L.M., a previously healthy 5-year-old boy, presented to the emergency department febrile, pale, tachycardic, tachypneic, and minimally responsive; his physical examination was otherwise normal. The morning before presentation, he had been in good health, but during the afternoon, he had abdominal pain, headache, and fever; by late evening, he was tachypneic and incoherent. He had not ingested any medications or known toxins, and results of a urine toxicology screen were negative. Results of other laboratory tests showed massive nonimmune intravascular hemolysis and hemoglobinuria. After resuscitation, L.M. was admitted to the hospital; the hemolysis resolved without further intervention. L.M. was of Greek ethnicity; his parents were unaware of a family history of hemolysis, although his mother had some cousins in Europe with a “blood problem.” Further inquiry revealed that the morning before admission, L.M. had been eating fava beans from the garden while his mother was working in the yard. The physician explained to the parents that L.M. probably was deficient for glucose-6-phosphate dehydrogenase (G6PD) and that because of this, he had become ill after eating fava beans. Subsequent measurement of L.M.'s erythrocyte G6PD activity confirmed that he had G6PD deficiency. The parents were counseled concerning L.M.'s risk for acute hemolysis after exposure to certain drugs and toxins and given a list of compounds that L.M. should avoid.
L.M.，一名先前健康的 5 岁男孩，因发热、苍白、心动过速、呼吸急促和轻微反应而到急诊科就诊;他的体格检查结果正常。就诊前的早上，他的健康状况很好，但下午时，他出现了腹痛、头痛和发烧;到深夜，他出现呼吸急促和语无伦次。他没有摄入任何药物或已知的毒素，尿液毒理学筛查结果为阴性。其他实验室检查结果显示大量非免疫性血管内溶血和血红蛋白尿。复苏后，L.M. 被送入医院;溶血无需进一步干预即可消退。L.M. 是希腊人;他的父母不知道溶血家族史，尽管他的母亲在欧洲有一些表亲患有“血液问题”。进一步的调查显示，在入院前的早上，L.M. 一直在吃花园里的蚕豆，而他的母亲在院子里工作。医生向父母解释说，L.M. 可能缺乏葡萄糖-6-磷酸脱氢酶 （G6PD），因此，他在吃了蚕豆后生病了。随后对 LM 红细胞 G6PD 活性的测量证实他患有 G6PD 缺陷。父母被告知 LM 在暴露于某些药物和毒素后发生急性溶血的风险，并给出了 LM 应避免的化合物清单。

G6PD deficiency (MIM 305900), a hereditary predisposition to hemolysis, is an X-linked disorder of antioxidant homeostasis that is caused by mutations in the G6PD gene. In areas in which malaria is endemic, G6PD deficiency has a prevalence of $5\mathrm{\%}$$5\mathrm{\%}$5%5 \% to $25\mathrm{\%}$$25\mathrm{\%}$25%25 \%; in nonendemic areas, it has a prevalence of less than $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \% (Fig. C-19). Like sickle cell disease, G6PD deficiency appears to have reached a substantial frequency in some areas because it confers some resistance to malaria and thus a survival advantage to individuals heterozygous for G6PD deficiency (see Chapter 9).
G6PD 缺陷症 （MIM 305900） 是一种遗传性溶血易感性，是一种由 G6PD 基因突变引起的抗氧化稳态 X 连锁疾病。在疟疾流行的地区，G6PD 缺乏症的患病率为 $5\mathrm{\%}$$5\mathrm{\%}$5%5 \% ; $25\mathrm{\%}$$25\mathrm{\%}$25%25 \% 在非流行地区，它的患病率低于 $0.5\mathrm{\%}$$0.5\mathrm{\%}$0.5%0.5 \% （图 C-19）。与镰状细胞病一样，G6PD 缺陷似乎在某些地区达到了相当大的频率，因为它赋予了对疟疾的一些抵抗力，从而为 G6PD 缺陷杂合子个体提供了生存优势（见第 9 章）。

G6PD is the first enzyme in the hexose monophosphate shunt, a pathway critical for generating nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is required for the
G6PD 是己糖单磷酸分流中的第一种酶，是产生烟酰胺腺嘌呤二核苷酸磷酸 （NADPH） 的关键途径。NADPH 是必需的
regeneration of reduced glutathione. Within erythrocytes, reduced glutathione is used for the detoxification of oxidants produced by the interaction of hemoglobin and oxygen and by exogenous factors such as drugs, infection, and metabolic acidosis.
还原型谷胱甘肽的再生。在红细胞内，还原型谷胱甘肽用于解毒由血红蛋白和氧气相互作用以及药物、感染和代谢性酸中毒等外源性因素产生的氧化剂。

Most G6PD deficiency arises because mutations in the X-linked G6PD gene decrease the catalytic activity or the stability of G6PD, or both. When G6PD activity is sufficiently depleted or deficient, insufficient NADPH is available to regenerate reduced glutathione during times of oxidative stress. This results in the oxidation and aggregation of intracellular proteins (Heinz bodies) (see Fig. 11-8) and the formation of rigid erythrocytes that readily hemolyze.
大多数 G6PD 缺陷是由于 X 连锁 G6PD 基因突变降低 G6PD 的催化活性或稳定性，或两者兼而有之。当 G6PD 活性充分耗尽或不足时，在氧化应激期间，不足的 NADPH 可用于再生还原的谷胱甘肽。这导致细胞内蛋白质（Heinz 小体）的氧化和聚集（见图 11-8）并形成容易溶血的刚性红细胞。

With the more common G6PD alleles, which cause the protein to be unstable, deficiency of G6PD within erythrocytes worsens as erythrocytes age. Because erythrocytes do not have nuclei, new G6PD mRNA cannot be synthesized; thus erythrocytes are unable to replace G6PD as it is degraded. During exposure to an oxidative stress episode, therefore, hemolysis begins with the oldest erythrocytes and progressively involves younger erythrocytes, depending on the severity of the oxidative stress.
对于更常见的 G6PD 等位基因，导致蛋白质不稳定，红细胞内的 G6PD 缺乏症会随着红细胞年龄的增长而恶化。因为红细胞没有细胞核，所以不能合成新的 G6PD mRNA;因此红细胞无法替代 G6PD，因为它已经降解。因此，在暴露于氧化应激发作期间，溶血从最古老的红细胞开始，并逐渐累及较年轻的红细胞，具体取决于氧化应激的严重程度。

As an X-linked disorder, G6PD deficiency predominantly and most severely affects males. Rare symptomatic females have a skewing of X chromosome inactivation such that the X chromosome carrying the mutant G6PD allele is the active X chromosome in erythrocyte precursors (see Chapter 6).
作为一种 X 连锁疾病，G6PD 缺乏症主要且最严重地影响男性。罕见的有症状的女性具有 X 染色体失活的偏斜，因此携带突变 G6PD 等位基因的 X 染色体是红细胞前体中的活性 X 染色体（参见第 6 章）。

The severity of G6PD deficiency depends not only on sex, but also on the specific G6PD mutation. In general, the mutation common in the Mediterranean basin (i.e., G6PD B- or Mediterranean) tends to be more severe than those mutations common in Africa (i.e., G6PD A- variants) (see Fig. C-19). In erythrocytes of patients with the Mediterranean variant, G6PD activity decreases to insufficient levels 5 to 10 days after erythrocytes appear in the circulation, whereas in the erythrocytes of patients with the G6PD A- variants, G6PD activity decreases to insufficient levels 50 to 60 days after erythrocytes appear in the circulation. Therefore most erythrocytes are susceptible to hemolysis in patients with severe forms of G6PD deficiency, such as G6PD Mediterranean, but only 20% to $30\mathrm{\%}$$30\mathrm{\%}$30%30 \% are susceptible in patients with G6PD A- variants.
G6PD 缺乏症的严重程度不仅取决于性别，还取决于特定的 G6PD 突变。一般来说，地中海盆地常见的突变（即 G6PD B- 或地中海）往往比非洲常见的突变（即 G6PD A- 变体）更严重（见图 C-19）。在 Mediterranean 变异患者的红细胞中，G6PD 活性在红细胞出现在循环中后 5 至 10 天降低到不足的水平，而在 G6PD A- 变异患者的红细胞中，G6PD 活性在红细胞出现在循环中后 50 至 60 天降低到不足的水平。因此，大多数红细胞在严重 G6PD 缺乏症（如 G6PD Mediterranean）患者中易溶血，但在 G6PD A- 变异患者中只有 20% $30\mathrm{\%}$$30\mathrm{\%}$30%30 \% 易溶血。

G6PD deficiency most commonly manifests as either neonatal jaundice or acute hemolytic anemia. The peak incidence of neonatal jaundice occurs during days 2 and 3 of life. The severity of the jaundice ranges from subclinical to levels compatible with kernicterus; the associated anemia is rarely severe. Episodes of acute hemolytic anemia usually begin within hours of an oxidative stress and end when G6PD-deficient erythrocytes have hemolyzed; therefore, the severity of the anemia associated with these acute hemolytic episodes is proportionate to the deficiency of G6PD and the oxidative stress. Viral and bacterial infections are the most common triggers, but many drugs and toxins can also precipitate hemolysis. The disorder called favism results from hemolysis secondary to the ingestion of fava beans by patients with more severe forms of G6PD deficiency, such as G6PD Mediterranean; fava beans contain $\beta$$\beta$beta\beta-glycosides, naturally occurring oxidants.
G6PD 缺乏症最常表现为新生儿黄疸或急性溶血性贫血。新生儿黄疸的发病率高峰发生在出生后第 2 天和第 3 天。黄疸的严重程度从亚临床到与核黄疸相符的水平不等;相关的贫血很少严重。急性溶血性贫血的发作通常在氧化应激后数小时内开始，并在 G6PD 缺陷红细胞溶血时结束;因此，与这些急性溶血发作相关的贫血的严重程度与 G6PD 缺乏和氧化应激成正比。病毒和细菌感染是最常见的诱因，但许多药物和毒素也可诱发溶血。这种称为 favism 的疾病是由于患有更严重的 G6PD 缺乏症（例如 G6PD Mediterranean）的患者摄入蚕豆后继发的溶血引起的;蚕豆含有 $\beta$$\beta$beta\beta -glyco苷，即天然存在的氧化剂。

Figure C-19 World distribution of G6PD
图 C-19 G6PD 的全球分布
deficiency. The frequencies of G6PD-deficient males in the various countries are also the allele frequencies because the gene is X-linked. See Sources & Acknowledgments.
缺乏。各国 G6PD 缺陷男性的频率也是等位基因频率，因为该基因是 X 连锁的。参见来源和致谢。

In addition to neonatal jaundice and acute hemolytic anemia, G6PD deficiency rarely causes congenital or chronic nonspherocytic hemolytic anemia. Patients with chronic nonspherocytic hemolytic anemia generally have a profound deficiency of G6PD that causes chronic anemia and an increased susceptibility to infection. The susceptibility to infection arises because the NADPH supply within granulocytes is inadequate to sustain the oxidative burst necessary for killing phagocytosed bacteria.
除了新生儿黄疸和急性溶血性贫血外，G6PD 缺乏很少引起先天性或慢性非球形红细胞溶血性贫血。慢性非球形红细胞溶血性贫血患者通常存在严重的 G6PD 缺乏症，导致慢性贫血和感染易感性增加。对感染的易感性是由于粒细胞内的 NADPH 供应不足以维持杀死吞噬细菌所需的氧化爆发。

G6PD deficiency should be suspected in patients of African, Mediterranean, or Asian ancestry who present with either an acute hemolytic episode or neonatal jaundice. G6PD deficiency is diagnosed by measurement of G6PD activity in erythrocytes; this activity should be measured only when the patient has had neither a recent transfusion nor a recent hemolytic episode. (Because G6PD deficiency occurs primarily in older erythrocytes, measurement of G6PD activity in the predominantly young erythrocytes present during or immediately after a hemolytic episode often gives a false-negative result.)
对于非洲、地中海或亚洲血统的患者，如果出现急性溶血发作或新生儿黄疸，应怀疑 G6PD 缺乏症。G6PD 缺乏症是通过测量红细胞中的 G6PD 活性来诊断的;只有当患者近期没有输血或近期溶血发作时，才应测量这种活动。（由于 G6PD 缺乏症主要发生在老年红细胞中，因此在溶血发作期间或之后立即测量主要年轻的红细胞的 G6PD 活性通常会给出假阴性结果。

The key to management of G6PD deficiency is prevention of hemolysis by prompt treatment of infections and avoidance of oxidant drugs (e.g., sulfonamides, sulfones, nitrofurans) and toxins (e.g., naphthalene). Although most patients with a hemolytic episode will not require medical intervention, those with severe anemia and hemolysis may require resuscitation and erythrocyte transfusions. Patients presenting with neonatal jaundice respond well to the same therapies as for other infants with neonatal jaundice (hydration, light therapy, and exchange transfusions).
管理 G6PD 缺乏症的关键是通过及时治疗感染和避免使用氧化剂药物（例如磺胺类、砜类、硝基呋喃类）和毒素（例如萘）来预防溶血。虽然大多数溶血发作的患者不需要医疗干预，但严重贫血和溶血的患者可能需要复苏和红细胞输注。新生儿黄疸患者对与其他新生儿黄疸婴儿相同的治疗（补液、光疗和换血疗法）反应良好。

Each son of a mother carrying a G6PD mutation has a 50% chance of being affected, and each daughter has a $50\mathrm{\%}$$50\mathrm{\%}$50%50 \% chance of being a carrier. Each daughter of an affected father will be a carrier, but each son will be unaffected because an affected father does not contribute an X chromosome to his sons. The risk that carrier daughters will have clinically significant symptoms is low because sufficient skewing of X chromosome inactivation is relatively uncommon.
携带 G6PD 突变的母亲的每个儿子都有 50% 的机会受到影响，每个女儿都有 $50\mathrm{\%}$$50\mathrm{\%}$50%50 \% 机会成为携带者。受影响父亲的每个女儿都是携带者，但每个儿子都不会受到影响，因为受影响的父亲不会给儿子提供 X 染色体。携带女儿出现临床显着症状的风险很低，因为 X 染色体失活的充分偏斜相对不常见。

Bunn HF: The triumph of good over evil: protection by the sickle gene against malaria, Blood 121:20-25, 2013.
Bunn HF：正义战胜邪恶：镰刀基因对疟疾的保护，血液 121：20-25,2013 年。
Howes RE, Battle KE, Satyagraha AW, et al: G6PD deficiency: global distribution, genetic variants and primaquine therapy, Adv Parasitol 81:133-201, 2013.
Howes RE、Battle KE、Satyagraha AW 等：G6PD 缺陷：全球分布、遗传变异和伯氨喹疗法，Adv Parasitol 81：133-201,2013 年。
Luzzatto L, Seneca E: G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications, Br J Haematol 164:469-480, 2014.
Luzzatto L，Seneca E：G6PD 缺陷：具有持续临床意义的药物遗传学的经典例子，Br J Haematol 164：469-480,2014 年。