Achieve Mastery of Medical Concepts

Study for medical school and boards with Lecturio

Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency

Glucose-6-phosphate dehydrogenase Glucose-6-phosphate dehydrogenase Pentose Phosphate Pathway ( G6PD G6PD Pentose Phosphate Pathway) deficiency is a type of intravascular hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia. The condition is inherited in an X-linked recessive X-Linked Recessive Duchenne Muscular Dystrophy manner. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship have episodic hemolysis due to an oxidative stressor that causes damage to red blood cells Red blood cells Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology, which lack sufficient NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (nmn) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2. Pentose Phosphate Pathway to protect them from oxidative injury.

Last updated: 8 Jan, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Epidemiology and Etiology

Epidemiology

  • Glucose-6-phosphate dehydrogenase Glucose-6-phosphate dehydrogenase Pentose Phosphate Pathway ( G6PD G6PD Pentose Phosphate Pathway) deficiency is the most common genetic enzyme disorder in humans.
  • Found in malarial endemic regions (as it offers relative resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing to Plasmodium Plasmodium A genus of protozoa that comprise the malaria parasites of mammals. Four species infect humans (although occasional infections with primate malarias may occur). These are plasmodium falciparum; plasmodium malariae; plasmodium ovale, and plasmodium vivax. Species causing infection in vertebrates other than man include: plasmodium berghei; plasmodium chabaudi; p. Vinckei, and plasmodium yoelii in rodents; p. Brasilianum, plasmodium cynomolgi; and plasmodium knowlesi in monkeys; and plasmodium gallinaceum in chickens. Antimalarial Drugs falciparum infection): Mediterranean countries, Africa, the Middle East
  • Presents exclusively in males as it is X-linked recessive X-Linked Recessive Duchenne Muscular Dystrophy
  • Females can be silent carriers Carriers The Cell: Cell Membrane.

Etiology

  • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the coding region of the G6PD G6PD Pentose Phosphate Pathway gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics 
  • A single nucleotide base change (single missense point mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations) that results in a single amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids substitution in the enzyme 
  • Almost 200 different mutations are known.
  • The mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations decreases the half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics of the enzyme. 
  • G6PD G6PD Pentose Phosphate Pathway deficiency results in a defect of the pentose phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes shunt during glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. Glycolysis.
  • Inheritance is X-linked recessive X-Linked Recessive Duchenne Muscular Dystrophy (band Xq28).
G6pd band xq28 illustration

G6PD G6PD Pentose Phosphate Pathway deficiency is an X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) disorder found on band Xq28.

Image by Lecturio.

Pathophysiology

  • G6PD G6PD Pentose Phosphate Pathway is the rate-limiting enzyme in the pentose phosphate pathway Pentose phosphate pathway The pentose phosphate pathway (also known as the hexose monophosphate (HMP) shunt)) is an important physiological process that can occur in 2 phases: oxidative and nonoxidative. The oxidative phase utilizes glucose-6-phosphate to produce NADPH and ribulose-5-phosphate. Pentose Phosphate Pathway.
  • G6PD G6PD Pentose Phosphate Pathway enzyme is responsible for:
    • Oxidation of glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance-6- phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes 
    • Reduction of nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes (NADP+) to NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway 
  • NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway maintains glutathione in its reduced form.
  • Reduced glutathione is needed to neutralize oxidative metabolites.
  • In RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology, this is the only pathway that produces NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway.
  • Thus, a lack of G6PD G6PD Pentose Phosphate Pathway results in a deficiency in NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway and increased oxidative damage.
  • Oxidative stressors can denature hemoglobin and cause intravascular hemolysis Intravascular hemolysis Hemolytic Anemia.
  • Extravascular hemolysis Extravascular hemolysis Hemolytic Anemia would be due to splenic clearance of the deformed RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology.
Table: Common oxidative stressors
Drugs Foods Other
  • Sulfas ( trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim/ sulfamethoxazole Sulfamethoxazole A bacteriostatic antibacterial agent that interferes with folic acid synthesis in susceptible bacteria. Its broad spectrum of activity has been limited by the development of resistance. Sulfonamides and Trimethoprim [TMP/SMX])
  • Quinolones Quinolones A group of derivatives of naphthyridine carboxylic acid, quinoline carboxylic acid, or nalidixic acid. Fluoroquinolones
  • Nitrofurantoin
  • Aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs)/nonsteroidal anti-inflammatory drugs ( NSAIDs NSAIDS Primary vs Secondary Headaches)
  • Methylene blue
  • Fava beans
  • Blue food coloring
  • Any infection (most common)
  • Naphthalene (mothballs)
  • Diabetic ketoacidosis Diabetic ketoacidosis A life-threatening complication of diabetes mellitus, primarily of type 1 diabetes mellitus with severe insulin deficiency and extreme hyperglycemia. It is characterized by ketosis; dehydration; and depressed consciousness leading to coma. Hyperglycemic Crises

Clinical Presentation

  • History of a trigger Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation for the oxidative stress Oxidative stress A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products. Cell Injury and Death
  • Episodic signs and symptoms of intravascular hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia:
    • Pallor
    • Shortness of breath Shortness of breath Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
    • Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
    • Flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure murmur (best heard at upper sternal borders)
    • Jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
    • Hemoglobinuria Hemoglobinuria The presence of free hemoglobin in the urine, indicating hemolysis of erythrocytes within the vascular system. After saturating the hemoglobin-binding proteins (haptoglobins), free hemoglobin begins to appear in the urine. Transfusion Reactions (cola-colored urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat), hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma
    • Neonates (males): prolonged pathological jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice/ icterus Icterus A clinical manifestation of hyperbilirubinemia, characterized by the yellowish staining of the skin, mucous membranes, and sclera. Clinical jaundice usually is a sign of liver dysfunction. Jaundice
Urinary sample with hematuria

Urinary sample with hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma

Image: “ hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma” by omicsonline.org. License: CC BY 4.0

Diagnosis

Glucose-6-phosphate dehydrogenase Glucose-6-phosphate dehydrogenase Pentose Phosphate Pathway deficiency is suspected in cases of episodic hemolytic symptoms. Diagnostic testing should include the following:

  • CBC
    • Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange
    • ↑ Reticulocytes
    • Lactate dehydrogenase Lactate Dehydrogenase Osteosarcoma ( LDH LDH Osteosarcoma)
    • ↓ Haptoglobin
    • Bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism
  • Peripheral blood smear Peripheral Blood Smear Anemia: Overview and Types
    • Heinz bodies Heinz bodies Abnormal intracellular inclusions, composed of denatured hemoglobin, found on the membrane of red blood cells. They are seen in thalassemias, enzymopathies, hemoglobinopathies, and after splenectomy. Asplenia (visible with supravital stains such as new methylene blue or crystal violet, but not with routine Romanowsky dyes; rarely performed today)
    • Bite cells, indicating RBC membrane damage Membrane Damage Cell Injury and Death
  • Beutler test 
    • Done 2–3 weeks after an acute episode (which eliminates the oldest, most G6PD G6PD Pentose Phosphate Pathway-deficient cells, so a period of time is allowed to pass to evaluate baseline levels)
    • Quantifies NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway/ G6PD G6PD Pentose Phosphate Pathway levels

Management

  • Prevention: avoid oxidative stressors ( infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, drugs, consumption of fava beans)
  • During hemolysis:
    • If Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange < 9 with hemolysis: blood transfusion
    • Neonatal jaundice Neonatal jaundice Yellow discoloration of the skin; mucous membrane; and sclera in the newborn. It is a sign of neonatal hyperbilirubinemia. Most cases are transient self-limiting (physiological neonatal jaundice) occurring in the first week of life, but some can be a sign of pathological disorders, particularly liver diseases. Jaundice: phototherapy Phototherapy Treatment of disease by exposure to light, especially by variously concentrated light rays or specific wavelengths. Hyperbilirubinemia of the Newborn or exchange transfusion
  • Splenectomy Splenectomy Surgical procedure involving either partial or entire removal of the spleen. Rupture of the Spleen should be considered in rare cases of chronic hemolytic anemia Chronic Hemolytic Anemia Anemia: Overview and Types.

Differential Diagnosis

  • Inherited hemolytic anemias:
    • Other enzyme deficiencies (e.g., pyruvate kinase Pyruvate kinase Atp:pyruvate 2-o-phosphotransferase. A phosphotransferase that catalyzes reversibly the phosphorylation of pyruvate to phosphoenolpyruvate in the presence of ATP. It has four isozymes (l, r, m1, and m2). Glycolysis)
    • Hemoglobinopathies Hemoglobinopathies A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. Anemia: Overview and Types (e.g., sickle cell disease Sickle cell disease Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease, thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia)
    • Membrane/cytoskeletal defects of RBC (e.g., hereditary spherocytosis Hereditary Spherocytosis Hereditary spherocytosis (HS) is the most common type of hereditary hemolytic anemia. The condition is caused by a cytoskeletal protein deficiency in the RBC membrane. This results in loss of membrane stability and deformability of the RBC, giving the cell its spherical shape (spherocyte). Hereditary Spherocytosis)
  • Acquired hemolytic anemias: may have an immune or non-immune etiology 

References

  1. Luzzatto L. Glucose 6-phosphate deficiency. (2018). In Jameson JL, et al. (Ed.), Harrison’s Principles of Internal Medicine (20th ed. Vol 1, pp 714-717). New York, NY: McGraw-Hill.
  2. Glader, B. (2019). Genetics and pathophysiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency. UpToDate. Retrieved September 1, 2020, from https://www.uptodate.com/contents/genetics-and-pathophysiology-of-glucose-6-phosphate-dehydrogenase-g6pd-deficiency?sectionName=Classification%20of%20G6PD%20variants&topicRef=7111&anchor=H5&source=see_link#H22470651 
  3. Glader, B. (2020). Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency. UpToDate. Retrieved September 2, 2020, from https://www.uptodate.com/contents/diagnosis-and-management-of-glucose-6-phosphate-dehydrogenase-g6pd-deficiency

USMLE™ is a joint program of the Federation of State Medical Boards (FSMB®) and National Board of Medical Examiners (NBME®). MCAT is a registered trademark of the Association of American Medical Colleges (AAMC). NCLEX®, NCLEX-RN®, and NCLEX-PN® are registered trademarks of the National Council of State Boards of Nursing, Inc (NCSBN®). None of the trademark holders are endorsed by nor affiliated with Lecturio.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

User Reviews

¡Hola!

Esta página está disponible en Español.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details