill Education, 2014)
• Luzzatto L, Nannelli C, Notaro R. Glucose-6-Phosphate Dehydrogenase Deficiency. Hematol Oncol Clin North Am. 2016;30(2):373-393.
• Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008;371(9606):64-74.
• WHO Working Group. Glucose-6-phosphate dehydrogenase deficiency. Bull World Health Organ. 1989;67(6):601-611.
• Frank JE. Diagnosis and management of G6PD deficiency. Am Fam Physician. 2005;72(7):1277-1282.