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| {{SI}} | | {{Glucose-6-phosphate dehydrogenase deficiency}} |
| {{CMG}}; '''Associate Editor(s)-In-Chief:''' [[Priyamvada Singh|Priyamvada Singh, M.D.]] [mailto:psingh@perfuse.org] | | {{CMG}}; '''Associate Editor(s)-In-Chief:''' [[Priyamvada Singh|Priyamvada Singh, M.D.]] [mailto:psingh13579@gmail.com] |
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| ==Overview== | | ==[[Glucose-6-phosphate dehydrogenase deficiency overview|Overview]]== |
| '''Glucose-6-phosphate dehydrogenase (G6PD) deficiency''' is an [[Sex-linked|X-linked recessive]] [[hereditary disease]] featuring abnormally low levels of the [[G6PD]] enzyme, which plays an important role in [[red blood cell]] function. Individuals with the disease may exhibit non-immune [[hemolytic anemia]] in response to a number of causes. It is closely linked to '''[[favism]]''', a disorder characterized by a hemolytic reaction to consumption of [[Vicia faba|broad bean]]s, with a name derived from the [[Italian language|Italian]] name of the broad bean (''fava''). Sometimes the name, [[favism]], is alternatively used to refer to the enzyme deficiency as a whole.
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| ==Epidemiology and Demographics== | | ==[[Glucose-6-phosphate dehydrogenase deficiency historical perspective|Historical Perspective]]== |
| * G6PDD is said to be the most common enzyme deficiency disease in the world, affecting approximately 400,000,000 people globally.<ref>http://www.rddiagnostics.com/g6pd_faq.htm</ref>
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| * A side effect of this disease is that it confers protection against [[malaria]], in particular the form of [[malaria]] caused by ''[[Plasmodium falciparum]]'', the most deadly form of [[malaria]].
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| * A similar relationship exists between [[malaria]] and [[sickle-cell disease]]. An explanation is that cells infected with the ''Plasmodium'' parasite are cleared more rapidly by the [[spleen]]. This phenomenon might give [[G6PD deficiency]] carriers an evolutionary advantage.
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| ==Classification== | | ==[[Glucose-6-phosphate dehydrogenase deficiency classification|Classification]]== |
| There are four forms of [[G6PD]]:
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| # [[Hereditary nonspherocytic hemolytic anemia]]
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| # Severe deficiency
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| # Mild deficiency
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| # Non-deficient variant
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| # [[Favism]] is a disorder characterized by [[hemolytic anemia]] in response to ingestion of fava beans. [[Favism]] as a diagnosis has been known since antiquity, perhaps in relation to Pythagoras, among others. All individuals with favism show [[G6PD deficiency]]. However, not all individuals with [[G6PD deficiency]] show [[favism]]. For example, in a small study of 757 Saudi men, more than 42% showed [[G6PD deficiency]], but none reported symptoms of [[favism]], despite fava in the diet.<ref>{{cite web |url=http://www.kfshrc.edu.sa/annals/166/95-371.html |title=Common G6PD variant from Saudi population |accessdate=2007-10-28 |format= |work=}}</ref> [[Favism]] is known to be more prevalent in infants and children, and [[G6PD]] genetic variant can influence chemical sensitivity. Other than this, the detailed chemical relationship between [[favism]] and [[G6PD]] is not well known.
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| ==Risk Factors==
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| * Ethnic groups
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| ** African American
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| ** Middle Eastern decent, particularly Kurdish or Sephardic Jewish
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| * Male
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| * Family history of the deficiency
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| ==Pathophysiology== | | ==[[Glucose-6-phosphate dehydrogenase deficiency pathophysiology|Pathophysiology]]== |
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| * [[Glucose-6-phosphate dehydrogenase]] ([[G6PD]]) is an [[enzyme]] in the [[pentose phosphate pathway]], a [[metabolic pathway]] that supplies reducing energy to cells (most notably [[erythrocyte]]s) by maintaining the level of the [[co-enzyme]] [[nicotinamide adenine dinucleotide phosphate|nicotinamide adenine dinucleotide phosphate]] (NADPH).
| | ==[[Glucose-6-phosphate dehydrogenase deficiency causes|Causes]]== |
| * The NADPH in turn maintains the level of [[glutathione]] in these cells that helps protect the red blood cells against [[oxidation|oxidative]] damage. G6PD converts [[glucose-6-phosphate]] into [[6-phosphoglucono-δ-lactone]] and is the rate-limiting enzyme of the ''pentose phosphate pathway''.
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| * Patients with [[G6PD deficiency]] are at risk of [[hemolytic anemia]] in states of [[oxidative stress]]. This can be in severe infection, [[medication]] and certain foods. [[Broad bean]]s contain high levels of vicine, divicine, convicine and isouramil — all are [[oxidant]]s.
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| * In states of oxidative stress, all remaining [[glutathione]] is consumed. Enzymes and other proteins (including [[hemoglobin]]) are subsequently damaged by the oxidants, leading to [[electrolyte]] imbalance, membrane cross-bonding and [[phagocytosis]] and [[spleen|splenic]] sequestration of red blood cells. The hemoglobin is metabolized to [[bilirubin]] (causing [[jaundice]] at high concentrations) or excreted directly by the [[kidney]] (causing [[acute renal failure]] in severe cases).
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| * Deficiency of G6PD in the alternative pathway causes the build up of glucose and thus there is an increase of [[advanced glycation endproduct]]s (AGE). The deficiency also causes a reduction of NADPH which is necessary for the formation of Nitric Oxide (NO). The high prevalence of [[diabetes mellitus type 2]] and [[hypertension]] in Afro-Caribbeans in the West could be directly related to G6PD deficiency.<ref>{{cite journal |author=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 |doi=}}</ref>
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| * Some other epidemiological reports have pointed out, however, that G6PD seems to decrease the susceptibility to [[cancer]], [[cardiovascular disease]] and [[stroke]].
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| * Although female carriers can have a mild form of G6PD deficiency (dependent on the degree of inactivation of the unaffected X chromosome - see ''[[lyonization]]''), homozygous females have been described; in these females there is co-incidence of a [[rare disease|rare]] [[immunology|immune disorder]] termed [[chronic granulomatous disease]] (CGD).
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| [[image:G6PD_mechanism.png|550px|left|Mechanism of G6PD]] | | ==[[Glucose-6-phosphate dehydrogenase deficiency differential diagnosis|Differentiating Glucose-6-phosphate dehydrogenase deficiency from other Diseases]]== |
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| | ==[[Glucose-6-phosphate dehydrogenase deficiency epidemiology and demographics|Epidemiology and Demographics]]== |
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| | ==[[Glucose-6-phosphate dehydrogenase deficiency risk factors|Risk Factors]]== |
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| | ==[[Glucose-6-phosphate dehydrogenase deficiency screening|Screening]]== |
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| | | ==[[Glucose-6-phosphate dehydrogenase deficiency natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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| ==History and Symptoms== | |
| ===History===
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| * Patients are almost exclusively male, due to the [[X-linked]] pattern of inheritance, but female carriers can be clinically affected due to [[lyonization]] where random inactivation of an X-chromosome in certain cells creates a population of [[G6PD]] deficient red cells coexisting with normal red cells.
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| * History of [[hemolysis|hemolytic]] crises occurs 2-4 days in response to:
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| ** Certain [[medication|drugs]]:
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| *** [[Primaquine]] (an [[malaria|antimalarial]])
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| *** [[Sulphonamide]] [[antibiotic]]s
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| *** Sulphones (e.g. [[dapsone]], used against [[leprosy]])
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| *** Other sulphur-containing drugs: [[glibenclamide]] (an [[anti-diabetic drug]])
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| *** [[Nitrofurantoin]] (an [[antibiotic]] often used for [[urinary tract infection]]s)
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| *** [[Vitamin K]] analogues
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| *** Several others<ref>{{cite web |url=http://www.rialto.com/g6pd/table2.htm |title=The G6PD Deficiency Homepage -- Table 2 |accessdate=2007-10-28 |format= |work=}}</ref>
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| *** [[Henna]] can cause a haemolytic crisis in G6PD deficient infants.<ref>{{cite journal |author=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=}}</ref>
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| ** Certain foods, most notably [[broad bean]]s
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| ** Illness (severe infections)
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| ** [[Diabetic ketoacidosis]]
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| ===Symptoms===
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| * Symptoms suggestive of anemia such as fatigue, palpitation
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| * Prolonged [[jaundice]]
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| * Hemolytic features like dark colored urine
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| * Abdominal or back pain
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| * Very severe crises can cause [[acute renal failure]]
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| ==Diagnosis== | | ==Diagnosis== |
| ===Laboratory diagnosis===
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| The diagnosis is generally suspected when patients from certain ethnic groups develop [[anemia]], [[jaundice]] and symptoms of [[hemolysis]] after challenge to any of the above causes, especially when there is a positive family history. The hemolysis spontaneously resolves in approximately 1 week as the older enzyme-depleted cells are replaced by new cells with sufficient G6PD to prevent further hemolysis.
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| Generally, tests will include:
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| * [[Complete blood count]] - Hemoglobin decreases by 3-4 g/dL
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| * Increased [[reticulocyte]] count
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| * [[Haptoglobin]] (decreased in hemolysis)
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| * [[Liver enzyme]]s (to exclude other causes of [[jaundice]])
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| * [[Thyroid-stimulating hormone|TSH]] measurement.
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| * A "[[Coombs test|direct antiglobulin test]]" (Coombs' test) - this should be negative, as [[hemolysis]] in G6PD is not immune-mediated
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| * Since, reticulocytes can have normal G6PD levels, measuring G6PD levels during an acute episode may produce a false-negative result.
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| ===Specific tests for G6PD anemia===
| | [[Glucose-6-phosphate dehydrogenase deficiency diagnostic study of choice|Diagnostic Study of Choice]] | [[Glucose-6-phosphate dehydrogenase deficiency history and symptoms|History and Symptoms]] | [[Glucose-6-phosphate dehydrogenase deficiency physical examination|Physical Examination]] | [[Glucose-6-phosphate dehydrogenase deficiency laboratory findings|Laboratory Findings]] | [[Glucose-6-phosphate dehydrogenase deficiency electrocardiogram|Electrocardiogram]] | [[Glucose-6-phosphate dehydrogenase deficiency chest x ray|Chest X Ray]] | [[Glucose-6-phosphate dehydrogenase deficiency CT|CT]] | [[Glucose-6-phosphate dehydrogenase deficiency MRI|MRI]] | [[Glucose-6-phosphate dehydrogenase deficiency echocardiography or ultrasound|Echocardiography or Ultrasound]] |
| * [[Heinz body|Heinz bodies]]
| | | [[Glucose-6-phosphate dehydrogenase deficiency other imaging findings|Other Imaging Findings]] | [[Glucose-6-phosphate dehydrogenase deficiency other diagnostic studies|Other Diagnostic Studies]] |
| * Beutler fluorescent spot test
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| * The Motulsky dye-decolouration test
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| * Direct DNA testing and/or sequencing of the G6PD gene.
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| ====Heinz bodies: Early diagnosis====
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| When a macrophage in the spleen "sees" an [[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 [[RBC]]s 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.
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| ====Beutler fluorescent spot test: Late diagosis====
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| The '''Beutler fluorescent spot test''' is a rapid and inexpensive test that visually identifies [[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 false-positive in patients who are actively hemolysing. It can therefore only be done several weeks after a hemolytic episode.
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| ====Bite or Blister cells====
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| * In glucose-6-phosphate dehydrogenase deficiency, "bite" or "blister" cells are produced when accumulated oxidized hemoglobin remains adherent to the erythrocyte membrane, which creates an adjacent membrane-bound clear zone.
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| ==Treatment== | | ==Treatment== |
| * In the acute phase of hemolysis, [[blood transfusion]]s might be necessary. Blood transfusion is an important symptomatic measure, as the transfused red cells are generally not G6PD deficient.
| | [[Glucose-6-phosphate dehydrogenase deficiency medical therapy|Medical Therapy]] | [[Glucose-6-phosphate dehydrogenase deficiency surgery|Surgery]] | [[Glucose-6-phosphate dehydrogenase deficiency primary prevention|Primary Prevention]] | [[Glucose-6-phosphate dehydrogenase deficiency secondary prevention|Secondary Prevention]] | [[Glucose-6-phosphate dehydrogenase deficiency cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Glucose-6-phosphate dehydrogenase deficiency future or investigational therapies|Future or Investigational Therapies]] |
| * [[Dialysis]] in [[acute renal failure]]
| | ==Case Studies== |
| * Some patients benefit from removal of the [[spleen]] ([[splenectomy]]), as this is an important site of [[red blood cell]] destruction. * [[Folic acid]] should be used in any disorder featuring a high [[red blood cell]] turnover.
| | [[Glucose-6-phosphate dehydrogenase deficiency case study one|Case #1]] |
| * Although [[vitamin E]] and [[selenium]] have antioxidant properties, their use does not decrease the severity of [[G6PD deficiency]].
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| ==Primary Prevention== | |
| * The most important measure is prevention - avoidance of the drugs and foods that cause [[hemolysis]].
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| *[[Vaccination]] against some common pathogens (e.g. [[hepatitis A]]) may prevent infection-induced attacks.
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| ==References== | | ==References== |