Postgrad Med J (1994) 70, 871 -877 © The Fellowship of Postgraduate Medicine, 1994

Review Article

Glucose-6-phosphate dehydrogenase deficiency

Atul B. Mehta

Department ofHaematology, Royal Free Hospital and School ofMedicine, Pond Street,London NW3 2QG, UK

Introduction

Glucose-6-phosphate dehydrogenase (G6PD)deficiency is the most commonly known inheriteddisorder in man, and is estimated to affect 400million people worldwide.' The highest prevalencerates (with gene frequencies in the range of 5-25%are found in tropical Africa, the Middle East,tropical and sub-tropical Asia, some parts of theMediterranean, and in Papua New Guinea. Thespectacular advances in molecular biology of thelast decade are helping to unravel the molecularbasis of its biochemical and clinical diversity. Itserves as a model for the clinician of the importanceof the environment in determining the clinicalexpression of genetic disease. For the populationbiologist, its study has yielded important insightsinto the interaction of host red cells with themalaria parasite and the influence of this interac-tion on human genetic polymorphism. Mosthuman pathology due to G6PD deficiency ispreventable by population screening andavoidance of precipitants, thus posing a challengefor epidemiologists and community physicians.There are several excellent recent reviews.2-5

Biochemical and genetic basis

G6PD is a cytoplasmic enzyme that is distributed inall cells. It catalyses the first step in the hexosemonophosphate pathway, to produce NADPH,which is required for reactions of various biosyn-thetic pathways as well as for the stability ofcatalase and the preservation and regeneration ofthe reduced form of glutathione (GSH). Catalaseand GSH are essential for the detoxification ofhydrogen peroxide, and the defence of cells againstthis compound depends ultimately and heavily onG6PD. This is especially true in red cells, which areexquisitely sensitive to oxidative damage and inwhich other NADPH-producing enzymes are lack-ing. G6PD in its active enzyme form is made up of

either two or four identical subunits, but thethree-dimensional structure of the protein remainsto be determined. The complete primary sequenceof 515 amino acids has been determined from thecDNA sequence, which was determined in 1986.6The gene encoding G6PD is on the long arm of theX chromosome (band Xq28), and spans 18 kb.G6PD deficiency is genetically heterogeneous andabout 400 different variant enzymes have beenreported. These have been categorized according tocriteria established by the World Health Organiza-tion,7'8 and are divided into five classes (Table I)according to residual enzyme activity. DNAsequence analysis of these mutants has been com-pleted for about 65 mutants2'9 and a number ofinteresting features have emerged:1. The overwhelming majority result from single

point mutations resulting in amino-acid subs-titution. Only three deletions have hitherto beenreported and the largest is only eight aminoacids.'0"' This is in keeping with the notion thatG6PD is a 'house-keeping' gene that is ubi-quitously expressed and a small amount ofG6PD activity is essential for all cells.

2. Many variants that were regarded as distinctbased on their biochemical features haveemerged as being identical; whereas some thatwere thought to be identical have been found tobe different. No clear structure-function rela-tionships have emerged thus far, though thecluster of Class 1 variants around residues 386and lysine 205 have led to the suggestion thatthese are the NADP+ and G6P binding sites,respectively.2

3. Very few of the severely deficient variants arepolymorphic, whereas most of the polymorphicvariants are associated with mild deficiency.This is further evidence that the selective pres-sure for the emergence of these mutations is therelative protection afforded against Plasmodiumfalciparum malaria. At least five polymorphicand mildly deficient 'double' mutants share themutation found in the non-deficient A +variant.

Correspondence: A.B. Mehta, M.A., M.D., M.R.C.P.,M.R.C.Path.Received: 1 July 1994

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Table I Summary of G6PD variants

Electrophoretic mobilityAltered

electrophoreticPolymorphic mobility

Class Number (%) Fast Normal Slow (%) Total

I 1 1 24 34 39 64 97II 37 30 31 37 54 70 122III 22 21 41 16 46 84 103IV 12 23 20 3 29 94 52V 2 0 2 100 2Total 72 19 118 90 168 76 376

The WHO classification is based on residual G6PD activity in red cells and on clinicalmanifestations as follows: Class I variants are associated with CNSHA; Class II variants have aG6PD activity of less than 10% normal; Class III variants have an activity of 10-60% normal;Class IV variants have near normal activity and no clinical manifestations; Class V variants haveincreased activity.

4. The only 'nonsense' mutation, that is, one thatintroduces a premature stop codon, has beenfound on one of the two X chromosomes of afemale with partial G6PD deficiency.2 The nowclassical concept that one of the two Xchromosomes in female cells is inactivated wasconceived because of the variable expression ofG6PD deficiency in females'2 and had long beenthe basis of the application of the use of G6PDexpression as a clonal marker.'3 The availabilityof molecular techniques for detecting G6PDpolymorphisms will lead to a wider applicationof these techniques in the future.'4The phenomenon of X-chromosome inactiva-

tion also offers a clue as to why femaleheterozygotes appear to have greater protectionagainst malaria than do deficient malehemizygotes. In vitro culture studies have shownthat the growth of malaria parasites is impairedupon first passage from normal to G6PD-deficientred cells but that through subsequent passages theycan adapt and grow normally.'5 Such 'adaptation'occurs as the parasite's own G6PD gene is inducedto protect it from oxidant stress.'6 The femaleheterozygote's red cell population is a mosaic ofdeficient and normal cells, and 'adaptation' doesnot occur in these circumstances.'7

Clinical manifestations

Most G6PD-deficient individuals are entirelyasymptomatic and the overwhelming majority ofthe remainder only develop symptoms in responseto oxidant stress. The commmonest clinicalmanifestations are neonatal jaundice and acutehaemolytic anaemia related to drugs, infection oringestion of fava beans. The critical role of

environmental precipitants has been recognizedsince the earliest descriptions of G6PD deficiency.Pythagoras is said to have warned his disciplesagainst the dangers of eating fava beans (Viciafaba; broad beans). Observant practitioners hadnoticed that favism appeared to 'run in families'.'8It was also clear that only some individuals weresusceptible to haemolytic anaemia caused by drugsbefore the discovery by Carson et al.'9 in Chicagothat primaquine-sensitive people had a very lowlevel of G6PD activity in their red cells.

Mechanism ofhaemolysis

The detailed mechanism of haemolysis is not fullyknown but it undoubtedly results from the inabilityof G6PD-deficient red cells to withstand theoxidative damage produced, directly or indirectlyby an exogenous trigger. The identity of the G6PDvariant, and hence the residual enzyme activity, isclearly an important variable. Residual activity isbelow a critical level in Class 1, NADPH produc-tion is inadequate for the steady-state requirementsof the red cell, and chronic non-spherocytichaemolytic anaemia (CNSHA) results. Neonatalerythrocytes have depressed levels of vitamin E,glutathione reductase and catalase,20'2' makingthem more susceptible to oxidant haemolysis.Certain drugs22 and infectious agents (for example,influenza A virus23) stimulate the hexosemonophosphate shunt pathway in normal red cells,indicating that in their presence increased NADPHproduction is required. Hydrogen peroxide isgenerated by activated polymorphonuclear neut-rophils.24 Based on studies of the effect of frac-tionated extracts on erythrocyte metabolism, thetoxic components of fava beans have been sug-gested to be the pyrimidine aglycones, divicine andisouramil25'26 in combination with ascorbic acid.

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A reasonable model for all of these situations isthat the red cell GSH level becomes so low thatcritical sulphydryl groups in some key proteins arenot maintained in reduced form, and intramolec-ular or intermolecular disulphides are formed.Such aggregates decrease red cell deformability,27and they may alter the cell surface sufficiently tomake it recognizable by macrophages as abnormal(much like an aged red cell), thus leading toextravascular haemolysis within the reticulo-endothelial system. Disturbed erythrocyte calciumhomeostasis (specifically, reduced activity of themembrane Ca2+-ATPase, leading to increasedintraerythrocytic calcium and decreased intra-erythrocytic potassium) has been suggested tomediate activation of proteolytic activity withinerythrocytes of favic subjects.28

Chronic non-spherocytic haemolytic anaemia

Some G6PD variants are characterized by overtchronic haemolytic anaemia, which is furtherexacerbated by oxidant stress. Such variants havebeen described (almost invariably in males within asingle kindred) in many parts of the world, regard-less of whether the common types of G6PDdeficiency are endemic in the region. Most patientspresent with or give a history of neonatal jaundice,often requiring exchange transfusion2930 and go onto develop infection and drug-induced haemolysis.Gallstones may be a prominent feature andsplenomegaly is usually present, G6PD activity islow in all tissues and, in rare cases, deficiency ingranulocytes is associated with granulocyte dys-function3" and haemolysis is worsened by increasedsusceptibility to infection.

Drug-induced haemolytic anaemia

A critical analysis of the data whereby individualdrugs have been implicated in the causation ofhaemolysis in G6PD-deficient subjects has beenconducted by Beutler32 who uncovered a discrep-ancy between the relatively small list of drugs forwhich there is strong evidence linking them tohaemolytic anaemia (Table II) and a much largerlist of agents for which the evidence is less secure.The degree of haemolysis is also influenced by theactivity of the host G6PD activity, the dose andduration of therapy, and the presence of additionaloxidant stress, for example, infection. Further-more, clinical and haematological assessment ofhaemolysis has notoriously low sensitivity, in thateven a two- to three-fold increase in red celldestruction may not produce a significant anaemiaor reticulocytosis. Clinical haemolysis andjaundicetypically begin within 2 to 3 days of starting thedrug. The haemolysis is largely intravascular and itis characteristically associated with haemoglo-

Table II Drugs causing haemolytic anaemia in G6PDdeficiency*

Anti-malarialst Primaquine, pamaquine, pentaquineSulphonamides Sulphanilamide, sulphacetamide, sul-

phapyridine, sulphamethoxazoleSulphones DapsoneNitrofurans NitrofurantoinMiscellaneous Nalidixic acid, naphthalene (moth-

balls), niridazole, ciprofloxacin,methylene blue

Note: The genetic heterogeneity of G6PD deficiencymeans that a drug found to be safe in some deficientsubjects is not necessarily safe in all. The risk and severityof haemolysis is usually dose related.*For references and further information see references 1,32, 73 and 74; tquinine, chloroquine and quinidine are allacceptable for the treatment of acute malaria, andchloroquine, mefloquine, halofantrine proguanil andpyrimethamine (but not Maloprim®, which containsdapsone, or Fansidar®, which contains a sulphonamide)are acceptable for malaria prophylaxis.

binuria. The anaemia worsens until the seventh toeighth day, a reticulocyte response then sets in, andthe haemoglobin level begins to recover on theeighth to tenth day. In vitro tests33'34 have beendeveloped aiming to predict whether a drug willcause haemolysis in vivo and they should be carriedout before a new drug is introduced to a populationin which G6PD deficiency is prevalent.

Infection-induced haemolysis

Infection is probably the most common cause ofhaemolysis in subjects with G6PD deficiency.Numerous bacterial, viral and rickettsial infectionshave been reported as precipitants, but particularlyimportant are infectious hepatitis,35,36 pneumonia37and typhoid fever.38 Viral infections affecting eitherthe upper respiratory tract or the gastrointestinaltract are reported39 to cause more severe haemolysisthan bacterial infections in G6PD-deficient children.

Haemolysis is again largely intravascular andrenal failure is a well-recognized complication inadults, 40,41 whereas it is rare in children.

Favism

All patients with favism are G6PD deficient; how-ever, not all G6PD-deficient subjects are sensitiveto fava beans, and even those who are sensitiveshow striking variability from one exposure to thenext. The reason for this discrepancy is not clear,and it seems likely that one or more factors inaddition to G6PD deficiency are required for thedevelopment of favism42'43 and to determine theseverity of the individual attack.

Clinical favism presents characteristically with

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sudden onset of acute haemolytic anaemia within24-48 hours of ingestion of the beans. Pallor,jaundice and haemoglobinuria are the hallmarks.Acute renal failure may supervene in adults, but itis very rare in children; however, fatalities inchildren were not uncommon prior to theavailability of transfusion therapy. The highestincidence is in boys aged 2-6 years. It is well-documented that heterozygous girls are affected,although the condition is usually milder in thesesubjects." Favism occurs after ingestion of fresh,dried or frozen beans, but fresh beans are by far thecommonest offender and therefore favism is com-monest during the spring season. Haemolysis inbreast-fed babies whose mothers have eaten favabeans is well documented.45The mainstay of prevention is avoidance of fava

beans. Experience in Sardinia has demonstratedthe value of neonatal screening and health educa-tion in reducing the incidence of favism within thatcommunity.' The mainstay of treatment remainsblood transfusion in severe cases. The originalobservation suggesting arrest of haemolysis bydesferrioxamine47 has been disputed,48 but a recentlarger study appears to confirm that a single bolusof desferrioxamine may be useful as an adjunct tored cell transfusion.49 The proposed mechanism isthat desferrioxamine reduces iron-dependent for-mation ofdamaging oxidant radicals (for example,hydroxyl ions).

It has been widely held that favism is onlyassociated with the more severely deficient amongstthe polymorphic variants of G6PD (particularlyG6PD Mediterranean); and specifically that G6PDA- in not associated with favism. This is notcorrect, as typical attacks of favism have been welldocumented in subjects of African origin with theA-variant.50

Neonataljaundice

G6PD deficiency is the commonest red cellenzymopathy to cause neonatal haemolysis andjaundice. The best population data are availablefrom West Africa,5' the Mediterranean52'53 and theFar East (for example, Thailand54) and it is clearthat perhaps as many as one third of all males withneonatal jaundice have G6PD deficiency, and asimilar proportion of male children with G6PDdeficiency develop neonatal jaundice (NNJ). Ker-nicterus has been described in all populationgroups. G6PD deficiency is a less frequent cause ofNNJ among subjects of African descent in theUSA, and of Greek ancestry in Australia, than inthe countries of origin of these populations,'although the differences are perhaps less markedthan originally thought. Environmental factorsthat may account for this include maternalexposure to oxidant drugs and use of herbal

remedies that may precipitate or exacerbate NNJ.Gestational age and maturity is an impotant con-sideration, as NNJ is more common, severe andpotentially harmful in premature infants.55Environmental factors will also affect the incidenceof neonatal infection, hypoglycaemia, acidosis andthe normal level of neonatal haemoglobin within apopulation. Cultural factors, including exposure toicterogenic agents, have been identified as impor-tant precipitants of NNJ amongst the G6PD-deficient population of Nigeria.56 Of genetic fac-tors, the type of G6PD variant that is prevalentwithin a population is likely to be relevant, and isclearly of importance with respect to unusual orsporadic variants in the USA.5758 In Sardinia,where at least three polymorphic variants areassociated with NNJ, the severity ofNNJ does notcorrelate with red cell G6PD activity,59 suggestingthat additional variables (for example, expressionand activity of the G6PD-deficient variant in theliver') may be important.

Diagnosis

This is based on the clinical history andhaematological findings, including anaemia,reticulocytosis and characteristic red cell changes(for example, 'bite' cells and Heinz bodies, pro-duced by adherance of oxidized and denatured redcell proteins, and haemoglobins to the cell memb-rane).

Assays ofG6PD activity6'-63 depend on measur-ing the rate ofproduction ofNADPH from NADPin red cells, and the assay may be performed on asequestrene (EDTA) or heparinized blood sample.Enzyme activity declines with red cell age and ishighest in reticulocytes. Assay results obtainedafter an acute haemolytic episode should always beconfirmed during the steady state, as areticulocytosis may rarely lead to a false-negativeresult. Most haematology laboratories in the UKutilize screening tests, which are rapid and canreliably distinguish between affected men andheterozygous females; formal biochemical charac-terization involves enzyme purification from redcells, assay of activity by spectrophotometry andenzyme electrophoresis, and is only necessary inselected cases (for example, if a new variant issuspected).

Treatment

The most important aspect of management is toavoid precipitating causes ofhaemolysis (for exam-ple, drugs, fava beans). Haemolysis is usuallyself-limiting, but in severe cases red cell transfusionmay be required. Red cells from G6PD-deficient

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donors are acceptable for transfusion purposes64except in the case of exchange transfusion forneonatal jaundice, which should be performedafter screening the donor unit for G6PDdeficiency.65 Folic acid (5 mg daily) is required longterm for all patients with chronic haemolysis andshould be given for 2-3 weeks following an acutehaemolytic event. Patients with CNSHA arevariably anaemic in the steady state and, if they aresymptomatic or require transfusion therapy,splenectomy should be considered. Long-termtherapy with vitamin E and oral selenium are not ofproven value.6667 All other patients with G6PDdeficiency should not be anaemic during the steadystate and, if they are, an alternative or additionaldiagnosis (for example, co-existence of G6PDdeficiency with another cause of CNSHA such aspyruvate kinase deficiency68) must be considered.Renal failure can complicate acute intravascularhaemolysis (particularly due to drugs and favabeans). Neonatal jaundice arising as a result ofhaemolytic anaemia requires closer monitoringand earlier therapy than jaundice due to othercauses, for example, breast milk jaundice.69 In theterm infant, phototherapy is required if thebilirubin exceeds 170 limol/l during the first 2 daysof life, or 240 ptmol/l on day 4 or later. Exchangetransfusion is indicated if the bilirubin exceeds250 lamol/l during the first 2 days, or 330 ftmol/l atany time.

Future prospects

In spite of the enormous increase in our under-standing, much remains to be learnt about G6PDdeficiency. The lack of detailed knowledge of thetertiary structure of the enzyme hampers attemptsto understand structure-function relationships.70Molecular analysis of deficient variants will helpbut there is an important need to continue toperform full biochemical characterization ofvariants subjected to DNA sequence analysis. Thelack of severe clinical effects in the overwhelmingmajority of deficient individuals means thatantenatal diagnosis (which has already been per-formed7") and gene replacement therapy2 willremain largely of theoretical interest. Much greaterpractical benefit will result from the institution ofcommunity screening programmes72 so that appro-priate educational material can be targetedtowards affected patients and their carers.

Acknowledgements

This review is based on work done in collaboration withProfessor Lucio Luzzatto of the Royal PostgraduateMedical School, London; work in his laboratory issupported by a Programme Grant from the MRC.

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