Published online Aug 14, 2020. doi: 10.3748/wjg.v26.i30.4537
Peer-review started: March 5, 2020
First decision: March 13, 2020
Revised: May 22, 2020
Accepted: June 23, 2020
Article in press: June 23, 2020
Published online: August 14, 2020
Although carcinoid syndrome (CS) is often the cause of diarrhoea among patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs), other causes to consider include pancreatic enzyme insufficiency (PEI), bile acid malabsorption (BAM) or small intestinal bacterial overgrowth (SIBO). 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.
CS diarrhoea has a considerable impact on patient quality of life, but the differential diagnosis of causes of diarrhoea in patients with GEP-NETs is a relatively unexplored area of research, and there is currently no formal guidance for clinicians.
The objective of this research was to synthesise evidence on the differential diagnosis of diarrhoea in patients with GEP-NETs, including: (1) The prevalence of different non-CS causes of diarrhoea in patients with GEP-NETs; (2) The diagnostic approaches for diarrhoea in patients with GEP-NETs, including initial investigations and clinical testing for specific gastrointestinal conditions; (3) The potential consequences for patients if the true cause(s) of diarrhoea are not ascertained; and (4) Suggestions and advice for improving differential diagnosis of diarrhoea.
Electronic databases were searched from inception to 12th September 2018 using terms for NETs and diarrhoea. Congresses, systematic literature review bibliographies and included articles were also hand-searched. Any study design and publication type were eligible for inclusion if relevant data on a cause(s) of diarrhoea in patients with GEP-NETs were reported. Framework synthesis was adapted to synthesise quantitative and qualitative data.
Forty-seven publications (44 studies) were included. Twenty-one articles (18 studies) reported on the prevalence of specific causes of diarrhoea; 9.5%–84% of patients with GEP-NETs had experienced steatorrhoea or PEI. Other causes of diarrhoea included BAM (80% of patients), SIBO (23.6%-62%), colitis (20%) and infection (7.1%). Initial approaches for investigation primarily included assessing possible progression of CS and patient history. Characteristics of diarrhoea or concomitant symptoms of such causes were also described. Diagnostic approaches for diarrhoea included faecal elastase or faecal fat testing (PEI), hydrogen and/or methane breath tests (SIBO), tauroselcholic (selenium-75) acid (SeHCAT) scan (BAM) and stool culture (infectious causes). Evidence on the effectiveness or diagnostic accuracy of these tests in patients with GEP-NETs was limited. Fourteen articles described consequences if the cause of diarrhoea is not correctly diagnosed: Patients or clinicians may perceive CS treatment as ineffective, may discontinue treatment targeted at CS and/or may use inappropriate interventions; also, diarrhoea is prolonged, and patients’ nutritional status may subsequently deteriorate. Improving patient and clinician awareness, directly asking patients about diarrhoea, and involving a multidisciplinary clinical team, including gastroenterologists, were reported as approaches to facilitate effective diagnosis of the underlying cause(s) of diarrhoea.
PEI has been found to be relatively frequent in patients with GEP-NETs undergoing somatostatin analogues therapy, with other reported occurrences of SIBO, BAM and infectious diarrhoea. While author recommendations were available, evidence or opinion on the accuracy of diagnostic approaches in patients with GEP-NETs specifically were either contradictory or lacking completely. Furthermore, no specific guidance for distinguishing between two synchronous causes of diarrhoea was identified. Observational and/or interventional research in patients with GEP-NETs experiencing persistent diarrhoea would be beneficial, in order to investigate the most effective diagnostic and management algorithms and the subsequent impact on patient outcomes, to facilitate development of clinical guidance.
There is a need for increased awareness and further research on the prevalence of non-CS diarrhoea aetiologies and on the suitability of diagnostic approaches, to determine the most effective algorithm for differential diagnosis of GEP-NET-related diarrhoea. In clinical practice, involvement of gastroenterology expertise alongside oncologists and endocrinologists would improve the management of patients with GEP-NETs and provide opportunities for improving quality of life.