Khan Mohid S, Walter Thomas, Buchanan-Hughes Amy, Worthington Emma, Keeber Lucie, Feuilly Marion, Grande Enrique
Department of Gastroenterology and Neuroendocrine Tumours, University Hospital of Wales, Cardiff CF14 4XW, United Kingdom.
Department d'Oncologie Médicale, Hospices Civils de Lyon, Lyon 69003, France.
World J Gastroenterol. 2020 Aug 14;26(30):4537-4556. doi: 10.3748/wjg.v26.i30.4537.
Approximately 20% of patients with neuroendocrine tumours (NETs) develop carcinoid syndrome (CS), characterised by flushing and diarrhoea. Somatostatin analogues or telotristat can be used to control symptoms of CS through inhibition of serotonin secretion. Although CS is often the cause of diarrhoea among patients with gastroenteropancreatic NETs (GEP-NETs), other causes to consider include pancreatic enzyme insufficiency (PEI), bile acid malabsorption and small intestinal bacterial overgrowth. If other causes of diarrhoea unrelated to serotonin secretion are mistaken for CS diarrhoea, these treatments may be ineffective against the diarrhoea, risking detrimental effects to patient quality of life.
To identify and synthesise qualitative and quantitative evidence relating to the differential diagnosis of diarrhoea in patients with GEP-NETs.
Electronic databases (MEDLINE, Embase and the Cochrane Library) were searched from inception to September 12, 2018 using terms for NETs and diarrhoea. Congresses, systematic literature review bibliographies and included articles were also hand-searched. Any study designs and publication types were eligible for inclusion if relevant data on a cause(s) of diarrhoea in patients with GEP-NETs were reported. Studies were screened by two independent reviewers at abstract and full-text stages. Framework synthesis was adapted to synthesise quantitative and qualitative data. The definition of qualitative data was expanded to include all textual data in any section of relevant publications.
Forty-seven publications (44 studies) were included, comprising a variety of publication types, including observational studies, reviews, guidelines, case reports, interventional studies, and opinion pieces. Most reported on PEI on/after treatment with somatostatin analogs; 9.5%-84% of patients with GEP-NETs had experienced steatorrhoea or confirmed PEI. Where reported, 14.3%-50.7% of patients received pancreatic enzyme replacement therapy. Other causes of diarrhoea reported in patients with GEP-NETs included bile acid malabsorption (80%), small intestinal bacterial overgrowth (23.6%-62%), colitis (20%) and infection (7.1%). Diagnostic approaches included faecal elastase, breath tests, tauroselcholic (selenium-75) acid (SeHCAT) scan and stool culture, although evidence on the effectiveness or diagnostic accuracy of these approaches was limited. Assessment of patient history or diarrhoea characteristics was also reported as initial approaches for investigation. From the identified evidence, if diarrhoea is assumed to be CS diarrhoea, consequences include uncontrolled diarrhoea, malnutrition, and perceived ineffectiveness of CS treatment. Approaches for facilitating differential diagnosis of diarrhoea include improving patient and clinician awareness of non-CS causes and involvement of a multidisciplinary clinical team, including gastroenterologists.
Diarrhoea in GEP-NETs can be multifactorial with misdiagnosis leading to delayed patient recovery and inefficient resource use. This systematic literature review highlights gaps for further research on prevalence of non-CS diarrhoea and suitability of diagnostic approaches, to determine an effective algorithm for differential diagnosis of GEP-NET diarrhoea.
约20%的神经内分泌肿瘤（NETs）患者会出现类癌综合征（CS），其特征为潮红和腹泻。生长抑素类似物或替洛曲肽可通过抑制5-羟色胺分泌来控制CS症状。虽然CS常是胃肠胰神经内分泌肿瘤（GEP-NETs）患者腹泻的原因，但其他需要考虑的原因包括胰腺酶分泌不足（PEI）、胆汁酸吸收不良和小肠细菌过度生长。如果将与5-羟色胺分泌无关的其他腹泻原因误诊为CS腹泻，这些治疗可能对腹泻无效，从而危及患者生活质量。
识别并综合与GEP-NETs患者腹泻鉴别诊断相关的定性和定量证据。
从数据库建立至2018年9月12日，使用NETs和腹泻相关术语检索电子数据库（MEDLINE、Embase和Cochrane图书馆）。还对手工检索了会议文献、系统文献综述书目及纳入的文章。如果报告了GEP-NETs患者腹泻原因的相关数据，则任何研究设计和出版类型均符合纳入标准。由两名独立评审员在摘要和全文阶段进行研究筛选。采用框架综合法综合定量和定性数据。定性数据的定义扩展至包括相关出版物任何部分的所有文本数据。
纳入47篇出版物（44项研究），包括多种出版类型，如观察性研究、综述、指南、病例报告、干预性研究和观点文章。大多数报告了生长抑素类似物治疗期间或之后的PEI情况；9.5%-84%的GEP-NETs患者出现过脂肪泻或确诊为PEI。报告中，14.3%-50.7%的患者接受了胰腺酶替代疗法。GEP-NETs患者报告的其他腹泻原因包括胆汁酸吸收不良（80%）、小肠细菌过度生长（23.6%-62%）、结肠炎（20%）和感染（7.1%）。诊断方法包括粪便弹性蛋白酶、呼气试验、牛磺鹅去氧胆酸（硒-75）酸（SeHCAT）扫描和粪便培养，尽管这些方法有效性或诊断准确性的证据有限。评估患者病史或腹泻特征也被报告为初步调查方法。从已识别的证据来看，如果将腹泻假定为CS腹泻，后果包括腹泻无法控制、营养不良以及CS治疗无效。促进腹泻鉴别诊断的方法包括提高患者和临床医生对非CS原因的认识以及多学科临床团队（包括胃肠病学家）的参与。
GEP-NETs患者的腹泻可能是多因素的，误诊会导致患者恢复延迟和资源利用低效。这项系统文献综述突出了非CS腹泻患病率及诊断方法适用性方面有待进一步研究的差距，以确定GEP-NET腹泻鉴别诊断的有效算法。
