Zieve's syndrome

Zieve syndrome is an acute alcohol-related metabolic disorder defined by the triad of haemolytic anaemia with spur cells, hyperlipoproteinaemia and jaundice, and abdominal pain is a frequent accompanying feature.Zieve 综合征是一种与酒精相关的急性代谢性疾病，以伴棘形红细胞的溶血性贫血、高脂蛋白血症与黄疸三联征为定义，腹痛是常见的伴随表现。

The syndrome arises during sustained heavy drinking or alcohol withdrawal and usually resolves within weeks of abstinence, which distinguishes it from progressive forms of alcoholic liver disease.该综合征在持续大量饮酒或酒精戒断期间发生，通常在戒酒后数周内缓解，这使其区别于进展型酒精性肝病。

Leslie Zieve first described the combination in 1958, and although the eponym is widely recognised, the disorder remains uncommon in clinical series and is probably underdiagnosed.Leslie Zieve 于 1958 年首次描述这一组合，尽管人名名称已被广泛认识，该病在临床系列中仍不常见，且很可能被低估诊断。

Terminology and classification

• The condition is known as Zieve syndrome or Zieve's syndrome, and the possessive form is conventional in English-language case reports even though most eponyms are now written without an apostrophe.本病称为 Zieve 综合征，英文病例报告中惯用所有格形式，尽管多数人名名称如今已不再加撇号。
• ICD-10 has no dedicated code and assigns the episode to K70.0, alcoholic fatty liver, while ICD-11 likewise provides no disease-specific stem and places it within the DB94 alcoholic liver disease block.ICD-10 没有专属编码，将该次发作归入 K70.0 酒精性脂肪肝，ICD-11 同样没有病种专属类目，而将其置于 DB94 酒精性肝病区块内。
• UMLS assigns C0267805 and Wikidata records the entity as Q199295, whereas MeSH, MONDO and Orphanet do not maintain a dedicated entry for the syndrome.UMLS 赋予 C0267805，Wikidata 记录为 Q199295，而 MeSH、MONDO 与 Orphanet 均未为该综合征单列条目。
• Zieve syndrome is classified as an acute, reversible alcohol-related disorder rather than a distinct chronic liver disease, and it may coexist with alcoholic hepatitis or steatohepatitis in the same admission.Zieve 综合征被归类为急性、可逆的酒精相关疾病，而非独立的慢性肝病，并可在同一次住院中与酒精性肝炎或脂肪性肝炎并存。
• The defining triad combines intravascular haemolysis, transient hypertriglyceridaemia and unconjugated hyperbilirubinaemia, and no single laboratory value is pathognomonic.定义性三联征包括血管内溶血、一过性高甘油三酯血症与非结合型高胆红素血症，没有任何单项实验室指标具有确诊特异性。
• Because the syndrome is not separately coded, epidemiological and outcome studies rely on case reports and small retrospective series rather than administrative datasets.由于该综合征未被单独编码，流行病学与结局研究只能依赖病例报告与小样本回顾性系列，而无法使用行政数据集。

History

• In 1958 Leslie Zieve described patients with alcoholic fatty liver or cirrhosis who developed jaundice, hyperlipaemia and haemolytic anaemia, and he proposed that this combination represented a previously unrecognised syndrome.1958 年 Leslie Zieve 描述了在酒精性脂肪肝或肝硬化基础上出现黄疸、高脂血症与溶血性贫血的患者，并提出这一组合是一种此前未被认识的综合征。^[1]
• The original report established the triad that still defines the disorder, and the eponym Zieve syndrome subsequently entered textbooks and case reports.原始报告确立了至今仍用于定义该病的三联征，Zieve 综合征这一人名名称随后进入教科书与病例报告。
• For decades the literature consisted almost entirely of isolated case reports, and a 2023 review could identify only 31 documented cases with enough clinical detail for analysis.数十年来文献几乎全部为孤立病例报告，2023 年一篇综述仅能识别出 31 例具备足够临床细节可供分析的已记录病例。^[2]
• Early pathogenetic work focused on red-cell metabolism, and the description of pyruvate kinase instability and lysolecithin-mediated haemolysis shaped later hypotheses.早期发病机制研究集中于红细胞代谢，丙酮酸激酶不稳定与溶血卵磷脂介导溶血的描述塑造了后来的假说。
• Recognition of acanthocytes and other spur cells on the peripheral smear became a practical clue, although these cells are not specific to Zieve syndrome.外周血涂片识别棘形红细胞及其他棘细胞成为实用的线索，尽管这些细胞对 Zieve 综合征并不特异。
• Modern case reports have added atypical presentations, including a patient with a normal reticulocyte count attributed to alcohol-induced marrow suppression, which broadened the recognised phenotype.现代病例报告补充了非典型表现，包括一例因酒精抑制骨髓而网织红细胞计数正常的患者，从而拓宽了对表型的认识。

Epidemiology

• The incidence and prevalence of Zieve syndrome are unknown because it is rarely coded and often mistaken for alcoholic hepatitis, and the largest available review identified only 31 published cases by 2023.Zieve 综合征的发病率与患病率未知，因为它很少被编码且常被误认为酒精性肝炎，截至 2023 年最大规模的综述仅识别出 31 例已发表病例。
• Reported cases occur in adults with chronic heavy alcohol use, and the episode is often precipitated by a binge or by abrupt withdrawal.已报告病例见于长期大量饮酒的成人，发作常由暴饮或突然戒断诱发。
• Both sexes are affected and the age range is broad, but the small number of cases prevents reliable estimates of sex ratio or age-specific incidence.男女均可受累且年龄跨度较大，但病例数过少，无法可靠估计性别比或年龄别发病率。
• No geographic, ethnic or occupational cluster has been documented, which is consistent with a disorder driven by alcohol exposure rather than by population genetics.尚无地理、种族或职业聚集的报道，这与该病由酒精暴露而非人群遗传驱动的特点相符。
• Under-recognition is likely because the triad is transient, because hyperlipidaemia may be attributed to fasting or pancreatitis, and because mild haemolysis can be overlooked.漏诊可能源于三联征为一过性、高脂血症可被归因于禁食或胰腺炎，以及轻度溶血容易被忽视。
• WHO estimates that about 400 million people, roughly 7 percent of adults, live with alcohol use disorders, yet only 31 Zieve cases had been published by 2023, fewer than one per year since 1958, a gap that points to under-recognition rather than extreme rarity alone.世界卫生组织估计约 4 亿人（约占成人 7%）患有酒精使用障碍，而截至 2023 年仅有 31 例 Zieve 综合征发表，自 1958 年以来平均每年不足一例，这一差距提示漏诊而非仅由极端罕见所致。
• No national or global surveillance system captures the syndrome, so GBD and WHO alcohol estimates cannot be used to derive its burden, and indexed case reports remain the main data source.没有任何国家或全球监测系统收录该综合征，因此无法用全球疾病负担与世卫组织酒精估计推算其负担，索引病例报告仍是主要数据来源。
• Mortality is low in published cases when alcohol is stopped, but severe hypertriglyceridaemia can complicate the course with acute pancreatitis or intracerebral haemorrhage.已发表病例在戒酒后死亡率较低，但严重高甘油三酯血症可并发急性胰腺炎或脑出血而使病程复杂化。

Pathophysiology

• The anaemia is haemolytic and Coombs-negative, with a falling haemoglobin, raised lactate dehydrogenase, low haptoglobin and indirect hyperbilirubinaemia indicating red-cell destruction.贫血为溶血性且 Coombs 试验阴性，血红蛋白下降、乳酸脱氢酶升高、触珠蛋白降低与非结合型高胆红素血症提示红细胞破坏。
• Peripheral blood contains acanthocytes and other spur cells, whose distorted membranes reflect altered lipid composition and increased membrane cholesterol during the haemolytic phase.外周血可见棘形红细胞及其他棘细胞，其变形膜反映溶血期膜脂组成改变与膜胆固醇增加。
• One proposed mechanism is instability of red-cell pyruvate kinase, which leaves cells vulnerable to circulating haemolysins such as lysolecithin generated during acute alcohol exposure.一种假说认为红细胞丙酮酸激酶不稳定，使细胞易受急性酒精暴露期间产生的溶血卵磷脂等循环溶血素攻击。
• The hyperlipidaemia is predominantly hypertriglyceridaemia and is thought to reflect increased hepatic very-low-density lipoprotein output together with impaired peripheral clearance during heavy drinking.高脂血症以高甘油三酯血症为主，被认为反映大量饮酒期间肝脏极低密度脂蛋白输出增加与外周清除受损。
• Jaundice results from both haemolysis and transient hepatocellular dysfunction, so bilirubin is predominantly unconjugated but may be mixed when alcoholic hepatitis coexists.黄疸既源于溶血也源于一过性肝细胞功能障碍，因此胆红素以非结合型为主，但与酒精性肝炎并存时可为混合型。
• Abdominal pain is usually attributed to acute hepatic distension from steatosis and oedema, and it should not be assumed to indicate pancreatitis without biochemical and imaging assessment.腹痛通常归因于脂肪变与水肿导致的急性肝包膜牵张，但不应在缺乏生化与影像评估时假定为胰腺炎。
• The syndrome is transient because alcohol removal restores red-cell membrane stability, hepatic lipid handling and bilirubin conjugation, and persistent abnormalities suggest another diagnosis.该综合征呈一过性，因为去除酒精后可恢复红细胞膜稳定性、肝脏脂质处理与胆红素结合，而持续异常提示其他诊断。

Clinical features

• Jaundice is usually the most visible feature and develops over days, often with dark urine and pale stools when cholestasis is also present.黄疸通常是最显著的表现，数日内出现，合并胆汁淤积时可伴尿色加深与大便变浅。
• Anaemia produces pallor, fatigue, exertional dyspnoea and tachycardia, and the degree is variable, ranging from mild to severe enough to require transfusion.贫血引起苍白、乏力、活动后气促与心动过速，程度不一，可从轻度到需输血的重度。
• Abdominal pain is commonly right upper quadrant or epigastric, may radiate to the back and is frequently accompanied by nausea, anorexia and tender hepatomegaly.腹痛多位于右上腹或上腹，可向背部放射，常伴恶心、食欲减退与肝区压痛及肝大。
• Some patients present with fever, tachycardia and leukocytosis, which can mimic infection or pancreatitis and delay recognition of the syndrome.部分患者出现发热、心动过速与白细胞增多，可模拟感染或胰腺炎并延误对该综合征的识别。
• The hyperlipidaemia is often asymptomatic, but extreme triglyceride elevation can produce lipaemic serum, eruptive xanthomas or lipaemia retinalis.高脂血症常无症状，但甘油三酯极度升高可产生脂血血清、发疹性黄瘤或视网膜脂血症。
• Severe hypertriglyceridaemia predisposes to acute pancreatitis and, in rare reports, to intracerebral haemorrhage, which are the main life-threatening complications.严重高甘油三酯血症易诱发急性胰腺炎，罕见报道还可引起脑出血，这些是主要的危及生命并发症。
• Neurological features of alcohol misuse, such as tremor, confusion or withdrawal seizures, may dominate the presentation and distract from the haematological and hepatic triad.酒精滥用的神经系统表现，如震颤、意识模糊或戒断性抽搐，可能主导临床表现并掩盖血液学与肝脏三联征。
• A normal reticulocyte count does not exclude the diagnosis, because alcohol can suppress erythropoiesis and blunt the expected marrow response.网织红细胞计数正常不能排除诊断，因为酒精可抑制红细胞生成并削弱预期的骨髓反应。

Diagnosis

• Diagnosis requires the triad of haemolytic anaemia, hyperlipidaemia and jaundice in a patient with recent heavy alcohol use, together with exclusion of other causes of each component.诊断要求在近期大量饮酒者中同时具备溶血性贫血、高脂血症与黄疸三联征，并排除各组成部分的其他病因。
• The blood count typically shows anaemia with reticulocytosis, and the peripheral smear should be examined specifically for acanthocytes and spur cells.血常规通常显示贫血伴网织红细胞增多，外周血涂片应专门寻找棘形红细胞与棘细胞。
• Haemolysis is supported by raised lactate dehydrogenase, low haptoglobin and indirect hyperbilirubinaemia, and a negative direct antiglobulin test separates it from autoimmune haemolysis.溶血可由乳酸脱氢酶升高、触珠蛋白降低与非结合型高胆红素血症支持，直接抗人球蛋白试验阴性可与自身免疫性溶血鉴别。
• Lipid testing usually reveals marked hypertriglyceridaemia, and the sample may be lipaemic, although the lipid abnormality can resolve quickly after alcohol cessation.血脂检查通常显示明显高甘油三酯血症，标本可呈脂血状，但戒酒后脂质异常可迅速缓解。
• Liver tests show non-specific abnormalities such as raised aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase, and macrocytosis is a common haematological clue to alcohol excess.肝功能检查显示天冬氨酸氨基转移酶、丙氨酸氨基转移酶与 γ-谷氨酰转移酶升高等非特异异常，大细胞增多是酒精过量的常见血液学线索。
• Abdominal ultrasound or computed tomography is used to demonstrate steatosis, assess the biliary tree and pancreas, and exclude obstruction or a pancreatic collection.腹部超声或计算机断层扫描用于显示脂肪变、评估胆道与胰腺，并排除梗阻或胰周积液。
• Reticulocytosis above about 2 percent and triglyceride concentrations above 11.3 millimoles per litre, equivalent to 1,000 milligrams per decilitre, are useful severity anchors, the latter marking a threshold at which pancreatitis risk rises steeply.网织红细胞高于约 2% 与甘油三酯高于 11.3 毫摩尔/升（相当于 1,000 毫克/分升）是有用的严重度锚点，后者标志胰腺炎风险陡增的阈值。
• The differential diagnosis includes alcoholic hepatitis, acute pancreatitis, G6PD deficiency, autoimmune haemolytic anaemia, Wilson disease, sepsis and drug-induced haemolysis.鉴别诊断包括酒精性肝炎、急性胰腺炎、G6PD 缺乏症、自身免疫性溶血性贫血、Wilson 病、脓毒症与药物性溶血。
• When the diagnosis remains uncertain, serial haemoglobin, bilirubin, triglycerides and liver enzymes after abstinence can confirm the characteristic rapid reversal.当诊断仍不明确时，戒酒后连续监测血红蛋白、胆红素、甘油三酯与肝酶可证实其特征性的快速逆转。

Management

• Definitive treatment is complete and sustained alcohol cessation, and the haematological and lipid abnormalities usually improve within days to weeks.确定性治疗是完全且持续地戒酒，血液学与脂质异常通常在天至数周内改善。
• Acute alcohol withdrawal should be managed with a structured protocol, including thiamine before glucose, folate, multivitamins and correction of magnesium, phosphate and potassium.急性酒精戒断应按规范流程处理，包括葡萄糖之前给予硫胺素、补充叶酸与多种维生素，并纠正镁、磷与钾。
• Nutritional support with adequate protein and calories is important, and enteral feeding should be preferred when oral intake is poor.提供足量蛋白质与热量的营养支持很重要，经口摄入不足时应优先考虑肠内营养。
• Severe hypertriglyceridaemia is managed with fasting as appropriate, insulin infusion or apheresis, and plasmapheresis has been used when triglycerides are extreme or complications are present.严重高甘油三酯血症可酌情禁食、使用胰岛素输注或血液分离，甘油三酯极高或出现并发症时可采用血浆置换。
• Plasmapheresis is reserved for patients with markedly elevated triglycerides, particularly those with a history of pancreatitis or intracerebral haemorrhage, to prevent further complications.血浆置换保留给甘油三酯显著升高者，尤其是有胰腺炎或脑出血病史者，以预防进一步并发症。
• Corticosteroids have been reported in an isolated case, but they are not established therapy and should not replace alcohol cessation or standard supportive care.糖皮质激素仅见个别病例报告，并非既定治疗，不应取代戒酒或标准支持治疗。
• The EASL 2018 clinical practice guidelines on alcohol-related liver disease recommend abstinence, nutritional support and structured withdrawal management, and they acknowledge that evidence specific to Zieve syndrome is limited to case reports.欧洲肝病学会 2018 年酒精相关肝病临床实践指南推荐戒酒、营养支持与规范的戒断管理，并承认针对 Zieve 综合征的证据仅限于病例报告。
• In reported cases jaundice and haemolysis improve within 7 to 21 days of abstinence and triglycerides fall over a similar period, whereas recurrence follows resumption of drinking.在已报告病例中，黄疸与溶血在戒酒后 7 至 21 天内改善，甘油三酯也在相近时间内下降，而重新饮酒则导致复发。
• Patients need monitoring for pancreatitis, hepatic decompensation, severe anaemia and electrolyte disturbances, with transfusion for symptomatic anaemia and imaging for suspected pancreatitis.患者需监测胰腺炎、肝功能失代偿、重度贫血与电解质紊乱，症状性贫血给予输血，怀疑胰腺炎时行影像检查。
• With abstinence, prognosis is generally good and recurrence is related to resumed drinking, whereas continued alcohol use risks recurrent haemolysis, pancreatitis and progression of underlying liver disease.戒酒后预后通常良好，复发与重新饮酒相关，而继续饮酒则有反复溶血、胰腺炎与基础肝病进展的风险。

Research and controversies

• The 2023 literature review of 31 cases highlighted how little is known about incidence, risk factors and long-term outcomes, and called for prospective registries rather than further isolated reports.2023 年对 31 例的文献综述凸显了对发病率、危险因素与长期结局的认识不足，并呼吁建立前瞻性登记而非继续发表孤立报告。
• The relative contributions of pyruvate kinase instability, membrane lipid changes and circulating haemolysins remain unresolved, and no animal model reproduces the full triad.丙酮酸激酶不稳定、膜脂改变与循环溶血素各自的相对贡献仍未阐明，也没有动物模型能复制完整三联征。
• Whether Zieve syndrome is a distinct entity or an extreme presentation of alcoholic hepatitis with haemolysis is debated, because the two conditions frequently coexist and share risk factors.Zieve 综合征是独立疾病还是酒精性肝炎伴溶血的极端表现仍有争议，因为两者常并存并共享危险因素。
• There are no randomised trials of plasmapheresis, corticosteroids or other therapies, and management recommendations are extrapolated from case series and from the treatment of severe hypertriglyceridaemia.尚无血浆置换、糖皮质激素或其他治疗的随机试验，管理建议来自病例系列及重度高甘油三酯血症的治疗经验。
• Triglyceride-lowering antisense and RNA-targeted agents such as volanesorsen and olezarsen are approved or in late development for familial chylomicronaemia syndrome and are plausible future options for extreme alcohol-related hypertriglyceridaemia, although neither has been tested in Zieve syndrome.Volanesorsen 与 olezarsen 等反义寡核苷酸及 RNA 靶向降甘油三酯药物已获批或处于后期开发阶段用于家族性乳糜微粒血症综合征，可能是极端酒精相关高甘油三酯血症的未来选择，但均未在 Zieve 综合征中试验。
• Better biomarkers of alcohol-related haemolysis and standardised acanthocyte counting could improve recognition, while alcohol-control policies remain the most effective population-level prevention.更好的酒精相关溶血生物标志物与标准化的棘形红细胞计数可提高识别率，而酒精控制政策仍是最有效的人群预防措施。