Angiolathyrism

Angiolathyrism is the vascular form of lathyrism, a group of disorders caused by prolonged consumption of seeds of the genus Lathyrus, and it is characterised by weakening of blood vessel walls.血管性山黧豆中毒是山黧豆中毒的血管型，后者由长期食用山黧豆属种子所致，其特点是血管壁变弱。

It is the rarest of the three forms, the others being neurolathyrism with spastic paraparesis and osteolathyrism with skeletal deformity, and human cases are far less well documented than the animal model.它是三种类型中最罕见的一种，其余两型为伴痉挛性截瘫的神经型山黧豆中毒与伴骨骼畸形的骨型山黧豆中毒，其人类病例的文献记录远不如动物模型充分。

Terminology and classification

• The term lathyrism derives from the genus name Lathyrus, and the three recognised forms are neurolathyrism, osteolathyrism and angiolathyrism, classified by the tissue predominantly affected.山黧豆中毒一词源自属名（Lathyrus），按主要受累组织分为神经型、骨型与血管型三种。
• Angiolathyrism affects the blood vessels, especially the tunica media of the aorta and large arteries, and spares the nervous system and skeleton relative to the other forms.血管型山黧豆中毒累及血管，尤其是主动脉与大动脉的中膜，相对其他两型较少累及神经系统与骨骼。
• The responsible toxin is beta-aminopropionitrile and related aminonitriles, whereas neurolathyrism is attributed mainly to beta-N-oxalylamino-L-alanine, known as ODAP.致病毒素为 β-氨基丙腈（β-aminopropionitrile）及相关氨基腈，而神经型主要归因于 β-N-草酰氨基-L-丙氨酸，即 ODAP。
• The grasses implicated include Lathyrus sativus, the grass pea, and to a lesser degree Lathyrus cicera, Lathyrus ochrus and Lathyrus clymenum.相关豆类包括山黧豆（Lathyrus sativus，即草豌豆），其次为（Lathyrus cicera）、（Lathyrus ochrus）与（Lathyrus clymenum）。
• Angiolathyrism is not a congenital connective tissue disorder, although its vascular lesions resemble those of Marfan syndrome and other heritable aortopathies.血管型山黧豆中毒不是先天性结缔组织病，尽管其血管病变类似马方综合征与其他遗传性主动脉病。
• In the International Classification of Diseases tenth revision the toxic effect of plants eaten as food is coded T62.2, and ICD-11 places such harmful exposures in category NE61.在国际疾病分类第十版中，食用植物所致毒性效应编码为 T62.2，ICD-11 将此类有害暴露置于 NE61 类目。
• The condition has no entry in MONDO or Orphanet, because it is a toxic nutritional disorder rather than a Mendelian disease, and it is usually indexed under lathyrism as a whole.该病在 MONDO 与 Orphanet 中无条目，因为它属于中毒性营养障碍而非孟德尔遗传病，通常整体归入山黧豆中毒。

History

• Lathyrism has been recognised since antiquity, and epidemics have repeatedly followed drought and famine when grass pea became the only available staple.山黧豆中毒自古即被认识，干旱与饥荒使草豌豆成为唯一可用主食时，疫情反复出现。
• A large epidemic occurred in Spain in the 1870s and was described by the physician Azañón, and the episode is still cited as Azañón disease in the Spanish literature.十九世纪七十年代西班牙发生大规模流行，由医生 Azañón 描述，该事件在西班牙文献中仍被称为 Azañón 病。^[1]
• Outbreaks were reported in central India in the 1960s and 1970s, particularly in Madhya Pradesh, Uttar Pradesh and Bihar, and they established the clinical picture of neurolathyrism.二十世纪六十与七十年代印度中部报告暴发，尤其在中央邦、北方邦与比哈尔邦，确立了神经型山黧豆中毒的临床图景。
• In 1954 Ponseti and Shepard produced skeletal and connective tissue lesions in rats fed sweet pea seeds, which defined osteolathyrism and focused attention on collagen cross-linking.1954 年 Ponseti 与 Shepard 给大鼠喂饲香豌豆种子，造成骨骼与结缔组织病变，从而定义骨型山黧豆中毒并把注意力引向胶原交联。
• Hosoda and colleagues described experimental angiolathyrism in a series of papers, and in 1968 they reported lesions of the vasa vasorum in dissecting aortic aneurysm produced by the lathyrogen.Hosoda 及其同事在一系列论文中描述实验性血管型山黧豆中毒，并于 1968 年报告致山黧豆素所致夹层主动脉瘤中滋养血管的病变。^[2]
• The toxic aminonitrile beta-aminopropionitrile was identified in the 1950s as the factor that inhibits lysyl oxidase and prevents normal collagen and elastin cross-linking.二十世纪五十年代确定毒性氨基腈 β-氨基丙腈为抑制赖氨酰氧化酶、阻止胶原与弹性蛋白正常交联的因子。
• Reviews published in 2016 and 2019 consolidated the history, epidemiology and mechanisms of the lathyrisms and emphasised that angiolathyrism is largely an experimental entity.2016 年与 2019 年发表的综述整合了各型山黧豆中毒的历史、流行病学与机制，并强调血管型在很大程度上属于实验性实体。^[3]
• A historical study published in 2009 documented how Spanish physicians described lathyrism in the years after the civil war, showing that epidemics continued well into the twentieth century.2009 年发表的一项历史研究记录了西班牙医生在内战后数年间如何描述山黧豆中毒，表明流行一直延续到二十世纪。^[4]

Epidemiology

• Lathyrism remains endemic in parts of Ethiopia, Bangladesh, India and Nepal, where grass pea is an important subsistence crop during drought.山黧豆中毒在埃塞俄比亚、孟加拉国、印度与尼泊尔部分地区仍呈地方性流行，当地草豌豆是干旱期重要的自给作物。
• Neurolathyrism is the form that dominates epidemiological surveys, and estimates of affected people run into tens of thousands in the worst-affected regions.神经型是流行病学调查中占主导的类型，在受影响最重的地区受累人数估计达数万。
• Angiolathyrism has no reliable population incidence, and human cases are sporadic and poorly documented, so its true frequency is unknown.血管型没有可靠的人群发病率，人类病例散在且记录不足，真实频率不明。
• Risk rises when grass pea forms more than a third of the diet for several months, especially during famine and when other pulses are unavailable.当草豌豆连续数月占膳食三分之一以上时风险升高，饥荒与其他豆类不可得时尤为突出。
• Animal studies show that young, growing animals are more susceptible to aortic lesions, which raises concern about exposure in childhood and adolescence.动物研究显示幼年生长中的动物更易发生主动脉病变，这引起对儿童与青少年期暴露的担忧。
• Male predominance is reported in neurolathyrism in some surveys, probably because of differences in food allocation and outdoor labour rather than a biological sex effect.部分调查报告神经型存在男性优势，可能源于食物分配与户外劳动的差异而非生物学性别效应。
• Global trade and food diversification have reduced exposure in high-income countries, but grass pea remains a famine food and a reservoir of risk in low-resource settings.全球贸易与食物多样化降低了高收入国家的暴露，但草豌豆仍是饥荒食物与资源匮乏地区的风险来源。

Pathophysiology

• Beta-aminopropionitrile inhibits lysyl oxidase, the copper-dependent enzyme that oxidises lysine residues so that collagen and elastin can form covalent cross-links.β-氨基丙腈抑制赖氨酰氧化酶，后者是依赖铜的酶，氧化赖氨酸残基以使胶原与弹性蛋白形成共价交联。
• Without cross-linking, newly synthesised collagen and elastin fibres are mechanically weak, and the tunica media of large arteries loses tensile strength.缺乏交联时新合成的胶原与弹性蛋白纤维力学强度不足，大动脉中膜丧失抗张强度。
• The weakened media undergoes cystic medial necrosis, with loss of smooth muscle cells, fragmentation of elastic lamellae and accumulation of basophilic ground substance.变弱的中膜发生囊性中膜坏死，表现为平滑肌细胞丢失、弹性板层断裂与嗜碱性基质积聚。
• These changes resemble those of Marfan syndrome, and the vessel may dilate, form an aneurysm or dissect under normal blood pressure.这些改变类似马方综合征，血管可在正常血压下扩张、形成动脉瘤或发生夹层。
• Hosoda's experiments showed that the vasa vasorum are also involved, and impairment of the small vessels supplying the media may aggravate ischaemic injury of the aortic wall.Hosoda 的实验显示滋养血管亦受累，供应中膜的小血管受损可加重主动脉壁的缺血性损伤。
• ODAP, the toxin of neurolathyrism, acts as an excitatory amino acid agonist at AMPA receptors and causes motor neuron degeneration, but it is not responsible for the vascular lesions.神经型的毒素 ODAP 作为兴奋性氨基酸激动剂作用于 AMPA 受体并引起运动神经元变性，但它不导致血管病变。
• In 2011 Nunn and colleagues proposed that depletion of brain glutathione contributes to the vulnerability of motor neurons in neurolathyrism, a mechanism distinct from the vascular toxicity of aminonitriles.2011 年 Nunn 及其同事提出脑内谷胱甘肽耗竭增加神经型山黧豆中毒中运动神经元的易感性，这一机制有别于氨基腈的血管毒性。^[5]
• In 2017 Xu and colleagues reviewed how nitrogen and sulfur metabolism determines the ODAP content of Lathyrus sativus, which is central to breeding safer varieties.2017 年 Xu 及其同事综述了氮与硫代谢如何决定山黧豆中 ODAP 含量，这对培育更安全的品种至关重要。^[6]
• The cross-linking defect affects all connective tissues, so skin, bone, cartilage and tendon may also show abnormal mechanical properties in experimental animals.交联缺陷累及所有结缔组织，因此实验动物的皮肤、骨、软骨与肌腱也可表现力学性能异常。
• Because mature cross-linked tissue turns over slowly, the vascular weakness may persist long after exposure ceases, which distinguishes it from acute toxic injuries.由于成熟的交联组织更新缓慢，血管脆弱可在暴露停止后长期持续，这有别于急性中毒性损伤。

Clinical features

• Angiolathyrism is usually asymptomatic until an aortic complication occurs, and there is no characteristic early clinical syndrome in humans.血管型山黧豆中毒通常无症状，直至发生主动脉并发症，人类没有特征性的早期临床综合征。
• The feared presentations are thoracic or abdominal aortic aneurysm, aortic dissection and sudden rupture, with chest or back pain, hypotension and collapse.令人担忧的表现是胸或腹主动脉瘤、主动脉夹层与猝然破裂，伴胸背痛、低血压与虚脱。
• In experimental animals the lesions include aortic dilatation, medial necrosis, dissecting aneurysm and rupture, often without preceding symptoms.在实验动物中，病变包括主动脉扩张、中膜坏死、夹层动脉瘤与破裂，且常无前驱症状。
• Reported human cases have generally been diagnosed after imaging for chest or abdominal pain, and a dietary history of grass pea consumption was obtained retrospectively.已报告的人类病例多在因胸腹痛行影像检查后诊断，草豌豆食用史为回顾性获得。
• Because the condition is systemic, other connective tissues may be affected, but a distinctive skin or skeletal phenotype has not been established in humans.由于该病为全身性，其他结缔组织也可能受累，但人类尚未确立特征性的皮肤或骨骼表型。
• Concurrent neurolathyrism may be present in the same patient, because the same diet contains both ODAP and beta-aminopropionitrile.同一患者可同时存在神经型山黧豆中毒，因为同一膳食中既含 ODAP 也含 β-氨基丙腈。

Diagnosis

• Diagnosis is based on the combination of vascular lesions and a documented history of prolonged grass pea consumption, as no specific laboratory test exists.诊断基于血管病变与有记录的长期草豌豆食用史的组合，因为不存在特异性实验室检查。
• Computed tomography angiography, magnetic resonance angiography and echocardiography are used to detect aneurysm, dissection and mural abnormalities.计算机断层血管造影、磁共振血管造影与超声心动图用于检出动脉瘤、夹层与管壁异常。
• Histology of resected aorta shows cystic medial necrosis with elastic fibre fragmentation, similar to other aortopathies and therefore not specific.切除主动脉的组织学显示囊性中膜坏死伴弹性纤维断裂，与其他主动脉病相似，因此不具特异性。
• The differential includes Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome, bicuspid aortic valve aortopathy, syphilitic aortitis and hypertensive dissection.鉴别诊断包括马方综合征、Loeys-Dietz 综合征、血管型 Ehlers-Danlos 综合征、二叶主动脉瓣相关主动脉病、梅毒性主动脉炎与高血压性夹层。
• Genetic testing for FBN1, TGFBR1, TGFBR2, ACTA2 and COL3A1 is used to exclude heritable aortopathy, especially in young patients without a clear dietary history.对 FBN1、TGFBR1、TGFBR2、ACTA2 与 COL3A1 的基因检测用于排除遗传性主动脉病，在无明确饮食史的年轻患者中尤为重要。
• A structured dietary survey of grass pea intake, including duration, proportion of diet and processing method, should be part of the assessment in endemic areas.在流行地区，评估应包括对草豌豆摄入的结构化膳食调查，涵盖持续时间、占膳食比例与加工方式。

Management

• There is no antidote, and management begins with stopping further exposure by diversifying the diet and avoiding grass pea as a staple.没有解毒剂，处理首先通过多样化膳食与避免以草豌豆为主食来停止进一步暴露。
• Aortic aneurysm and dissection require urgent vascular or cardiothoracic assessment, with surgical or endovascular repair when indicated.主动脉瘤与夹层需紧急血管外科或心胸外科评估，有指征时行开放手术或腔内修复。
• Blood pressure control and beta-blockade are used to reduce wall stress in patients with aortic dilatation, following the principles applied to other aortopathies.对主动脉扩张患者采用血压控制与 β 受体阻滞剂以降低管壁应力，遵循其他主动脉病的处理原则。
• Regular imaging surveillance is reasonable when a dilated aorta is found, because progression may be silent until rupture.发现主动脉扩张时定期影像监测是合理的，因为进展可静默直至破裂。
• Public health measures include food diversification, supplementation with other pulses and education about soaking, boiling and fermentation to reduce toxin content.公共卫生措施包括食物多样化、补充其他豆类，以及教育民众通过浸泡、煮沸与发酵降低毒素含量。
• The United Nations designated 2016 the International Year of Pulses to promote underused legumes including grass pea, although the crop remains a famine food in many regions.联合国将 2016 年定为国际豆类年，以推广包括草豌豆在内的利用不足的豆类，但在许多地区该作物仍是饥荒食物。
• Breeding of low-ODAP and low-aminonitrile grass pea varieties is a long-term strategy, but adoption has been limited by yield and farmer preference.培育低 ODAP 与低氨基腈草豌豆品种是长期策略，但因产量与农户偏好而推广有限。
• In famine settings, provision of alternative protein sources is the most effective preventive measure, because grass pea remains the crop that survives drought.在饥荒环境中，提供替代蛋白来源是最有效的预防措施，因为草豌豆仍是能在干旱中存活的作物。

Research and controversies

• Whether angiolathyrism occurs in humans at all is debated, because most evidence comes from rodents and turkeys given large doses of beta-aminopropionitrile.血管型山黧豆中毒是否真的发生在人类仍有争议，因为多数证据来自接受大剂量 β-氨基丙腈的啮齿动物与火鸡。
• Beta-aminopropionitrile remains a widely used experimental tool to create aortic aneurysm and dissection models, which shows that the mechanism is real even if human cases are rare.β-氨基丙腈仍是制作主动脉瘤与夹层模型的常用实验工具，这表明机制真实存在，即便人类病例罕见。
• The relative importance of ODAP, beta-aminopropionitrile and other aminonitriles in human disease is unresolved, and different Lathyrus species contain different proportions.ODAP、β-氨基丙腈与其他氨基腈在人类疾病中的相对重要性尚未明确，不同山黧豆属物种所含比例不同。^[6]
• Low-ODAP varieties have been developed, but their stability across environments and their acceptance by farmers remain unresolved problems.已培育出低 ODAP 品种，但其跨环境稳定性与农户接受度仍未解决。
• Sensitive biomarkers of chronic vascular injury from lathyrogens are lacking, so subclinical disease is probably missed in endemic populations.缺乏敏感的慢性山黧豆素血管损伤生物标志物，因此地方性流行人群中的亚临床病变很可能被漏诊。
• The interaction between lathyrogen exposure, malnutrition and other environmental factors in determining who develops vascular rather than neurological disease is poorly understood.山黧豆素暴露、营养不良与其他环境因素如何共同决定个体发生血管型而非神经型，仍知之甚少。