Glucose-6-phosphate dehydrogenase (G6PD) deficiency

INTRODUCTION — 

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited, X-linked, red blood cell (RBC) disorder caused by a pathogenic variant in the G6PD gene. It is the most common enzymatic disorder of RBCs.

The severity of hemolytic anemia varies among individuals with G6PD deficiency, making diagnosis more challenging in some cases. Identification of G6PD deficiency and patient education regarding safe and unsafe medications and foods is critical to preventing future episodes of hemolysis.

This topic review discusses the clinical manifestations, diagnosis, and management of G6PD deficiency. Separate topic reviews discuss genetic testing, other RBC enzyme deficiencies, and an overall approach to the patient with unexplained hemolytic anemia.

●G6PD genetic testing – (See "Gene test interpretation: G6PD".)

●Other RBC enzyme deficiencies

•Pyruvate kinase – (See "Pyruvate kinase deficiency".)

•Glycolysis enzymes, glutathione and hexose monophosphate shunt, nucleotide metabolism – (See "Rare RBC enzyme disorders".)

●Hemolytic anemias

•Diagnostic approach in children – (See "Overview of hemolytic anemias in children".)

•Diagnostic approach in adults – (See "Diagnosis of hemolytic anemia in adults".)

G6PD ENZYME FUNCTION — 

G6PD is the enzyme that catalyzes the initial step in the hexose monophosphate (HMP or pentose phosphate) shunt, oxidizing glucose-6-phosphate to 6-phosphogluconolactone and reducing nicotinamide adenine dinucleotide phosphate (NADP) to NADPH (figure 1). In red blood cells (RBCs), the HMP shunt is the only source of NADPH, a cofactor important in glutathione metabolism.

The main function of the HMP shunt is to protect RBCs against oxidative injury via the production of NADPH [1]. RBCs contain relatively high concentrations of reduced glutathione (GSH), a sulfhydryl-containing tripeptide that functions as an intracellular reducing agent, thereby protecting against oxidant injury. Oxidants including superoxide anion (O2-) and hydrogen peroxide are formed within RBCs via reactions of hemoglobin with oxygen and can also be produced by drugs and infection. If these oxidants accumulate within RBCs, hemoglobin and other proteins are oxidized, leading to loss of function and cell death.

Tight coupling of the HMP shunt to glutathione metabolism is responsible for protecting intracellular proteins from oxidative injury. Under normal circumstances, oxidant accumulation does not occur, since these compounds are rapidly inactivated by GSH in conjunction with glutathione peroxidase. These reactions result in the conversion of GSH to oxidized glutathione (GSSG). GSH levels are restored by glutathione reductase, which catalyzes the reduction of GSSG to GSH. This reaction requires the NADPH generated by G6PD.

The monomeric form of G6PD contains 515 amino acids, but the active form of G6PD is a dimer that contains tightly bound NADP [2,3]. Amino acid 205 is the binding site for glucose-6-phosphate, while amino acids 386 and 387 may be involved in binding to NADP [2,4].

Almost all hemolytic episodes related to altered HMP shunt and glutathione metabolism are due to G6PD deficiency. Rarely, hemolysis results from deficiencies in GSH synthetic enzymes. (See "Rare RBC enzyme disorders", section on 'Disorders of the HMP shunt and glutathione metabolism'.)

PATHOPHYSIOLOGY

X-linked inheritance — G6PD deficiency is an X-linked disorder [5-8].

●Males – Males who inherit a pathogenic variant in G6PD are hemizygous for the variant; all of their red blood cells (RBCs) are affected. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Sex-linked patterns'.)

●Females – Even though females have two X chromosomes per cell and males have one, males and females normally have the same enzyme activity in their RBCs because one of the X chromosomes in each cell of the female embryo is inactivated and remains inactive throughout subsequent cell divisions (Lyon hypothesis of random X inactivation) [9].

•Heterozygosity – The presence and severity of hemolytic anemia in females varies depending on the magnitude of deficiency in the affected RBCs and whether there is skewed X-inactivation (lyonization) that results in a greater expression from the abnormal allele in a large percentage of RBCs [10]. Heterozygous females usually do not have severe hemolytic anemia, since one-half of their RBCs express the normal G6PD allele and one-half express the abnormal allele [1,10]. A heterozygous female with 50 percent normal G6PD activity has 50 percent normal RBCs and 50 percent G6PD-deficient RBCs. However, the deficient cells are as vulnerable to hemolysis as the enzyme-deficient RBCs in males, so some hemolysis may occur in carrier females.

In one study, the incidence of G6PD deficiency in Chinese females ≥80 years of age was several-fold greater than what was expected from population screening at birth [11]. It is thought that this is due to age-related skewed X-inactivation.

•Biallelic variants – Homozygosity or compound heterozygosity for a pathogenic variant in the G6PD gene has been reported in as many as 1 percent of American females [10,12,13]. These females are as severely affected as males.

Dr. Ernest Beutler, a pioneer in the understanding of this disorder, has published an interesting historical review of the discovery of this condition, its clinical manifestations, detection, population genetics, and molecular biology [14].

Classification of G6PD variants — Over 200 G6PD pathogenic variants have been described [1].

The gene variants are almost all missense point mutations, although a few deletions have been described [2,15]. Large deletions or frame shift mutations have not been identified, suggesting that complete absence of G6PD may be lethal [2].

By international agreement, standardized methods have been used to characterize these enzyme variants, which differ on the basis of their biochemical properties, such as kinetic activity and the Michaelis constant for its substrate glucose-6-phosphate and cofactor NADP [16,17]. However, differences between some enzymatic variants are subtle and may not represent true enzyme differences; molecular studies indicate many of these variants are due to the same genetic variant.

For several years, these variants have been classified by the World Health Organization (WHO) according to the magnitude of the enzyme deficiency and the severity of hemolysis [18,19]. This classification has provided some approximation of the magnitude of hemolysis an individual might experience under oxidative stress.

●Class I (rare) – Severe enzyme deficiency (<10 percent of normal) and chronic hemolytic anemia. Most Class I variants that are associated with chronic hemolytic anemia have abnormalities in the glucose-6-phosphate binding or NADP binding site of the enzyme [2].

●Class II - Severe enzyme deficiency (<10 percent of normal) with intermittent hemolysis associated with infection, drugs, or chemicals.

●Class III – Moderate enzyme deficiency (10 to 60 percent of normal) with intermittent hemolysis usually associated with infection, drugs, or chemicals.

●Class IV – No enzyme deficiency or hemolysis.

●Class V – Increased enzyme activity.

The WHO classification is being modified. Data to support this reclassification of G6PD have been reported, but the updated classification has not yet been published in the WHO Bulletin or formally adopted [20,21].

●Revised WHO classification – The Malaria Policy Advisory Group of the WHO proposed that this classification should be modified [22]. The main reason for reclassification is that there is significant overlap in enzyme activity and clinical hemolysis between Class II and III variants; thus, the distinction between "severe" and "moderate to mild" is not useful [20]. For practical purposes, the previous Class V has been deleted because there had only been one patient described (G6PD Hektoen) and no others since that time [23]. The proposed new classification includes four classes (A, B, C, and U) based on median G6PD activity and characteristics of hemolysis:

•Class A – Class A variants have <20 percent G6PD activity associated with chronic hemolysis. For practical purposes this is the same as the previous Class I group.

•Class B – Class B variants have <45 percent G6PD activity and can have hemolysis triggered by oxidant stresses. As with the previous Class II and III variants, hemolysis is intermittent, and there is no hemolysis in the absence of exogenous stresses.

•Class C – Class C variants have 60 to 150 percent G6PD activity but no hemolysis (similar to previous Class IV G6PD).

No male hemizygous or female homozygous individuals have been reported with 45 to 60 percent G6PD activity. If found, such an individual (Class U) should be followed to see if they are associated with hemolysis (Class B) or pose no hemolytic risk (Class C).

Class A G6PD variants have low in vitro activity and/or marked instability of the molecule, and most have pathogenic variants that affect the glucose-6-phosphate or NADP binding sites [2]. These sites are central to the function of G6PD, which oxidizes glucose-6-phosphate and reduces NADP to NADPH (figure 1). It is presumed that the functional deficit is so severe that the RBCs cannot withstand even the normal oxidative stresses encountered in the circulation [2].

Clinical consequences of these variants are discussed below. (See 'Clinical manifestations' below.)

Wild-type enzyme — The wild-type enzyme, G6PD B, is found in most individuals with ancestry from Europe, Asia, and Africa. It has normal catalytic activity and is not associated with hemolysis. Its function is described below. (See 'G6PD enzyme function' above.)

A common variant found in 20 to 30 percent of Black individuals from Africa is G6PD A⁺ [24]. It differs from G6PD B by the single amino acid substitution of asparagine for aspartate at the amino acid 126 [25]. The A⁺ enzyme has much faster electrophoretic mobility than B (the letters A and B refer to relative electrophoretic mobilities). G6PD A⁺ has normal catalytic properties and does not cause hemolysis.

G6PD A- variant — The G6PD A^- variant (202G>A/376A>G) is the most common variant in individuals of African ancestry and is associated with primaquine sensitivity. This is the most common variant associated with mild to moderate hemolysis (Class B). It is found in 10 to 15 percent of African Americans, with similar frequencies in western and central Africa [26].

G6PD A^- has an electrophoretic mobility identical to that of G6PD A⁺. However, G6PD A^- is an unstable enzyme and its catalytic activity, which is nearly normal in bone marrow cells and reticulocytes [27], decreases markedly in older red cells due to increased catabolism (the "+" and "-" denote enzyme activity) [28].

G6PD A^- represents at least three different genotypes. All have a point mutation at nucleotide 376 (A—>G), which also is the nucleotide substitution characteristic of G6PD A⁺ [2,29,30]. However, the G6PD A^- variants have a second mutation, which is usually at nucleotide 202 (G—>A) [2,29]. Less often, there is a point mutation at nucleotide 680 (G—>T) or nucleotide 968 (T—>C) [30].

A number of G6PD variants originally described in non-African individuals have one of the known G6PD A^- point mutations. As examples, some patients with G6PD Betica, a Spanish variant, or G6PD Matera, an Italian variant, have base substitutions at nucleotides 376 and 202, identical to the more common G6PD A^- variant [31,32].

The enzymatic activity of this G6PD A^- variant is normal in reticulocytes but declines more rapidly than the wild-type enzyme (half-life, 13 days, compared with 62 days for the wild-type enzyme) [27,33]. As a result, only the oldest RBCs undergo hemolysis upon exposure to oxidant stress.

G6PD Mediterranean variant — G6PD Mediterranean (563C>T) is the most common pathogenic variant found in individuals from Europe, particularly those whose origins are in the Mediterranean and Middle-Eastern regions [34]. The electrophoretic mobility of G6PD Mediterranean is identical to that of G6PD B, but it is synthesized at a reduced rate and its catalytic activity is markedly reduced [27]. It is a Class B variant, and hemolysis can be severe.

Although G6PD Mediterranean involves many different ethnic groups, most affected individuals have the same genotype, a single base substitution (C—>T) at nucleotide 563 [31,32]. Many variants previously referred to by different names based on biochemical properties of the enzyme in the laboratory (eg, G6PD Birmingham, G6PD Cagili, G6PD Dallas) are now recognized to have the pathogenic variant as G6PD Mediterranean [35,36].

The half-life of this variant is measured in hours. Thus, the majority of circulating RBCs have grossly deficient G6PD enzyme activity and will undergo hemolysis upon exposure to an oxidant stress. However, in the absence of oxidant stress, hemolysis typically does not occur and there is no anemia or reticulocytosis. (See 'Acute hemolytic anemia' below.)

Variants in people with Asian ancestry — Several G6PD variants occur in people with ancestry from countries in Asia [37,38].

●In China, three major Class B variants are recognized; these account for >70 percent of G6PD cases. The most common is G6PD Canton (1376G>T), followed by G6PD Kaiping (1388G>A) and G6PD Gaohe (95A>G) [39].

●In Southeast Asia, the most common variant is G6PD Mahidol (487G>A).

●Although India borders China, none of the Chinese G6PD variants are found in India, where the most common type is G6PD Mediterranean (563C>T).

Mechanism of hemolysis — The importance of G6PD for RBC integrity was first recognized following the observation that some African American soldiers taking the antimalarial drug primaquine developed acute hemolytic anemia with hemoglobinuria. Subsequently, the activity of G6PD, one of the enzymes needed to maintain adequate GSH levels, was shown to be deficient in affected RBCs [40].

G6PD enzyme activity declines exponentially as RBCs age; wild-type G6PD has an in vivo half-life of 62 days [27]. While older RBCs contain sufficient G6PD activity to maintain GSH levels in the face of oxidant stress, abnormal G6PD can have a half-life that is much shorter. As an example, the enzymatic activity of G6PD A^- is normal in reticulocytes and declines rapidly thereafter, with a half-life of 13 days [27,33]. G6PD Mediterranean is even more unstable, with a half-life measured in hours [27].

With most G6PD variants, hemolysis occurs when older, more deficient RBCs are exposed to drugs having a high redox potential (including the antimalarial drug primaquine and certain sulfa drugs) or to fava beans, selected infections, or metabolic abnormalities (table 1), resulting in sudden RBC destruction. (See 'Inciting drugs, chemicals, foods, illnesses' below.)

●G6PD A^- – Individuals with G6PD A^- usually have hemolysis limited to older RBCs. (See 'G6PD A- variant' above and 'Acute hemolytic anemia' below.)

●G6PD Mediterranean – Individuals with G6PD Mediterranean have grossly deficient G6PD activity in RBCs of all ages. In the absence of oxidant stress, G6PD Mediterranean RBCs have only modestly shorter survival than unaffected RBCs [41]. However, due to the low G6PD activity, the entire RBC population is susceptible to oxidant-induced injury, which can lead to severe hemolytic anemia upon exposure to oxidant drugs or infection. (See 'G6PD Mediterranean variant' above.)

When RBCs become depleted of GSH, there is oxidation of other sulfhydryl-containing proteins [42].

●Hemoglobin – Oxidation of the sulfhydryl groups on hemoglobin leads to the formation of methemoglobin and then denatured globin or sulfhemoglobin, which form insoluble masses that attach to the red cell membrane (called Heinz bodies) [43]. This oxidative denaturation of hemoglobin leads to its crossbonding; as a result, hemoglobin is no longer free to flow in the cytosol, producing the puddling of hemoglobin and bite or hemiblister cells in the peripheral smear (picture 1).

●Membrane proteins – Oxidation of membrane sulfhydryl groups leads to the accumulation of membrane polypeptide aggregates, presumably due to disulfide bond formation between spectrin dimers and between spectrin and other membrane proteins [42,44,45]. The number of aggregates increases with the fall in GSH in the RBC [44].

The net effect is that G6PD-deficient RBCs become rigid and nondeformable, making them susceptible to stagnation and destruction by reticuloendothelial macrophages in the marrow, spleen, and liver [46,47]. Although this type of hemolysis is predominantly extravascular, intravascular hemolysis also occurs, leading to hemoglobinemia and hemoglobinuria.

EPIDEMIOLOGY — 

G6PD deficiency is the most common enzymatic disorder of red blood cells (RBCs), affecting 400 to 500 million people worldwide in a global distribution (figure 2) [1,48-53]. It occurs most often in the tropical and subtropical zones of the Eastern Hemisphere (eg, Africa, Europe, Middle East, Asia), with prevalences of 20 percent or more in some regions [1,2,54]. Examples of prevalence numbers include people from the following populations or countries:

●Kurdish Jews – 60 to 70 percent [34]

●Sardinians – 4 to 35 percent, depending on the village [55]

●Bahrain – 23 to 31 percent [56-58]

●Nigeria – 22 percent [59]

●Thailand – 17 percent [60]

●African Americans – 11 to 12 percent [61,62]

●Saudi Arabia – 8 percent [63]

●Black people from Brazil – 8 percent [64]

●Greece – 6 percent [65]

●South China – 6 percent (approximate) [66]

●Egypt – 4 percent [67]

●India – 3 percent [68]

●Japan and Korea – 0 to 1 percent [69,70]

This geographic distribution is highly correlated with regions in which malaria was once endemic, leading to the hypothesis that G6PD deficiency may have conferred a selective advantage against infection by Plasmodium falciparum, similar to observations with other gene variants affecting RBC properties. (See "Protection against malaria by variants in red blood cell (RBC) genes".)

CLINICAL MANIFESTATIONS

Overview of clinical findings — The clinical expression of G6PD deficiency encompasses a spectrum of disease severity that depends on the degree of the enzyme deficiency, which in turn is determined by the characteristics of the G6PD variant. (See 'Classification of G6PD variants' above.)

●The majority of individuals are asymptomatic and do not have hemolysis in the steady state [1]. They lack anemia and evidence of hemolysis, although a modest shortening of RBC survival can be demonstrated by isotopic techniques [41,71]. This includes almost all individuals with the most prevalent G6PD variants, G6PD A^- and G6PD Mediterranean. However, episodes of acute hemolysis with hemolytic anemia may be triggered by medications, fava beans, and acute illnesses, especially infections. (See 'Acute hemolytic anemia' below.)

●Rare individuals with severe disease (Class A variants) usually have chronic hemolysis. (See 'Congenital nonspherocytic hemolytic anemia and chronic hemolysis' below.)

●In neonates with G6PD deficiency, decreased bilirubin elimination may play an important role in the development of jaundice [72,73]. (See 'Neonatal jaundice' below.)

In many cases, females who have inherited one abnormal G6PD allele are unaffected carriers. However, those with skewed lyonization may have clinical disease. Females who are homozygous or compound heterozygous for pathogenic variants in the G6PD gene will have a phenotype similar to males. (See 'X-linked inheritance' above.)

Hemolysis occurring after oxidant injury is usually due to G6PD deficiency. However, a similar sequence can occur with hemoglobin H and some unstable hemoglobinopathies since these abnormal hemoglobins are highly susceptible to mild oxidant stress. (See "Unstable hemoglobin variants" and "Pathophysiology of thalassemia", section on 'Terminology and disease classification'.)

Acute hemolytic anemia — Some individuals with G6PD deficiency have episodes of acute hemolysis from oxidant injury due to medications, acute illnesses, or fava beans (table 1). Episodes of acute hemolysis are more common in individuals with G6PD Mediterranean, which has a half-life measured in hours, than with G6PD A^-, which has a half-life measured in days. (See 'Inciting drugs, chemicals, foods, illnesses' below.)

Typical presentation and blood smear findings — The typical episode of hemolysis is illustrated by the course of an acute hemolytic episode following the administration of primaquine to an individual with G6PD A^-, the variant most commonly seen in individuals of African ancestry [74]. (See 'G6PD A- variant' above.)

●Hemolysis appears rapidly (within 24 hours and up to 72 hours) after drug or fava bean ingestion, there is sudden onset of jaundice, pallor, and dark urine, with an abrupt fall in the hemoglobin concentration by 3 to 4 g/dL. There may be abdominal pain and/or back pain.

●Hemolysis may be mild and self-limiting in some individuals and severe and life-threatening in others [75]. A series of 94 individuals from the Brazilian Amazon with the G6PD A^- variant (some heterozygous and some homozygous) who were treated with primaquine for malaria found a high frequency of severe anemia (59 percent), hemoglobinuria (48 percent), and acute kidney injury (28 percent) [76]. Blood transfusion was required in 50 percent, four were admitted to the intensive care unit, and one died. An editorial commented that point-of-care rapid diagnostic testing for G6PD deficiency could be especially helpful in settings such as this. (See 'Point-of-care tests under investigation' below.)

●The peripheral blood smear reveals microspherocytes, eccentrocytes or "bite" cells, and "blister cells" with hemoglobin puddled to one side (picture 1). Special stains can document Heinz bodies, which are collections of denatured globin chains often attached to the RBC membrane. Hemolysis is both extravascular and intravascular. (See "Unstable hemoglobin variants", section on 'Hemoglobin precipitation and Heinz body formation'.)

Anemia induces an appropriate stimulation of reticulocytosis, apparent within five days and maximal at 7 to 10 days after the onset of hemolysis. Reticulocytes and younger RBCs have the highest levels of G6PD activity, often sufficient to withstand the oxidative stress of ongoing drug exposure. As a result, in those with G6PD A^-, the acute hemolytic process ends after approximately one week, with ultimate reversal of the anemia, even with continued drug ingestion.

More severe hemolysis may be seen in individuals with G6PD Mediterranean, the variant most commonly seen in individuals from Mediterranean countries and the Middle East. The anemia is more severe because a larger population of circulating RBCs is vulnerable to hemolysis, since the half-life of G6PD Mediterranean is shorter and fewer RBCs have sufficient G6PD activity to prevent oxidant injury. Hemolysis in these individuals may continue well after the drug is discontinued [77,78]. (See 'G6PD Mediterranean variant' above.)

Inciting drugs, chemicals, foods, illnesses — Sources of oxidant injury that may elicit an episode of acute hemolysis in an individual with G6PD include a number of medications and chemicals, as well as several foods and certain acute illnesses, especially infections.

●In a series of 102 patients with G6PD deficiency that categorized 119 episodes of acute hemolysis, 46 (39 percent) were precipitated by a medication alone, and 73 (61 percent) appeared to be related solely to a concurrent illness [79].

●In a 2024 report of a cohort of 31,962 Israeli individuals identified in a medical records database as having G6PD deficiency (based on G6PD <6 units/gram of hemoglobin), there were 71 major hemolytic events requiring hospitalization [80]. Of these, 51 (72 percent) were caused by fava bean ingestion, six (9 percent) were associated with acute infection, and three (4 percent) were with medications (nitrofurantoin, phenazopyridine, and "a pain killer").

Avoiding these inciting substances is important in management. (See 'Avoidance of unsafe drugs and chemicals' below.)

●Medications and chemicals – The table lists medications that can precipitate hemolysis in G6PD-deficient individuals (table 1).

Classic examples include the antibiotics primaquine and dapsone and the anti-uricemic drugs rasburicase and pegloticase. Additional chemicals such as henna compounds used in hair dyes and tattoos, aniline dyes, and naphthaline (found in mothballs, lavatory deodorants, and some gardening products) may also cause hemolysis [81]. Mothballs are used infrequently in the United States but are used more commonly in other areas such as South Asia [82]. Safe amounts of these drugs or safe G6PD activity levels have not been established, so avoidance is the best approach.

Conflicting information may be found regarding certain medications, such as those that modestly shorten the RBC lifespan. These may appear on some lists as "safe" and others as "unsafe" [83]. One such example is sulfamethoxazole, a component of the commonly used trimethoprim-sulfamethoxazole [83-85]. Sulfamethoxazole has been widely used, and cases of well-documented hemolysis in individuals with G6PD deficiency are uncommon. Clinical judgment should be used in deciding if it is safe for a specific individual; if it was used previously and found to be safe (eg, before the diagnosis was made) it may be reasonable to treat it as safe for that individual. A similar approach may be used for other sulfa-containing medications. Other drugs may have initially been labeled as "unsafe" when in fact hemolysis was caused by an infection that the drug was administered to treat (eg, aspirin).

In the large Israeli series noted above, no cases of hemolysis were reported with other commonly used antibiotics including ciprofloxacin, ofloxacin, and sulfa-containing medications [80]. While one individual in this cohort had severe hemolysis with nitrofurantoin, another 1366 G6PD-deficient individuals who were prescribed nitrofurantoin had no reported severe hemolysis.

Chloroquine and hydroxychloroquine are listed in some tables of unsafe drugs, but many experts believe these are probably safe when used in standard doses [14,83,86]. Off-label use of these drugs has occurred in patients with COVID-19, and a few scattered case reports suggest that hydroxychloroquine causes acute hemolysis [87,88]. However, the causal relationship between hydroxychloroquine and hemolysis is unclear since it is difficult to separate out the role of infection itself as a hemolytic trigger [89].

The sexual enhancement drug "RUSH," which may contain amyl nitrite or isobutyl nitrite, has been reported to cause hemolysis in individuals with G6PD deficiency [90]. This drug can also cause methemoglobinemia. (See "Methemoglobinemia", section on 'Acquired causes'.)

The common denominator of drugs that can precipitate hemolysis is their interaction with hemoglobin and oxygen, leading to the formation of H₂O₂ and other oxidizing radicals within RBCs [2,54,83,91]. As these oxidants accumulate within enzyme-deficient RBCs, glutathione levels are reduced, while hemoglobin and other proteins are oxidized, thereby leading to cell lysis. (See 'Mechanism of hemolysis' above.)

●Foods – Fava beans (also called broad beans) are the one food that can trigger hemolysis in individuals with G6PD deficiency.

Other names for fava beans in various languages in countries where G6PD deficiency is common include:

•Spanish (Spain, Mexico, parts of Latin America) – Haba beans

•Hindi (India) - Hawai-amubi

•Arabic (Iraq) – Bagilla bean

•Persian (Iran) – Baghalee

Ingestion of fava beans is probably the most common cause of hemolysis in individuals with G6PD deficiency [1,92]. In a large Israeli study of hemolysis requiring hospitalization, 72 percent were due to fava bean ingestion [80].

In contrast, other beans (chickpeas, soybeans, green beans, lupine beans) are safe [1].

Fava beans can induce hemolysis whether eaten raw, cooked, or dried (picture 2). (See 'Dietary restrictions' below.)

Fava beans contain high concentrations of two pyrimidine-nucleosides, vicine and convicine. After fava bean ingestion, vicine and convicine undergo hydrolysis by glucosidases present in both the beans and the gastrointestinal tract. This releases the respective aglycones divicine and isouramil, both of which are highly reactive redox compounds that generate oxygen free radicals and hydrogen peroxide (H₂O₂).

Acute intravascular hemolysis upon ingestion of fava beans, referred to as favism, occurs most commonly in male children between the ages of one and five years. However, female children and male or female adults can also be affected [1]. The ratio of fava beans consumed to body weight may account in large part for the observation that favism attacks are much more common and more severe in children than adults [1,92].

Symptoms of an attack begin within 5 to 24 hours after ingestion of the food and include headache, nausea, back pain, chills, and fever, and are followed by hemoglobinuria and jaundice [92,93]. The fall in hemoglobin concentration is acute, often severe, and, in the absence of transfusion, can be fatal.

●Medical illnesses – Infection is the most common illness that causes hemolysis in G6PD-deficient individuals, and it is likely to be the most common inciting factor for hemolytic anemia once the individual is aware of the diagnosis and avoids oxidant medications.

•Hemolysis can occur with a variety of organisms (eg, viral, bacterial, rickettsial) and sites of infection (eg, pneumonia, hepatitis). Coronavirus disease 2019 (COVID-19) may lead to hemolysis, similar to other acute infectious illnesses. G6PD deficiency may first come to medical attention during hospitalization and/or treatment for COVID-19 [87,94,95]. Individuals with COVID-19 who develop hemolytic anemia should be assessed for G6PD deficiency as part of the comprehensive evaluation [96]. (See "Diagnosis of hemolytic anemia in adults", section on 'Post-diagnostic testing to determine the cause'.)

•Hemolytic anemia associated with infections can range from mild and self-limited to severe enough to cause acute kidney failure [79,97-104].

•In a series of patients from a classic report in 1966, pneumonia was the most common inciting infection [79]. In the setting of viral hepatitis, the combination of an increased bilirubin load from hemolysis and a damaged liver unable to process bilirubin as well as normal results in an exaggerated elevation in the serum bilirubin concentration.

The factors responsible for accelerated destruction of G6PD-deficient RBCs during infection are not known. One possible explanation is that the cells are damaged by oxidants generated by phagocytes [105].

Diabetic ketoacidosis has also been reported to precipitate hemolysis in individuals with G6PD deficiency, although one study of patients with the G6PD Mediterranean variant found no such correlation [79,106,107]. Both acidosis and hyperglycemia are potential precipitating factors, and correction of the abnormalities has been associated with reversal of the hemolytic process [108]. In some patients with diabetes and G6PD deficiency, occult infection may be a common trigger for both acute hemolysis and ketoacidosis.

Neonatal jaundice — Neonates with G6PD deficiency have an increased incidence of neonatal jaundice.

The clinical picture differs from neonatal jaundice due to hemolytic disease of the fetus and newborn (HDFN) due to RhD or other blood group antigens in two main respects.

●In contrast to jaundice due to HDFN that occurs at or shortly after birth, G6PD deficiency-related neonatal jaundice is rarely present at birth, the peak incidence occurring after two to three days [109].

●There is more jaundice than anemia with G6PD deficiency, and the anemia is rarely severe [110]. Often, it is only hyperbilirubinemia that leads to the diagnosis of G6PD deficiency. The severity of jaundice varies widely, from being subclinical to imposing the threat of kernicterus if it is not treated [72,73].

Anemia and jaundice are often first noted in the newborn period in individuals with severe G6PD deficiency (Class A variants). The degree of jaundice is quite variable; in severe cases, there is a risk of bilirubin-induced neurologic dysfunction and kernicterus (permanent neurologic damage) if the patient is not treated aggressively [111]. (See "Unconjugated hyperbilirubinemia in neonates: Risk factors, clinical manifestations, and neurologic complications", section on 'Clinical manifestations'.)

In neonates with Class B G6PD deficiency, jaundice is rarely present at birth; the peak of onset is two to three days after birth [73]. Jaundice is more prominent than anemia, which is rarely severe. Jaundice can be seen in neonates with G6PD Mediterranean, Asian, and African American variants. Monitoring of jaundice and serum bilirubin levels in infants known to be G6PD-deficient is critical [112,113].

The risk of neonatal hyperbilirubinemia associated with G6PD deficiency was illustrated in a 2015 meta-analysis of cohort studies that included 21,585 neonates, 877 of whom had hyperbilirubinemia [114]. The relative risk of hyperbilirubinemia in neonates with G6PD deficiency was 3.92 (95% CI 2.13-7.20). Data from the USA Kernicterus Registry from 1992 to 2004, which were not included in the meta-analysis, indicate that over 30 percent of kernicterus cases are associated with G6PD deficiency [111]. Thus, routine testing for G6PD deficiency is performed in many neonates with hyperbilirubinemia and/or those with less dramatic bilirubin elevations who are of Mediterranean, Nigerian, or East-Asian ancestry. (See 'Diagnostic evaluation' below and "Unconjugated hyperbilirubinemia in term and late preterm newborns: Screening", section on 'Determining follow-up and need for additional evaluation and/or treatment'.)

Observations related to specific populations include the following:

●Neonates with the rare Class A variants are at greatest risk of neonatal jaundice; however, most infants with hyperbilirubinemia due to G6PD deficiency have more common variants and come from the Mediterranean region or Asia [115-118]. In one series of 43 cases from Italy, for example, 39 had G6PD Mediterranean, one had G6PD A^-, and three had other variants [115]. Among affected Chinese children, most cases are associated with G6PD Canton [117].

●The risk of neonatal hyperbilirubinemia is lower in African Americans than in people from Africa and Jamaica, despite both groups generally having the same G6PD A^- variant [119-121]. Untreated hyperbilirubinemia in Black African and Black Jamaican infants frequently leads to kernicterus with severe neurologic injury or death [120,122]. Likewise, the risk of neonatal hyperbilirubinemia is lower in infants of Greek ancestry who are born in Greece than in infants of Greek ancestry born in Australia [123]. These differences in risk with the same G6PD variant may be related to local customs and differences in oxidant exposure. (See 'Inciting drugs, chemicals, foods, illnesses' above.)

The pathogenesis of hyperbilirubinemia and neonatal jaundice due to G6PD deficiency remains uncertain [124,125]. Some experts believe that decreased hepatic bilirubin elimination is a key factor [2,72,120,126,127]. Others believe that hyperbilirubinemia is exclusively due to increased hemolysis and that there is no need to invoke liver involvement beyond the normal immaturity of the neonatal bilirubin-conjugating mechanism [126].

One study compared the incidence of severe jaundice (bilirubin >15 mg/dL [>257 micromol/L]) among infants with varying combinations of G6PD deficiency and the Gilbert variant [128]. Neither G6PD deficiency nor the Gilbert variant alone increased the incidence of hyperbilirubinemia (incidence: 7 to 15 percent) compared with controls (incidence: 10 percent), but the presence of both variants in combination did (incidence: 32 to 50 percent). (See "Unconjugated hyperbilirubinemia in neonates: Etiology and pathogenesis" and "Gilbert syndrome", section on 'Long-term complications'.)

Indirect evidence such as a lower incidence of neonatal hyperbilirubinemia in immigrants to the United States supports the importance of local environmental variables, although often there is no obvious oxidant exposure [123,129]. Possible exposures may include maternal ingestion of oxidant foods, herbs used in traditional Chinese medicine, and clothing impregnated with naphthalene [130,131]. Some neonates with G6PD Mediterranean have a partial defect in bilirubin glucuronide conjugation similar to that seen in Gilbert's disease [132]. In support of this hypothesis are the observations that carboxyhemoglobin production, a marker of hemolysis or RBC breakdown, is the same in G6PD Mediterranean deficient neonates with and without hyperbilirubinemia [124]. The relative importance of this Gilbert variant is supported by the observed lack of anemia and hemolysis in most jaundiced G6PD-deficient neonates [133]. (See "Unconjugated hyperbilirubinemia in neonates: Etiology and pathogenesis".)

In the United States, there is concern that changes in health care delivery with early discharge of newborn infants may increase the risk. One report described three African-American newborns and one mixed Peruvian/Chinese newborn infants with G6PD deficiency who developed kernicterus following early hospital discharge, even though there was adherence to the early neonatal discharge guidelines of the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists [134].

Congenital nonspherocytic hemolytic anemia and chronic hemolysis — Chronic hemolysis is not characteristic of G6PD deficiency. Rarely, some with severe deficiency (activity <10 percent at baseline) can have chronic hemolysis with or without chronic anemia, even in the absence of oxidant injury from medications or illnesses [135-139]. These individuals may also be referred to as having congenital nonspherocytic hemolytic anemia (CNSHA). Variants that produce chronic hemolytic anemia are referred to as Class A variants. (See 'Classification of G6PD variants' above.)

The term nonspherocytic is somewhat of a misnomer, as these individuals may have spherocytes on the peripheral blood smear. However, this term is useful in distinguishing individuals with G6PD deficiency, in whom spherocytes are relatively infrequent at baseline, from those with hereditary spherocytosis, in whom spherocytes are abundant. (See 'Differential diagnosis' below.)

Most individuals with chronic hemolysis have mild to moderate anemia (hemoglobin 8 to 10 g/dL) with a reticulocyte count of 10 to 15 percent. Pallor is uncommon, scleral icterus is intermittent, and splenomegaly is rare. Hemolysis can be exaggerated by exposure to drugs or chemicals with oxidant potential or exposure to fava beans [139]. Some drugs with relatively mild oxidant potential that are safe in patients with Class B G6PD variants may increase hemolysis in patients with Class A variants.

The typically mild degree of anemia reflects the ability of increased erythropoiesis to compensate for the hemolysis. Thus, as with other chronic hemolytic anemias, the anemia may be worsened by diminished erythropoietic capacity due to infection or to parvovirus-induced aplastic crises. Such a crisis may be the event that first leads to examination of the blood and establishment of a diagnosis of G6PD deficiency. (See "Clinical manifestations and diagnosis of parvovirus B19 infection".)

Neutrophil dysfunction — G6PD is used by other cells besides RBCs to reduce oxidant injury. Rarely, individuals with the most severe G6PD deficiency may have neutrophil dysfunction due to a lack of NADPH production, leading to an impaired respiratory burst, decreased bactericidal activity, and recurrent infections with catalase-positive organisms, similar to that in chronic granulomatous disease [140]. In our experience, however, individuals with G6PD deficiency do not appear to have increased susceptibility to infections. Reduced enzyme activity in neutrophils may particularly affect patients with enzyme deficiency more severe than G6PD Mediterranean [140-142]. However, this abnormality is rarely associated with functional impairment of leukocytes and platelets due to their normally short survival [141,143].

Underestimation of blood glucose by HbA1C — With all hemolytic anemias, increased RBC turnover leads to lower values for glycated hemoglobin (HbA1C) and inaccurate estimates of blood glucose levels over time. In G6PD deficiency, where hemolysis is minimal in the absence of oxidant stress, there nevertheless are lower HbA1C levels than in individuals without G6PD deficiency at the same level of fasting blood glucose. This may reflect the slightly reduced RBC lifespan in the absence of oxidant stress that has been reported [71].

The impact of G6PD deficiency on HbA1C measurements was illustrated in a 2024 cohort study that evaluated 3913 patients with G6PD deficiency and 19,565 matched controls who had testing for fasting blood glucose levels and HbA1C [144]. Despite similar fasting glucose levels in both groups, HbA1C levels underestimated glucose levels and resulted in discrepancies in diabetes care:

●Mean HbA1C values were lower in individuals with G6PD deficiency (4.79 ± 0.85 percent) relative to controls (5.50 ± 0.88 percent).

●A HbA1C of 6.5 percent correlated with higher fasting glucose levels (155 mg/dL in females with G6PD deficiency, 168 mg/dL in males with G6PD deficiency, and 126 mg/dL in controls).

●In individuals with diabetes, those with G6PD deficiency were less likely to be prescribed diabetes medications (glucagon-like peptide 1 [GLP-1] receptor agonists, sodium–glucose cotransporter 2 [SGLT2] inhibitors) and more likely to have diabetes complications (severe kidney disease, heart disease, neuropathy).

These findings reinforce the importance of using other measures of blood glucose for management in individuals with G6PD deficiency. (See "Screening for type 2 diabetes mellitus and prediabetes", section on 'Glycated hemoglobin (A1C)' and "Measurements of chronic glycemia in diabetes mellitus", section on 'Unexpected or discordant values'.)

Possible protection against malaria — Because of its high prevalence in areas in which malaria was once endemic (figure 2), G6PD deficiency may have conferred a selective advantage against infection by Plasmodium falciparum [48,55,145-148]. This issue remains unresolved as some studies have shown conflicting results [2,149-152]. Possible mechanisms are discussed separately. (See "Protection against malaria by variants in red blood cell (RBC) genes", section on 'Evolutionary selection pressure from malaria'.)

DIAGNOSTIC EVALUATION

Indications for evaluation — Testing for G6PD deficiency may be appropriate in the following settings:

●Evaluation of neonatal jaundice or unexplained hemolytic anemia. (See 'Evaluation for the cause of neonatal jaundice or hemolysis' below.)

●Asymptomatic individuals at high risk of G6PD deficiency prior to administration of certain medications. (See 'Prior to treatment with an oxidant medication' below.)

●Certain other populations (eg, certain newborn screening or asymptomatic relatives of affected individuals). (See 'Role of population screening' below and 'Genetic counseling and prenatal testing' below.)

Testing may be performed using an initial screening test followed by a confirmatory test or using the confirmatory test initially, depending on available resources and institutional guidelines. (See 'Screening tests' below and 'Confirmatory tests' below.)

Evaluation for the cause of neonatal jaundice or hemolysis — Testing for G6PD deficiency is appropriate in infants with unexplained neonatal jaundice and individuals of any age with unexplained direct antiglobulin (Coombs)-negative hemolytic anemia, especially those from kindreds with a history of inherited anemia and those from populations most likely to be affected (eg, individuals with African, Southern European, Middle Eastern, Chinese, or Southeast Asian ancestry). (See 'Epidemiology' above.)

In those with a strong suspicion for G6PD deficiency, this testing may be done early in the evaluation. In others, it may be done following negative testing for more likely causes of unexplained anemia or hemolysis. (See 'Timing of G6PD assay' below and "Approach to the child with anemia" and "Diagnostic approach to anemia in adults" and "Diagnosis of hemolytic anemia in adults".)

Prior to treatment with an oxidant medication — Testing for G6PD deficiency is appropriate for individuals who require treatment with oxidant drugs including dabrafenib, dapsone, glipizide, glyburide, methylene blue, pegloticase, primaquine, quinine, rasburicase, and others. A common example is a patient who requires presumptive anti-relapse therapy with primaquine to eradicate the liver stages of Plasmodium vivax or P. ovale. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae", section on 'Preventing relapse' and "Prevention of malaria infection in travelers".)

In most cases, it is prudent to screen for G6PD deficiency if a patient requires a drug that could potentially cause oxidant injury (eg, dapsone in a patient with HIV infection) or treatment with rasburicase, which can cause hemolysis in individuals with G6PD deficiency [153]. However, there may be cases in which testing can reasonably be omitted, such as treatment with a sulfonylurea or nitrofurantoin, which rarely cause severe hemolysis, or if the individual has already received the particular drug in the past (or is currently receiving the drug) without appreciable symptoms of hemolysis [80].

It is possible that newly available drugs may cause hemolysis in individuals with G6PD deficiency; however, a single case report showing an association is generally not sufficient to infer causation.

Testing for G6PD deficiency prior to administration of medicines that can produce oxidant injury is consistent with information provided in drug labeling by the US Food and Drug Administration (FDA), as summarized on a website on pharmacogenetics hosted by the FDA [154].

Specific drug label information should be consulted to determine whether patients with G6PD deficiency should consider the drug to be contraindicated or whether the drug can be administered with increased monitoring.

Timing of G6PD assay — An important aspect of diagnosing G6PD deficiency is that testing is based on direct measurements of G6PD activity in a population of RBCs. In an acute hemolytic episode, the RBCs with the most severely reduced G6PD activity will have hemolyzed, and thus their G6PD activity will not be measured in the assay. This situation can produce false-negative results in some patients who are tested in the midst of a severe hemolytic episode.

False-negative results are most likely to occur in individuals who have populations of RBCs that are severely G6PD-deficient and RBCs that are not severely deficient, such as individuals of African ancestry, in whom G6PD activity declines gradually as RBCs age, and females, most of whom are heterozygous and have a mixture of normal and G6PD-deficient RBCs. False-negative results are also most likely to be seen during the period of initial reticulocytosis, when there is the highest proportion of reticulocytes, which typically have normal G6PD activity.

Thus, if initial testing is negative and a suspicion for G6PD deficiency remains, molecular diagnostic studies are available but costly. Alternatively, biochemical testing can be repeated approximately three months after the hemolytic episode has resolved (ie, the typical time it takes for a new population of circulating RBCs to be produced). During this three-month period, it would be prudent to avoid potential sources of oxidant injury. (See 'Avoidance of unsafe drugs and chemicals' below and 'Dietary restrictions' below.)

Screening tests — Many medical center laboratories perform qualitative screening tests for G6PD deficiency that can provide results in a short period of time (one to two hours). These assays all work by assaying the normal function of the G6PD enzyme, reduction of NADP (nicotinamide adenine dinucleotide phosphate) to NADPH (figure 1), which is the initial step in the hexose monophosphate (HMP) shunt.

In the screening test, adequate G6PD activity with NADPH generation is determined by monitoring a fluorescent spot under ultraviolet light. For the most part, screening tests are semiquantitative. Thus, if positive, they typically should be followed by a quantitative confirmatory test. (See 'Confirmatory tests' below.).

However, under conditions where it is urgent to know G6PD status (eg, administration of rasburicase prior to initiating chemotherapy), results from the screening test can be used for guidance. It has been suggested that any institution that treats patients with acute leukemia or lymphoma who may require emergency screening for G6PD deficiency should have an on-site test available [91].

If the initial screening test is negative, it should be repeated approximately three months after the hemolytic episode has resolved. If testing remains negative, evaluation for other RBC enzyme deficiencies and/or other hemolytic anemias is appropriate. (See 'Timing of G6PD assay' above and 'Differential diagnosis' below.)

Confirmatory tests — Confirmatory testing is performed for individuals with a positive screening test (or in some cases as the initial test) depending on available resources, cost, and institutional practices. Quantitative G6PD assays are available at several reference laboratories (Mayo Clinic Laboratories, Arup Laboratories, Stanford RBC Special Studies Laboratory) [155-157]. Turnaround time for results from outside laboratories is often at least seven days.

G6PD activity results are expressed as units of enzyme activity per gram of hemoglobin. Normal ranges may differ depending on the methodology used and the assay temperature.

●Typical normal range at 25°C: 5.5 to 8.8 units/gram of hemoglobin

●Typical normal range at 37°C: 8.0 to 13.5 units/gram of hemoglobin

However, a "safe" level of G6PD activity has not been established, and any individual who has had hemolysis related to G6PD deficiency should avoid subsequent exposures regardless of their absolute activity level. (See 'Avoidance of unsafe drugs and chemicals' below.)

Levels of G6PD are higher in newborns than in adults [13,158]. When higher-than-normal levels are seen in older patients, this almost invariably reflects the presence of a young RBC population with reticulocytosis.

Confirmatory testing using molecular/genetic methods is available, although this approach is not used routinely. Molecular testing may be appropriate when it is necessary to identify a heterozygous female with borderline enzyme activity. There are several academic and commercial laboratories available for gene studies; these can be found on the Genetic Testing Registry website.

Additional information about G6PD genetic testing is presented separately. (See "Gene test interpretation: G6PD".)

Point-of-care tests under investigation — The need for point-of-care tests to be used on-site (eg, prior to administration of antimalarial drugs) has been emphasized by various groups [159]. Available tests that can be performed on a fingerstick and scored visually (ie, that do not require additional equipment to get the result) have been reviewed [160]. Quantitative point-of-care enzyme testing in potentially affected infants is being assessed as a means of risk reduction for neonatal kernicterus [161]. (See "Unconjugated hyperbilirubinemia in neonates: Risk factors, clinical manifestations, and neurologic complications", section on 'Chronic bilirubin encephalopathy (kernicterus)'.)

Role of population screening — The question of whether testing for G6PD deficiency should be included in newborn screening programs worldwide has been raised [162]. This screening has not been widely implemented; however, routine newborn screening is done in some populations with a high incidence of G6PD deficiency, as discussed separately. (See "Overview of newborn screening".)

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of G6PD deficiency includes other causes of hemolytic anemia and other causes of neonatal jaundice:

●Inherited hemolytic anemias – Other inherited hemolytic anemias include:

•Other enzyme deficiencies (eg, pyruvate kinase [PK], rare red blood cell enzymes)

•Hemoglobinopathies (eg, thalassemia, sickle cell disease)

•Membrane/cytoskeletal disorders (eg, hereditary spherocytosis [HS])

Like G6PD deficiency, these can present with varying degrees of direct antiglobulin (Coombs)-negative hemolysis (with increased reticulocytes, decreased haptoglobin, increased lactate dehydrogenase [LDH], and anemia), and like G6PD deficiency, these may not be diagnosed until adulthood (or may be misclassified), especially if hemolysis is mild. Like many of these inherited disorders, G6PD deficiency is seen at greater frequency in populations from regions where malaria was once endemic, likely due to a protective effect.

Unlike these other inherited hemolytic anemias, G6PD deficiency is characterized by low G6PD enzyme activity at baseline, and testing such as hemoglobin analysis, osmotic fragility, and band 3 flow cytometry will be normal in individuals with G6PD deficiency.

Overviews and discussions of specific disorders are presented separately. (See "Overview of hemolytic anemias in children", section on 'Intrinsic hemolytic anemias' and "Diagnosis of hemolytic anemia in adults" and "Pyruvate kinase deficiency" and "Rare RBC enzyme disorders".)

●Acquired hemolytic anemias – Acquired hemolytic anemias include a number of immune and non-immune causes of hemolysis. Like G6PD deficiency, in some cases an acute medical illness or exposure to a drug may precede hemolysis. Like G6PD deficiency, these can present with varying degrees of hemolysis (with increased reticulocytes, decreased haptoglobin, increased LDH, and anemia). Unlike these acquired conditions, G6PD deficiency is characterized by low G6PD enzyme activity at baseline, and testing such as direct antiglobulin tests will be normal in individuals with G6PD deficiency. (See "Overview of hemolytic anemias in children", section on 'Extrinsic hemolytic anemias' and "Diagnosis of hemolytic anemia in adults" and "Drug-induced hemolytic anemia".)

●Conditions causing neonatal hyperbilirubinemia – Neonatal hyperbilirubinemia can be caused by conditions associated with increased bilirubin production, such as hemolytic disease of the fetus and newborn (HDFN) or decreased bilirubin clearance (anatomic obstruction, metabolic disorders affecting bilirubin clearance). Like G6PD deficiency, the former condition may be associated with anemia and neonatal jaundice. Unlike G6PD deficiency, these conditions may be more likely to present with hyperbilirubinemia at birth (versus two to three days after birth for G6PD deficiency), and these other conditions are associated with normal G6PD enzyme activity. (See "Unconjugated hyperbilirubinemia in neonates: Etiology and pathogenesis".)

MANAGEMENT — 

The cornerstone of management of G6PD deficiency is the avoidance of oxidative stress to red blood cells (RBCs). This is usually straightforward once the diagnosis is known. However, there may be instances in which an oxidant drug is absolutely required, or cases in which oxidative stress comes from an infection or other acute medical condition that cannot be avoided. In these settings, management depends on the severity of hemolysis and anemia and the patient's age and comorbidities.

Treatment of neonatal jaundice and chronic hemolysis — The management of neonatal jaundice due to G6PD deficiency does not differ from that recommended for neonatal jaundice arising from other causes. Mild cases generally do not require treatment; intermediate cases require phototherapy; and severe cases may require exchange transfusion. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Initial management".)

For G6PD-deficient individuals who do not have chronic hemolysis, there is no need for supplemental folic acid. For those rare individuals with chronic hemolysis, just as with any individual with chronic hemolysis, routine supplementation with folic acid is reasonable. In such cases, a dose of 1 mg daily or a multivitamin with folate is adequate.

Treatment of acute hemolytic episodes — Whenever hemolysis occurs in an individual with G6PD deficiency, any inciting agent(s) should be removed as soon as possible [2].

Other interventions may include aggressive hydration for acute intravascular hemolysis or transfusion for severe anemia. (See "Indications and hemoglobin thresholds for RBC transfusion in adults".)

Various treatments directed at the source of oxidant injury or NADPH production have been evaluated and found to be ineffective (eg, xylitol, vitamin E) [2,41,163,164].

Avoidance of unsafe drugs and chemicals — The principal intervention for reducing hemolysis in individuals with G6PD deficiency is avoiding exposure to drugs, chemicals, and foods known to trigger hemolysis.

There is not universal agreement on which drugs are safe; different sources provide lists that may differ slightly [1,2,83]. A list of commonly implicated drugs and chemicals based on a synthesis of information from the literature is provided in the table (table 1). (See 'Inciting drugs, chemicals, foods, illnesses' above.)

There may be circumstances in which it is especially important to give one of these drugs, and this may be possible in individuals with mild hemolysis. (See 'Classification of G6PD variants' above.)

As examples:

●Primaquine antimalarial prophylaxis has been given to individuals with the G6PD A^- variant as long as a low dose is used (15 mg/day or 45 mg once or twice weekly) and the complete blood count (CBC) is monitored closely [165]. The mild anemia that may ensue is corrected by the compensatory increase in reticulocyte production and does not recur unless the dose of the drug is escalated. (See "Antimalarial drugs: An overview", section on 'Primaquine'.)

●In other cases, the drug may be lifesaving and may need to be administered before the results of G6PD testing are available (eg, administration of rasburicase for tumor lysis syndrome). In these situations, it may be prudent to provide the drug and maintain a high index of suspicion for hemolysis that will facilitate rapid treatment if hemolysis occurs. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Rasburicase'.)

●Chloroquine or hydroxychloroquine may be listed in some tables of drugs to avoid in individuals with G6PD deficiency; however, many experts consider them to be probably safe when used at standard doses, as discussed above. (See 'Inciting drugs, chemicals, foods, illnesses' above.)

The potential increased risk of hemolysis in an individual with a severe viral infection such as COVID-19 is unknown. (See 'Inciting drugs, chemicals, foods, illnesses' above.)

●In other cases, an alternative drug may be effective. The use of ascorbic acid (vitamin C) rather than methylene blue to treat methemoglobinemia in individuals with G6PD deficiency is discussed separately. (See "Methemoglobinemia", section on 'Ascorbic acid (vitamin C)'.)

There are no high-quality data to suggest a certain level of G6PD deficiency is "safe" to administer these medications.

Data regarding dietary supplements and herbs are challenging to evaluate. In a systematic review of published reports, no evidence of harm was observed for vitamin C, vitamin E, vitamin K, ginkgo biloba, or alpha-lipoic acid [166]. We neither prescribe nor proscribe any of these supplements for G6PD-deficient individuals. Just as for any questionable food, we ask our patients and their families/caregivers to be observant of any changes suggestive of increased hemolysis (change in stamina, scleral icterus, dark [cola-colored] urine) associated with the use of supplements. There are no data to evaluate whether high doses of these supplements or vitamins are a risk factor for hemolysis.

Dietary restrictions — It has also been known since antiquity that ingestion of fava beans can cause acute hemolytic anemia in some individuals. In 1958, it was recognized that all individuals with favism had G6PD deficiency [167,168].

Individuals with G6PD deficiency should avoid ingestion of fava beans, also referred to as "broad beans," which can cause hemolysis in some but not all affected individuals [92,169]. However, unlike certain medications that induce hemolysis in all individuals with G6PD deficiency, sensitivity to the fava bean is more variable. Other names for fava beans are listed above. (See 'Inciting drugs, chemicals, foods, illnesses' above.)

The G6PD variants most commonly implicated in favism are G6PD Mediterranean and G6PD Canton. Favism occurs most often in people from Italy, Greece, North Africa, the Middle East, and Asia [2]. People from Africa and African-Americans with G6PD deficiency are much less susceptible, although there are very rare cases of favism associated with the African variant, G6PD A^- [170]. In addition, the response to the bean by the same individual at different times may not be consistent [171]. Other genetic factors, perhaps related to the hepatic metabolism of potentially oxidant compounds within the fava bean, may play a role in determining the severity of the reaction [171-173].

As discussed above, the ratio of fava beans consumed to body weight may account in large part for the observation that favism attacks are much more common and more severe in children than adults [1,92]. (See 'Inciting drugs, chemicals, foods, illnesses' above.)

Favism most often results from the ingestion of fresh (rather than preserved) fava beans (picture 2). Consequently, the peak seasonal incidence of favism in Mediterranean regions coincides with harvesting of the bean during April and May [171]. However, equally severe hemolysis can occur after consuming fried fava beans, a popular Chinese snack (picture 2). Favism also has been reported in nursing infants whose mothers have eaten fava beans.

The safety of falafel, a common Middle Eastern food, depends on the ingredients. Egyptian falafel is made from fava beans, whereas falafel made elsewhere in the world is usually made from chickpeas, which are safe for people with G6PD deficiency. However, in some areas, falafel is made from a mixture of fava beans and chickpeas.

In our practice, aside from advising people to avoid fava beans, we do not advise any other dietary restrictions.

The mechanism by which fava beans induce hemolysis involves the pyrimidine metabolites divicine and isouramil (aglycones of the glucosides) [174-176]. These compounds act as strong reducing agents, which in the presence of oxygen form an unstable intermediate that oxidizes reduced glutathione. In G6PD-deficient red blood cells with diminished GSH-generating capacity, this may have a direct effect on RBC function. In vitro studies have shown that divicine reduces the activity of catalase which, like the glutathione pathway, contributes to hydrogen peroxide removal, and requires NADPH for maintenance of normal activity [176].

Pregnancy — Overall, pregnancy in individuals who are heterozygous for G6PD deficiency is safe. However, drugs and chemicals known to be unsafe (table 1) should be avoided. Some of these drugs can cross the placenta and put the fetus at risk, and some can be present in breast milk and put the neonate at risk. (See 'Inciting drugs, chemicals, foods, illnesses' above.)

For the drugs that are considered "probably safe," there are no published data to suggest that risk of hemolysis would be increased in a breastfed infant who had G6PD deficiency. Decisions about the use of these drugs will depend on the individual case and the availability of good alternatives, as discussed in topic reviews on specific conditions. (See "Lactational mastitis", section on 'Treatment'.)

Whenever a known female carrier for G6PD deficiency delivers an infant, particularly a male infant, the child's pediatrician should be aware of the possibility of neonatal hyperbilirubinemia. (See 'Neonatal jaundice' above.)

Blood donation — As a general rule, donated blood is not screened for G6PD deficiency, and individuals with G6PD deficiency can donate blood as long as they are otherwise able to donate and do not have anemia (ie, not Class A deficiency). This is because the typical lifespan of transfused G6PD-deficient RBCs is thought to be relatively normal, and it is unlikely for a patient to be transfused with multiple units of G6PD-deficient blood and have clinically significant hemolysis, even in areas of high prevalence [2]. (See "Blood donor screening: Overview of recipient and donor protections".)

One exception may be blood used for exchange transfusion of newborn infants, which poses a theoretical risk if a large enough volume of G6PD-deficient cells is transfused. (See "Red blood cell (RBC) transfusions in the neonate" and "Red blood cell transfusion in infants and children: Administration and complications".)

Genetic counseling and prenatal testing — G6PD deficiency is an X-linked disorder. (See 'X-linked inheritance' above.)

Affected males have a 100 percent chance of transmitting the pathogenic variant to their daughters, who will be heterozygous. Affected females have a 50 percent chance of transmitting the pathogenic variant to their sons and daughters.

In general, males who inherit a pathogenic variant in G6PD are more likely to have clinically significant disease, and heterozygous females are likely to be unaffected carriers. However, females can have hemolysis if they have skewed lyonization or if they are homozygous or compound heterozygous for a pathogenic variant in G6PD, which can happen in populations with a high prevalence of G6PD deficiency.

Prenatal testing for G6PD deficiency is not routinely performed. (See "Prenatal care: Initial assessment".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in adults".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Glucose-6-phosphate dehydrogenase deficiency (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Disease definition and epidemiology – Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited red blood cell (RBC) enzyme abnormality, affecting 400 million people worldwide (figure 2). Individuals of certain ethnic groups are at higher risk, including individuals from the Middle East; Black individuals from sub-Saharan Africa or Brazil; African Americans; and people from Thailand, Sardinia, Greece, South China, and India (areas where malaria was once endemic). G6PD deficiency is X-linked; males are more likely to be affected, and heterozygous females are typically unaffected carriers, but females who are homozygous, compound heterozygous, or heterozygous with skewed lyonization can have clinically significant hemolysis. (See 'Epidemiology' above.)

●Genetics and pathophysiology – Clinically significant G6PD variants are classified as Class A or B by whether chronic hemolysis is present (Class A) or absent (Class B) and how severely enzyme activity is reduced (<20 percent for Class A; <45 percent for Class B). Common variants and their geographic distributions are discussed above. (See 'Classification of G6PD variants' above and "Gene test interpretation: G6PD".)

G6PD deficiency has been proposed to be protective against malaria by an unknown mechanism. (See "Protection against malaria by variants in red blood cell (RBC) genes", section on 'G6PD deficiency'.)

●Clinical features – Clinical manifestations of G6PD deficiency include acute hemolytic anemia, typically induced by medications (table 1), chemicals (eg, henna, naphthaline), ingestion of fava beans (picture 2), or illnesses (typically, infections) that cause oxidant injury. Most individuals have intermittent hemolysis, but severely affected individuals can have life-threatening neonatal jaundice and/or chronic hemolytic anemia. Glycated hemoglobin (HbA1C) values underestimate glucose levels, which can interfere with diabetes screening and diabetes care and necessitate additional testing. Kindreds with very severe deficiency can have increased susceptibility to infection, due to a lack of NADPH production in phagocytes. (See 'Clinical manifestations' above and "Myeloperoxidase deficiency and other enzymatic WBC defects causing immunodeficiency", section on 'Glucose-6-phosphate dehydrogenase deficiency'.)

●When to suspect G6PD deficiency – Evaluation for G6PD deficiency is appropriate in individuals with unexplained neonatal jaundice or direct antiglobulin (Coombs)-negative hemolytic anemia, and in high-risk individuals prior to treatment with known oxidant medications (table 1). First-degree relatives of affected individuals and certain other populations may benefit from testing. (See 'Indications for evaluation' above.)

●Evaluation – Available testing includes semi-quantitative screening tests, some of which are done at the point of care, and quantitative tests that report G6PD enzyme activity per gram of hemoglobin. The principle of these assays involves generation of NADPH by RBCs (figure 1). False-negative results may occur in some individuals with acute hemolysis because the most severely G6PD-deficient cells have been destroyed; in such cases, testing should be repeated three months after the hemolytic episode has resolved. DNA testing is available but not used routinely. (See 'Timing of G6PD assay' above and 'Screening tests' above and 'Confirmatory tests' above.)

●Differential diagnosis – The differential diagnosis of G6PD deficiency includes a number of other inherited and acquired hemolytic anemias and causes of neonatal jaundice. (See 'Differential diagnosis' above.)

●Management – Management depends on the severity of the deficiency and the clinical setting. Specific recommendations for neonatal jaundice, acute hemolytic episodes, chronic hemolysis, and avoidance of unsafe medications (table 1) and foods are presented above. The only food we recommend avoiding is fava beans. Many drugs commonly listed for avoidance are actually safe. Pregnancy is safe, and individuals with G6PD deficiency can donate blood as long as they are not anemic. (See 'Management' above.)

●Other conditions – Evaluation of hemolytic anemias and discussions of other RBC enzyme disorders are presented separately. (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults" and "Pyruvate kinase deficiency" and "Rare RBC enzyme disorders".)

ACKNOWLEDGMENTS

UpToDate gratefully acknowledges Stanley L Schrier, MD, who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges extensive contributions of Donald H Mahoney, Jr, MD, to earlier versions of this topic review.