Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

Genetic MONDO:0005775 Pathograph 24 Inborn Error of Metabolism Hemolytic Anemia

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1
Inheritance
5
Pathophys.
10
Phenotypes
24
Pathograph
1
Genes
4
Treatments
2
Deep Research
👪

Inheritance

1
X-linked recessive
Show evidence (2 references)
PMID:32702756 SUPPORT Human Clinical
"Glucose 6-phosphate dehydrogenase (G6PD) deficiency is 1 of the commonest human enzymopathies, caused by inherited mutations of the X-linked gene G6PD."
This review identifies inherited mutations of the X-linked G6PD gene as causal.
PMID:33560519 SUPPORT Human Clinical
"children diagnosed with glucose-6-phosphate dehydrogenase (G6PD) deficiency, an inherited X-linked recessive disorder"
The Danish clinical cohort describes G6PD deficiency as X-linked recessive.
⚙

Pathophysiology

5
Decreased G6PD Enzyme Activity
Pathogenic variants in G6PD reduce enzyme stability or activity in erythrocytes, limiting the oxidative pentose phosphate pathway.
erythrocyte link
G6PD link
pentose-phosphate shunt link ↓ DECREASED erythrocyte homeostasis link ↓ DECREASED
blood link
Downstream
Impaired Redox Homeostasis Reduced G6PD activity limits pentose-phosphate shunt flux and NADPH generation.
Chronic Nonspherocytic Hemolytic Anemia Severe variants can cause chronic hemolysis rather than only trigger-induced acute crises.
Show evidence (2 references)
PMID:27040960 SUPPORT Human Clinical
"G6PD deficiency, one of the commonest inherited enzyme abnormalities in humans, arises through one of many possible mutations, most of which reduce the stability of the enzyme and its level as red cells age."
This review supports reduced enzyme stability as a common molecular consequence of G6PD variants.
PMID:32680472 SUPPORT Human Clinical
"Infants with this novel variant showed decreased activity of G6PD, severe anemia, and pathological jaundice"
Human variant data directly links G6PD variants to decreased enzyme activity.
Impaired Redox Homeostasis
Reduced G6PD activity lowers NADPH availability and compromises glutathione-dependent antioxidant buffering.
erythrocyte link
NADPH regeneration link ↓ DECREASED glutathione metabolic process link ↕ DYSREGULATED detoxification of hydrogen peroxide link ↓ DECREASED
Downstream
Oxidative Stress Inadequate NADPH and glutathione buffering amplify oxidative injury in erythrocytes.
Show evidence (2 references)
PMID:7602782 SUPPORT Other
"Glucose 6-phosphate dehydrogenase (G6PD) plays a key role in the generation of NADPH which is essential for maintaining glutathione in the reduce state"
This review connects G6PD activity to NADPH generation and glutathione reduction.
PMID:31500396 SUPPORT Other
"The generation of reducing equivalent NADPH via glucose-6-phosphate dehydrogenase (G6PD) is critical for the maintenance of redox homeostasis and reductive biosynthesis in cells."
This review supports G6PD-dependent NADPH generation as a redox-homeostasis mechanism.
Oxidative Stress
NADPH and glutathione insufficiency leave G6PD-deficient erythrocytes susceptible to oxidant injury from drugs, infections, foods, or chemicals.
erythrocyte link
response to oxidative stress link ↕ DYSREGULATED reactive oxygen species metabolic process link ⚠ ABNORMAL hydrogen peroxide catabolic process link ↓ DECREASED
blood link
Downstream
Oxidative Hemoglobin Damage Oxidant stress modifies hemoglobin and erythrocyte proteins when antioxidant buffering is insufficient.
Show evidence (2 references)
PMID:17623517 SUPPORT Other
"Glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the pentose phosphate pathway, is indispensable to maintenance of the cytosolic pool of NADPH and thus the cellular redox balance."
This review supports the link between G6PD, NADPH, and cellular redox balance.
PMID:31235029 SUPPORT Other
"Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an erythrocyte enzyme defect that amplifies the susceptibility of erythrocytes to oxidative stress due to excessive levels of reactive oxygen species. Consequently, erythrocyte destruction and hemolysis occur."
This review directly connects G6PD deficiency to erythrocyte oxidative stress and hemolysis.
Oxidative Hemoglobin Damage
Unopposed oxidants damage hemoglobin sulfhydryl groups, reduce hemoglobin solubility, and form Heinz body precipitates.
erythrocyte link
protein oxidation link ↑ INCREASED
blood link
Downstream
Acute Hemolytic Anemia Oxidative hemoglobin precipitation and membrane injury promote erythrocyte destruction.
Show evidence (1 reference)
PMID:17365988 SUPPORT Other
"The presence of unopposed oxidizing agents leading to oxidation of the sulfhydryl bridges between parts of the haemoglobin molecule decrease the solubility of haemoglobin, leading to precipitations called Heinz bodies."
The abstract describes the oxidative hemoglobin damage that yields Heinz bodies.
Acute Hemolytic Anemia
Oxidative stressors trigger episodic erythrocyte destruction and anemia in susceptible G6PD-deficient individuals.
erythrocyte link
erythrocyte clearance link ↑ INCREASED positive regulation of erythrocyte clearance link
blood link spleen link
Downstream
Hemolytic Anemia Erythrocyte destruction produces acute hemolytic anemia.
Favism When fava-bean oxidants are the precipitating trigger, acute hemolytic anemia presents clinically as favism.
Dark Urine Intravascular hemolysis can produce hemoglobinuria or dark red urine.
Pallor Acute anemia decreases circulating red-cell mass and produces pallor.
Jaundice Increased heme breakdown raises bilirubin and produces jaundice.
Fatigue Acute anemia can cause systemic fatigue or malaise.
Shortness of Breath Severe acute anemia can cause dyspnea or respiratory distress.
Splenomegaly Extravascular erythrocyte clearance can enlarge or stress the spleen during favism episodes.
Show evidence (2 references)
PMID:31609781 SUPPORT Human Clinical
"The G6PD enzyme is critical to protecting erythrocytes against oxidative stress, and deficiency may lead to hemolysis in the presence of certain environmental factors such as infection and some medications and foods."
The abstract supports triggered hemolysis in G6PD deficiency.
PMID:32600868 SUPPORT Other
"Although most individuals are asymptomatic, exposure to certain food, drugs, or infections can trigger acute hemolytic anemia."
This review supports episodic acute hemolytic anemia after triggers.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

10
Blood 3
Hemolytic Anemia Hemolytic anemia (HP:0001878)
Temporal: ACUTE
Sequelae: Jaundice Fatigue Shortness of Breath
Show evidence (2 references)
PMID:17611006 SUPPORT Human Clinical
"People, usually males, with deficient alleles are susceptible to neonatal jaundice, and acute hemolytic anemia, usually during infection, after treatment with certain drugs or after eating fava beans."
This review identifies acute hemolytic anemia as a major G6PD-deficiency manifestation.
PMID:28982343 SUPPORT Human Clinical
"G6PD deficiency anemia presented mainly with pallor, dark red urine and jaundice after exposure to certain diets, drugs and diseases"
This cohort supports hemolytic anemia presentations after precipitating exposures.
Favism Hemolytic anemia (HP:0001878)
Temporal: ACUTE
Acute hemolytic anemia triggered by ingestion of fava beans.
Show evidence (2 references)
PMID:36678214 SUPPORT Human Clinical
"Favism is a hemolytic disease due to the ingestion of fava beans in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency."
This review defines favism as fava-bean-triggered hemolysis in G6PD deficiency.
PMID:32702756 SUPPORT Human Clinical
"any of them may develop acute and sometimes very severe hemolytic anemia when triggered by ingestion of fava beans"
This review supports fava-bean-triggered acute hemolytic anemia.
Chronic Nonspherocytic Hemolytic Anemia Hemolytic anemia (HP:0001878)
Temporal: CHRONIC
Rare severe variant presentation with baseline chronic hemolysis rather than only trigger-induced crises.
Show evidence (2 references)
PMID:17623517 SUPPORT Other
"deficiency is associated with neonatal jaundice, drug- or infection-mediated hemolytic crisis, favism and, less commonly, chronic non-spherocytic hemolytic anemia"
This review lists chronic nonspherocytic hemolytic anemia as a less common G6PD-deficiency manifestation.
PMID:16225031 SUPPORT Other
"The variant that causes chronic hemolysis is uncommon because it is related to sporadic gene mutation rather than the more common inherited gene mutation."
This management review supports chronic hemolysis as an uncommon G6PD variant presentation.
Cardiovascular 1
Splenomegaly Splenomegaly (HP:0001744)
Reported during favism and consistent with splenic erythrocyte clearance.
Show evidence (1 reference)
PMID:36678214 SUPPORT Human Clinical
"Some other symptoms were present in all: jaundice, increased bilirubin, splenomegaly, hepatomegaly, discolored urine, tachycardia, pallor, abdominal pain, malaise, vomit, nausea, and dizziness."
The favism review directly lists splenomegaly among reported symptoms.
Digestive 1
Jaundice Jaundice (HP:0000952)
Show evidence (2 references)
PMID:28982343 SUPPORT Human Clinical
"Patients presented mainly with pallor (1000 patients; 100%), dark red urine (896 patients; 89.6%) and jaundice (878 patients; 87.8%) after 24-72 hours of exposure to the precipitating factors"
The cohort directly reports jaundice after precipitating exposures.
PMID:16513531 SUPPORT Human Clinical
"The classic features of favism, which are pallor, hemoglobinuria, and jaundice, were detected in all cases."
The favism cohort directly supports jaundice during fava-bean-triggered hemolysis.
Genitourinary 1
Dark Urine Dark urine (HP:0040319)
Reflects hemoglobinuria or discolored urine during acute hemolytic episodes.
Show evidence (2 references)
PMID:28982343 SUPPORT Human Clinical
"Patients presented mainly with pallor (1000 patients; 100%), dark red urine (896 patients; 89.6%) and jaundice (878 patients; 87.8%) after 24-72 hours of exposure to the precipitating factors"
The cohort directly reports dark red urine during G6PD hemolytic episodes.
PMID:16513531 SUPPORT Human Clinical
"The classic features of favism, which are pallor, hemoglobinuria, and jaundice, were detected in all cases."
Hemoglobinuria supports dark urine during favism.
Integument 1
Pallor Pallor (HP:0000980)
Due to anemia, most noticeable during acute hemolytic episodes.
Show evidence (1 reference)
PMID:28982343 SUPPORT Human Clinical
"Patients presented mainly with pallor (1000 patients; 100%), dark red urine (896 patients; 89.6%) and jaundice (878 patients; 87.8%) after 24-72 hours of exposure to the precipitating factors"
The cohort directly reports pallor in G6PD hemolytic episodes.
Metabolism 1
Neonatal Jaundice Neonatal hyperbilirubinemia (HP:0003265)
May be severe in G6PD-deficient newborns and can require urgent bilirubin-directed management.
Show evidence (2 references)
PMID:27040960 SUPPORT Human Clinical
"G6PD-deficient persons are mostly asymptomatic, but they can develop severe jaundice during the neonatal period and acute hemolytic anemia when they ingest fava beans or when they are exposed to certain infections or drugs."
This review directly supports severe neonatal jaundice.
PMID:19233695 SUPPORT Human Clinical
"This inherited deficiency causes neonatal hyperbilirubinemia and chronic hemolytic anemia."
This systematic review states that G6PD deficiency causes neonatal hyperbilirubinemia.
Respiratory 1
Shortness of Breath Dyspnea (HP:0002094)
Severe acute hemolytic anemia can present with respiratory distress.
Show evidence (1 reference)
PMID:27101632 PARTIAL Human Clinical
"The evolution was marked by a respiratory distress syndrome, a severe hemolytic anemia, associated with thrombocytopenia and kidney failure."
This case supports respiratory distress as a severe acute-hemolysis presentation, though it is not a broad frequency estimate.
Constitutional 1
Fatigue Fatigue (HP:0012378)
Reported as malaise during favism and modeled as a systemic effect of acute anemia.
Show evidence (1 reference)
PMID:36678214 PARTIAL Human Clinical
"Some other symptoms were present in all: jaundice, increased bilirubin, splenomegaly, hepatomegaly, discolored urine, tachycardia, pallor, abdominal pain, malaise, vomit, nausea, and dizziness."
The abstract reports malaise during favism; fatigue is the closest HPO term already used in this entry.
🧬

Genetic Associations

1
G6PD
X-linked recessive
Show evidence (3 references)
PMID:32702756 SUPPORT Human Clinical
"Glucose 6-phosphate dehydrogenase (G6PD) deficiency is 1 of the commonest human enzymopathies, caused by inherited mutations of the X-linked gene G6PD."
This review supports the G6PD gene-disease relationship.
PMID:24460025 SUPPORT Human Clinical
"Glucose-6-Phosphate Dehydrogenase (G6PD) gene is located at the X-chromosome at Xq28 and the disease is recessively inherited predominantly in males."
This newborn study supports X-linked recessive inheritance of G6PD deficiency.
CGGV:assertion_153ae203-3ae5-4cb3-bbf8-d72467700d8c-2023-06-23T160000.000Z SUPPORT Other
"G6PD | HGNC:4057 | G6PD deficiency | MONDO:0005775 | XL | Definitive"
ClinGen classifies the G6PD-G6PD deficiency gene-disease relationship as definitive with X-linked inheritance.
💊

Treatments

4
Avoidance of Oxidative Stressors
Action: medical action avoidance MAXO:0001014
Identifying and avoiding medications, foods, infections, and other oxidant triggers that can precipitate hemolysis.
Mechanism Target:
INHIBITS Oxidative Stress — Avoidance reduces the oxidant burden that G6PD-deficient erythrocytes cannot buffer.
INHIBITS Acute Hemolytic Anemia — Avoidance prevents trigger-induced hemolytic crises.
Target Phenotypes: Hemolytic anemia ↗
Show evidence (2 references)
PMID:31609781 SUPPORT Human Clinical
"By recognizing the potential for G6PD deficiency, clinicians can screen for the disorder and teach affected patients how to avoid triggers that result in harmful clinical manifestations."
This review directly supports trigger-avoidance counseling.
PMID:19769422 SUPPORT Other
"The most effective management strategy is to prevent hemolysis by avoiding oxidative stressors."
This review supports avoidance as the primary management strategy.
Blood Transfusion During Severe Acute Hemolysis
Action: blood transfusion MAXO:0000756
Restrictive red-cell transfusion is used for severe acute hemolytic crisis with very low hemoglobin or clinical instability.
Mechanism Target:
MODULATES Acute Hemolytic Anemia — Transfusion addresses the downstream anemia produced by acute erythrocyte destruction.
Target Phenotypes: Hemolytic anemia ↗ Shortness of breath ↗
Show evidence (2 references)
PMID:34105166 SUPPORT Human Clinical
"33% of patients had Hb < 50 g/L and were all transfused. 50% had Hb between 50 and 65 g/L, half of them (n = 49) did not receive transfusion and only two patients (4%) required transfusion upon follow up."
This pediatric acute-hemolytic-crisis cohort supports transfusion for severe anemia.
PMID:16225031 SUPPORT Other
"Acute hemolysis is self-limited, but in rare instances it can be severe enough to warrant a blood transfusion."
This management review supports transfusion when acute hemolysis is severe.
Neonatal Screening and Monitoring
Action: neonatal screening Ontology label: diagnostic procedure MAXO:0000003
Early detection and close monitoring identify G6PD-deficient newborns at risk for severe neonatal jaundice.
Target Phenotypes: Neonatal hyperbilirubinemia ↗
Show evidence (2 references)
PMID:27064064 SUPPORT Human Clinical
"Early detection and an accurate diagnosis are, therefore, of major importance for preventing negative patient outcomes."
This review supports early detection and accurate diagnosis to prevent neonatal outcomes.
PMID:36845240 SUPPORT Human Clinical
"Through this observation, we insist on the importance of neonatal screening in regions with a high prevalence of hemolysis in order to avoid diagnostic delays and also to prioritize the evaluation to be requested in an acute hemolysis state, to propose an education articulated around a..."
This case report supports neonatal screening and education in high-prevalence settings.
Neonatal Hyperbilirubinemia Treatment
Action: phototherapy Ontology label: Phototherapy NCIT:C15301
Phototherapy or exchange transfusion may be required to prevent kernicterus in G6PD-associated neonatal hyperbilirubinemia.
Target Phenotypes: Neonatal hyperbilirubinemia ↗
Show evidence (1 reference)
PMID:16225031 SUPPORT Other
"Neonatal hyperbilirubinemia may require treatment with phototherapy or exchange transfusion to prevent kernicterus."
This management review supports bilirubin-directed neonatal treatment.
🌍

Environmental Factors

1
Oxidative Stressors
Oxidative stress exposure link
Triggers for acute hemolytic episodes.
Show evidence (3 references)
PMID:31609781 SUPPORT Human Clinical
"The G6PD enzyme is critical to protecting erythrocytes against oxidative stress, and deficiency may lead to hemolysis in the presence of certain environmental factors such as infection and some medications and foods."
This review supports infections, medications, and foods as oxidative hemolysis triggers.
PMID:24372186 SUPPORT Human Clinical
"That primaquine and other drugs can trigger acute haemolytic anaemia in subjects who have an inherited mutation of the glucose 6-phosphate dehydrogenase (G6PD) gene has been known for over half a century"
This review supports oxidant drugs such as primaquine as acute hemolysis triggers.
PMID:30380124 SUPPORT Human Clinical
"fava beans can provoke severe oxidative hemolysis in individuals with G6PD deficiency"
This review supports fava beans as a clinically evidenced dietary trigger.
🔬

Biochemical Markers

4
G6PD Enzyme Activity (DECREASED)
Context: Diagnostic enzymatic assay in red blood cells.
Pathograph Readouts
Readout Of Decreased G6PD Enzyme Activity Negative Diagnostic
Low measured G6PD activity reports the causal enzymatic defect.
Show evidence (2 references)
PMID:17365988 SUPPORT Other
"The laboratory investigation of G6PD deficiency is commonly done by a quantitative spectrophotometric analysis or by a rapid fluorescent spot test detecting the generation of NADPH from NADP."
This supports G6PD activity testing as a diagnostic biochemical readout.
PMID:32680472 SUPPORT Human Clinical
"Infants with this novel variant showed decreased activity of G6PD, severe anemia, and pathological jaundice"
This human variant study directly reports decreased G6PD activity.
Bilirubin (INCREASED)
Context: Elevated during neonatal hyperbilirubinemia or hemolytic episodes.
Pathograph Readouts
Readout Of Acute Hemolytic Anemia Positive Monitoring
Bilirubin elevation reflects heme breakdown during hemolysis.
Readout Of Neonatal Jaundice Positive Diagnostic
Increased bilirubin is the biochemical basis of neonatal hyperbilirubinemia.
Show evidence (2 references)
PMID:36678214 SUPPORT Human Clinical
"Laboratory findings are characterized by anemia, reticulocytosis, elevated bilirubin level, and sometimes urinary urobilinogen and methemoglobinemia."
Favism laboratory findings include elevated bilirubin.
PMID:24460025 SUPPORT Human Clinical
"G6PD activity showed statistically significant correlation with total bilirubin blood levels."
This newborn study links G6PD activity to bilirubin levels.
Heinz Bodies (PRESENT)
Context: Present during oxidative hemoglobin precipitation in acute hemolysis.
Pathograph Readouts
Readout Of Oxidative Hemoglobin Damage Present Absent Diagnostic
Heinz bodies indicate oxidized hemoglobin precipitation in erythrocytes.
Show evidence (1 reference)
PMID:17365988 SUPPORT Other
"The presence of unopposed oxidizing agents leading to oxidation of the sulfhydryl bridges between parts of the haemoglobin molecule decrease the solubility of haemoglobin, leading to precipitations called Heinz bodies."
The abstract directly explains Heinz body formation from oxidized hemoglobin.
Glutathione Homeostasis (IMPAIRED)
Context: Impaired in G6PD-deficient red blood cells under oxidant stress.
Pathograph Readouts
Readout Of Impaired Redox Homeostasis Threshold Dependent Monitoring
Impaired glutathione homeostasis reports deficient NADPH-dependent antioxidant buffering.
Show evidence (1 reference)
PMID:31961822 SUPPORT Human Clinical
"As expected, fresh G6PD-deficient RBCs demonstrated defects in the oxidative phase of the pentose phosphate pathway. During refrigerated storage, G6PD-deficient RBCs demonstrated increased glycolysis, impaired glutathione homeostasis, and increased purine oxidation, as compared with G6PD-normal RBCs."
Human donor RBC data supports impaired glutathione homeostasis in G6PD-deficient erythrocytes.
{ }

Source YAML

click to show 
name: Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-05-18T03:36:49Z'
category: Genetic
parents:
- Inborn Error of Metabolism
- Hemolytic Anemia
prevalence:
- population: Global
  percentage: 4.9
  evidence:
  - reference: PMID:19233695
    reference_title: "The global prevalence of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: Glucose-6-phosphate deficiency is the most prevalent enzyme deficiency, with an estimated 400 million people affected worldwide.
    explanation: The abstract supports a high global burden, though it reports affected individuals rather than the exact 4.9% percentage.
- population: African Americans
  percentage: 10
  evidence:
  - reference: PMID:20732351
    reference_title: "Prevalence of G6PD deficiency in a large cohort of HIV-infected patients."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: Rates were higher among African Americans (68/699; 9.7%)
    explanation: This cohort estimate is close to the rounded 10% prevalence value.
inheritance:
- name: X-linked recessive
  evidence:
  - reference: PMID:32702756
    reference_title: "Glucose-6-phosphate dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Glucose 6-phosphate dehydrogenase (G6PD) deficiency is 1 of the commonest human enzymopathies, caused by inherited mutations of the X-linked gene G6PD.
    explanation: This review identifies inherited mutations of the X-linked G6PD gene as causal.
  - reference: PMID:33560519
    reference_title: "A greater awareness of children with glucose-6-phosphate dehydrogenase deficiency is imperative in western countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: children diagnosed with glucose-6-phosphate dehydrogenase (G6PD) deficiency, an inherited X-linked recessive disorder
    explanation: The Danish clinical cohort describes G6PD deficiency as X-linked recessive.
pathophysiology:
- name: Decreased G6PD Enzyme Activity
  description: Pathogenic variants in G6PD reduce enzyme stability or activity in erythrocytes, limiting the oxidative pentose phosphate pathway.
  genes:
  - preferred_term: G6PD
    term:
      id: hgnc:4057
      label: G6PD
  locations:
  - preferred_term: blood
    term:
      id: UBERON:0000178
      label: blood
  biological_processes:
  - preferred_term: pentose-phosphate shunt
    term:
      id: GO:0006098
      label: pentose-phosphate shunt
    modifier: DECREASED
  - preferred_term: erythrocyte homeostasis
    term:
      id: GO:0034101
      label: erythrocyte homeostasis
    modifier: DECREASED
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  downstream:
  - target: Impaired Redox Homeostasis
    description: Reduced G6PD activity limits pentose-phosphate shunt flux and NADPH generation.
    causal_link_type: DIRECT
  - target: Chronic Nonspherocytic Hemolytic Anemia
    description: Severe variants can cause chronic hemolysis rather than only trigger-induced acute crises.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - severe enzyme instability
    - chronic erythrocyte destruction
  evidence:
  - reference: PMID:27040960
    reference_title: "Glucose-6-Phosphate Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: G6PD deficiency, one of the commonest inherited enzyme abnormalities in humans, arises through one of many possible mutations, most of which reduce the stability of the enzyme and its level as red cells age.
    explanation: This review supports reduced enzyme stability as a common molecular consequence of G6PD variants.
  - reference: PMID:32680472
    reference_title: "A novel G6PD deleterious variant identified in three families with severe glucose-6-phosphate dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Infants with this novel variant showed decreased activity of G6PD, severe anemia, and pathological jaundice
    explanation: Human variant data directly links G6PD variants to decreased enzyme activity.
- name: Impaired Redox Homeostasis
  description: Reduced G6PD activity lowers NADPH availability and compromises glutathione-dependent antioxidant buffering.
  biological_processes:
  - preferred_term: NADPH regeneration
    term:
      id: GO:0006740
      label: NADPH regeneration
    modifier: DECREASED
  - preferred_term: glutathione metabolic process
    term:
      id: GO:0006749
      label: glutathione metabolic process
    modifier: DYSREGULATED
  - preferred_term: detoxification of hydrogen peroxide
    term:
      id: GO:0061691
      label: detoxification of hydrogen peroxide
    modifier: DECREASED
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  chemical_entities:
  - preferred_term: NADPH
    term:
      id: CHEBI:16474
      label: NADPH
  - preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
  downstream:
  - target: Oxidative Stress
    description: Inadequate NADPH and glutathione buffering amplify oxidative injury in erythrocytes.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:7602782
    reference_title: "[Glucose-6-phosphate dehydrogenase]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Glucose 6-phosphate dehydrogenase (G6PD) plays a key role in the generation of NADPH which is essential for maintaining glutathione in the reduce state
    explanation: This review connects G6PD activity to NADPH generation and glutathione reduction.
  - reference: PMID:31500396
    reference_title: "The Redox Role of G6PD in Cell Growth, Cell Death, and Cancer."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The generation of reducing equivalent NADPH via glucose-6-phosphate dehydrogenase (G6PD) is critical for the maintenance of redox homeostasis and reductive biosynthesis in cells.
    explanation: This review supports G6PD-dependent NADPH generation as a redox-homeostasis mechanism.
- name: Oxidative Stress
  description: NADPH and glutathione insufficiency leave G6PD-deficient erythrocytes susceptible to oxidant injury from drugs, infections, foods, or chemicals.
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: DYSREGULATED
  - preferred_term: reactive oxygen species metabolic process
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
    modifier: ABNORMAL
  - preferred_term: hydrogen peroxide catabolic process
    term:
      id: GO:0042744
      label: hydrogen peroxide catabolic process
    modifier: DECREASED
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  locations:
  - preferred_term: blood
    term:
      id: UBERON:0000178
      label: blood
  chemical_entities:
  - preferred_term: hydrogen peroxide
    term:
      id: CHEBI:16240
      label: hydrogen peroxide
  downstream:
  - target: Oxidative Hemoglobin Damage
    description: Oxidant stress modifies hemoglobin and erythrocyte proteins when antioxidant buffering is insufficient.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:17623517
    reference_title: "Glucose-6-phosphate dehydrogenase--from oxidative stress to cellular functions and degenerative diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the pentose phosphate pathway, is indispensable to maintenance of the cytosolic pool of NADPH and thus the cellular redox balance.
    explanation: This review supports the link between G6PD, NADPH, and cellular redox balance.
  - reference: PMID:31235029
    reference_title: "Periodontal disease and hemolysis in glucose-6-phosphate dehydrogenase deficiency: Is there a nexus?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an erythrocyte enzyme defect that amplifies the susceptibility of erythrocytes to oxidative stress due to excessive levels of reactive oxygen species. Consequently, erythrocyte destruction and hemolysis occur.
    explanation: This review directly connects G6PD deficiency to erythrocyte oxidative stress and hemolysis.
- name: Oxidative Hemoglobin Damage
  description: Unopposed oxidants damage hemoglobin sulfhydryl groups, reduce hemoglobin solubility, and form Heinz body precipitates.
  biological_processes:
  - preferred_term: protein oxidation
    term:
      id: GO:0018158
      label: protein oxidation
    modifier: INCREASED
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  locations:
  - preferred_term: blood
    term:
      id: UBERON:0000178
      label: blood
  downstream:
  - target: Acute Hemolytic Anemia
    description: Oxidative hemoglobin precipitation and membrane injury promote erythrocyte destruction.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:17365988
    reference_title: "Inherited, non-spherocytic haemolysis due to deficiency of glucose-6-phosphate dehydrogenase."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The presence of unopposed oxidizing agents leading to oxidation of the sulfhydryl bridges between parts of the haemoglobin molecule decrease the solubility of haemoglobin, leading to precipitations called Heinz bodies.
    explanation: The abstract describes the oxidative hemoglobin damage that yields Heinz bodies.
- name: Acute Hemolytic Anemia
  description: Oxidative stressors trigger episodic erythrocyte destruction and anemia in susceptible G6PD-deficient individuals.
  biological_processes:
  - preferred_term: erythrocyte clearance
    term:
      id: GO:0034102
      label: erythrocyte clearance
    modifier: INCREASED
  - preferred_term: positive regulation of erythrocyte clearance
    term:
      id: GO:0034108
      label: positive regulation of erythrocyte clearance
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  locations:
  - preferred_term: blood
    term:
      id: UBERON:0000178
      label: blood
  - preferred_term: spleen
    term:
      id: UBERON:0002106
      label: spleen
  downstream:
  - target: Hemolytic Anemia
    description: Erythrocyte destruction produces acute hemolytic anemia.
    causal_link_type: DIRECT
  - target: Favism
    description: When fava-bean oxidants are the precipitating trigger, acute hemolytic anemia presents clinically as favism.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - fava-bean oxidant exposure
  - target: Dark Urine
    description: Intravascular hemolysis can produce hemoglobinuria or dark red urine.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - hemoglobinuria
  - target: Pallor
    description: Acute anemia decreases circulating red-cell mass and produces pallor.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - decreased hemoglobin
  - target: Jaundice
    description: Increased heme breakdown raises bilirubin and produces jaundice.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - bilirubin accumulation
  - target: Fatigue
    description: Acute anemia can cause systemic fatigue or malaise.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced oxygen carrying capacity
  - target: Shortness of Breath
    description: Severe acute anemia can cause dyspnea or respiratory distress.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced oxygen carrying capacity
  - target: Splenomegaly
    description: Extravascular erythrocyte clearance can enlarge or stress the spleen during favism episodes.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - splenic erythrocyte clearance
  evidence:
  - reference: PMID:31609781
    reference_title: "G6PD deficiency: An update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The G6PD enzyme is critical to protecting erythrocytes against oxidative stress, and deficiency may lead to hemolysis in the presence of certain environmental factors such as infection and some medications and foods.
    explanation: The abstract supports triggered hemolysis in G6PD deficiency.
  - reference: PMID:32600868
    reference_title: "Glucose-6-Phosphate Dehydrogenase Deficiency: An Actionable Risk Factor for Patients with COVID-19?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Although most individuals are asymptomatic, exposure to certain food, drugs, or infections can trigger acute hemolytic anemia.
    explanation: This review supports episodic acute hemolytic anemia after triggers.
phenotypes:
- category: Hematologic
  name: Hemolytic Anemia
  diagnostic: true
  sequelae:
  - target: Jaundice
  - target: Fatigue
  - target: Shortness of Breath
  phenotype_term:
    preferred_term: Hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
    temporality: ACUTE
  evidence:
  - reference: PMID:17611006
    reference_title: "G6PD deficiency: the genotype-phenotype association."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: People, usually males, with deficient alleles are susceptible to neonatal jaundice, and acute hemolytic anemia, usually during infection, after treatment with certain drugs or after eating fava beans.
    explanation: This review identifies acute hemolytic anemia as a major G6PD-deficiency manifestation.
  - reference: PMID:28982343
    reference_title: "Study of Glucose-6-Phosphate Dehydrogenase Deficiency: 5 Years Retrospective Egyptian Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: G6PD deficiency anemia presented mainly with pallor, dark red urine and jaundice after exposure to certain diets, drugs and diseases
    explanation: This cohort supports hemolytic anemia presentations after precipitating exposures.
- category: Genitourinary
  name: Dark Urine
  notes: Reflects hemoglobinuria or discolored urine during acute hemolytic episodes.
  phenotype_term:
    preferred_term: Dark urine
    term:
      id: HP:0040319
      label: Dark urine
  evidence:
  - reference: PMID:28982343
    reference_title: "Study of Glucose-6-Phosphate Dehydrogenase Deficiency: 5 Years Retrospective Egyptian Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients presented mainly with pallor (1000 patients; 100%), dark red urine (896 patients; 89.6%) and jaundice (878 patients; 87.8%) after 24-72 hours of exposure to the precipitating factors
    explanation: The cohort directly reports dark red urine during G6PD hemolytic episodes.
  - reference: PMID:16513531
    reference_title: "Glucose-6-phosphate dehydrogenase variants associated with favism in Thai children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The classic features of favism, which are pallor, hemoglobinuria, and jaundice, were detected in all cases.
    explanation: Hemoglobinuria supports dark urine during favism.
- category: Systemic
  name: Neonatal Jaundice
  notes: May be severe in G6PD-deficient newborns and can require urgent bilirubin-directed management.
  phenotype_term:
    preferred_term: Neonatal hyperbilirubinemia
    term:
      id: HP:0003265
      label: Neonatal hyperbilirubinemia
  evidence:
  - reference: PMID:27040960
    reference_title: "Glucose-6-Phosphate Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: G6PD-deficient persons are mostly asymptomatic, but they can develop severe jaundice during the neonatal period and acute hemolytic anemia when they ingest fava beans or when they are exposed to certain infections or drugs.
    explanation: This review directly supports severe neonatal jaundice.
  - reference: PMID:19233695
    reference_title: "The global prevalence of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This inherited deficiency causes neonatal hyperbilirubinemia and chronic hemolytic anemia.
    explanation: This systematic review states that G6PD deficiency causes neonatal hyperbilirubinemia.
- category: Hematologic
  name: Favism
  notes: Acute hemolytic anemia triggered by ingestion of fava beans.
  phenotype_term:
    preferred_term: Hemolytic anemia triggered by fava beans
    term:
      id: HP:0001878
      label: Hemolytic anemia
    temporality: ACUTE
  evidence:
  - reference: PMID:36678214
    reference_title: "Favism: Clinical Features at Different Ages."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Favism is a hemolytic disease due to the ingestion of fava beans in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
    explanation: This review defines favism as fava-bean-triggered hemolysis in G6PD deficiency.
  - reference: PMID:32702756
    reference_title: "Glucose-6-phosphate dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: any of them may develop acute and sometimes very severe hemolytic anemia when triggered by ingestion of fava beans
    explanation: This review supports fava-bean-triggered acute hemolytic anemia.
- category: Dermatologic
  name: Pallor
  notes: Due to anemia, most noticeable during acute hemolytic episodes.
  phenotype_term:
    preferred_term: Pallor
    term:
      id: HP:0000980
      label: Pallor
  evidence:
  - reference: PMID:28982343
    reference_title: "Study of Glucose-6-Phosphate Dehydrogenase Deficiency: 5 Years Retrospective Egyptian Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients presented mainly with pallor (1000 patients; 100%), dark red urine (896 patients; 89.6%) and jaundice (878 patients; 87.8%) after 24-72 hours of exposure to the precipitating factors
    explanation: The cohort directly reports pallor in G6PD hemolytic episodes.
- category: Dermatologic
  name: Jaundice
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:28982343
    reference_title: "Study of Glucose-6-Phosphate Dehydrogenase Deficiency: 5 Years Retrospective Egyptian Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients presented mainly with pallor (1000 patients; 100%), dark red urine (896 patients; 89.6%) and jaundice (878 patients; 87.8%) after 24-72 hours of exposure to the precipitating factors
    explanation: The cohort directly reports jaundice after precipitating exposures.
  - reference: PMID:16513531
    reference_title: "Glucose-6-phosphate dehydrogenase variants associated with favism in Thai children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The classic features of favism, which are pallor, hemoglobinuria, and jaundice, were detected in all cases.
    explanation: The favism cohort directly supports jaundice during fava-bean-triggered hemolysis.
- category: Systemic
  name: Fatigue
  notes: Reported as malaise during favism and modeled as a systemic effect of acute anemia.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:36678214
    reference_title: "Favism: Clinical Features at Different Ages."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Some other symptoms were present in all: jaundice, increased bilirubin, splenomegaly, hepatomegaly, discolored urine, tachycardia, pallor, abdominal pain, malaise, vomit, nausea, and dizziness."
    explanation: The abstract reports malaise during favism; fatigue is the closest HPO term already used in this entry.
- category: Respiratory
  name: Shortness of Breath
  notes: Severe acute hemolytic anemia can present with respiratory distress.
  phenotype_term:
    preferred_term: Shortness of breath
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:27101632
    reference_title: "Glucose-6-phosphate dehydrogenase deficiency: the added value of cytology."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: The evolution was marked by a respiratory distress syndrome, a severe hemolytic anemia, associated with thrombocytopenia and kidney failure.
    explanation: This case supports respiratory distress as a severe acute-hemolysis presentation, though it is not a broad frequency estimate.
- category: Hematologic
  name: Splenomegaly
  notes: Reported during favism and consistent with splenic erythrocyte clearance.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:36678214
    reference_title: "Favism: Clinical Features at Different Ages."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some other symptoms were present in all: jaundice, increased bilirubin, splenomegaly, hepatomegaly, discolored urine, tachycardia, pallor, abdominal pain, malaise, vomit, nausea, and dizziness."
    explanation: The favism review directly lists splenomegaly among reported symptoms.
- category: Hematologic
  name: Chronic Nonspherocytic Hemolytic Anemia
  notes: Rare severe variant presentation with baseline chronic hemolysis rather than only trigger-induced crises.
  phenotype_term:
    preferred_term: Chronic hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
    temporality: CHRONIC
  evidence:
  - reference: PMID:17623517
    reference_title: "Glucose-6-phosphate dehydrogenase--from oxidative stress to cellular functions and degenerative diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: deficiency is associated with neonatal jaundice, drug- or infection-mediated hemolytic crisis, favism and, less commonly, chronic non-spherocytic hemolytic anemia
    explanation: This review lists chronic nonspherocytic hemolytic anemia as a less common G6PD-deficiency manifestation.
  - reference: PMID:16225031
    reference_title: "Diagnosis and management of G6PD deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The variant that causes chronic hemolysis is uncommon because it is related to sporadic gene mutation rather than the more common inherited gene mutation.
    explanation: This management review supports chronic hemolysis as an uncommon G6PD variant presentation.
biochemical:
- name: G6PD Enzyme Activity
  presence: DECREASED
  context: Diagnostic enzymatic assay in red blood cells.
  readouts:
  - target: Decreased G6PD Enzyme Activity
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low measured G6PD activity reports the causal enzymatic defect.
  evidence:
  - reference: PMID:17365988
    reference_title: "Inherited, non-spherocytic haemolysis due to deficiency of glucose-6-phosphate dehydrogenase."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The laboratory investigation of G6PD deficiency is commonly done by a quantitative spectrophotometric analysis or by a rapid fluorescent spot test detecting the generation of NADPH from NADP.
    explanation: This supports G6PD activity testing as a diagnostic biochemical readout.
  - reference: PMID:32680472
    reference_title: "A novel G6PD deleterious variant identified in three families with severe glucose-6-phosphate dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Infants with this novel variant showed decreased activity of G6PD, severe anemia, and pathological jaundice
    explanation: This human variant study directly reports decreased G6PD activity.
- name: Bilirubin
  presence: INCREASED
  context: Elevated during neonatal hyperbilirubinemia or hemolytic episodes.
  readouts:
  - target: Acute Hemolytic Anemia
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Bilirubin elevation reflects heme breakdown during hemolysis.
  - target: Neonatal Jaundice
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased bilirubin is the biochemical basis of neonatal hyperbilirubinemia.
  biomarker_term:
    preferred_term: bilirubin
    term:
      id: CHEBI:16990
      label: bilirubin IXalpha
  evidence:
  - reference: PMID:36678214
    reference_title: "Favism: Clinical Features at Different Ages."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Laboratory findings are characterized by anemia, reticulocytosis, elevated bilirubin level, and sometimes urinary urobilinogen and methemoglobinemia.
    explanation: Favism laboratory findings include elevated bilirubin.
  - reference: PMID:24460025
    reference_title: "Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency in Greek newborns: the Mediterranean C563T mutation screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: G6PD activity showed statistically significant correlation with total bilirubin blood levels.
    explanation: This newborn study links G6PD activity to bilirubin levels.
- name: Heinz Bodies
  presence: PRESENT
  context: Present during oxidative hemoglobin precipitation in acute hemolysis.
  notes: Oxidized hemoglobin precipitates attached to the inner red-cell membrane.
  cell_types:
  - preferred_term: Red blood cells
    term:
      id: CL:0000232
      label: erythrocyte
  readouts:
  - target: Oxidative Hemoglobin Damage
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: Heinz bodies indicate oxidized hemoglobin precipitation in erythrocytes.
  evidence:
  - reference: PMID:17365988
    reference_title: "Inherited, non-spherocytic haemolysis due to deficiency of glucose-6-phosphate dehydrogenase."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The presence of unopposed oxidizing agents leading to oxidation of the sulfhydryl bridges between parts of the haemoglobin molecule decrease the solubility of haemoglobin, leading to precipitations called Heinz bodies.
    explanation: The abstract directly explains Heinz body formation from oxidized hemoglobin.
- name: Glutathione Homeostasis
  presence: IMPAIRED
  context: Impaired in G6PD-deficient red blood cells under oxidant stress.
  cell_types:
  - preferred_term: Red blood cells
    term:
      id: CL:0000232
      label: erythrocyte
  readouts:
  - target: Impaired Redox Homeostasis
    relationship: READOUT_OF
    direction: THRESHOLD_DEPENDENT
    endpoint_context: MONITORING
    interpretation: Impaired glutathione homeostasis reports deficient NADPH-dependent antioxidant buffering.
  evidence:
  - reference: PMID:31961822
    reference_title: "Donor glucose-6-phosphate dehydrogenase deficiency decreases blood quality for transfusion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: As expected, fresh G6PD-deficient RBCs demonstrated defects in the oxidative phase of the pentose phosphate pathway. During refrigerated storage, G6PD-deficient RBCs demonstrated increased glycolysis, impaired glutathione homeostasis, and increased purine oxidation, as compared with G6PD-normal RBCs.
    explanation: Human donor RBC data supports impaired glutathione homeostasis in G6PD-deficient erythrocytes.
genetic:
- name: G6PD
  gene_term:
    preferred_term: G6PD
    term:
      id: hgnc:4057
      label: G6PD
  presence: Pathogenic Variants
  inheritance:
  - name: X-linked recessive
  evidence:
  - reference: PMID:32702756
    reference_title: "Glucose-6-phosphate dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Glucose 6-phosphate dehydrogenase (G6PD) deficiency is 1 of the commonest human enzymopathies, caused by inherited mutations of the X-linked gene G6PD.
    explanation: This review supports the G6PD gene-disease relationship.
  - reference: PMID:24460025
    reference_title: "Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency in Greek newborns: the Mediterranean C563T mutation screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Glucose-6-Phosphate Dehydrogenase (G6PD) gene is located at the X-chromosome at Xq28 and the disease is recessively inherited predominantly in males.
    explanation: This newborn study supports X-linked recessive inheritance of G6PD deficiency.
  - reference: CGGV:assertion_153ae203-3ae5-4cb3-bbf8-d72467700d8c-2023-06-23T160000.000Z
    reference_title: "G6PD / G6PD deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "G6PD | HGNC:4057 | G6PD deficiency | MONDO:0005775 | XL | Definitive"
    explanation: ClinGen classifies the G6PD-G6PD deficiency gene-disease relationship as definitive with X-linked inheritance.
environmental:
- name: Oxidative Stressors
  notes: Triggers for acute hemolytic episodes.
  effect: Triggering factor
  examples:
  - Medications (e.g., antimalarials, sulfonamides, rasburicase)
  - Infections
  - Ingestion of fava beans
  chemicals:
  - primaquine
  - dapsone
  exposure_term:
    preferred_term: Oxidative stress exposure
    term:
      id: ECTO:0000231
      label: exposure to chemical
  evidence:
  - reference: PMID:31609781
    reference_title: "G6PD deficiency: An update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The G6PD enzyme is critical to protecting erythrocytes against oxidative stress, and deficiency may lead to hemolysis in the presence of certain environmental factors such as infection and some medications and foods.
    explanation: This review supports infections, medications, and foods as oxidative hemolysis triggers.
  - reference: PMID:24372186
    reference_title: "G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: That primaquine and other drugs can trigger acute haemolytic anaemia in subjects who have an inherited mutation of the glucose 6-phosphate dehydrogenase (G6PD) gene has been known for over half a century
    explanation: This review supports oxidant drugs such as primaquine as acute hemolysis triggers.
  - reference: PMID:30380124
    reference_title: "Dietary restrictions for people with glucose-6-phosphate dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: fava beans can provoke severe oxidative hemolysis in individuals with G6PD deficiency
    explanation: This review supports fava beans as a clinically evidenced dietary trigger.
treatments:
- name: Avoidance of Oxidative Stressors
  description: Identifying and avoiding medications, foods, infections, and other oxidant triggers that can precipitate hemolysis.
  treatment_term:
    preferred_term: medical action avoidance
    term:
      id: MAXO:0001014
      label: medical action avoidance
  target_mechanisms:
  - target: Oxidative Stress
    treatment_effect: INHIBITS
    description: Avoidance reduces the oxidant burden that G6PD-deficient erythrocytes cannot buffer.
  - target: Acute Hemolytic Anemia
    treatment_effect: INHIBITS
    description: Avoidance prevents trigger-induced hemolytic crises.
  target_phenotypes:
  - preferred_term: Hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  evidence:
  - reference: PMID:31609781
    reference_title: "G6PD deficiency: An update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: By recognizing the potential for G6PD deficiency, clinicians can screen for the disorder and teach affected patients how to avoid triggers that result in harmful clinical manifestations.
    explanation: This review directly supports trigger-avoidance counseling.
  - reference: PMID:19769422
    reference_title: "Perioperative management of the glucose-6-phosphate dehydrogenase deficient patient: a review of literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The most effective management strategy is to prevent hemolysis by avoiding oxidative stressors.
    explanation: This review supports avoidance as the primary management strategy.
- name: Blood Transfusion During Severe Acute Hemolysis
  description: Restrictive red-cell transfusion is used for severe acute hemolytic crisis with very low hemoglobin or clinical instability.
  treatment_term:
    preferred_term: blood transfusion
    term:
      id: MAXO:0000756
      label: blood transfusion
  target_mechanisms:
  - target: Acute Hemolytic Anemia
    treatment_effect: MODULATES
    description: Transfusion addresses the downstream anemia produced by acute erythrocyte destruction.
  target_phenotypes:
  - preferred_term: Hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  - preferred_term: Shortness of breath
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:34105166
    reference_title: "Management of children with glucose-6-phosphate dehydrogenase deficiency presenting with acute haemolytic crisis during the SARs-COV-2 pandemic."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 33% of patients had Hb < 50 g/L and were all transfused. 50% had Hb between 50 and 65 g/L, half of them (n = 49) did not receive transfusion and only two patients (4%) required transfusion upon follow up.
    explanation: This pediatric acute-hemolytic-crisis cohort supports transfusion for severe anemia.
  - reference: PMID:16225031
    reference_title: "Diagnosis and management of G6PD deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Acute hemolysis is self-limited, but in rare instances it can be severe enough to warrant a blood transfusion.
    explanation: This management review supports transfusion when acute hemolysis is severe.
- name: Neonatal Screening and Monitoring
  description: Early detection and close monitoring identify G6PD-deficient newborns at risk for severe neonatal jaundice.
  treatment_term:
    preferred_term: neonatal screening
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  target_phenotypes:
  - preferred_term: Neonatal hyperbilirubinemia
    term:
      id: HP:0003265
      label: Neonatal hyperbilirubinemia
  evidence:
  - reference: PMID:27064064
    reference_title: "National G6PD neonatal screening program in Gaza Strip of Palestine: rationale, challenges and recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Early detection and an accurate diagnosis are, therefore, of major importance for preventing negative patient outcomes.
    explanation: This review supports early detection and accurate diagnosis to prevent neonatal outcomes.
  - reference: PMID:36845240
    reference_title: "Glucose-6-phosphate dehydrogenase (G6PD) deficiency in girls: a diagnosis not to be missed (a case report)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Through this observation, we insist on the importance of neonatal screening in regions with a high prevalence of hemolysis in order to avoid diagnostic delays and also to prioritize the evaluation to be requested in an acute hemolysis state, to propose an education articulated around a preventive approach in children with this disease.
    explanation: This case report supports neonatal screening and education in high-prevalence settings.
- name: Neonatal Hyperbilirubinemia Treatment
  description: Phototherapy or exchange transfusion may be required to prevent kernicterus in G6PD-associated neonatal hyperbilirubinemia.
  treatment_term:
    preferred_term: phototherapy
    term:
      id: NCIT:C15301
      label: Phototherapy
  target_phenotypes:
  - preferred_term: Neonatal hyperbilirubinemia
    term:
      id: HP:0003265
      label: Neonatal hyperbilirubinemia
  evidence:
  - reference: PMID:16225031
    reference_title: "Diagnosis and management of G6PD deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Neonatal hyperbilirubinemia may require treatment with phototherapy or exchange transfusion to prevent kernicterus.
    explanation: This management review supports bilirubin-directed neonatal treatment.
review_notes: G6PD deficiency is an X-linked red-cell metabolic disorder. Reduced G6PD activity limits oxidative pentose-phosphate shunt flux and NADPH regeneration, impairing glutathione-dependent antioxidant buffering. Oxidant exposures then produce erythrocyte oxidative stress, hemoglobin oxidation with Heinz bodies, and acute hemolytic anemia with jaundice, dark urine, pallor, fatigue or malaise, dyspnea in severe cases, and splenic involvement. Neonatal hyperbilirubinemia is a distinct high-risk presentation requiring early detection and bilirubin-directed management. Management remains centered on trigger avoidance, monitoring, and supportive transfusion for severe acute hemolysis.
disease_term:
  preferred_term: G6PD deficiency
  term:
    id: MONDO:0005775
    label: G6PD deficiency
📚

References & Deep Research

Deep Research

2
Disorder ▸

Disorder

  • Name: Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
  • Category: Genetic
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 89

Key Pathophysiology Nodes

  • Decreased G6PD Enzyme Activity
  • Impaired Redox Homeostasis
  • Oxidative Stress
  • Acute Hemolytic Anemia
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1016/j.tips.2021.07.002
  • DOI:10.1155/2021/5529256
  • DOI:10.3390/biom13081262
  • DOI:10.3390/cells11193041
  • DOI:10.4314/sokjmls.v10i1.35
  • DOI:10.5195/ijms.2020.637
Falcon ▸
Pathophysiology description
Edison Scientific Literature 18 citations 2025-12-15T09:18:34.595268

Pathophysiology description G6PD deficiency is an X-linked enzymopathy that reduces activity of the rate-limiting enzyme of the oxidative pentose phosphate pathway (PPP). In red blood cells (RBCs), which lack mitochondria, PPP-derived NADPH is the dominant source of reducing equivalents to maintain the glutathione system and broader redox homeostasis. In G6PD deficiency, diminished NADPH generation impairs glutathione reductase-mediated recycling of oxidized glutathione (GSSG) to reduced glutathione (GSH). This lowers cellular antioxidant capacity, promoting oxidative modification of hemoglobin (Heinz bodies), membrane lipid peroxidation, band 3 clustering, decreased deformability, and premature clearance or intravascular hemolysis. Oxidative stressors—especially certain drugs, infections, and oxidant foods such as fava beans—precipitate acute hemolytic anemia. Clinical phenotypes range from asymptomatic baseline to episodic hemolysis, neonatal jaundice, and in severe variants, chronic nonspherocytic hemolytic anemia (URLs: https://doi.org/10.3390/biom13081262, Aug 2023; https://doi.org/10.1155/2021/5529256, Apr 2021; https://doi.org/10.1016/j.tips.2021.07.002, Oct 2021) (orrico2023oxidativestressin pages 10-11, dore2021thecontroversialrole pages 1-2, garcia2021treatmentstrategiesfor pages 1-2).

1) Core Pathophysiology - Primary mechanisms - PPP/NADPH impairment: G6PD catalyzes the first, rate-limiting step of the oxidative PPP that produces NADPH; reduced enzyme activity lowers NADPH supply in RBCs (URLs: https://doi.org/10.3390/biom13081262; https://doi.org/10.1155/2021/5529256) (orrico2023oxidativestressin pages 10-11, dore2021thecontroversialrole pages 1-2). - Glutathione redox failure: Inadequate NADPH limits glutathione reductase recycling of GSSG to GSH, compromising detoxification of hydrogen peroxide and organic peroxides (URLs: https://doi.org/10.3390/biom13081262; https://doi.org/10.1016/j.tips.2021.07.002) (orrico2023oxidativestressin pages 10-11, garcia2021treatmentstrategiesfor pages 1-2). - RBC oxidative injury: Hemoglobin oxidative denaturation (Heinz bodies), membrane lipid peroxidation, and cytoskeletal alterations reduce deformability and promote hemolysis (URLs: https://doi.org/10.3390/biom13081262; https://doi.org/10.4314/sokjmls.v10i1.35) (orrico2023oxidativestressin pages 10-11, kwaifa2025pathophysiologyandcurrent pages 1-2). - Triggered hemolysis: Exposures that increase oxidant load—e.g., primaquine, sulfonamides, dapsone; infections; and fava bean metabolites (vicine/divicine)—precipitate acute hemolytic anemia in deficient individuals (URLs: https://doi.org/10.3390/biom13081262; https://doi.org/10.5195/ijms.2020.637) (orrico2023oxidativestressin pages 10-11, ravikumar2020glucose6phosphatedehydrogenasedeficiency pages 1-2). - Neonatal hyperbilirubinemia: In neonates with G6PD deficiency, unconjugated hyperbilirubinemia can occur rapidly, sometimes with minimal overt hemolysis, reflecting immature bilirubin conjugation/excretion superimposed on increased heme turnover and impaired antioxidant defenses (URL: https://doi.org/10.5195/ijms.2020.637) (ravikumar2020glucose6phosphatedehydrogenasedeficiency pages 1-2).

  • Dysregulated molecular pathways
  • Oxidative PPP and NADPH regeneration (G6PD; 6-phosphogluconate dehydrogenase) are diminished, altering the balance between glycolytic and PPP flux and limiting antioxidant capacity (URLs: https://doi.org/10.1155/2021/5529256; https://doi.org/10.3390/biom13081262) (dore2021thecontroversialrole pages 1-2, orrico2023oxidativestressin pages 10-11).

  • Antioxidant systems dependent on NADPH (glutathione reductase, peroxiredoxins, catalase in non-RBC tissues) are secondarily compromised in RBCs, with GSH depletion central to susceptibility (URLs: https://doi.org/10.3390/biom13081262; https://doi.org/10.1016/j.tips.2021.07.002) (orrico2023oxidativestressin pages 10-11, garcia2021treatmentstrategiesfor pages 1-2).

  • Affected cellular processes

  • Redox homeostasis; ROS detoxification; hemoglobin stability; membrane integrity; erythrocyte deformability and survival (URLs: https://doi.org/10.3390/biom13081262; https://doi.org/10.4314/sokjmls.v10i1.35) (orrico2023oxidativestressin pages 10-11, kwaifa2025pathophysiologyandcurrent pages 1-2).

2) Key Molecular Players - Genes/Proteins (HGNC) - G6PD (HGNC:4421): X-linked enzyme catalyzing oxidation of glucose-6-phosphate to 6-phosphogluconolactone with reduction of NADP+ to NADPH (URLs: https://doi.org/10.1155/2021/5529256; https://doi.org/10.3390/biom13081262) (dore2021thecontroversialrole pages 1-2, orrico2023oxidativestressin pages 10-11). - GSR/glutathione reductase (HGNC:4635): NADPH-dependent enzyme for GSH regeneration; functionally impacted by NADPH deficit (URL: https://doi.org/10.1016/j.tips.2021.07.002) (garcia2021treatmentstrategiesfor pages 1-2). - Hemoglobin (HBB/HBA): Target of oxidation leading to Heinz bodies and precipitates (URL: https://doi.org/10.3390/biom13081262) (orrico2023oxidativestressin pages 10-11).

  • Chemical Entities (CHEBI)

  • NADPH (CHEBI:16474); reduced glutathione GSH (CHEBI:16856); oxidized glutathione GSSG (CHEBI:57925); hydrogen peroxide (CHEBI:16240); primaquine (CHEBI:8365); dapsone (CHEBI:4320). These entities mediate redox reactions and/or act as triggers of oxidative hemolysis (URLs: https://doi.org/10.3390/biom13081262; https://doi.org/10.1016/j.tips.2021.07.002) (orrico2023oxidativestressin pages 10-11, garcia2021treatmentstrategiesfor pages 1-2).

  • Cell Types (CL)

  • Erythrocyte (CL:0000232): Primary clinically affected cell; uniquely PPP-dependent for NADPH (URL: https://doi.org/10.3390/biom13081262) (orrico2023oxidativestressin pages 10-11).

  • Leukocytes (e.g., neutrophils, CL:0000096): G6PD-dependent NADPH can modulate oxidative burst; severe deficiency can impair host defense (supportive background) (URL: https://doi.org/10.3390/cells11193041) (garciadominguez2022glucose6pdehydrogenase—an pages 5-6).

  • Anatomical Locations (UBERON)

  • Blood (UBERON:0000178): Intravascular hemolysis, circulating RBCs (URL: https://doi.org/10.3390/biom13081262) (orrico2023oxidativestressin pages 10-11).
  • Spleen (UBERON:0002106): Extravascular culling of damaged RBCs (URL: https://doi.org/10.4314/sokjmls.v10i1.35) (kwaifa2025pathophysiologyandcurrent pages 1-2).
  • Liver (UBERON:0002107): Bilirubin conjugation/excretion relevant to neonatal hyperbilirubinemia (URL: https://doi.org/10.5195/ijms.2020.637) (ravikumar2020glucose6phosphatedehydrogenasedeficiency pages 1-2).

3) Biological Processes (GO annotations) - Pentose-phosphate shunt, oxidative branch (GO:0006098): Diminished flux due to G6PD deficiency (URLs: https://doi.org/10.1155/2021/5529256; https://doi.org/10.3390/biom13081262) (dore2021thecontroversialrole pages 1-2, orrico2023oxidativestressin pages 10-11). - NADPH regeneration (GO:0006739): Reduced capacity in RBCs (URL: https://doi.org/10.1016/j.tips.2021.07.002) (garcia2021treatmentstrategiesfor pages 1-2). - Glutathione metabolic process (GO:0006749) and response to oxidative stress (GO:0006979): Impaired GSH homeostasis increases susceptibility to ROS-mediated RBC injury (URLs: https://doi.org/10.3390/biom13081262; https://doi.org/10.4314/sokjmls.v10i1.35) (orrico2023oxidativestressin pages 10-11, kwaifa2025pathophysiologyandcurrent pages 1-2). - Hemolysis (GO:0002937): Triggered by oxidant stress in G6PD-deficient RBCs (URL: https://doi.org/10.3390/biom13081262) (orrico2023oxidativestressin pages 10-11).

4) Cellular Components - Cytosol: PPP enzymes and GSH/GSSG cycling occur in the RBC cytosol (URL: https://doi.org/10.3390/biom13081262) (orrico2023oxidativestressin pages 10-11). - RBC membrane/cytoskeleton: Oxidative damage to spectrin/ankyrin and band 3 promotes rigidity and splenic sequestration (URL: https://doi.org/10.4314/sokjmls.v10i1.35) (kwaifa2025pathophysiologyandcurrent pages 1-2). - Heinz bodies (inclusions): Oxidized hemoglobin precipitates attached to the inner membrane (URL: https://doi.org/10.4314/sokjmls.v10i1.35) (kwaifa2025pathophysiologyandcurrent pages 1-2).

5) Disease Progression - Initial trigger: exposure to oxidant drug (e.g., primaquine, sulfonamides, dapsone), intercurrent infection (inflammation-driven ROS), or fava bean ingestion (vicine/divicine) increases oxidant burden (URL: https://doi.org/10.3390/biom13081262) (orrico2023oxidativestressin pages 10-11). - Molecular defect: limited PPP flux reduces NADPH; GSH/GSSG ratio declines; peroxides accumulate (URLs: https://doi.org/10.1155/2021/5529256; https://doi.org/10.3390/biom13081262) (dore2021thecontroversialrole pages 1-2, orrico2023oxidativestressin pages 10-11). - Cellular injury: hemoglobin denaturation (Heinz bodies), membrane lipid peroxidation, band 3 clustering; decreased deformability (URL: https://doi.org/10.4314/sokjmls.v10i1.35) (kwaifa2025pathophysiologyandcurrent pages 1-2). - Clinical hemolysis: intravascular and/or extravascular hemolysis with anemia, jaundice, hemoglobinuria; in neonates, rapid unconjugated hyperbilirubinemia can develop with risk for bilirubin neurotoxicity if not promptly managed (URL: https://doi.org/10.5195/ijms.2020.637) (ravikumar2020glucose6phosphatedehydrogenasedeficiency pages 1-2).

6) Phenotypic Manifestations (HPO) - Acute hemolytic anemia (HP:0001878): fatigue, pallor, tachycardia following oxidative triggers (URL: https://doi.org/10.3390/biom13081262) (orrico2023oxidativestressin pages 10-11). - Neonatal hyperbilirubinemia (HP:0002904) and jaundice (HP:0000952): often early, can be severe, occasionally with limited overt signs of hemolysis (URL: https://doi.org/10.5195/ijms.2020.637) (ravikumar2020glucose6phosphatedehydrogenasedeficiency pages 1-2). - Hemoglobinuria (HP:0002905) during intravascular hemolysis; splenomegaly (HP:0001744) with recurrent/extravascular hemolysis; Heinz bodies (HP:0011893) on smear (URL: https://doi.org/10.4314/sokjmls.v10i1.35) (kwaifa2025pathophysiologyandcurrent pages 1-2).

Recent developments and latest research (2023–2024 priority) - RBC oxidative stress in health and disease (2023): Comprehensive review underscoring the central role of PPP-derived NADPH and glutathione in RBC redox control; details oxidative triggers of hemolysis in G6PD deficiency, including drugs, infections, and fava beans (URL: https://doi.org/10.3390/biom13081262, Aug 2023) (orrico2023oxidativestressin pages 10-11). - Systems and tissue perspectives (2022–2021): Although slightly older, state-of-the-art reviews in Cells and Trends in Pharmacological Sciences integrate PPP/NADPH biochemistry with clinical G6PD phenotypes and therapeutic concepts (URLs: https://doi.org/10.3390/cells11193041, Sep 2022; https://doi.org/10.1016/j.tips.2021.07.002, Oct 2021) (garciadominguez2022glucose6pdehydrogenase—an pages 5-6, garcia2021treatmentstrategiesfor pages 1-2).

Current applications and real-world implementations - Avoidance of oxidant drugs and triggers: Clinical management relies on patient education and screening to prevent exposure to high-risk drugs (e.g., primaquine, sulfonamides, dapsone) that precipitate hemolysis (URL: https://doi.org/10.3390/biom13081262) (orrico2023oxidativestressin pages 10-11). - Newborn screening and early diagnosis: Programs increasingly screen for G6PD activity to mitigate neonatal hyperbilirubinemia risk; prompt phototherapy and supportive care reduce neurotoxicity (URL: https://doi.org/10.5195/ijms.2020.637) (ravikumar2020glucose6phosphatedehydrogenasedeficiency pages 1-2). - Therapeutic concepts under evaluation: Small-molecule stabilization/activation of G6PD, augmentation of GSH pools (e.g., N-acetylcysteine), and compensatory NADPH pathways are discussed as future strategies (URL: https://doi.org/10.1016/j.tips.2021.07.002) (garcia2021treatmentstrategiesfor pages 1-2).

Expert opinions and analysis - Consensus across recent and foundational reviews emphasizes that in RBCs, “erythrocytes rely solely on PPP-derived NADPH” and that “G6PD deficiency thus impairs GSH regeneration, reducing disposal of oxidants and predisposing to oxidative membrane damage and hemolysis.” These mechanistic insights underpin current prevention-first clinical strategies and motivate development of enzyme-stabilizing therapies (URLs: https://doi.org/10.3390/biom13081262; https://doi.org/10.1155/2021/5529256; https://doi.org/10.1016/j.tips.2021.07.002) (orrico2023oxidativestressin pages 10-11, dore2021thecontroversialrole pages 1-2, garcia2021treatmentstrategiesfor pages 1-2).

Relevant statistics and data - Prevalence and genetics: G6PD deficiency is the most common human enzymopathy, with hundreds of variants producing a spectrum of residual activity and phenotypes; X-linked inheritance yields higher expression in males (URL: https://doi.org/10.5195/ijms.2020.637) (ravikumar2020glucose6phosphatedehydrogenasedeficiency pages 1-2). - Triggers and risk: Multiple commonly used drugs can trigger hemolysis in deficient individuals; infections and fava beans are frequent natural precipitants (URL: https://doi.org/10.3390/biom13081262) (orrico2023oxidativestressin pages 10-11).

Gene/protein annotations and ontology terms - Gene/Protein (HGNC): - G6PD (HGNC:4421) (dore2021thecontroversialrole pages 1-2, orrico2023oxidativestressin pages 10-11) - GSR (HGNC:4635) (garcia2021treatmentstrategiesfor pages 1-2)

  • Biological Process (GO):
  • GO:0006098 pentose-phosphate shunt, oxidative branch (dore2021thecontroversialrole pages 1-2, orrico2023oxidativestressin pages 10-11)
  • GO:0006739 NADPH regeneration (garcia2021treatmentstrategiesfor pages 1-2)

  • GO:0006749 glutathione metabolic process; GO:0006979 response to oxidative stress (orrico2023oxidativestressin pages 10-11, kwaifa2025pathophysiologyandcurrent pages 1-2)

  • Cellular Component (GO/CC):

  • Cytosol; plasma membrane/cytoskeleton; Heinz body inclusion (orrico2023oxidativestressin pages 10-11, kwaifa2025pathophysiologyandcurrent pages 1-2)

  • Cell Types (CL):

  • CL:0000232 erythrocyte; CL:0000096 neutrophil (orrico2023oxidativestressin pages 10-11, garciadominguez2022glucose6pdehydrogenase—an pages 5-6)

  • Anatomical Locations (UBERON):

  • UBERON:0000178 blood; UBERON:0002106 spleen; UBERON:0002107 liver (orrico2023oxidativestressin pages 10-11, kwaifa2025pathophysiologyandcurrent pages 1-2, ravikumar2020glucose6phosphatedehydrogenasedeficiency pages 1-2)

  • Chemical Entities (CHEBI):

  • CHEBI:16474 NADPH; CHEBI:16856 glutathione (GSH); CHEBI:57925 oxidized glutathione (GSSG); CHEBI:16240 hydrogen peroxide; CHEBI:8365 primaquine; CHEBI:4320 dapsone (orrico2023oxidativestressin pages 10-11, garcia2021treatmentstrategiesfor pages 1-2)

Phenotype associations (HPO) - HP:0001878 acute hemolytic anemia; HP:0002904 neonatal hyperbilirubinemia; HP:0000952 jaundice; HP:0002905 hemoglobinuria; HP:0001744 splenomegaly; HP:0011893 Heinz bodies (orrico2023oxidativestressin pages 10-11, kwaifa2025pathophysiologyandcurrent pages 1-2, ravikumar2020glucose6phosphatedehydrogenasedeficiency pages 1-2).

Evidence items with PMIDs/identifiers, URLs, dates - Orrico F, et al. Oxidative Stress in Healthy and Pathological Red Blood Cells. Biomolecules. Aug 2023. URL: https://doi.org/10.3390/biom13081262 (mechanisms, triggers, RBC redox) (orrico2023oxidativestressin pages 10-11). - Dore MP, et al. The Controversial Role of G6PD Deficiency on Cardiovascular Disease. Oxid Med Cell Longev. Apr 2021. URL: https://doi.org/10.1155/2021/5529256 (PPP/NADPH overview in G6PD) (dore2021thecontroversialrole pages 1-2). - García-Domínguez E, et al. Glucose 6-P Dehydrogenase—Regulatory Functions. Cells. Sep 2022. URL: https://doi.org/10.3390/cells11193041 (systems implications; immune/redox) (garciadominguez2022glucose6pdehydrogenase—an pages 5-6). - Garcia AA, et al. Treatment strategies for G6PD deficiency. Trends Pharmacol Sci. Oct 2021. URL: https://doi.org/10.1016/j.tips.2021.07.002 (therapeutic concepts; GSH/NADPH) (garcia2021treatmentstrategiesfor pages 1-2). - Kwaifa IK, et al. Pathophysiology and current laboratory investigations. Sokoto J Med Lab Sci. Jun 2025. URL: https://doi.org/10.4314/sokjmls.v10i1.35 (mechanistic summaries; Heinz bodies, hemolysis) (kwaifa2025pathophysiologyandcurrent pages 1-2). - Ravikumar N, Greenfield G. G6PD Deficiency: A Review. Int J Med Students. Dec 2020. URL: https://doi.org/10.5195/ijms.2020.637 (clinical overview; neonatal jaundice) (ravikumar2020glucose6phosphatedehydrogenasedeficiency pages 1-2).

Notes on evidence strength and gaps - Mechanistic foundations (PPP/NADPH/GSH and RBC hemolysis) are consistent across reviews. The most recent RBC-focused review (2023) supports current understanding and clinical triggers. High-quality 2023–2024 primary mechanistic studies specific to neonatal bilirubin handling in G6PD deficiency were not retrieved in the provided evidence; therefore, neonatal mechanistic details are supported primarily by clinical overviews and prior reviews.

References

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