Glucose6phosphate dehydrogenase deficiency

G6PD deficiency is the commonest genetically determined enzyme deficiency in the world population, with an estimated 400 million people being affected. At least 127 different variants associated with deficient enzyme activity have been described, as well as a number of polymorphisms that do not affect the enzyme activity. The G6PD variants have been classified into four groups according to their activity relative to the 'wild-type' G6PD type B (Table 9.2). In Africa, the variant G6PD A- is the predominant polymorphism with equivalent activity to G6PD type B.

Table 9.2 Classification of G6PD deficiency (WHO).

Class

Enzyme activity (% normal)

Examples

Clinical Effects

Santiago de Cuba (Gly447Arg)

Mediterranean (Ser188Phe) Canton (Arg459Leu) Orissa (Ala44Gly)

A- (Val68Met; Aas126Asp)

CNSHA, acute exacerbations Favism

AIVHA (drug induced) Neonatal jaundice

AIVHA (drug induced), neonatal jaundice

None None

Figure 9.13 Global distribution of G6PD gene variants causing G6PD deficiency. Shaded areas indicate the prevalence of G6PD deficiency. The coloured dots depict the distribution of 14 of the most common variants (from Luzzatto & Notaro, 2001, Science 293: 442, with permission).

G6pddeficiency Map

Frequency of G6PD-deficient Polymorphic G6PD variants males (%) # A_ (202A) Chatham Mediterranean ■ Taipei <0.5 £ 7.0-9.9 A- (968C) * Coimbra V Mahidol ■ Union

0.5-2.9 10.0-14.9 • Aures Cosenza # Santamaria #Viangchan

■ 3.0-6.9 ■ 15.0-126.0 ■ Canton Kaiping ■ Seattle • Local variant

Frequency of G6PD-deficient Polymorphic G6PD variants males (%) # A_ (202A) Chatham Mediterranean ■ Taipei <0.5 £ 7.0-9.9 A- (968C) * Coimbra V Mahidol ■ Union

0.5-2.9 10.0-14.9 • Aures Cosenza # Santamaria #Viangchan

■ 3.0-6.9 ■ 15.0-126.0 ■ Canton Kaiping ■ Seattle • Local variant

Epidemiology

G6PD deficiency is widely disseminated throughout Africa, the Mediterranean basin, the Middle East, South-East Asia, and indigenous populations of the Indian subcontinent. G6PD A- is common in Africa (it has a second mutation in the G6PD A- gene - see Figure 9.12), the Mediterranean variant in southern Italy, Sardinia and other places around the Mediterranean basin, and G6PD Canton in southern China. These variants are only the most common amongst many different mutations in these areas and throughout the rest of the affected world (Figure 9.13). This distribution of the deficiency equates with areas where Plasmodium falciparum malaria is common, and this is thought to be the evolutionary drive that produced such widespread polymorphisms (Figure 9.13). It has subsequently been confirmed that G6PD deficiency does indeed protect against lethal falciparum malaria, particularly in childhood, and this protection, especially in hyperendemic areas, more than outweighs the haematological problems associated with deficiency.

Clinical features

There are four main syndromes associated with G6PD deficiency. In all four syndromes, haemolysis is aggravated or promoted by exposure to oxidative stress through infection or ingestion of oxidative foods or drugs, but the clinical presentations differ. Age always modifies the clinical effects although not always as might be expected. The four syndromes are neonatal jaundice, favism, CNSHA and drug-induced haemolytic anaemia. The neonatal jaundice syndrome has been described in class I, II and III variants: favism in mainly, although not exclusively, class II, CNHSA in class I and the drug-induced haemolysis mainly class III. Although G6PD deficiency is most common in males, the prevalence of the gene in many parts of the world (Figure 9.13) means that female homozygotes are not uncommon, and heterozygous females are often susceptible to oxidat-ive stress because of the effects of X-inactivation and marked lyonization in leaving a significant population of deficient red cells.

Neonatal jaundice and G6PD deficiency in infancy Neonatal jaundice is a severe manifestation of G6PD deficiency and is a major source of potential morbidity from kernicterus. Most common variants have been associated with the syndrome, including the A- and Mediterranean variants. In parts of the world where the mutations are common, the deficiency is the most prevalent cause of neonatal jaundice. The jaundice probably starts in utero in the perinatal period, but the clinical problem becomes apparent only about the second or third day after birth. Between 10% and 50% of deficient infants are affected. Phototherapy or exchange transfusion may be required to prevent neurological sequelae. Anaemia is not a feature, and it is thought that this is a manifestation of liver enzyme deficiency, coupled perhaps to the physiological underdevelopment of neonatal liver function or the co-inheritance of UDP-glucuronyl transferase 1 deficiency of Gilbert's syndrome.

Acute haemolytic crises may occur in G6PD-deficient infants, usually through exposure to oxidative stress, including nitrites or nitrates in water or the ingestion of fava beans by the mother but, in some cases of severe acute haemolysis, even fatal, no cause has been obvious.

Favism

Favism is the term given to the G6PD syndrome when acute intravascular haemolysis may be precipitated by exposure to the broad bean Vicia fava. Fresh, dried or frozen beans or even exposure to pollen may precipitate the crisis. The offending agent is divicine, or its aglycone isouramil, which can produce free oxygen radicals on autoxidation. Divicine is not present in peas or beans of other types, which may be eaten without effect. The amount of haemolysis is dose related, which may explain the marked variation in susceptibility not only between children and adults, but also in the same individual at different times. There is variation in divicine content between different culti-vars; some fungi can break down the compound and the amount may vary in different seasonal environments. In children, acute haemolysis, sometimes life-threatening, is common, but renal failure is uncommon although there may be systemic symptoms of fever and loin pain. Renal failure occurs more often in adults, possibly because of comorbidity. Favism is usual in class II variants, for example Mediterranean and Canton, but may occur in others, including the African A- variant. Although fava beans give the syndrome its name, some other compounds with which affected individuals may come in contact can cause acute haemolysis, including topical henna and some of the pulses used to make up local sweetmeats.

In between attacks of favism or exposure to oxidizing substance, the blood count is normal, with no evidence of haemolysis. The coincidence of infection, which promotes the formation of hydrogen peroxide following the oxygen burst in neutrophils and macrophages, with ingestion of oxidizing substances, even mild ones such as chloramphenicol, may promote haemolysis even although the drug on its own does not.

Chronic non-spherocytic haemolytic anaemia Sporadic cases in virtually all populations of CNHSA are found with underlying G6PD deficiency. Many of the mutations that cause CNHSA occur on exon 10 and affect the formation of dimers or tetramers (Figures 9.11 and 9.12). The haemolysis is extravascular, although additional oxidative stress may provoke an acute intravascular episode.

Drug-induced acute haemolysis

The introduction of primaquine and its derivative pamaquine as antimalarials to replace quinine during the Pacific phase of the Second World War and the later Korean War revealed that a portion of men exposed, particularly in the black population, suffered from sever acute intravascular haemolysis. Intensive studies by Carson and others from the University of Chicago, working at the Statesville Penitentiary Malaria Project, finally identified the problem as G6PD deficiency and identified that young red cells and reticulocytes had sufficient activity to withstand the oxidative stress so that haemolysis lessened as the reticulocyte level rose. It became apparent that many other drugs could also produce haemolysis, but mostly fava beans did not. The common A- variant of Africa is the main example of class III mutations producing this type of haemolysis.

The haemolysis is dose related and may be self-limiting. Although it is important to recognize which drugs are likely to produce haemolysis (Table 9.3), it is also important to realize that the disease for which the drugs may be needed, for example falciparum malaria, may be fatal and the haemolysis is a lesser problem.

Laboratory diagnosis

The acute intravascular haemolysis raises the suspicion of G6PD deficiency. The blood film shows red cells with contracted Hb in 'ghost' membrane (Figure 9.14). Haemoglobinuria may be gross, producing almost black urine without red cells in the centrifuge deposit.

Several screening tests have been devised to identify G6PD deficiency in red blood cells. The most widely used tests have been the brilliant Cresyl blue decolorization test, the MetHb reduction test and an ultraviolet spot test. These tests can reliably distinguish between deficient or not deficient individuals, but are not reliably quantitative. Hemizygous deficient males and homozygous deficient females will be identified, the threshold being a G6PD activity of about 30% of normal.

If a screening test indicates deficiency or is doubtful, the ideal follow-up test for definitive diagnosis is quantification of G6PD activity by spectrophotometric assay. Standardized methods have been published. There are two clinical situations in which quantification is especially important. First, during a haemolytic attack, the oldest red cells (with the least G6PD activity) are destroyed selectively, and therefore the surviving red cells have a relatively higher (but still deficient) G6PD activity. This increases further as the reticulocyte response sets in over the

Table 9.3 Drugs to be avoided in G6PD deficiency*.

Antimalarials

Primaquine (can be given at reduced dosage, 15 mg daily or

45 mg twice weekly under survelliance) Pamaquine

Sulphonamides and sulphones Sulphanilamide Sulphapyridine Sulphadimidine Sulphacetamide (Albucid)

Salicylazosulphapyridine (Salazopyrin)

Dapsonef

Sulphoxonef

Glucosulphone sodium (Promin) Septrin

Other antibacterial compounds Nitrofurans Nitrofurantoin Furazolidone Nitrofurazone Nalidixic acid

Analgesics

Acetylsalicylic acid (aspirin); moderate doses can be used

Acetophenetidin (phenacetin); safe alternative, paracetamol

Antihelminthics P-Naphthol Stibophan Niridazole

Miscellaneous

Vitamin K analogues (1 mg menaphthone can be given to babies)

Naphthalene (mothballs^

Probenecid

Dimercaprol (BAL)

Methylene blue

Toluidine blue

*This list is compiled on the basis of data available for patients with the 'A-' variant of G6PD deficiency. It can be generally assumed to be applicable to patients from Africa and of African descent. For patients with the Mediterranean type of G6PD deficiency, with an unknown variant, or with CNSHA, the following should also be added: acetanilide, chloramphenicol, chloroquine (may be used under surveillance when required for prophylaxis or treatment of malaria), mepacrine, p-amino salicylic acid and thiazosulphone. Many other drugs may produce haemolysis in particular individuals.

fThese drugs may cause haemolysis in normal individuals if taken in large doses.

Haemolytic Anaemia

following days. During this time, a screening test might yield a false-normal result and, rarely, even a quantitative test might do so. In such cases, the best counsel is to repeat the test a couple of weeks later. Alternatively, the oldest remaining cells can be isolated by differential centrifugation and they can be shown to have a low G6PD activity. The diagnosis of heterozygous females can be especially difficult; in extreme cases, it can only be done by family studies. However, from the practical point of view, it must be borne in mind that the probability of clinically significant haemolysis in a heterozygote roughly correlates with the proportion of G6PD-deficient red cells in her blood. Therefore, if a normal level of G6PD activity is found in a heterozygote, she is unlikely to be at risk of G6PD-related haemolysis. In regions where G6PD has a high prevalence and the main variants are known, DNA analysis is the most effective way of identifying heterozygotes.

Management

Mostly, management is dictated by the symptoms and signs in

Table 9.4 Association between G6PD deficiency and jaundice in male newborns.

Groups of newborns

n

G6PD deficiency %

Normal

500

22.5

Mild jaundice (bilirubin 150-200)

38

45

Severe jaundice (bilirubin >230)

70

60

Admitted with kernicterus

20

78

Data collected in Ibadan, Nigeria. Bilirubin values in |lmol/L.

Data collected in Ibadan, Nigeria. Bilirubin values in |lmol/L.

the patient, although education in the avoidance of oxidizing substances is important (Table 9.3). In many populations, the condition is well known and the need for avoidance recognized. Neonatal jaundice may need urgent therapy to prevent neurological damage (Table 9.4). Extreme hyperbilirubinaemia can be prevented by administration of Sn-mesoporphyrin if the diagnosis is known at birth. Acute intravascular haemolysis may require transfusion but the anaemia is often self-limiting (Table 9.5). High fluid intake should be encouraged to prevent renal damage. CNSHA may be severe enough to warrant active treatment and splenectomy may be helpful.

cell, its main function is as an antioxidant. GSH is synthesized from glutamate, cysteine and glycine by the link reactions of two enzymes; y-glutamylcysteine synthetase and glutathione synthetase (Figure 9.10). GSH exerts its function in preserving thiol groups and reducing hydrogen peroxide and free oxygen radicals through reactions catalysed by the enzymes glutathione-S-transferase and glutathione peroxidase respectively. The oxidized glutathione (GSSG) is reduced back to GSH by the action of glutathione reductase, the hydrogen donor being NADPH (Figure 9.10). Failure to maintain the GSH level as a result of deficiency in the synthetic pathways or deficiency in the recycling process leads to chronic haemolytic anaemia and increased susceptibility to oxidative stress.

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