Anorexia nervosa affects up to 3% of young women and has the highest mortality rate of any psychiatric disorder^{1, 2}, with approximately 5% of patients dying within four years of the diagnosis¹. Severe weight loss and malnutrition can cause widespread damage to organs that may persist over time, even if anorexia nervosa is ultimately well-managed^{1, 2}. However, the factors involved in the high mortality associated with anorexia nervosa remain unclear³.

Among a longitudinal cohort of 1,298,890 women from the Maintenance and Use of Data for the Study of Hospital Clientele registry⁴ in the province of Quebec, Canada, we identified women admitted to hospital for anorexia nervosa between 1989 and 2016. A comparison group of women of similar age who presented for either delivery or pregnancy termination and were representative of the large majority of women in Quebec was also identified. We measured anorexia nervosa as a binary variable (yes, no), and included a categorical variable for the total number of anorexia admissions (0, 1, 2, ≥3 admissions) to capture disease severity.

We followed the women over time to identify in-hospital deaths up to March 31, 2018. We categorized the cause of death as anorexia nervosa, suicide, cardiovascular, pulmonary (including pneumonia), cancer, liver and other digestive disease, infectious (other than pneumonia), kidney, nervous system, diabetes and other endocrine disease, shock and organ failure, obstetric, other, or unknown causes.

We used Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for each cause of death, adjust­ed for baseline age, pre-existing morbidity (depression, anxiety, and alcohol, tobacco or other substance use at or before cohort entry), socioeconomic deprivation, rurality, and the time period of index hospitalization. We included quadratic time interaction terms to determine associations by year of follow-up.

There were 5,169 women with anorexia nervosa in the cohort, including 227 who died during follow-up. Mortality was higher for women with anorexia than no anorexia (3.24 vs. 0.38 per 1,000 person-years). In adjusted models, anorexia was associated with 2.47 times the risk of death compared with no anorexia (95% CI: 2.01-3.04). Women with three or more anorexia admissions had 4.05 times the risk of death over time (95% CI: 2.85-5.75). Anorexia nervosa was associated with 9.01 times the risk of death at 5 years (95% CI: 7.28-11.16), 7.18 times the risk at 10 years (95% CI: 6.07-8.51), and 2.90 times the risk at 20 years (95% CI: 2.16-3.89), but was not significantly associated with mortality at 25 years of follow-up (HR=1.47, 95% CI: 0.88-2.45).

Anorexia nervosa was associated with death from suicide (HR=4.90, 95% CI: 1.93-12.46), pulmonary disease (HR=3.49, 95% CI: 1.77-6.89), diabetes and other endocrine disease (HR=7.58, 95% CI: 1.89-30.42), liver and other digestive disease (HR=3.27, 95% CI: 1.33-8.06), and shock and organ failure (HR=3.59, 95% CI: 1.23-10.49). Among pulmonary causes, anorexia was most strongly associated with death due to pneumonia (HR=8.19, 95% CI: 2.78-24.14). The cause of death was specified as anorexia nervosa for five patients (2.2%). There was no long-term association with death from cardiovascular or other causes.

Risk of death was particularly elevated for diabetes and pneumonia, disorders that may be underappreciated conditions associated with anorexia nervosa. While it is plausible that severe calorie restriction has effects on pancreatic and lung function, it is also known that women with type 1 diabetes are at greater risk of developing eating disorders⁵. Diabetic women with anorexia nervosa sometimes manipulate their insulin injections to control weight, increasing the risk of hyperglycemic episodes, diabetic ketoacidosis, and life-threatening complications such as diabetic coma⁵. Women with anorexia nervosa may be at risk of pneumonia due to food aspiration. The elevated risk of pneumonia mortality may also be due to a reduced immune response to bacterial infections, leading to delayed diagnosis or treatment and more severe pulmonary infections^{6, 7}.

Suicide was also a leading cause of death. Anorexia nervosa frequently clusters with depression, anxiety, and personality disorders, as well as substance use². Alcohol use in particular is associated with a high risk of suicide attempt in patients with anorexia nervosa^{8, 9}. However, some data suggest that mortality rates are elevated even in women with anorexia nervosa who do not have psychiatric comorbidities⁹. In the present study, anorexia nervosa was associated with greater mortality even after adjusting for depression and anxiety, suggesting that at least some of the pathways linking anorexia nervosa with mortality are independent of comorbid mental disorders.

In contrast to the frequent involvement of the cardiovascular system in acute anorexia nervosa³, cardiovascular disease was not a leading cause of death in this analysis. In a prior study of 6,009 Swedish women, anorexia nervosa was similarly more strongly as­sociated with suicide, respiratory and endocrine-related causes than cardiovascular death⁶. It may be that low weight due to decreased calorie intake mitigates damage to the cardiovascular system⁶.

This study has limitations. We assessed severe anorexia nervosa requiring hospitalization, not milder anorexia adequately managed in outpatient settings. We did not have information on anorexia relapse or recovery status, body mass index, physical activity, or nutrition. Cause of death data were partially missing before 2006. We used a comparison group comprised of fertile women. Our results may therefore differ from studies using the general population as a reference group.

The long-term role of anorexia nervosa in mortality has yet to be fully appreciated. In this study with 29 years of follow-up, anorexia nervosa hospitalization was associated with an increased risk of death up to 20 years later and was strongly associated with mortality due to diabetes, pneumonia and suicide. As the risk of death was most pronounced in the first two decades, earlier interventions to treat anorexia nervosa may have greatest potential for reducing harm. To improve survival and reduce morbidity, better documentation of the impact of anorexia nervosa over the life course is needed.

神经性厌食症影响多达 3% 的年轻女性，并且在所有精神疾病中死亡率最高^{1, 2}，大约 5% 的患者在诊断后四年内死亡¹。严重的体重减轻和营养不良会对器官造成广泛的损害，这种损害可能会随着时间的推移而持续存在，即使神经性厌食症最终得到妥善管理^{1, 2}。然而，与神经性厌食症相关的高死亡率所涉及的因素仍不清楚³。

在来自加拿大魁北克省医院客户登记处⁴的维护和使用数据研究的 1,298,890 名妇女的纵向队列中，我们确定了 1989 年至 2016 年间因神经性厌食症入院的妇女。还确定了年龄相近的分娩或终止妊娠，并且代表了魁北克的绝大多数妇女。我们将神经性厌食症作为二元变量（是、否）进行测量，并包括厌食症住院总数（0、1、2、≥3 次住院）的分类变量，以捕捉疾病严重程度。

我们对这些女性进行了一段时间的跟踪，以确定截至 2018 年 3 月 31 日的院内死亡。我们将死因归类为神经性厌食症、自杀、心血管、肺部（包括肺炎）、癌症、肝脏和其他消化系统疾病、传染性（其他肺炎）、肾脏、神经系统、糖尿病和其他内分泌疾病、休克和器官衰竭、产科、其他或未知原因。

我们使用 Cox 回归模型来估计每种死因的风险比 (HR) 和 95% 置信区间 (CI)，并根据基线年龄、既往发病率（抑郁、焦虑以及在在队列进入之前）、社会经济剥夺、农村地区和住院指标的时间段。我们包括二次时间交互项来确定随访年份的关联。

该队列中有 5,169 名患有神经性厌食症的女性，其中 227 名在随访期间死亡。患有厌食症的女性的死亡率高于没有厌食症的女性（每 1,000 人年为 3.24 对 0.38）。在调整后的模型中，与没有厌食症相比，厌食症导致的死亡风险高 2.47 倍（95% CI：2.01-3.04）。随着时间的推移，患有 3 次或以上厌食症的女性死亡风险是其 4.05 倍（95% CI：2.85-5.75）。神经性厌食症与 5 年死亡风险的 9.01 倍（95% CI：7.28-11.16）、10 年死亡风险的 7.18 倍（95% CI：6.07-8.51）和 20 年死亡风险的 2.90 倍相关（ 95% CI：2.16-3.89），但与 25 年随访时的死亡率无显着相关性（HR=1.47，95% CI：0.88-2.45）。

神经性厌食症与自杀死亡 (HR=4.90, 95% CI: 1.93-12.46)、肺部疾病 (HR=3.49, 95% CI: 1.77-6.89)、糖尿病和其他内分泌疾病 (HR=7.58, 95%) 相关CI：1.89-30.42）、肝脏和其他消化系统疾病（HR=3.27，95% CI：1.33-8.06），以及休克和器官衰竭（HR=3.59，95% CI：1.23-10.49）。在肺部原因中，厌食症与肺炎死亡的相关性最强（HR=8.19，95% CI：2.78-24.14）。5 名患者 (2.2%) 的死因被指定为神经性厌食症。与心血管或其他原因导致的死亡没有长期关联。

糖尿病和肺炎的死亡风险特别高，这些疾病可能是与神经性厌食症相关的被低估的疾病。虽然严格限制热量摄入可能会影响胰腺和肺功能，但众所周知，患有 1 型糖尿病的女性患饮食失调的风险更大⁵。患有神经性厌食症的糖尿病女性有时会通过注射胰岛素来控制体重，从而增加高血糖发作、糖尿病酮症酸中毒和危及生命的并发症（如糖尿病昏迷）的风险⁵. 患有神经性厌食症的女性可能因食物吸入而有患肺炎的风险。肺炎死亡风险升高也可能是由于对细菌感染的免疫反应降低，导致诊断或治疗延迟以及更严重的肺部感染^{6, 7}。

自杀也是导致死亡的主要原因。神经性厌食症经常与抑郁、焦虑和人格障碍以及物质使用相结合²。特别是饮酒与神经性厌食症患者自杀企图的高风险有关^{8, 9}。然而，一些数据表明，即使在没有精神疾病^{9 的}神经性厌食症女性中，死亡率也会升高。在本研究中，即使在调整了抑郁和焦虑后，神经性厌食症仍与更高的死亡率相关，这表明至少有一些将神经性厌食症与死亡率联系起来的途径与共病精神障碍无关。

与心血管系统频繁参与急性神经性厌食症^{3 不同}，在本分析中，心血管疾病并不是主要的死亡原因。在之前对 6,009 名瑞典女性进行的研究中，神经性厌食症与自杀、呼吸和内分泌相关原因的相关性同样高于心血管死亡⁶。可能是由于卡路里摄入量减少导致的低体重减轻了对心血管系统^{6 的}损害。

这项研究有局限性。我们评估了需要住院治疗的严重神经性厌食症，而不是在门诊环境中得到充分管理的轻度厌食症。我们没有关于厌食症复发或恢复状态、体重指数、身体活动或营养的信息。2006 年之前的死因数据部分缺失。我们使用了一个由生育妇女组成的对照组。因此，我们的结果可能与使用一般人群作为参照组的研究不同。

神经性厌食症在死亡率中的长期作用尚未得到充分认识。在这项为期 29 年的随访研究中，神经性厌食症住院与 20 年后的死亡风险增加有关，并且与糖尿病、肺炎和自杀引起的死亡率密切相关。由于死亡风险在前 20 年最为明显，因此早期治疗神经性厌食症的干预措施可能最有可能减少伤害。为了提高生存率并降低发病率，需要更好地记录神经性厌食症对整个生命过程的影响。