View source for Medicine:Glucose-6-phosphate dehydrogenase deficiency

{{Infobox medical condition (new)
| name          = Glucose-6-phosphate dehydrogenase deficiency
| synonyms      = Favism<ref name=GHR2017/>
| image         = G6PD - 3D structure - PDB1qki.png
| caption       = [[Biology:Glucose-6-phosphate dehydrogenase|Glucose-6-phosphate dehydrogenase]]
| field         = Medical genetics
| symptoms      = [[Medicine:Jaundice|Yellowish skin]], dark urine, shortness of breath<ref name=GHR2017/>
| complications = [[Medicine:Anemia|Anemia]], newborn jaundice<ref name=NORD2017/><ref name=GHR2017/>
| onset         = Within a few days of a trigger<ref name=NORD2017/>
| duration      =
| types         =
| causes        = Genetic (X-linked recessive)<ref name=GHR2017/>
| risks         = Triggered by [[Medicine:Infection|infection]]s, certain medication, stress, foods such as fava beans<ref name=GHR2017/><ref name=NIH2017/>
| diagnosis     = Based on symptoms, blood test, [[Medicine:Genetic testing|genetic testing]]<ref name=NORD2017/>
| differential  = Pyruvate kinase deficiency, hereditary spherocytosis, sickle cell anemia<ref name=NORD2017/>
| prevention    =
| treatment     = Avoiding triggers, medications for infection, stopping offending medication, blood transfusions<ref name=NIH2017/>
| medication    =
| prognosis     =
| frequency     = 400 million<ref name=GHR2017/>
| deaths        = 33,000 (2015)<ref name=GBD2015De/>
}}
<!-- Definition and symptoms -->
'''Glucose-6-phosphate dehydrogenase deficiency''' ('''G6PDD'''), which is the most common enzyme deficiency worldwide,<ref>{{Cite journal |last=Frank |first=Jennifer E. |date=2005-10-01 |title=Diagnosis and Management of G6PD Deficiency |url=https://www.aafp.org/afp/2005/1001/p1277.html |journal=American Family Physician |volume=72 |issue=7 |pages=1277–1282 |pmid=16225031 |issn=0002-838X}}</ref> is an inborn error of metabolism that predisposes to [[Medicine:Hemolysis|red blood cell breakdown]].<ref name=GHR2017/> Most of the time, those who are affected have no symptoms.<ref name=NIH2017/> Following a specific trigger, symptoms such as [[Medicine:Jaundice|yellowish skin]], dark urine, shortness of breath, and feeling tired may develop.<ref name=GHR2017/><ref name=NORD2017>{{cite web|title=Glucose-6-Phosphate Dehydrogenase Deficiency|url=https://rarediseases.org/rare-diseases/glucose-6-phosphate-dehydrogenase-deficiency/|website=NORD (National Organization for Rare Disorders)|access-date=11 December 2017|date=2017}}</ref> Complications can include [[Medicine:Anemia|anemia]] and newborn jaundice.<ref name=NORD2017/> Some people never have symptoms.<ref name=NIH2017/>

<!-- Cause and diagnosis -->
It is an X-linked recessive disorder that results in defective [[Biology:Glucose-6-phosphate dehydrogenase|glucose-6-phosphate dehydrogenase]] enzyme.<ref name=GHR2017/> Glucose-6-phosphate dehydrogenase is an enzyme which protects red blood cells, which carry oxygen from the lungs to tissues throughout the body. A defect of the enzyme results in the premature breakdown of red blood cells. This destruction of red blood cells is called [[Medicine:Hemolysis|hemolysis]].<ref name="medlineplus.gov">{{Cite web |title=Glucose-6-phosphate dehydrogenase deficiency: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/condition/glucose-6-phosphate-dehydrogenase-deficiency/ |access-date=2022-03-21 |website=medlineplus.gov |language=en}}</ref> Red blood cell breakdown may be triggered by [[Medicine:Infection|infection]]s, certain medication, stress, or foods such as fava beans.<ref name=GHR2017/><ref name=NIH2017>{{cite web|title=Glucose-6-phosphate dehydrogenase deficiency|url=https://rarediseases.info.nih.gov/diseases/6520/glucose-6-phosphate-dehydrogenase-deficiency|website=Genetic and Rare Diseases Information Center (GARD)|access-date=10 December 2017|language=en|date=2017|archive-date=27 April 2021|archive-url=https://web.archive.org/web/20210427154113/https://rarediseases.info.nih.gov/diseases/6520/glucose-6-phosphate-dehydrogenase-deficiency|url-status=dead}}</ref> Depending on the specific [[Biology:Mutation|mutation]] the severity of the condition may vary.<ref name=NORD2017/> Diagnosis is based on symptoms and supported by blood tests and [[Medicine:Genetic testing|genetic testing]].<ref name=NORD2017/>

Affected persons must avoid dietary triggers,<ref name=NIH2017/> notably fava beans.<ref>{{Cite news |last=Horowitz |first=Jason |date=2023-05-13 |title=It's May in Rome: A Time to Revere, and Fear, Fava Beans |language=en-US |work=The New York Times |url=https://www.nytimes.com/2023/05/13/world/europe/rome-fava-beans-favism.html |access-date=2023-05-16 |issn=0362-4331}}</ref> This can be difficult, as fava beans may be called "broad beans" and are used in many foods, whole or as flour. Falafel is probably the best known, but fava beans are also often used as filler in meatballs and other foods. Since G6PD deficiency is not an allergy, food regulations in most countries do not require that fava beans be highlighted as an allergen on the label.{{citation needed|date=February 2021}}

<!-- Treatment and prognosis -->
Treatment of acute episodes may include medications for infection, stopping the offending medication, or blood transfusions.<ref name=NIH2017/> Jaundice in newborns may be treated with bili lights.<ref name=NORD2017/> It is recommended that people be tested for G6PDD before certain medications, such as [[Chemistry:Primaquine|primaquine]], are taken.<ref name=NORD2017/>

<!-- Epidemiology and culture -->
About 400 million people have the condition globally.<ref name=GHR2017>{{cite web|title=Glucose-6-phosphate dehydrogenase deficiency|url=https://ghr.nlm.nih.gov/condition/glucose-6-phosphate-dehydrogenase-deficiency|website=Genetics Home Reference|access-date=10 December 2017|language=en|date=6 December 2017}}</ref> It is particularly common in certain parts of Africa, Asia, the Mediterranean, and the [[Place:Middle East|Middle East]].<ref name=GHR2017/> Males are affected more often than females.<ref name=GHR2017/> In 2015 it is believed to have resulted in 33,000 deaths.<ref name=GBD2015De>{{cite journal |author1=((GBD 2015 Mortality and Causes of Death Collaborators)) |title=Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015.|journal=Lancet|date=8 October 2016|volume=388|issue=10053|pages=1459–1544|pmid=27733281|doi=10.1016/s0140-6736(16)31012-1|pmc=5388903}}</ref>

==Signs and symptoms==
Most individuals with G6PD deficiency are [[Medicine:Asymptomatic|asymptomatic]].{{citation needed|date=September 2021}}

Most people who develop symptoms are male, due to the X-linked pattern of inheritance, but female carriers can be affected due to unfavorable lyonization or [[Biology:Skewed X-inactivation|skewed X-inactivation]], where random inactivation of an X-chromosome in certain cells creates a population of G6PD-deficient [[Biology:Red blood cell|red blood cell]]s coexisting with unaffected red blood cells. A female with one affected X chromosome will show the deficiency in approximately half of her red blood cells. However, in some cases, including double X-deficiency, the ratio can be much more than half, making the individual almost as sensitive as males.{{citation needed|date=September 2021}}

Red blood cell breakdown (also known as [[Medicine:Hemolysis|hemolysis]]) in G6PD deficiency can manifest in a number of ways, including the following:{{citation needed|date=September 2021}}
* Prolonged [[Medicine:Neonatal jaundice|neonatal jaundice]], possibly leading to [[Medicine:Kernicterus|kernicterus]] (arguably the most serious complication of G6PD deficiency)
* [[Medicine:Hemolysis|Hemolytic crises]] in response to:
** Illness (especially infections)
** Certain [[Chemistry:Medication|drugs]] (see below)
** Certain foods, most notably [[Biology:Broad bean|broad bean]]s, from which the word ''favism'' derives
** Certain chemicals
** [[Medicine:Diabetic ketoacidosis|Diabetic ketoacidosis]]
* Hemoglobinuria (red or brown urine)
* Very severe crisis can cause [[Medicine:Acute kidney injury|acute kidney injury]]

'''Favism''' is a hemolytic response to the consumption of fava beans, also known as broad beans. Though all individuals with favism show G6PD deficiency, not all individuals with G6PD deficiency show favism. The condition is known to be more prevalent in infants and children, and G6PD genetic variant can influence chemical sensitivity.<ref>Luzzatto, L. "GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY." Advanced Medicine-Twelve: Proceedings of a Conference Held at the Royal College of Physicians of London, 11–14 February 1985. Vol. 21. Churchill Livingstone, 1986.</ref> Other than this, the specifics of the chemical relationship between favism and G6PD are not well understood.{{citation needed|date=September 2021}}

==Cause==
G6PD deficiency results from mutations in the G6PD gene. G6PD gene contributes to the production of [[Biology:Glucose-6-phosphate dehydrogenase|glucose-6-phosphate dehydrogenase]]. Chemical reactions involving glucose-6-phosphate dehydrogenase produce compounds that prevent [[Biology:Reactive oxygen species|reactive oxygen species]] from building up to toxic levels within red blood cells. If reduction in the amount of glucose-6-phosphate dehydrogenase or alteration of structure occurs due to the mutations of G6PD gene, the enzyme loses its protective role and leads to the accumulation of reactive oxygen species and thus damage of red blood cells.<ref name="medlineplus.gov"/>

===Triggers===
Carriers of the underlying mutation do not show any symptoms unless their red blood cells are exposed to certain triggers, which can be of four main types:
* Foods (fava beans is the [[Medicine:Pathognomonic|hallmark]] trigger for G6PD mutation carriers),
* Certain medicines including [[Chemistry:Aspirin|aspirin]], [[Chemistry:Quinine|quinine]] and other [[Chemistry:Antimalarial medication|antimalarials]] derived from quinine.
* [[Biology:Mothball|Moth balls]] ([[Chemistry:Naphthalene|naphthalene]])<ref>{{Cite web|url=https://www.slhd.nsw.gov.au/rpa/neonatal/content/pdf/guidelines/g6pdd.pdf|title=Triggers of G6PD crisis|website=Sydney Local Health District|access-date=2018-06-05|archive-date=2020-07-31|archive-url=https://web.archive.org/web/20200731210718/https://www.slhd.nsw.gov.au/rpa/neonatal/content/pdf/guidelines/g6pdd.pdf|url-status=dead}}</ref>
* Stress from a [[Medicine:Pathogenic bacteria|bacterial]] or [[Medicine:Viral disease|viral infection]].<ref name="JGDC"/>

====Drugs====
Many substances are potentially harmful to people with G6PD deficiency. Variation in response to these substances makes individual predictions difficult. Antimalarial drugs that can cause acute hemolysis in people with G6PD deficiency include [[Chemistry:Primaquine|primaquine]], [[Chemistry:Pamaquine|pamaquine]], [[Chemistry:Chloroquine|chloroquine]], and [[Chemistry:Hydroxychloroquine|hydroxychloroquine]].<ref>{{cite book  |title=2010 Nurse's Drug Handbook |date=2010 |publisher=Jones & Bartlett Learning |isbn=978-0-7637-7900-9 |page=497 |url=https://books.google.com/books?id=vJjv0U6o8YEC&dq=G6PD+Hydroxychloroquine&pg=PA497 }}</ref> There is evidence that other antimalarials may also exacerbate G6PD deficiency, but only at higher doses. [[Medicine:Sulfonamide|Sulfonamides]] (such as [[Chemistry:Sulfanilamide|sulfanilamide]], [[Chemistry:Sulfamethoxazole|sulfamethoxazole]], and [[Chemistry:Mafenide|mafenide]]), thiazolesulfone, [[Chemistry:Methylene blue|methylene blue]], and [[Chemistry:Naphthalene|naphthalene]] should also be avoided by people with G6PD deficiency as they antagonize folate synthesis, as should certain [[Biology:Analgesic|analgesic]]s (such as [[Chemistry:Phenazopyridine|phenazopyridine]] and [[Chemistry:Acetanilide|acetanilide]]) and a few non-sulfa antibiotics ([[Chemistry:Nalidixic acid|nalidixic acid]], [[Chemistry:Nitrofurantoin|nitrofurantoin]], [[Chemistry:Isoniazid|isoniazid]], [[Chemistry:Dapsone|dapsone]], and [[Biology:Furazolidone|furazolidone]]).<ref name=Frank>{{cite journal |author=Frank JE |title=Diagnosis and management of G6PD deficiency |journal=Am Fam Physician |volume=72 |issue=7 |pages=1277–82 |date=October 2005 |pmid=16225031 |url=http://www.aafp.org/afp/20051001/1277.html |access-date=2008-08-23 |archive-date=2021-08-28 |archive-url=https://web.archive.org/web/20210828093709/https://www.aafp.org/afp/2005/1001/p1277.html |url-status=dead }}</ref><ref name="OHM">{{cite book |last=Warrell |first=David A. |author2=Timothy M. Cox |author3=John D. Firth |author4=Edward J. Benz |title=Oxford Textbook of Medicine |volume=3 |publisher=Oxford University Press |year=2005 |pages=720–5 | isbn=978-0-19-857013-4 }}</ref><ref>A comprehensive list of drugs and chemicals that are potentially harmful in G6PD deficiency can be found in {{cite journal |author=Beutler E |title=G6PD deficiency |journal=Blood |volume=84 |issue=11 |pages=3613–36 |date=December 1994 |pmid=7949118 |doi= 10.1182/blood.V84.11.3613.bloodjournal84113613|doi-access=free }}.</ref> Henna has been known to cause hemolytic crisis in G6PD-deficient infants.<ref>{{cite journal |vauthors=Raupp P, Hassan JA, Varughese M, Kristiansson B |title=Henna causes life threatening haemolysis in glucose-6-phosphate dehydrogenase deficiency |journal=Arch. Dis. Child. |volume=85 |issue=5 |pages=411–2 |year=2001 |pmid=11668106|doi=10.1136/adc.85.5.411 |pmc=1718961}}</ref> [[Chemistry:Rasburicase|Rasburicase]] is also contraindicated in G6PD deficiency. High dose [[Chemistry:Intravenous therapy|intravenous]] [[Biology:Vitamin C|vitamin C]] has also been known to cause haemolysis in G6PD deficiency carriers;<ref>{{cite journal|last1=Rees|first1=DC|last2=Kelsey|first2=H|last3=Richards|first3=JD|title=Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency.|journal=BMJ (Clinical Research Ed.)|date=27 March 1993|volume=306|issue=6881|pages=841–2|pmid=8490379|pmc=1677333|doi=10.1136/bmj.306.6881.841}}</ref><ref>{{cite journal|last1=Mehta|first1=JB|last2=Singhal|first2=SB|last3=Mehta|first3=BC|title=Ascorbic-acid-induced haemolysis in G-6-PD deficiency.|journal=Lancet|date=13 October 1990|volume=336|issue=8720|pages=944|pmid=1976956|doi=10.1016/0140-6736(90)92317-b|s2cid=30959794|doi-access=free}}</ref> therefore, G6PD deficiency testing is routine before infusion of doses of 25 g or more.

===Genetics===
Two variants (G6PD A− and G6PD Mediterranean) are the most common in human populations. G6PD A− has an occurrence of 10% of Africans and African-Americans while G6PD Mediterranean is prevalent in the Middle East. The known distribution of the mutated allele is largely limited to people of Mediterranean origins (Spaniards, Italians, Greeks, Armenians, Sephardi Jews and other Semitic peoples).<ref name="britannica.com">{{Cite web | url=http://www.britannica.com/EBchecked/topic/202897/favism |title = Favism &#124; genetic disorder| date=December 2023 }}</ref> Both variants are believed to stem from a strongly protective effect against ''[[Biology:Plasmodium falciparum|Plasmodium falciparum]]'' and ''[[Biology:Plasmodium vivax|Plasmodium vivax]]'' malaria.<ref>Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009-05-28). Robbins and Cotran Pathologic Basis of Disease, Professional Edition: Expert Consult - Online (Robbins Pathology) (Kindle Locations 33351-33354). Elsevier Health. Kindle Edition.</ref> It is particularly frequent in the Kurdish Jewish population, wherein approximately 1 in 2 males have the condition and the same rate of females are carriers.<ref name="JGDC"/> It is also common in African American, Saudi Arabian, Sardinian males, some African populations, and Asian groups.<ref name="JGDC">''Glucose-6-Phosphate Dehydogenase Deficiency (G6PD)'' on The Jewish Genetic Disease Consortium (JGDC) website [http://www.mazornet.com/genetics/g6pd.htm].{{webarchive|url=https://web.archive.org/web/20170701120909/http://www.jewishgeneticdiseases.org/diseases/glucose-6-phosphate-dehydogenase-deficiency-g6pd/|date=1 July 2017}}</ref>

All mutations that cause G6PD deficiency are found on the long arm of the [[Biology:X chromosome|X chromosome]], on band Xq28. The G6PD gene spans some 18.5 kilobases.<ref name="OHM"/> The following variants and mutations are well-known and described:
{|width="95%"  class="wikitable"
|+Descriptive mutations
|-
!colspan="4" align="center" bgcolor="#FACEDA"| Mutation
!colspan="3" align="center" bgcolor="#FACEDA"| Gene
!colspan="3" align="center" bgcolor="#FACEDA"| Protein
|-
!Designation
!Short name
!Isoform<br>G6PD-Protein
!OMIM-Code
!Type
!Subtype
!Position
!Position
!Structure change
!Function change
|-
|valign="top"|G6PD-A(+)
|valign="top"|Gd-A(+)
|valign="top"|G6PD A
|valign="top"|+305900.0001
|valign="top"|Polymorphism nucleotide
|valign="top"|[[Chemistry:Adenine|A]]→[[Chemistry:Guanine|G]]
|valign="top"|376<br />(Exon 5)
|valign="top"|126
|valign="top"|[[Chemistry:Asparagine|Asparagine]]→[[Chemistry:Aspartic acid|Aspartic acid]] (ASN126ASP)
|valign="top"|No enzyme defect (variant)
|-
|valign="top"|G6PD-A(-)
|valign="top"|Gd-A(-)
|valign="top"|G6PD A
|valign="top"|+305900.0002
|valign="top"|Substitution nucleotide
|valign="top"|[[Chemistry:Guanine|G]]→[[Chemistry:Adenine|A]]
|valign="top"|376<br />(Exon 5)<br />and<br />202
|valign="top"|68<br />and<br />126
|valign="top"|[[Chemistry:Valine|Valine]]→[[Chemistry:Methionine|Methionine]] (VAL68MET)<br />[[Chemistry:Asparagine|Asparagine]]→[[Chemistry:Aspartic acid|Aspartic acid]] (ASN126ASP)
|valign="top"|
|-
|valign="top"|G6PD-Mediterranean
|valign="top"|Gd-Med
|valign="top"|G6PD B
|valign="top"|+305900.0006
|valign="top"|Substitution nucleotide
|valign="top"|[[Chemistry:Cytosine|C]]→[[Chemistry:Thymine|T]]
|valign="top"|563<br />(Exon 6)
|valign="top"|188
|valign="top"|[[Chemistry:Serine|Serine]]→[[Chemistry:Phenylalanine|Phenylalanine]] (SER188PHE)
|valign="top"|Class II
|-
|valign="top"|G6PD-Canton
|valign="top"|Gd-Canton
|valign="top"|G6PD B
|valign="top"|+305900.0021
|valign="top"|Substitution nucleotide
|valign="top"|[[Chemistry:Guanine|G]]→[[Chemistry:Thymine|T]]
|valign="top"|1376
|valign="top"|459
|valign="top"|[[Chemistry:Arginine|Arginine]]→[[Chemistry:Leucine|Leucine]] (ARG459LEU)
|valign="top"|Class II
|-
|valign="top"|G6PD-Chatham
|valign="top"|Gd-Chatham
|valign="top"|G6PD
|valign="top"|+305900.0003
|valign="top"|Substitution nucleotide
|valign="top"|[[Chemistry:Guanine|G]]→[[Chemistry:Adenine|A]]
|valign="top"|1003
|valign="top"|335
|valign="top"|[[Chemistry:Alanine|Alanine]]→[[Chemistry:Threonine|Threonine]] (ALA335THR)
|valign="top"|Class II
|-
|valign="top"|G6PD-Cosenza
|valign="top"|Gd-Cosenza
|valign="top"|G6PD B
|valign="top"|+305900.0059
|valign="top"|Substitution nucleotide
|valign="top"|[[Chemistry:Guanine|G]]→[[Chemistry:Cytosine|C]]
|valign="top"|1376
|valign="top"|459
|valign="top"|[[Chemistry:Arginine|Arginine]]→[[Chemistry:Proline|Proline]] (ARG459PRO)
|valign="top"|G6PD-activity <10%, thus high portion of patients.
|-
|valign="top"|G6PD-Mahidol
|valign="top"|Gd-Mahidol
|valign="top"|G6PD
|valign="top"|+305900.0005
|valign="top"|Substitution nucleotide
|valign="top"|[[Chemistry:Guanine|G]]→[[Chemistry:Adenine|A]]
|valign="top"|487<br />(Exon 6)
|valign="top"|163
|valign="top"|[[Chemistry:Glycine|Glycine]]→[[Chemistry:Serine|Serine]] (GLY163SER)
|valign="top"|Class III
|-
|valign="top"|G6PD-Orissa
|valign="top"|Gd-Orissa
|valign="top"|G6PD
|valign="top"|+305900.0047
|valign="top"|Substitution nucleotide
|valign="top"|[[Chemistry:Cytosine|C]]→[[Chemistry:Guanine|G]]
|valign="top"|131
|valign="top"|44
|valign="top"|[[Chemistry:Alanine|Alanine]]→[[Chemistry:Glycine|Glycine]] (ALA44GLY)
|valign="top"|NADP-binding place affected. Higher stability than other variants.
|-
|valign="top"|G6PD-Asahi
|valign="top"|Gd-Asahi
|valign="top"|G6PD A-
|valign="top"|+305900.0054
|valign="top"|Substitution nucleotide (several)
|valign="top"|[[Chemistry:Adenine|A]]→[[Chemistry:Guanine|G]]<br />±<br />[[Chemistry:Guanine|G]]→[[Chemistry:Adenine|A]]
|valign="top"|376<br />(Exon 5)<br />202
|valign="top"|126<br />68
|valign="top"|[[Chemistry:Asparagine|Asparagine]]→[[Chemistry:Aspartic acid|Aspartic acid]] (ASN126ASP)<br />[[Chemistry:Valine|Valine]]→[[Chemistry:Methionine|Methionine]] (VAL68MET)
|valign="top"|Class III.
|-
|}

==Pathophysiology==
[[File:Pathology of G6PD deficiency.png|right|500px]]
Glucose-6-phosphate dehydrogenase (G6PD) is an [[Biology:Enzyme|enzyme]] in the [[Biology:Pentose phosphate pathway|pentose phosphate pathway]] (see image, also known as the HMP shunt pathway). G6PD converts glucose-6-phosphate into 6-phosphoglucono-δ-lactone and is the rate-limiting enzyme of this [[Biology:Metabolic pathway|metabolic pathway]] that supplies [[Chemistry:Redox|reducing]] energy to cells by maintaining the level of the reduced form of the co-enzyme [[Chemistry:Nicotinamide adenine dinucleotide phosphate|nicotinamide adenine dinucleotide phosphate]] (NADPH). The NADPH maintains the supply of reduced [[Chemistry:Glutathione|glutathione]] in the cells that is used to mop up free radicals that cause oxidative damage. The pathway also stimulates catalase, an antioxidant enzyme.<ref name=":1">{{Cite book |last=Martin |first=Richard J. |title=Fanaroff and Martin's Neonatal-Perinatal Medicine |publisher=Elsevier |year=2020}}</ref>

The G6PD / NADPH pathway is the ''only'' source of reduced glutathione in red blood cells (erythrocytes). The role of red cells as oxygen carriers puts them at substantial risk of damage from oxidizing free radicals except for the protective effect of G6PD/NADPH/glutathione.<ref name=":1" />

People with G6PD deficiency are therefore at risk of hemolytic anemia in states of [[Biology:Oxidative stress|oxidative stress]]. Oxidative stress can result from infection and from chemical exposure to [[Chemistry:Medication|medication]] and certain foods. [[Biology:Broad bean|Broad bean]]s, e.g., fava beans, contain high levels of [[Chemistry:Vicine|vicine]], [[Chemistry:Divicine|divicine]], convicine and [[Chemistry:5,6-Dihydroxycytosine|isouramil]], all of which create oxidants.<ref name="pmid7140776">{{cite journal | vauthors = Chevion M, Navok T, Glaser G, Mager J | title = The chemistry of favism-inducing compounds. The properties of isouramil and divicine and their reaction with glutathione | journal = European Journal of Biochemistry | volume = 127 | issue = 2 | pages = 405–9 | date = October 1982 | pmid = 7140776 | doi = 10.1111/j.1432-1033.1982.tb06886.x | issn=1432-1033}}</ref>

When all remaining reduced [[Chemistry:Glutathione|glutathione]] is consumed, enzymes and other proteins (including [[Biology:Hemoglobin|hemoglobin]]) are subsequently damaged by the oxidants, leading to cross-bonding and protein deposition in the red cell membranes. Damaged red cells are [[Biology:Phagocytosis|phagocytosed]] and sequestered (taken out of circulation) in the [[Biology:Spleen|spleen]]. The hemoglobin is metabolized to [[Chemistry:Bilirubin|bilirubin]] (causing [[Medicine:Jaundice|jaundice]] at high concentrations). The red cells rarely disintegrate in the circulation, so hemoglobin is rarely excreted directly by the kidney, but this can occur in severe cases, causing [[Medicine:Acute kidney injury|acute kidney injury]].{{citation needed|date=September 2021}}

Deficiency of G6PD in the alternative pathway causes the buildup of glucose and thus there is an increase of advanced glycation endproducts (AGE). The deficiency also reduces the amount of NADPH, which is required for the formation of nitric oxide (NO). The high prevalence of [[Medicine:Diabetes mellitus type 2|diabetes mellitus type 2]] and [[Medicine:Hypertension|hypertension]] in Afro-Caribbeans in the West could be directly related to the incidence of G6PD deficiency in those populations.<ref>{{cite journal |vauthors=Gaskin RS, Estwick D, Peddi R |title=G6PD deficiency: its role in the high prevalence of hypertension and diabetes mellitus |journal=Ethnicity & Disease |volume=11 |issue=4 |pages=749–54 |year=2001 |pmid=11763298 }}</ref>

Although female carriers can have a mild form of G6PD deficiency (dependent on the degree of inactivation of the unaffected X chromosome – see ''[[Biology:Skewed X-inactivation|Skewed X-inactivation]]''), homozygous females have been described; in these females there is co-incidence of a [[Medicine:Rare disease|rare]] [[Biology:Immunology|immune disorder]] termed chronic granulomatous disease (CGD).{{citation needed|date=September 2021}}

==Diagnosis==
The diagnosis is generally suspected when patients from certain ethnic groups (see epidemiology) develop [[Medicine:Anemia|anemia]], [[Medicine:Jaundice|jaundice]] and symptoms of [[Medicine:Hemolysis|hemolysis]] after challenges from any of the above causes, especially when there is a positive family history.<ref name=BSHguideline>{{cite journal | vauthors = Roper D, Layton M, Rees D, Lambert C, Vulliamy T, De la Salle B, D'Souza C | title = Laboratory diagnosis of G6PD deficiency. A British Society for Haematology Guideline | journal = British Journal of Haematology | volume = 189 | issue = 1 | pages = 24–38 | date = April 2020 | pmid = 31991476 | doi = 10.1111/bjh.16366 | doi-access=free }}</ref>

Generally, tests will include:{{citation needed|date=September 2021}}
* [[Medicine:Complete blood count|Complete blood count]] and [[Biology:Reticulocyte|reticulocyte]] count; in active G6PD deficiency, Heinz bodies can be seen in [[Biology:Red blood cell|red blood cell]]s on a [[Medicine:Blood film|blood film]];
* Liver enzymes (to exclude other causes of [[Medicine:Jaundice|jaundice]]);
* [[Biology:Lactate dehydrogenase|Lactate dehydrogenase]] (elevated in hemolysis and a marker of hemolytic severity)
* [[Biology:Haptoglobin|Haptoglobin]] (decreased in hemolysis);
* A "[[Medicine:Coombs test|direct antiglobulin test]]" (Coombs' test) – this should be negative, as [[Medicine:Hemolysis|hemolysis]] in G6PD is not immune-mediated;

When there are sufficient grounds to suspect G6PD, a direct test for G6PD is the "Beutler fluorescent spot test", which has largely replaced an older test (the Motulsky dye-decolouration test). Other possibilities are direct DNA testing and/or sequencing of the G6PD gene.<ref name="pmid18156501">{{cite journal | vauthors = Beutler E | title = Glucose-6-phosphate dehydrogenase deficiency: a historical perspective | journal = Blood | volume = 111 | issue = 1 | pages = 16–24 | date = January 2008 | pmid = 18156501 | doi = 10.1182/blood-2007-04-077412 | doi-access = free }}</ref>

The ''Beutler fluorescent spot test'' is a rapid and inexpensive test that visually identifies [[Chemistry:Nicotinamide adenine dinucleotide phosphate|NADPH]] produced by G6PD under ultraviolet light. When the blood spot does not fluoresce, the test is positive; it can be falsely negative in patients who are actively hemolysing. It can therefore only be done 2–3 weeks after a hemolytic episode.<ref name=BSHguideline/>

When a macrophage in the spleen identifies a RBC with a Heinz body, it removes the precipitate and a small piece of the membrane, leading to characteristic "bite cells". However, if a large number of Heinz bodies are produced, as in the case of G6PD deficiency, some Heinz bodies will nonetheless be visible when viewing RBCs that have been stained with crystal violet. This easy and inexpensive test can lead to an initial presumption of G6PD deficiency, which can be confirmed with the other tests.{{citation needed|date=September 2021}}

Testing during and for many weeks after a haemolytic episode will lead to false negative results as the G6PD deficient RBC will have been excreted and the young RBC (reticulocytes) will not yet be G6PD deficient. False negative results will also be likely following any blood transfusions.  For this reason, many hospitals wait for 3 months after a haemolytic episode before testing for G6PD deficiency.  Females should have their G6PD activity measured by quantitative assay to avoid being misclassified by screening tests.<ref name=BSHguideline/>

===Classification===
The [[Organization:World Health Organization|World Health Organization]] classifies G6PD genetic variants into five classes, the first three of which are deficiency states.<ref>{{cite journal|last=WHO Working Group|title=Glucose-6-phosphate dehydrogenase deficiency.|journal=Bulletin of the World Health Organization|year=1989|volume=67|issue=6|pages=601–11|pmid=2633878|pmc=2491315}}</ref>
* Class I: Severe deficiency (<10% activity) with chronic (nonspherocytic) hemolytic anemia
* Class II: Severe deficiency (<10% activity), with intermittent hemolysis
* Class III: Moderate deficiency (10–60% activity), hemolysis with stressors only
* Class IV: Non-deficient variant, no clinical sequelae
* Class V: Increased enzyme activity, no clinical sequelae

===Differential diagnosis===
6-phosphogluconate dehydrogenase (6PGD) deficiency has similar symptoms and is often mistaken for G6PD deficiency, as the affected enzyme is within the same pathway, however these diseases are not linked and can be found within the same person.{{citation needed|date=September 2021}}

==Treatment==
The most important measure is prevention – avoidance of the drugs and foods that cause hemolysis. [[Biology:Vaccination|Vaccination]] against some common pathogens (e.g. [[Medicine:Hepatitis A|hepatitis A]] and [[Medicine:Hepatitis B|hepatitis B]]) may prevent infection-induced attacks.<ref name="pmid18159462">{{cite journal |vauthors=Monga A, Makkar RP, Arora A, Mukhopadhyay S, Gupta AK |title=Case report: Acute hepatitis E infection with coexistent glucose-6-phosphate dehydrogenase deficiency |journal=Can J Infect Dis |volume=14 |issue=4 |pages=230–1 |date=July 2003 |pmid=18159462 |pmc=2094938 |doi= 10.1155/2003/913679|doi-access=free }}</ref>

In the acute phase of hemolysis, [[Medicine:Blood transfusion|blood transfusion]]s might be necessary, or even [[Engineering:Kidney dialysis|dialysis]] in acute kidney failure. Blood transfusion is an important symptomatic measure, as the transfused red cells are generally not G6PD deficient and will live a normal lifespan in the recipient's circulation. Those affected should avoid drugs such as [[Chemistry:Aspirin|aspirin]].{{citation needed|date=September 2021}}

Some patients may benefit from removal of the [[Biology:Spleen|spleen]] ([[Medicine:Splenectomy|splenectomy]]),<ref name="pmid15621740">{{cite journal |vauthors=Hamilton JW, Jones FG, McMullin MF |title=Glucose-6-phosphate dehydrogenase Guadalajara – a case of chronic non-spherocytic haemolytic anaemia responding to splenectomy and the role of splenectomy in this disorder |journal=Hematology |volume=9 |issue=4 |pages=307–9 |date=August 2004 |pmid=15621740 |doi=10.1080/10245330410001714211 |s2cid=71268494 }}</ref> as this is an important site of red cell destruction. Folic acid should be used in any disorder featuring a high red cell turnover. Although [[Chemistry:Vitamin E|vitamin E]] and [[Chemistry:Selenium|selenium]] have antioxidant properties, their use does not decrease the severity of G6PD deficiency.{{citation needed|date=December 2021}}

AG1, a recently discovered small molecule, has been shown to increase the activity of the G6PD enzyme in the three common variants of the deficiency. Due to the absence of medications to treat G6PD, AG1 is a promising precursor in developing a pharmacological treatment effective for multiple G6PD enzymopathies.<ref name="pmid30279493">{{cite journal | vauthors = Hwang S, Mruk K, Rahighi S, Raub AG, Chen CH, Dorn LE, Horikoshi N, Wakatsuki S, Chen JK, Mochly-Rosen D | title = Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator | journal = Nature Communications | volume = 9 | issue = 1 | pages = 4045 | date = October 2018 | pmid = 30279493 | pmc = 6168459 | doi = 10.1038/s41467-018-06447-z | bibcode = 2018NatCo...9.4045H }}</ref>

==Prognosis==
G6PD-deficient individuals do not appear to acquire any illnesses more frequently than other people, and may have less risk than other people for acquiring ischemic heart disease and cerebrovascular disease.<ref>[http://medical-dictionary.thefreedictionary.com/G6PD+deficiency+anaemia thefreedictionary.com > glucose-6-phosphate dehydrogenase deficiency] citing: Gale Encyclopedia of Medicine. Copyright 2008</ref>
However, a recent study revealed that G6PD deficiency increases the cardiovascular risk up to 70%. The risk conferred by G6PD deficiency is moderate compared with the impact of primary cardiovascular risk factors.<ref name="pmid30731288">{{cite journal | vauthors = Pes GM, Parodi G, Dore MP | title = Glucose-6-phosphate dehydrogenase deficiency and risk of cardiovascular disease: A propensity score-matched study | journal = Atherosclerosis | volume = 282 | issue = | pages = 148–153 | date = March 2019 | pmid = 30731288 | doi = 10.1016/j.atherosclerosis.2019.01.027 | s2cid = 73423975 }}</ref> Besides, a published review hypothesized that G6PD deficiency  could reduce the antiplatelet efficacy of clopidogrel (clopidogrel resistance).<ref>{{cite journal |vauthors=Alkattan A, Alkhalifah A, Alsalameen E, Alghanim F, Radwan N |title=Polymorphisms of genes related to phase II metabolism and resistance to clopidogrel |journal=Pharmacogenomics |volume=23 |issue=1 |pages=61–79 |date=2022 |doi=10.2217/pgs-2021-0092 |pmid=34866404|s2cid=244936625 }}</ref>

==Epidemiology==
G6PD deficiency is the second most common human enzyme defect after [[Biology:ALDH2|ALDH2]] deficiency, being present in more than 400 million people worldwide.<ref>{{cite journal |vauthors=Cappellini MD, Fiorelli G |title=Glucose-6-phosphate dehydrogenase deficiency |journal=Lancet |volume=371 |issue=9606 |pages=64–74 |date=January 2008 |pmid=18177777 |doi=10.1016/S0140-6736(08)60073-2 |s2cid=29165746 }}</ref> G6PD deficiency resulted in 4,100 deaths in 2013 and 3,400 deaths in 1990.<ref name=GDB2013>{{cite journal |author1=((GBD 2013 Mortality and Causes of Death Collaborators)) |title=Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. |journal=Lancet |date=17 December 2014 |pmid=25530442|doi= 10.1016/S0140-6736(14)61682-2 |pmc=4340604 |volume=385 |issue=9963 |pages=117–71}}</ref> The [[Place:Mediterranean Basin|Mediterranean Basin]] is where favism is most common, especially among Mizrahi Jews, Sardinians, Cypriots, Greeks, Egyptians, and some African populations, including those who have these ancestries.<ref name=":0">{{Cite journal |last=Askar |first=A. |date=1986 |title=Food Science: Faba Beans (Vicia Faba L.) and their Role in the Human Diet |journal=Food and Nutrition Bulletin |language=en |volume=8 |issue=3 |pages=1–11 |doi=10.1177/156482658600800309 |issn=0379-5721|doi-access=free }}</ref><ref name="GelabertOlalde2017">{{cite journal | vauthors = Gelabert P, Olalde I, de-Dios T, Civit S, Lalueza-Fox C | title = Malaria was a weak selective force in ancient Europeans | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 1377 | date = May 2017 | pmid = 28469196 | pmc = 5431260 | bibcode=2017NatSR...7.1377G|doi = 10.1038/s41598-017-01534-5 }}</ref><ref>{{Cite web |title=G-6-PD FAQ section |url=http://www.rddiagnostics.com/g6pd_faq.htm |website=www.rddiagnostics.com}}</ref> Favism has also been documented outside of the Mediterranean basin, in other Middle Eastern and East Asian nations like Iraq, Iran, Bulgaria and China. Sardinia has the highest reported frequency of favism, with five instances per every 1,000 people.<ref name=":0" />

A side effect of this disease is that it confers protection against [[Medicine:Malaria|malaria]],<ref>{{cite journal |vauthors=Mehta A, Mason PJ, Vulliamy TJ |title=Glucose-6-phosphate dehydrogenase deficiency |journal=Best Practice & Research Clinical Haematology |volume=13 |issue=1 |pages=21–38 |year=2000 |pmid=10916676 |doi=10.1053/beha.1999.0055|pmc=2398001 }}</ref> in particular the form of malaria caused by ''[[Biology:Plasmodium falciparum|Plasmodium falciparum]]'', the most deadly form of malaria. A similar relationship exists between malaria and sickle-cell disease. One theory to explain this is that cells infected with the ''Plasmodium'' parasite are cleared more rapidly by the [[Biology:Spleen|spleen]]. This phenomenon might give G6PD deficiency carriers an evolutionary advantage by increasing their fitness in malarial endemic environments.
In vitro studies have shown that the ''Plasmodium falciparum'' is very sensitive to oxidative damage. This is the basis for another theory, that is that the genetic defect confers resistance due to the fact that the G6PD-deficient host has a higher level of oxidative agents that, while generally tolerable by the host, are deadly to the parasite.<ref>{{cite book|last1=Nelson|first1=David L.|last2=Cox|first2=Michael M.|title=Lehninger Principles of Biochemistry|date=13 February 2013|publisher=Macmillan Higher Education|location=Basingstoke, England|isbn=978-1-4641-0962-1|page=576|edition=6th}}</ref>

==History==
The modern understanding of the condition began with the analysis of patients who exhibited sensitivity to [[Chemistry:Primaquine|primaquine]].<ref>{{cite journal |vauthors=Alving AS, Carson PE, Flanagan CL, Ickes CE |title=Enzymatic deficiency in primaquine-sensitive erythrocytes |journal=Science |volume=124 |issue=3220 |pages=484–5 |date=September 1956 |pmid=13360274 |doi= 10.1126/science.124.3220.484-a|bibcode=1956Sci...124..484C|s2cid=41112750 }}</ref> The discovery of G6PD deficiency relied heavily upon the testing of prisoner volunteers at Illinois State Penitentiary, a type of study which today is considered unethical and cannot be performed. When some prisoners were given the drug primaquine, some developed hemolytic anemia but others did not. In spite of these results, the US military administered the drug widely during the Korean War to prevent the relapsing infection caused by ''[[Biology:Plasmodium vivax|Plasmodium vivax]]'' hypnozoites. Numerous cases of hemolytic anemia were observed in US soldiers of North African and Mediterranean descent.<ref>{{cite journal| pmc=4455359 | pmid=25943156 | doi=10.1179/2047773215Y.0000000016 | volume=109 | issue=3 | title=Origins and implications of neglect of G6PD deficiency and primaquine toxicity in Plasmodium vivax malaria | year=2015 | author=Baird K | journal=Pathog Glob Health | pages=93–106}}</ref>

After studying the mechanism through [[Chemistry:Chromium|Cr<sup>51</sup>]] testing, it was conclusively shown that the hemolytic effect of primaquine was due to an intrinsic defect of erythrocytes.<ref name="beutler">{{cite journal |author=Beutler E |title=Glucose-6-phosphate dehydrogenase deficiency: a historical perspective |journal=Blood |volume=111 |issue=1 |pages=16–24 |date=January 2008 |pmid=18156501 |doi=10.1182/blood-2007-04-077412 |doi-access=free }}</ref>

==Society and culture==
In both legend and mythology, favism has been known since antiquity. The priests of various [[History:Greco-Roman world|Greco-Roman era]] cults were forbidden to eat or even mention beans, and [[Biography:Pythagoras|Pythagoras]] had a strict rule that to join the society of the [[Philosophy:Pythagoreanism|Pythagoreans]] one had to swear off beans.<ref>{{cite book |last=Simoons |first=F.J. |title=Plants of Life, Plants of Death |date=1996-08-30 |publisher=University of Wisconsin Press |isbn=978-0299159047 |page=216 |chapter=8}}</ref> This ban was supposedly because beans resembled male genitalia, but it is possible that this was because of a belief that beans and humans were created from the same material.<ref>{{cite book |author1=Rendall, Steven |author2=Riedweg, Christoph |title=Pythagoras: his life, teaching, and influence |publisher=Cornell University Press |location=Ithaca, N.Y |year=2005 |isbn=978-0-8014-4240-7 |url-access=registration |url=https://archive.org/details/pythagorashislif00ried }}</ref>

==References==
{{reflist}}

== External links ==
{{Medical resources
|  ICD10          = {{ICD10|D|55|0|d|55}}
|  ICD9           = {{ICD9|282.2}}
|  OMIM           = 305900
|  DiseasesDB     = 5037
|  MedlinePlus    = 000528
|  eMedicineSubj  = med
|  eMedicineTopic = 900
|  MeshID         = D005955
}}
* [http://www.fpnotebook.com/Hemeonc/Hemolysis/G6pdDfcncy.htm Family Practice Notebook/G6PD Deficiency (Favism)]

{{Diseases of RBCs}}
{{Inborn errors of carbohydrate metabolism}}
{{X-linked disorders}}

{{DEFAULTSORT:Glucose-6-Phosphate Dehydrogenase Deficiency}}
[[Category:Wikipedia medicine articles ready to translate]]

{{Sourceattribution|Glucose-6-phosphate dehydrogenase deficiency}}