Differential diagnosis of diarrhoea in patients with neuroendocrine tumours: A systematic review

Table 2 A summary of clinical tests used to confirm cause of diarrhoea

Condition or cause	Diagnostic test	Diagnostic criteria	Evaluation or opinion on accuracy of diagnostic test
Pancreatic enzyme insufficiency (PEI)	Faecal elastase[6,33,40,60-64]	Donnelly 2017 defined an abnormal test result as “< 200” but units were not specified[33]. Lamarca 2018: PEI defined as either an FE1 value below the normal limit (< 200 μg/g) or a reduction of ≥ 21%a[6]. Other articles only mentioned the test in passing, for example stating that FE was evaluated or presenting a proportion of patients with abnormal FE	Chaudhry 2017: 22/32 patients had steatorrhoea with a normal faecal elastase, sensitivity of FE test for detecting steatorrhoea in patients with NETs was 15.4%. The authors concluded that there is a lack of association between FE and steatorrhoea in patients with NETs[40]. Donnelly 2017 reported that only 17% of patients with NETs and steatorrhoea had abnormal faecal elastase[33]. Lamarca 2018 acknowledged that there is a risk of false positives from diarrhoea, but concluded that faecal elastase testing is feasible, accessible and recommended for patients who develop symptoms of PEI, and report it was the basis for diagnosis in 67% of patients who developed PEI[6]
	Faecal fat: 72-h stool fat testing[37,38,63]; Sudan stain of a spot stool measurement[38]	-	Faecal fat quantification is the cheapest and easiest way to confirm a diagnosis of PEI[38]. Sudan stain of a spot stool measurement is easier but a quantitative 72-h collection is more reliable (no clear evidence is provided to support this)[38]. Faecal fat test could be utilised for assessing response to PERT[38]
Bile acid malabsorption	SeHCAT scan[33,61]	SeHCAT < 20% retention	-
Colitis	CT scan[34]	-	-
Dumping syndrome	Provocative meal test[44]	-	-
Infectious diarrhoea	Bacterial: Stool culture for Salmonella, Campylobacter, Shigella and Yersinia, as well as Clostridium difficile, enteropathogenic Vibrio species, or Escherichia coli strains[50]; Viral: Stool analyses for cytomegaly virus[50]; Parasitical: Stool analysis for Entamoeba histolytica or Giardia lamblia[50]	-	-
Intestinal ischaemia	Angiography[44] (type of angiography was not further specified)	-	-
Laxative abuse	KOH stool preparation, intestinal secretion[42,43]	-	-
PCI (induced by sunitinib)	CT scan[46]	-	-
SBS	Urinary sodium (undetectable)[61]	-	-
SIBO	Breath tests: Hydrogen breath test[61], with glucose[33] or lactulose substrate[32]; Methane breath test[32,61]	-	Whyand et al[32] assessed the sensitivity of additional MBT and lactulose HBT testing on 12 (out of 55) patients who tested negative for SIBO with glucose HBT, but whose diarrhoea did not abate. This was under the rationale that patients with NETs are more likely to have distal SIBO (due to influences such as ileocoecal valve resection), whereas glucose HBT may be more sensitive to proximal SIBO as glucose rarely reaches the colon. This testing yielded an additional 3 positive results, and led the authors to conclude that lactulose HBT and MBT increase sensitivity for detecting SIBO in patients with NETs who have previously undergone hemicolectomy

^aA reduction in faecal elastase value by ≥ 21% was applied by the authors in this study, but is not a standard definition in clinical practice. BAM: Bile acid malabsorption; CS: Carcinoid syndrome; CT: Computed tomography; FE: Faecal elastase; FF: Faecal fat; GEP-NET: Gastroenteropancreatic neuroendocrine tumour; HBT: Hydrogen breath test; KOH: Potassium hydroxide; LAR: Long acting release; MBT: Methane breath test; PEI: Pancreatic enzyme insufficiency; PERT: Pancreatic enzyme replacement therapy; SeHCAT: Tauroselcholic [75 selenium] acid; SIBO: Small intestinal bacterial overgrowth; SSA: Somatostain analogue.