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1 Gastroenterol Hepatol. 2016;xxx(xx):xxx---xxx
2
Gastroenterología y Hepatología
www.elsevier.es/gastroenterologia
REVIEW IN GASTROENTEROLOGY
3 Chronic diarrhoea: Definition, classification and

4 diagnosis夽
5 Q2 Fernando Fernández-Bañaresa,i,∗ , Anna Accarinob,i , Agustín Balboac ,
6 Eugeni Domènechd,i , Maria Estevea,i , Esther Garcia-Planellae , Jordi Guardiolaf ,
7 Xavier Molerob,i , Alba Rodríguez-Lunag , Alexandra Ruiz-Cerullaf , Javier Santosb,i ,
8 Eva Vaqueroh,i
a
9 Servicios de Digestivo, Hospital Universitari Mútua de Terrassa, Terrassa, Barcelona, Spain
b
10 Servicios de Digestivo, Hospital Universitari Vall d’Hebron, Barcelona, Spain
c
11 Servicios de Digestivo, Hospital Teknon, Barcelona, Spain
d
12 Servicios de Digestivo, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
e
13 Servicios de Digestivo, Hospital de Sant Pau, Barcelona, Spain
f
14 Servicios de Digestivo, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
g
15 Medicina de Familia, CAP Sur, Terrassa, Barcelona, Spain
h
16 Servicios de Digestivo, Hospital Clínic, Barcelona, Spain
i
17 Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain
18 Received 19 June 2015; accepted 30 September 2015
19 KEYWORDS Abstract Chronic diarrhoea is a common presenting symptom in both primary care medicine
20 Chronic diarrhoea; and in specialised gastroenterology clinics. It is estimated that >5% of the population has chronic
21 GRADE system; diarrhoea and nearly 40% of these patients are older than 60 years. Clinicians often need to
22 Evidence-based select the best diagnostic approach to these patients and choose between the multiple diagnos-
23 recommendations; tic tests available. In 2014 the Catalan Society of Gastroenterology formed a working group with
24 Consensus document the main objective of creating diagnostic algorithms based on clinical practice and to evaluate
25 diagnostic tests and the scientific evidence available for their use. The GRADE system was used
26 to classify scientific evidence and strength of recommendations. The consensus document con-
27 tains 28 recommendations and 6 diagnostic algorithms. The document also describes criteria
28 for referral from primary to specialised care.
29 © 2015 Elsevier España, S.L.U., AEEH and AEG. All rights reserved.
30
夽
Please cite this article as: Fernández-Bañares F, Accarino A, Balboa A, Domènech E, Esteve M, Garcia-Planella E, et al. Diarrea crónica:
definición, clasificación y diagnóstico. Gastroenterol Hepatol. 2016. http://dx.doi.org/10.1016/j.gastrohep.2015.09.018
∗ Corresponding author.
E-mail address: ffbanares@mutuaterrassa.es (F. Fernández-Bañares).
2444-3824/© 2015 Elsevier España, S.L.U., AEEH and AEG. All rights reserved.
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2 F. Fernández-Bañares et al.
31
PALABRAS CLAVE Diarrea crónica: definición, clasificación y diagnóstico
Diarrea crónica;
32 Resumen La diarrea crónica es un síntoma de presentación frecuente, tanto en las consultas
Sistema GRADE;
33 de medicina de familia como en las de digestivo. Se estima que >5% de la población sufre
Recomendaciones
34 diarrea crónica y que cerca del 40% de estos sujetos son mayores de 60 años. El clínico se
basadas en la
35 enfrenta con frecuencia a la necesidad de decidir cuál es el mejor enfoque diagnóstico de
evidencia;
36 estos pacientes y elegir entre las múltiples pruebas diagnósticas existentes. En 2014 la Societat
Documento de
37 Catalana de Digestologia creó un grupo de trabajo con el objetivo principal de crear algoritmos
consenso
38 diagnósticos en base a la práctica clínica y evaluar las pruebas diagnósticas disponibles y la
39 evidencia científica para su utilización. Para clasificar la evidencia científica y la fuerza de
40 las recomendaciones se utilizó el sistema GRADE. Se han establecido 28 recomendaciones y
41 6 algoritmos diagnósticos. Se describen los criterios de derivación desde medicina primaria a
42 digestivo de un paciente con diarrea crónica.
43 © 2015 Elsevier España, S.L.U., AEEH y AEG. Todos los derechos reservados.
44 Introduction the different categories used to grade certainty (or quality) 83
of the evidence (CE) and strength of recommendation (SR).9 84
45 Purpose of the consensus document

Definition of chronic diarrhoea 85
46 Chronic diarrhoea is a common complaint seen by both pri-

47 mary care doctors and gastroenterologists. According to Chronic diarrhoea is defined as the passage of loose or liquid 86
48 estimates, chronic diarrhoea has a prevalence of over 5%, stools, urgent need to evacuate or feelings of abdominal dis- 87
49 with over 40% of cases occurring in the over-60 age group.1 comfort, or increased frequency of these, lasting more than 88
50 The list of possible causes is long (Table 1), and various diag- 4 weeks.2,5 Stool consistency is determined by the relation- 89
51 nostic tests are usually needed before reaching a definitive ship between faecal water and the water-holding capacity 90
52 diagnosis.1---5 Clinicians are often faced with the challenge of of insoluble faecal solids. As stools consist predominantly of 91
53 deciding the best diagnostic approach in these patients, and water (60---85%), consistency is difficult to quantify, and for 92
54 must choose between the broad array of diagnostic tests cur- this reason stool weight is used as a reasonable indirect esti- 93
55 rently available. A definitive diagnosis all too often proves mation of consistency. Diarrhoea, therefore, can be defined 94
56 elusive, and many patients are diagnosed with functional or by the weight or volume of stools measured over 24---72 h 95
57 idiopathic diarrhoea. (on average, 2---3 days). The normal weight of stool output 96
58 Several clinical practice guidelines have been published over a 24-h period in children and adults is less that 200 g; 97
59 for the purpose of establishing the best investigation pro- thus, stool weight >200 g/24 h is an objective definition of 98
60 tocol in patients with chronic diarrhoea.2,4,6 The aim of diarrhoea. However, it is important to note that up to 20% of 99
61 these recommendations is to maximise positive diagnoses patients with liquid diarrhoea, and thus a lower stool weight, 100
62 while minimising examinations. These guidelines need to are excluded from this definition. 101
63 be updated and adapted to current clinical practice, as in A pragmatic definition incorporates the following ele- 102
64 recent years a series of diseases with an underlying organic ments: passage of loose or liquid stools more than 3 times 103
65 cause presenting with the characteristics of a ‘‘functional’’ daily and/or an output of 200 g/day of loose or liquid stools. 104
66 disease have been identified. In fact, some authors have
67 challenged the very existence of functional diarrhoea per
68 se.7,8 Patient history and classification 105
69 In 2014, with the aim of helping clinicians diagnose

70 chronic diarrhoea, the SocietatCatalana de Digestologia A detailed medical history and physical examination are 106
71 proposed creating a working group to draw up a consen- essential in the assessment of patients with chronic 107
72 sus document on the issue. The document was presented diarrhoea.3---5 When taking the medical history, clinicians 108
73 at the association’s annual conference in January 2015, should first evaluate the patient’s family history of diseases 109
74 and an abbreviated version is available online (http://www. such as coeliac disease or inflammatory bowel disease, both 110
75 scdigestologia.org/index.php?link=docs posicio). The pri- of which have a familial component, their history of travel 111
76 mary aim of the group was to create diagnostic algorithms to regions where diarrhoea is endemic, engagement in risky 112
77 based on clinical practice, and to evaluate existing diagnos- sexual practices, history of systemic diseases (for exam- 113
78 tic tests and the clinical evidence supporting their use. ple, diabetes mellitus, systemic or neurological diseases, 114
79 Scientific evidence and strength of recommendation amyloidosis, etc.) and gastrointestinal surgery (for exam- 115
80 were classified according to the Grading of Recommenda- ple, cholecystectomy, intestinal resection), use of medicinal 116
81 tions Assessment, Development and Evaluation (GRADE) sys- products that could cause diarrhoea, or use of chewing gum 117
82 tem (http://www.gradeworkinggroup.org/). Table 2 shows or sweets with a high sorbitol content. 118
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Q1 Chronic diarrhoea: Definition, classification and diagnosis 3
Table 1 Classification of chronic diarrhoea. Table 1 (Continued)

Chronic watery diarrhoea Chronic diarrhoea with steatorrhoea
1. Osmotic Enteric causes
Osmotic laxatives (Mg+2 , PO− , SO4−2 ) Mucosal diseases: coeliac, Whipple, giardiasis,
Carbohydrate malabsorption lymphoma, Crohn, radiation enteritis,
Excessive consumption of poorly absorbed gastrointestinal lymphangiectasia, amyloidosis,
carbohydrates eosinophilic gastroenteritis, tropical sprue, sprue,
Lactulose collagenous colitis.
Sorbitol and mannitol (‘‘sugar-free’’ chewing gum) Short bowel syndrome
Fructose (fruit, soft drinks) Bacterial overgrowth
2. Secretory Chronic mesenteric ischaemia
Congenital chloride diarrhoea Maldigestion syndromes
Bacterial enterotoxins Exocrine pancreatic insufficiency
Bile acid malabsorption Low bile acid levels in the intestinal lumen
Inflammatory bowel disease
Ulcerative colitis
Crohn disease
Microscopic colitis The differential diagnosis of diarrhoea has tradition- 119
Vasculitis ally been based on its causative mechanisms. Diarrhoea is 120
Laxative abuse associated with 4 pathophysiological mechanisms: osmotic, 121
Drugs secretory, exudative and altered motility. This classification, 122
Food allergies however useful from an academic perspective, is imprac- 123
Heavy metal poisoning tical in routine practice, because, in addition to other 124
Dysmotility considerations, more than 1 mechanism is often present. 125
Post-vagotomy diarrhoea From a practical standpoint, it is more useful to classify 126
Post-sympathectomy diarrhoea patients presenting with symptoms of diarrhoea according 127
Diabetic autonomic neuropathy to ‘‘functional’’ or ‘‘organic’’ characteristics (Algorithm 1, 128
Irritable bowel syndrome Fig. 1). 129
Faecal impaction Accordingly, the first step in the diagnostic process 130
Faecal incontinence involves evaluating signs, symptoms and analytical tests sug- 131
Endocrine disorders gestive of organic disease (Table 3). Alarm symptoms or 132
Addison disease abnormal findings in blood tests point to an organic cause. 133
Hyperthyroidism In these cases, diarrhoea can be characterised as inflam- 134
Gastrinoma matory, malabsorption (steatorrhoea), or watery diarrhoea. 135
VIPoma The medical history will often help locate the intestinal 136
Somatostatinoma segment causing the diarrhoea. The presence of large quan- 137
Carcinoid syndrome tities of liquid or pasty stools with a shiny appearance, 138
Mastocytosis
Other neoplasms
Colorectal cancer
Table 2 GRADE system.
Small bowel lymphoma
Secretory villous adenoma of the rectum Quality of the evidence (CE)
Idiopathic secretory diarrhoea High Further research is very unlikely to
Others: amyloidosis change our confidence in the estimate of
Chronic inflammatory diarrhoea effect.
Inflammatory bowel disease Moderate Further research is likely to have an
Ulcerative colitis important impact on our confidence in
Crohn disease the estimate of effect and may change
Diverticulitis the estimate.
Ulcerative jejunoileitis Low Further research is very likely to have an
Infectious diseases important impact on our confidence in
Bacteria: Shigella, Salmonella, Campylobacter, the estimate of effect and is likely to
Yersinia, Clostridium difficile change the estimate.
Viruses: herpes simplex, CMV Very low Any estimate of effect is very uncertain.
Parasites: amoebiasis, strongyloidesstercoralis Grade of recommendation (SR)
Ischaemic colitis Strong Benefits clearly outweigh risk and
Radiation colitis burdens, or vice versa.
Neoplasms Weak Benefits closely balanced with risks and
Colorectal cancer burdens, or some uncertainty in the
Lymphoma estimates of benefits and risks.
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Chronic diarrhoea
Definition
Patient history Physical examination Basic investigations
Basic laboratory tests

Complete blood count Microbiological stool studies
Biochemistry tests (with CRP, albumin, Faecal culture*
calcium, prothrombin time, ferritin,
folate) Parasites in stool
Coeliac serology (anti-tTG)
Stool tests (FOB‡, calprotectin)
Risk markers for organic disease
Yes No
Chronic diarrhoea with Chronic diarrhoea with functional
organic characteristics characteristics
Figure 1 Algorithm 1. Initial approach in patients with chronic diarrhoea.

*Faecal culture is only indicated in immunocompromisedpatients or patients receiving immunosuppressants (in many cases these
tests will have been performed during the acute phase of the disease, before the duration of symptoms suggests a chronic process).
**The faecal occult blood test has high sensitivity for intestinal inflammation.
CRP: C-reactive protein; FOB: faecal occult blood; tTG: tissue transglutaminase IgA test.
accompanied by cramp-like pain in the umbilical area (sug- 139

Table 3 Chronic diarrhoea: signs, symptoms and analytical
gestive of malabsorption diarrhoea), would point to an origin 140
findings suggestive of an organic cause.
in the proximal small intestine or pancreas. Small quantities 141
Blood in stools of loose or liquid stools, however, mixed with blood, mucous 142
Fever or pus, associated with urgent evacuation or tenesmus and 143
Recent weight loss (>5 kg) (in absence of concomitant pain in the hypogastrium or sacrum, are more suggestive 144
depression) of an origin in the left colon and/or rectum (inflammatory 145
Recent onset of symptoms, or change in the characteristics diarrhoea). 146
of previous symptoms The ‘‘functional’’ diarrhoea group, meanwhile, includes 147
Onset at an advanced age (≥50 years) some entities with an organic origin and functional diar- 148
Family history of colorectal cancer or polyps rhoea per se; these will be differentiated in the section 149
Nocturnal diarrhoea on functional diarrhoea. These patients frequently present 150
Diarrhoea persists after fasting chronic non-bloody diarrhoea in either recurrent form, with 151
High-volume stool output or steatorrhoea frequent watery stools interspersed with episodes of nor- 152
Weight of stool output over 24 h >400 g/day mal bowel function, or in a persistent form, with passage 153
Abnormalities on physical examination (pallor, of loose or liquid stools. The frequency of bowel movement 154
hepatosplenomegaly, adenopathies, abdominal mass, will vary in these cases, but some patients may report up 155
etc.) to 10---15 movements daily. Other common symptoms are 156
Anaemia, macrocytosis, hypoprothrombinaemia, urgency and faecal incontinence, which can prevent the 157
hypoalbuminaemia or other laboratory findings (e.g. patient from engaging in their normal activity and dimin- 158
elevated ESR or C-reactive protein) ish their quality of life. Patients can also present moderate 159
Positive faecal occult blood test, elevated faecal weight loss secondary to reduced food intake associated 160
calprotectin with an astringent or restrictive diet designed to prevent 161
diarrhoea. 162
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Chronic diarrhoea: Definition, classification and diagnosis 5
Inflammatory diarrhoea
(a) blood or pus in stools
(b) systemic symptoms (persistent or recurrent fever, weight loss)
(c) elevated acute phase proteins
(d) faecal calprotectin >150 mg/kg in 2 samples in patients not taking NSAIDs
negative or
incomplete Predominantly rectal symptoms +
Ileocolonoscopy risky sexual practices
Imaging studies
Small bowel
MR enterography
CT enterography Colonoscopy
Additional studies if Capsule endoscopy
Crohn disease found Barium enema
Biopsy if lesions found
Biopsies for culture2
Warn pathologist of
If small bowel lesions requiring clinical suspicion3
histological confirmation
1
If clinical suspicion of specific entities
Enteroscopy with
biopsies
Figure 2 Algorithm 2. Diagnosis of chronic inflammatory diarrhoea

1
Certain entities may be hard to diagnose without initial clinical suspicion (for example, Whipple disease). In these cases,
enteroscopy is indicated to obtain biopsy samples from the small bowel.
2
Biopsy for gonorrhoea culture.
3
Tissue PCR for lymphogranulomavenereum and herpes simplex.
163 Chronic diarrhoea with organic characteristics IV contrast medium can be performed. This technique is sim- 188
ilar in terms of diagnostic accuracy to both MR and CT, but is 189
less costly, available in most centres, and does not irradiate 190
164 Inflammatory diarrhoea the patient.12 Because of this, abdominal ultrasound is an 191
attractive choice for a preliminary study, particularly in pae- 192
165 Chronic inflammatory diarrhoea is traditionally defined as diatric patients. Ultrasound, however, can only accurately 193
166 the presence of white blood cells in stools. As these tests are explore the terminal ileum, and is operator-dependent, two 194
167 not performed in most centres, a more practical definition drawbacks that considerably limit its usefulness in our set- 195
168 is the following: (a) blood or pus in faeces; (b) accompanied ting. If ultrasound, MR or CT are unavailable, a barium 196
169 by systemic symptoms (persistent or recurring fever, weight enema can be performed, although this technique has sev- 197
170 loss) or extra intestinal inflammatory manifestations (mainly eral drawbacks: lower diagnostic accuracy than MR, because 198
171 affecting the joints, skin or eyes); and (c) elevated acute it cannot detect extra intestinal complications; consider- 199
172 phase reactants (C-reactive protein, erythrocyte sedimenta- able radiation; and lack of training in this technique among 200
173 tion rate, platelet count) or faecal calprotectin >150 mg/kg the younger generation of radiologists. For all these rea- 201
174 in 2 samples taken at different times in patients not taking sons, barium enemas should be avoided. Abnormal findings 202
175 NSAIDs.10,11 from any of the foregoing will indicate the need for further 203
176 As evaluation of the intestinal mucosa and histologi- studies, such as gastroduodenoscopy, enteroscopy, capsule 204
177 cal confirmation are required for the diagnosis of most endoscopy or specific imaging scans. 205
178 entities causing chronic inflammatory diarrhoea (Table 1), Chronic inflammatory diarrhoea secondary to infec- 206
179 colonoscopy should initially be performed (with or without tion is rarely found except in the immuno compromised 207
180 ileoscopy, depending on symptoms and colonoscopic findings patient population; the principle causes are summarised in 208
181 as far as the caecum) (Algorithm 2, Fig. 2). If colonoscopy Table 4. Faecal cultures, therefore, are only indicated in 209
182 (with or without ileoscopy) is incomplete, or if findings are immuno compromised patients or those receiving immuno 210
183 unremarkable, other small bowel imaging techniques should suppressants, and are typically tested for Salmonella, 211
184 be used. Of these, magnetic resonance (MR) enterography, Shigella, Yersinia and Campylobacter. Serial sampling is 212
185 which is similar to CT enterography as regards diagnostic not necessary, and samples can be refrigerated. Several 213
186 accuracy but with no harmful radiation, is the technique of methods can be used to test for Clostridium difficile (stool 214
187 choice. Alternatively, abdominal ultrasound with or without toxin assay, faecal culture, cytotoxin assay, and glutamate 215
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Table 4 Causative agents of chronic infectious diarrhoea.a

Recommendations 236
Bacteraemia (rare) Protozoa Viruses

(Immunocompromised)
1 Determination of faecal calprotectin is recommended as a 237
Salmonella Giardia Norovirus useful biomarker for chronic diarrhoea caused by inflam- 238
Shigella Cryptosporidium Citomegalovirus mation (CE, high; SR, strong). 239
Yersinia Blastocystishominis 2 Initial investigation in a patient with suspected chronic 240
Campylobacter Entamoebahistolytica inflammatory diarrhoea is colonoscopy (CE, high; SR, 241

Aeromonas Diantomoeba strong). 242
Escherichia coli Helmintos
3 If colonoscopy is negative, incomplete, or ileoscopy 243
(enteroinvasive) (Strongyloides)
Clostridium difficile
could not be performed, other studies, preferably MR 244
a enterography, should be performed to evaluate the small 245

Faecal culture is only indicated in immunocompromisedpa-
tients or patients receiving immunosuppressants. intestine (CE, high; SR, strong). 246
Chronic diarrhoea due to malabsorption 247

216 dehydrogenase tests), although none has been shown to be
217 clearly superior13 ; no single test will give maximum sensitiv-
Maldigestion is typically defined as decreased intralumi- 248
218 ity and specificity while minimising costs and analysis time,
nal hydrolysis of foodstuffs, and malabsorption as the 249
219 and diagnostic algorithms recommend basing diagnosis on 2
reduced mucosal absorption of nutrients. Although this dis- 250
220 or 3 consecutive tests.
tinction is useful in terms of pathophysiology, maldigestion 251
221 Testing for parasites must be performed on 2 fresh sam-
and malabsorption have similar clinical presentations and 252
222 ples taken on alternate days. If fresh samples cannot be
complications. For this reason, only the term malabsorption 253
223 obtained, patients can be given an appropriate container
will be used in these guidelines. 254
224 and medium for providing ‘‘fixed’’ refrigerated faeces sam-
In clinical practice, it is important to differentiate 255
225 ples. Parasites (trophozoite, cysts and eggs) are identified
between diarrhoea due to enteropathy, diarrhoea due to 256
226 under direct microscopy, and the sensitivity of the test will
bacterial overgrowth, and diarrhoea due to pancreatic dis- 257
227 depend on the intensity of colonisation, the freshness of the
ease. Diagnosis of each of these entities is described in a 258
228 sample, and the expertise of laboratory personnel.
specific algorithm (Algorithms 3 and 4, Figs. 3 and 4). 259
229 Special mention should be made of sexually transmitted
230 gastrointestinal infections,14 which are usually charac-
231 terised by rectal symptoms (rectal discharge, tenesmus, or Diarrhoea due to enteropathy 260
232 faecal incontinence). These infections are associated with

233 specific aetiological agents, they can mimic inflammatory This is caused by malabsorption of nutrients secondary to 261
234 lesions or tumours on endoscopy, and require specific diag- enterocyte dysfunction. Coeliac disease is the paradigm 262
235 nostic methods (Table 5). of chronic diarrhoea due to enteropathy, and is by far 263
the most frequent cause of villous atrophy, although it 264
can also be caused by other entities (Table 6).15---20 Duo- 265
Table 5 Diagnosis of sexually transmitted proctitis. denal biopsy (6 samples: 2 from the duodenal bulb and 266
4 from the distal duodenum) will usually yield a diag- 267

Aetiology Diagnostic test of choice
nosis, or at least confirm the existence of enteropathy, 268
Gonorrhoea Biopsy culture irrespective of its aetiology. In some cases, such as amy- 269
Lymphogranulomavenereum Tissue PCR can identify loidosis or Whipple disease, a duodenal biopsy is diagnostic 270
serotypes, but is not widely due to the characteristic histopathological appearance of 271
available. the tissue.21 Intestinal lesions caused by coeliac disease, 272
Serology is useful for however, are non-specific (for any grade of lesion, from lym- 273
diagnosing patients with phocytic enteritis to atrophy) (Tables 6 and 7).22---25 Diagnosis 274
compatible symptoms and should be complemented or confirmed with other ana- 275
endoscopic findings, but lytical tests (serology, genetic studies, lymphocyte subset 276
given the high prevalence of tests) and clinical evaluations (good response to gluten- 277
Chlamydia infection in free diet).26 As none of the foregoing criteria are in 278
sexually active patients, the themselves sufficient for a diagnosis of coeliac disease, 279
test is not specific for acute the use of score-based tests, such as the ‘‘4 out of 5’’ 280
infection rule, has been suggested (Table 8).27 Nonetheless, when 281
Syphilis Dark field microscopy diarrhoea due to enteropathy is suspected, an intestinal 282
findings of treponema in biopsy must be performed to either confirm suspicion or 283
rectal exudate has low determine the extent of the lesion. The clinical context 284
sensitivity but high (epidemiological and/or family history, radiation enteri- 285
specificity (valid in early tis caused by radiation therapy, bone marrow transplant 286
stages of infection) in the case of graft-versus-host disease, pharmaceutical 287
Positive serology from 2 or 3 therapy, etc.) will guide diagnosis. Table 6 shows the 288
weeks after first infection main causes of enteropathy-related diarrhoea, together 289
Herpes simplex PCR ulcer biopsy with diagnostic methods and the quality of the support- 290
ing evidence. It also describes the diagnostic process for 291
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Table 6 Principle causes of enteropathy that can cause diarrhoea, and diagnosis.
Pathological Histopathological findings Special Other diagnostic methods CE
entity stains/molecular
biology
Coeliac Lymphocytic enteritis to CD3 Serology (Se, 85%-99%; Sp, H
disease atrophy immunostaining 91%-100%)a M
(Classification Table 7) (CE, M) Genetic testing (S, 93% Sp, M
/Non-specific lesion 77%)a M
Flow cytometry study of GS
lymphocyte subsets (Se, 85%;
Sp, 100%)
4 out of 5 rule (Table 8)
Giardiasis Presence of Giardia/Specific No Parasites detected in stool
lesion Formalin-ethyl acetate GS
Normal mucosa (53%-96%) concentration (FEAC)
Atrophy (3%) Direct vision of eggs or cysts
Nodular lymphoid hyperplasia
(35%)
Eosinophilic infiltrate (35%)
Tropical sprue Lymphocytic enteritis to CD3 Therapeutic response to L
atrophy (more frequently immunostaining antibiotics, folic acid and
subtotal atrophy) (CE, M) vitamin B12
/Non-specific lesion Negative coeliac serology
Epidemiological exposure
Collagenous Lymphocytic enteritis to Trichrome No response to gluten-free diet L
sprue atrophy (more frequently Tenascin Negative coeliac serology
atrophy) Response to steroids
Collagenous band > 10 Possible association with
␮m refractory coeliac disease and
/Specific lesion lymphoma (see below)
Refractory coeliac disease (RCD):

Type I Atrophy CD3 Ensure gluten-free diet
/Non-specific lesion immunostaining Flow cytometry study of
Normal phenotype lymphocyte subsets: no M
aberrant phenotype
Type II Atrophy Immunostaining: Flow cytometry: aberrant M
/Non-specific lesion Aberrant immunophenotype CD3␧+CD8−
phenotype (CE, M) and monoclonality
Clonality testing Negative coeliac serology
(PCR) (CE, M) (previously positive)
Ulcerative Lymphocytic enteritis to CD3 Capsule endoscopy L
jejunitis atrophy immunostaining
/Non-specific lesion (CE, M)
Enteropathy- Atrophy Immunostaining: Flow cytometry: aberrant M
associated Atypical lymphocytic infiltrate aberrant immunophenotype CD3␧+CD8−
T-cell /Specific lesion phenotype (CE, M) and monoclonality L
lymphoma Clonality testing Capsule endoscopy
(PCR) (CE, M)
Other B and T Lymphoid hyperplasia or Immunostainingb Imaging techniques L
lymphomasb atypical lymphocytic infiltrate Subsets, Capsule endoscopy
(e.g. MALT) /Lesion not always specific or proliferation and Double-balloon enteroscopy
not detectable with biopsy apoptosis Cross-sectional radiography
forceps
Drug-induced Lymphocytic enteritis to CD3 Negative coeliac serology L
enteropa- atrophy immunostaining Positive genetic testing for L
thy - /Non-specific lesion (CE, M) coeliac disease 50%-60% H
olmesartan Mucosa normalised after
withdrawal of therapy
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Table 6 (Continued)
Pathological Histopathological findings Special Other diagnostic methods CE

entity stains/molecular
biology
Whipple Isolation of macrophages with Immunostaining Isolation of T. whipplei in fluids M
disease PAS+ stain around T. or otherinvolved tissues
Tropherymawhipplei whipplei-specific (synovial, CSF, stools, etc.)
/Specific lesion PCR
(CE, M)
Amyloidosis Amyloide in submucosal vessels Polarized light Immunohistochemistry for: M
and possibly in mucosa (Congo red) (CE, AL proteins (primary A)
/Specific lesion M) AA proteins (secondary A)
CE: quality of the evidence (H, high; M, moderate; L, low); GS: gold standard.
a Coeliac serology: anti-endomysial, anti-tissue transglutaminase, anti-deamidatedgliadin peptide antibodies. Sensitivity (Se) and speci-
ficity (Sp) levels generally refer to coeliac disease with atrophy. In lymphocytic enteritis due to coeliac disease, sensitivity can be as low
as 15%.
b B- and T-cell lymphoma classification: WHO 2008.30
Diarrhoea due to
malabsorption/maldigestion
Enteropathy Bacterial
Pancreatic disease
overgrowth¶
Suspected enteropathy?*
Hydrogen breath test See algorithm 4
C14 D-Xylose breath test
Duodenal biopsy
Normal Abnormal
Abnormal Normal
Special techniques
- Anti-CD3 IHC (coeliac)
Consider therapeutic testing
Trichrome/Tenascin (collagenous
Enteropathy unlikely with antibiotics
sprue)
-Clonality testing
(refractory coeliac disease
/lymphoma
Consider complementary studies

-Genetic testing for coeliac disease
-Flow cytometry for lymphocyte
subsets (difficult to diagnose or
refractory coeliac disease/lymphoma)
-Imaging techniques (ulcerative
jejunitis, lymphoma)
Figure 3 Algorithm 3. Diagnosis of chronic diarrhoea due to enteropathy and bacterial overgrowth
*Suspectedenteropathy: risk group for coeliac disease (family members, Down syndrome, organ-specific systemic autoimmune dis-
eases, compatible symptoms, etc.), visits to tropical countries, poorly controlled coeliac disease, olmesartan therapy, etc.
**Suspected bacterial overgrowth: structural changes in the small bowel (e.g. by-pass, stenosis) or motility disorder.
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Patient with chronic diarrhoea and

suspected exocrine pancreatic
insufficiency (EPI) (A)
1. Serum amylase and

lipase levels
2. Faecal elastase (B)
Amylase and/or lipase < normal + Yes

Probable primary EPI
elastase < 200 μg/g?
No
Pathological faecal elastase? (C) Aetiological study of

pancreatic pathology
Yes No Pancreatic imaging studies

Probable EPI
(CT, MR, EUS)
Pancreatic imaging studies Pancreatic atrophy, signs of advanced No

(CT, MR, EUS) pancreatic disease or suspected
pancreatic cancer? (D)
Yes
Pathological? (D) Treat with pancreatic

enzymes for 3-4
weeks (E)
Yes No
Probable
Consider causes of No EPI unlikely as cause
primary Efectivo?
secondary EPI (Table 10) of chronic
pancreatic
diarrhoea (F)
insufficiency
Yes
Primary EPI
Figure 4 Algorithm 4. Diagnosis of chronic diarrhoea due to exocrine pancreatic insufficiency.

(A) Strong suspicion. Patients with heavy alcohol consumption and smoking habit, history of acute or recurrent pancreatitis, chronic
pancreatic-type abdominal pain, suspicion of mutation in the cystic fibrosis gene (bronchiectasis, male sterility, family history of
cystic fibrosis), suspicion or diagnosis of pancreatic cancer, previous pancreatectomy.
Suspicion. Occasional smoker, diabetes mellitus, gastrectomy, advanced age, diarrhoea improves with fasting, no anorexia.
(B) Faecal elastase is the most widely used pancreatic function test, and is available in most hospitals. It is performed on a solid
stool sample. Liquid stool samples can give falsely low elastase levels.
(C) Concentrations below 100 ␮g/g are definitely pathological. Concentrations between 100 and 200 ␮g/g are also pathological,
but with lower sensitivity and specificity; they should be viewed with caution. In patients with pancreatectomy, concentrations
<200 ␮g/g can indicate exocrine insufficiency.
(D) Although it is a cause of primary pancreatic insufficiency, pancreatic atrophy can in itself be primary (due to pancreatic disease)
or secondary to other factors, such as prolonged malnutrition or advanced age.
(E) Response to enzyme therapy should be evaluated following administration of an appropriate dose, and in the absence of bacterial
overgrowth or other causes of enzyme inactivation or that contribute to the diarrhoea. Recommended initial lipsasedose: 25000 IU
with small meals, and 50000 IU with large meals (±proton pump inhibitor).
(F) Therapeutic testing can be used when no other cause for diarrhoeais found, and suspicion of exocrine insufficiency persists.
292 some specific entities, such as tropical sprue,28 refractory Diagnosis is generally made in childhood, and suspicion is 298
293 coeliac disease and gastrointestinal lympho proliferative rarely guided by the enteropathy caused by these condi- 299
294 disorders.20,29,30 tions, but rather by the clinical context and laboratory 300
295 In addition to the foregoing, other less common diseases, results (low levels of apoprotein B, triglycerides and choles- 301
296 such as abetalipoproteinemia, hypobetalipoproteinemia terol, in the former, and hypogammaglobulinemia with no B 302
297 or hypogammaglobulinemia, can also cause diarrhoea. lymphocytes in the latter). 303
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Table 7 Histopathological classification systems in coeliac disease.

Marsh 199222 Oberhuber 199923 Corazza 200524 Ensari 201025
Type 1 Infiltrative lesion Type 1 Infiltrative Grade A Type 1
lesion
Type 2 Crypt hyperplasia Type 2 Crypt Removed. Added Removed. Added
hyperplasia to Grade A to Type 1
Type 3 Atrophy Type 3 Atrophy Atrophy Atrophy
Type 3A. Partial Grade B1 Type 2
Type 3B. Subtotal Grade B1 Type 2
Type 3C. Total Grade B2 Type 3
Type 4 Destructive lesion Type 4 Destructive Obsolete Obsolete
lesion
anaerobes, may be partially replaced with colic bacteria 327

Table 8 The gold standard 4 out of 5 rule for the diagnosis
(coliforms and anaerobes: Bacteroides and Clostridium), 328
of coeliac disease.
causing an increase in certain enzymes, such as colilamidase 329
1. Typical symptoms (e.g., diarrhoea, growth delay, and protease. Colilamidasesde conjugate bile salts, which 330
anaemia, etc.) are then more easily absorbed by passive transport in 331
2. Positive for high titres of class A antibodies (IgG the proximal jejunum. This hampers micelle production, 332
accepted in case of IgA deficiency, IgG leading to malabsorption of fats. The increased proteases 333
anti-deamidatedgliadinpeptideantibodies strengthen reduce villous surface enzymes, such as the disacchari- 334
diagnosis) dases, thus causing carbohydrate malabsorption. Small 335
3. Positive for HLA-DQ2 and/or HLA-DQ8 genotypes bowel bacterial overgrowth (SBBO) can be caused by a num- 336
4. Enteropathy on intestinal biopsy (includes Marsh ber of diseases, and should be suspected in any situation 337
1 ---positive serology or associated with subepithelial associated with impaired motility due to either structural 338
deposits --- to Marsh 3) (stenosis, by-pass, etc.,) or functional (pseudo-obstruction, 339
5. Clinical and serological improvement with gluten-free diabetic enteropathy, etc.) disorders. Increased pH in 340
diet (histological improvement in sero-negative patients) the duodenum or proximal jejunum (caused by proton 341
pump inhibitor [PPI] therapy, gastrectomy or atrophic 342

Source: adapted from Catassi and Fasano.27
gastritis) increases the risk of SBBO due to absence of the 343
bacteriostatic effect of the acid environment. The role of 344
304 Recommendations SBBO in the pathophysiology of irritable bowel syndrome 345
(particularly associated with diarrhoea and/or distension) 346
305 (See Table 6 for the quality of evidence of each diagnostic is still unclear, although it could be a causative factor in 347
306 study.) some patient subgroups. There is insufficient conclusive 348
evidence to recommend the routine study of SBBO in these 349
307 1 Determination of IgA anti-tissue transglutaminase anti- patients. Table 9 summarises the studies recommended for 350
308 body levels is the test of choice to screen for coeliac detecting bacterial overgrowth. Small-bowel aspiration and 351
309 disease in patients with chronic diarrhoea (CE, high; SR, quantitative culture is considered the gold standard, but 352
310 strong). the complexity of the test rules out its use in routine clinical 353
311 2 If blood tests are negative for coeliac disease, the pres- practice. As an alternative, the 14 C/13 C d-xylose breath 354
312 ence of HLA-DQ2.5 should be determined. If positive, test has been shown to be the most accurate, but has less 355
313 intestinal biopsies should be taken to rule out coeliac supporting evidence than hydrogen breath tests.33,34 356
314 disease (CE, moderate; SR, strong). Some authors have proposed therapeutic testing with 357
315 3 In the case of suspected malabsorption syndrome, distal antibiotics to detect SBBO when pre-test probability is 358
316 duodenal biopsy is indicated to diagnose coeliac disease high (clear predisposing cause and compatible clinical 359
317 or other types of enteropathy (CE, moderate; SR, strong). presentation).33 Nevertheless, it is important to bear in mind 360
that SBBO should usually be treated cyclically, and thus calls 361
for an objective diagnostic test. 362

318 Diarrhoea due to bacterial overgrowth
319 Diarrhoea due to bacterial overgrowth (BO) is caused Recommendations 363
320 by malabsorption of foodstuffs, including fats and

321 carbohydrates.31,32 Certain situations involving high pH 1 The hydrogen breath test has low sensitivity but adequate 364
322 values, stasis or delayed gastric emptying can give rise specificity for diagnosing SBBO, and is useful when results 365
323 to qualitative and quantitative changes in the bacteria are positive. Hydrogen breath testing with glucose is rec- 366
324 colonising the proximal intestine, with a significant impact ommended (CE, high; SR, strong). 367
325 on the gut microbiota. The usual gut flora, consisting of 2 A therapeutic test with antibiotics can be used to 368
326 lactobacilli, enterococci, and gram-positive facultative diagnose SBBO when pre-test probability is high (clear 369
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Table 9 Recommended tests for bacterial overgrowth.

Technique Diagnostic Level of
accuracy evidence
Quantitative Complex technique. Special sample collection Gold standard
culture of techniques for anaerobic bacteria, avoiding
jejunal fluid contamination from pharyngeal bacteria, and rapid
aspirate plating for anaerobic and aerobic bacteria.
Bacterial overgrowth >105 CFU/ml in the proximal
jejunum
False positives: collection of samples from a
diverticulum
False negatives: collection of samples proximal to the
structural abnormality
Hydrogen 50 g glucose challenge: bacterial overgrowth > 20 ppm of Se 62.5% H
breath test H2 for 2 h after administration
10 g lactulose challenge: bacterial overgrowth > 20 ppm Sp 81.8%
of H2 in the first 90 min (early peak), or presence of a
double peak, or sustained increase >10 ppm over
baseline value
False negatives: Non-H2 producing flora Se 52.5%
False positives: Very rapid oro-caecal transit (e.g., Sp 85.7%
gastrectomy)
C14 d-xylose Administration of 1 g of 14 C-labelled D-xylose Se and Sp, H
breath test ∼85---90%
Bacterial overgrowth: detection of 14 Cin exhaled breath
Fewer false positives for D-xylose. Absorbed in small
bowel and does not reach colon
CFU: colony forming units; Se: sensitivity; Sp: specificity.
370 predisposing cause and compatible clinical presentation),

371 and the hydrogen breath test is negative or not available
372 (CE, low; SR, weak).
Table 10 Causes of exocrine pancreatic insufficiency.
Primary causes
373 Chronic diarrhoea caused by exocrine pancreatic 1. Chronic pancreatitis
374 insufficiency 2. Cystic fibrosis
3. Pancreatic cancer
375 Pancreatic enzyme deficiency results in malabsorption of 4. Acute pancreatitis (generally transient)
376 foodstuffs (particularly fats), which results in loose or liq- 5. Duct obstruction (including ampulloma, cysts and
377 uid stools and increased daily stool output. Steatorrhoea is MPTs)
378 defined as the elimination of >7 g/day fat with a dietary 6. Pancreatectomy
379 intake of 100 g fat/day (fat absorption coefficient <93%). 7. Senile pancreatic atrophy, acquired (persistent severe
380 Pancreatic steatorrhoea only occurs when the functional malnutrition) or congenital (BDS, Johanson-Blizzard,
381 reserve capacity of the pancreas is severely depleted.35 pancreatic lipomatosis, dorsal pancreatic agenesis,
382 Moderate steatorrhoea might not be associated with diar- MODY) atrophy
383 rhoea. Constipation is a common symptom in patients with Secondary causes
384 chronic pancreatitis or cystic fibrosis and severe pancreatic 1. Coeliac disease and other enteropathies (Crohn
385 insufficiency. Diarrhoea secondary to primary pancreatic disease, common variable immune deficiency with
386 disease is not usually particularly voluminous, hardly ever intestinal involvement, eosinophilic enteritis, etc.)
387 watery (can be oily), and improves with fasting. Patients 2. Gastrectomy --- pancreatic stent (postprandial
388 may suffer weight loss without anorexia, unless insufficiency asynchrony)
389 is due to pancreatic cancer. 3. Zollinger-Ellison syndrome
390 Pancreatic insufficiency can be primary (due to pancre- 4. Drugs (long-term octreotide therapy)
391 atic disease) or secondary. In the latter, suboptimal enzyme Of uncertain origin
392 levels are only partially responsible for the diarrhoea. How- 1. Diabetes mellitus
393 ever, administration of enzymes can improve symptoms in 2. Irritable bowel syndrome
394 some cases, such as gastrectomy, diabetes mellitus and pan- 3. Chronic renal failure
395 creatic cancer. Table 10 summarises the causes of pancreatic
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396 insufficiency. The most common primary cause is chronic other factors (for example, bacterial overgrowth). In a 453
397 pancreatitis, followed by cystic fibrosis and pancreatic can- preliminary analysis, a cut off value of <200 ␮g/g was 454
398 cer. found to have a sensitivity of 63% for mild and 100% 455
for moderate to severe insufficiency (compared with 456
the cerulein-secretin test), with a specificity of 93% 457

399 Tests for exocrine pancreatic insufficiency
and significant correlation with enzyme and bicarbonate 458
secretion.41 Values under 100 ␮g/g have a sensitivity and 459

400 We will address the diagnosis of pancreatic insufficiency as
specificity for steatorrhea of 93% and 81%, respectively.42 460
401 a cause of chronic diarrhoea, and not as a factor in the
In patients with pancreaticoduodenectomy, faecal elas- 461
402 diagnosis of chronic pancreatitis. More than 20 tests for
tase concentrations of <200 ␮g/g are accompanied by 462
403 pancreatic insufficiency have been described, but none give
steatorrhea.42 Sensitivity for detecting steatorrhoea in 463
404 optimal results in clinical practice. Some are non-diagnostic
these cases is 91%, but specificity is only 35%.43 The 464
405 (cerulein-secretin stimulation test), or are no longer in use
difference in these cases arises because exocrine insuffi- 465
406 (faecal chymotrypsin). As far as common clinical studies
ciency is accompanied by anatomical abnormalities that 466
407 are concerned, the sensitivity, specificity and predictive
prevent optimal mixing of nutrients with bile salts and 467
408 value of the tests will depend to a large extent on the cho-
with the enzymes and bicarbonate secreted by the pan- 468
409 sen reference value (steatorrhoea vs. chronic pancreatitis)
creatic remnant (postprandial asynchrony). 469
410 and the underlying disease (cystic fibrosis, pancreatectomy,
4 Faecal chymotrypsin. Enzyme levels <3 U/g have a speci- 470
411 chronic pancreatitis, etc.).
ficity of between 49% and 100% and a sensitivity of 471
between 50% and 90% for chronic pancreatitis. The speci- 472
412 Tests that yield relevant clinical information ficity for pancreatic disease is extremely high (90---100%) 473
for determining both the origin of steatorrhoea44 and 474
413 1 Serum amylase, lipase and trypsin levels. Due to their for detecting pancreatic insufficiency in patients with 475
414 low sensitivity, these tests are rarely used. However, cystic fibrosis.45 The test has a sensitivity of 69% and a 476
415 low levels of these enzymes are indicative and specific specificity of 89% for detecting pancreatic insufficiency 477
416 (>90%) for primary exocrine insufficiency, particularly in patients with chronic pancreatitis.41 When used with 478
417 in patients with cystic fibrosis, advanced chronic pan- watery stools, it can yield false positives. Test kits are 479
418 creatitis, pancreatic cancer and Shwachman---Diamond not widely available. 480
13
419 syndrome. As diarrhoea only occurs with severely 5 Cmixedtriglyceride breath test. In this test, concen- 481
420 impaired pancreatic function, pancreatic enzymes could trations of 13 C in exhaled breath are measured following 482
421 have adequate sensitivity in cases of chronic diarrhoea; intake of triglycerides labelled with 13 C. It has a sensi- 483
422 however, this hypothesis has not been tested. tivity of 89% and a specificity of 81% for the diagnosis of 484
423 2 Evidence. In paediatric patients with cystic fibrosis, low pancreatic steatorrhoea.46 Compared with direct secre- 485
424 lipase and trypsin levels correlate with steatorrhoea,36 tion tests (secretin-cerulein) and with faecal elastase 486
425 with a sensitivity of 95% and 93%, respectively, and a and chymotrypsin, it has a sensitivity of 85% and a 487
426 specificity of 86% and 92%.37 In patients with chronic pan- specificity of 100% for diagnosing severe pancreatic 488
427 creatitis, low trypsin or amylase levels have a sensitivity insufficiency, but only 69% and 46%, respectively, for 489
428 of 70---85% for steatorrhea38 , but less than 50% for mild moderate insufficiency. The test is not superior to the 490
429 exocrine insufficiency measured by the secretin stimu- sensitivity and specificity of the faecal elastase test.47 491
430 lation test.39 Specificity for pancreatic steatorrhoea is Presence of bacterial overgrowth can give false neg- 492
431 between 90% and 100%.40 Low or undetectable serum atives, particularly in patients with pancreatectomy.48 493
432 lipase levels are typical of congenital lipase deficiency, Other factors that can distort results are a diet rich in 494
433 a disease that presents with steatorrhoea and normal foodstuffs containing 13 C, abnormal gastric emptying, 495
434 faecal elastase. physical exercise, and basal CO2 production. Drawbacks 496
435 3 Faecal pancreatic elastase determination. This is the include the duration of the test (between 6 and 8 h), 497
436 gold standard for detecting pancreatic insufficiency, the requirement for patients to fast and abstain from 498
437 and is recommended in British guidelines for chronic exercise, and the need for specially trained personnel. 499
438 diarrhoea.5 The test determines levels of human pan- 6 Faecal fat and coefficient of fat absorption. Quan- 500
439 creatic elastase (but not enzymes) in stool. Results tification of faecal fat is a good marker of exocrine 501
440 are not affected by pancreatic enzyme therapy. It insufficiency in patients with a known pancreatic 502
441 is a simple, inexpensive and reproducible test (15% parenchymal lesion. The total fat content in stool sam- 503
442 individual variability),41 but can yield false positives ples taken over 72 h is measured. Patients are required 504
443 when used with liquid stool samples. Concentrations to eat a diet containing 100 g fat/day for 2 days prior to 505
444 of >200 ␮g/gelastase per g of stool are normal, while the start of the test. Faecal fat >7 g/day indicates steat- 506
445 concentrations of <100 indicate severe pancreatic insuf- orrhoea (coefficient of fat absorption <93%). Although 507
446 ficiency. Concentrations of between 100 and 200 are this is the gold standard for steatorrhoea screening,43 it 508
447 suggestive of pancreatic disease, but should be consid- is not specific for pancreatic disease. 509
448 ered in the general context of the case. Evidence for 7 Endoscopic pancreatic function test. This test is only 510
449 sensitivity and specificity levels is conflicting, but it is performed in some hospitals Pancreatic secretions in 511
450 generally considered a useful screening test for severe response to secretin or cerulein stimulation are aspi- 512
451 pancreatic insufficiency, which is the clinical situation rated through the endoscope at certain time intervals. 513
452 associated with chronic diarrhoea, in the absence of The test has a sensitivity of 83% and a specificity of 87% 514
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Chronic, watery, non-bloody diarrhoea
Inflammatory causes: “Functional”

calproctectin>150 mg/kg characteristics
Measure stool output
> 1 L (often > 3L) <1L

(persists after fasting) (usually resolves after fasting)
CHO Bacterial Bile salts Diabetes***‡

Neuroendocrine Laxatives **¶ Others: Serology and
overgrowth SeHCAT test Microscopic colitis
↑ Osmotic Multifactorial
tumour Faecal Mastocytosis genetic testing
gap (advanced age, (diagnosis of Colon biopsies
*VIPoma electrolytes (intestinal biopsy, for coeliac
anatomical exclusion)
Carcinoid Osmotic gap special staining) disease, duodenal ↓ pH abnormalities)
Gastrinoma Mg, PO4 Villous adenoma biopsy
Hydrogen
Medullary thyroid Melanosis coli (hypokalaemia, breath test Breath test
cancer (colonoscopy) alkalosis)
Figure 5 Algorithm 5. Diagnosis of chronic watery non-bloody diarrhoea.

Other causes of <1 L/day: pharmacological therapy, hyperthyroidism, alcohol.
*Serum peptide panels have a false positive rate of 45% (positive predictive value <1%); only request these when there are signs and
symptoms of neoplasm (Table 11) or when CT/MR or octreoscan findings indicate a tumour.
**Can be high- or low-volume, depending on the dose administered; can respond to fasting. A finding of melanosiscoli on colonoscopy
suggests regular use of anthraquinone laxatives, such as senna and cascara sagrada.
***In diabetic patients, diarrhoea can have multifactorial causes: excess fructose consumption, bacterial overgrowth, increased
risk of coeliac disease, and microscopic colitis in type 1 DM, some pharmacological therapies (metformin, acarbose), autonomic
neuropathy.
CHO: carbohydrates (lactose, fructose and/or sorbitol).
515 for diagnosis of chronic pancreatitis.49 A reduced ver- standard for evaluating exocrine pancreatic insufficiency 546
516 sion of the test, in which secretions are aspirated over (CE, high; SR, strong). The labelled triglyceride test can 547
517 15 min, also gives good results.50 be a good alternative in hospitals where this test has been 548
518 8 Secretin-enhanced magnetic resonancecholangiopan- validated (CE, moderate; SR, weak). 549
519 creatography. The test quantifies duodenal secretions in 2 If the findings of the former test are inconclusive, mor- 550
520 response to secretin infusion. Imaging findings can dis- phological abnormalities on imaging studies can indicate 551
521 criminate patients (chronic pancreatitis) from healthy exocrine pancreatic insufficiency (CE, low; SR, strong). 552
522 volunteers,51 and correlate with faecal elastase test 3 If diagnostic tests are inconclusive, or when pancreatic 553
523 findings.52 The test only measures volume of secretions, insufficiency is merely a contributing factor to chronic 554
524 and is not standardised. diarrhoea, therapeutic testing with pancreatic enzymes 555
525 9 Morphological investigations. The greater the morpho- may be indicated (CE, low; SR, weak). 556
526 logical abnormalities in imaging studies, the greater the

527 pancreatic dysfunction. Pancreatic insufficiency rarely
528 occurs in patients with normal pancreatic morphology. Watery, non-bloody diarrhoea with organic 557
529 Correlation between imaging and direct function test characteristics 558
530 results is good, but not perfect.53,54 In patients with

531 partial pancreatectomy (in whom pancreatic function In patients with chronic watery, non-bloody diarrhoea with 559
532 testing is difficult or inaccurate), the main duct diam- organic characteristics (Table 3), diagnosis is based on the 560
533 eter/parenchymal thickness ratio correlates well with strategy outlined in algorithm 5 (Fig. 5). These usually 561
534 exocrine insufficiency.55 involve secretory diarrhoea characterised by large-volume, 562
535 10 Therapeutic testing with pancreatic enzymes. Thera- watery stools, often more than 1 L per day; persistence 563
536 peutic testing is used when there is a strong suspicion of diarrhoea after fasting; and stool-water tests that show 564
537 of pancreatic insufficiency and the results of other tests measured osmolality to be identical to that calculated from 565
538 have proved inconclusive, and is a useful confirmatory its electrolyte concentration (see below).57 Agents causing 566
539 test. For example, in a group of patients with diarrhoea- secretions that can lead to chronic diarrhoea include vari- 567
540 predominant irritable bowel syndrome, 6% had faecal ous hormones and substances produced by neuroendocrine 568
541 elastase levels <100 mg/g, and symptoms improved after tumours (Table 11).57---59 However, watery, secretory diar- 569
542 enzyme therapy.56 rhoea is only caused by such tumours in 1 in 5000 to 1 in 570
500,000 patients with chronic diarrhoea, depending on the 571
type of tumour. 572

543 Recommendations Some patients present chronic secretory diarrhoea due 573
to abuse of laxatives. The presence or absence of large- 574
544 1 In chronic diarrhoea investigations, determination of fae- volume watery stools will depend on the laxative dose taken, 575
545 cal elastase in non-watery stool samples is the gold and symptoms will improve with fasting. This aetiology 576
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Table 11 Neuroendocrine tumours that cause diarrhoea, and their markers.

Tumour Characteristic symptoms Tumour marker
Gastrinoma Zöllinger-Ellison syndrome: peptic ulcer, diarrhoea, Gastrin
steatorrhoea
VIPoma Verner-Morrison syndrome: diarrhoea (>3 L/day), VIP
hypokalaemia, hypochlorhydria
Medullary thyroid Thyroid nodule Calcitonin,
cancer prostaglandins
Carcinoid Flushing, bronchospasm, right-sided valve disease Serotonin, kinins
Somatostatinoma Diabetes mellitus, gall stones, steatorrhoea Somatostatin
Glucagonoma Rash (necrolytic migratory erythema), diabetes Glucagon
Mastocytosis Flushing, urticariapigmentosa, abdominal pain, vomiting Histamine
577 should be suspected in the following circumstances60,61 : (a) laxatives and other drugs.66 Abuse of laxatives derived from 620
578 bulimic patients (usually young or adolescent women con- magnesium sulphate, phosphates and other sulphates can be 621
579 cerned about their body weight, or with confirmed eating detected with electrolyte and stool osmotic gap panels67 . 622
580 disorders); (b) patients with an ulterior motive (economic, Normal stool osmotic gap values are between 50 and 125 623
581 manipulation of family members); (c) Munchhausen syn- (the osmotic gap is the results of subtracting stool osmolal- 624
582 drome (patients with a psychological need to be a diagnostic ity [290mOsm] from 2* Na++ + K+ in stool water). In secretory 625
583 challenge); and (d) Munchhausen’s syndrome by proxy (chil- diarrhoea, the osmotic gap is less than 50, while in osmotic 626
584 dren or dependent adults given laxatives by their guardian diarrhoea it increases to >125. Patients with diarrhoea sec- 627
585 or carer in order to seek personal benefit). ondary to Mg2++ present high osmotic gap values and stool 628
586 In patients with chronic secretory diarrhoea associated Mg2+ >50 mmol/L. Diarrhoea caused by intake of sodium 629
587 with hypokalaemia and metabolic alkalosis, large villous sulphate (Na2 SO4 ) and disodium sulphate (Na2 PO4 ) mimic 630
588 adenomas should be suspected secretory diarrhoea and can be diagnosed by findings of low 631
Cl− concentration in faecal water (usually <20 mmol/L). 632
In factitious diarrhoea, attempts to tamper with findings 633

589 Diagnosis can involve the addition of water or urine to stool samples. 634
This can be detected with stool osmolality testing, and is 635

590 Routine testing for gastrointestinal peptides in blood or shown as reduced values (<25 mOsm) in the case of contam- 636
591 urine has a false positive rate of 45%, and is not rec- ination with hypotonic urine or water, or increased values 637
592 ommended in the diagnosis of patients with chronic (>375 mOsm) in the case of contamination with concentrated 638
593 diarrhoea.62 Considering, moreover, that the pre-test prob- urine. If suspicion is high, spectrofluorimetry or chromatog- 639
594 ability of diagnosing a neuroendocrine tumour as the cause raphy studies may be needed to determine the presence of 640
595 of chronic secretory diarrhoea is extremely low, the posi- laxatives in urine or stool samples. 641
596 tive predictive value of these tests is less than 1%. Serum
597 determination of these peptides or their urinary metabo-
598 lites should therefore only be performed in patients with
599 chronic diarrhoea and signs and symptoms consistent with Recommendations 642
600 neoplasia (Table 11) or with evidence of a neuroendocrine

601 tumour on imaging studies (CT, MR, EUS). Most neuroen- 1 Serum peptide panels to screen for a neuroendocrine 643
602 docrine tumours secrete chromogranin A; however, routine tumour in patients with chronic diarrhoea have a posi- 644
603 testing for this protein contributes little to diagnosis, as tive predictive value of less than 1%, and routine use is 645
604 high levels have been described in other types of can- discouraged (CE, moderate; SR, strong). 646
605 cer (pancreatic, prostate, small cell lung cancer), renal 2 CT and MR scans are useful for diagnosing and staging neu- 647
606 failure, diarrhoea-predominant IBS, inflammatory bowel dis- roendocrine tumours. An octreotide scan, or octreoscan, 648
607 ease, and collagenous colitis, as well as in atrophic gastritis can be useful for identifying functioning neuroendocrine 649
608 and PPI therapy, probably due to enterochromaffin cell tumours (CE, high; SR, strong). 650
609 hyperplasia.63,64 The specificity of this marker for diagnosis 3 Routine determination of chromogranin A in patients with 651
610 of neuroendocrine tumours is only 10---35%, with a sensitiv- chronic watery diarrhoea has low specificity and is of little 652
611 ity of around 60%.63 An octreotide scan, or octreoscan, can diagnostic value (CE, high; SR strong). 653
612 be useful for identifying peptide-producing neuroendocrine 4 A histological finding of pseudomelanosiscoli in biopsy 654
613 tumours.65 samples from a macroscopically normal colon is non- 655
614 A finding of melanosiscoli on colonoscopy suggests reg- specific and should not be taken as a marker of laxative 656
615 ular use of anthraquinone laxatives, such as senna and abuse, as it has also been associated with administration 657
616 cascara sagrada. However, a histological finding of pseu- of other drugs (CE, moderate; SR, strong). 658
617 domelanosiscoli in biopsy samples from a macroscopically 5 Stool osmotic gap measurements can be useful in the 659
618 normal colon is non-specific, and has been associated with diagnosis of chronic large-volume watery diarrhoea (CE, 660
619 increased epithelial apoptosis secondary to use of these moderate; SR, strong). 661
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Table 12 Differential diagnosis of functional diarrhoea. Table 13 Recommended investigations in patients with
suspected functional diarrhoea.
Drug-induced diarrhoea
Sugar malabsorption Clinical situation Investigations
Lactose All patients with chronic Basic blood testswith serology
Fructose-sorbitol diarrhoea for coeliac disease
Bile acid malabsorption
Stool parasite test
Microscopic colitis Mainly postprandial Therapeutic testing with
Coeliac disease diarrhoea cholestyramine
Giardiasis
SeHCAT test (if available)
Bacterial overgrowth Diarrhoea with Hydrogen or methane breath
Exocrine pancreatic insufficiency abdominal distension test with lactose
Inflammatory bowel disease
Hydrogen or methane breath
test with fructose-sorbitol
Hydrogen or methane breath
662 Chronic diarrhoea with functional test with glucose
663 characteristics Nocturnal diarrhoea Faecal calprotectin test
Total colonoscopy with
664 Functional diarrhoea multiple biopsies
Diarrhoea in patients Total colonoscopy with
665 Chronic functional diarrhoea is defined as the persistent or over 50 years of age multiple biopsies
666 recurrent passage of loose or liquid stools for more than Diarrhoea in patients Apply colorectal cancer
667 4 weeks with no obvious organic cause. If symptoms have with family history of prevention protocol, taking
668 lasted for at least 6 months, and occur in more than 75% colorectal cancer multiple colon biopsies
669 of bowel movements in the previous 3 months, a diagno- Diarrhoea in patients Faecal calprotectin test
670 sis of functional diarrhoea can be established according to with family history of
671 Rome III diagnostic criteria for functional gastrointestinal inflammatory bowel
672 disorders. According these criteria, diarrhoea accompanied disease
673 by abdominal pain that improves or is associated with Diarrhoea in patients Genetic testing for coeliac
674 loose stools indicates a diagnosis of diarrhoea-predominant with family history of disease: if positive -
675 irritable bowel syndrome.68 coeliac disease gastroscopy with duodenal
676 Functional diarrhoea may affect around 5% of the gen- biopsies
677 eral population,68 and differential diagnosis must consider Refractory diarrhoea Genetic testing for coeliac
678 a wide range of disorders that can cause chronic diarrhoea disease
679 (Table 12) (Algorithm 6, Fig. 6). In young patients with no Gastroscopy with duodenal
680 alarm signs or symptoms, an unremarkable physical exam- biopsies
681 ination, and mild diarrhoea with no night symptoms and Total colonoscopy with
682 little impact on the patient’s daily activity, general labora- multiple biopsies
683 tory tests including serology for coeliac disease and a stool Faecal elastane
684 parasite test should be performed. If symptoms persist, are
685 incapacitating, or significantly impact the patient’s quality
686 of life, other investigations will be needed to rule out an Table 14 Histopathological diagnostic criteria for micro-
687 organic aetiology (Table 13).7,69---72 Some organic diseases, scopic colitis.
688 such as microscopic colitis, choleretic diarrhoea or sugar Collagenous colitis
689 malabsorption diarrhoea, can mimic functional diarrhoea, Subepithelial collagenous band >10 ␮m
690 and are discussed below. Total intraepithelial lymphocytes >7 per 100 epithelial cells
Epithelial lesion (detachment, flattening)
691 Microscopic colitis Chronic inflammation of the lamina propia
Lymphocytic colitis
692 Microscopic colitis (MC) is a generic term used mainly to Total intraepithelial lymphocytes >20 per 100 epithelial
693 describe 2 entities: collagenous colitis (CC) and lympho- cells
694 cytic colitis (LC). MC describes a form of chronic, recurrent Epithelial lesion (detachment, flattening)
695 inflammatory bowel disease characterised by (a) chronic Chronic inflammation of the lamina propia
696 or intermittent passage of non-bloody watery stools; (b) Subepithelial collagenous band <10 ␮m
697 macroscopically normal or nearly normal colonic mucosa on
698 colonoscopy; and (c) characteristic histopathological find-
699 ings (Table 14).73 unfamiliar with their diagnosis. A recent epidemiological 704
700 In both these entities, symptoms are usually similar to study carried out in Spain reported a mean annual incidence 705
701 functional diarrhoea or irritable bowel syndrome, and gen- of MC of 4.8/105 inhabitants/year.74 Although it can present 706
702 eral laboratory tests are usually negative. Both CC and LC in young patients, incidence peaks in women aged 60 years 707
703 are rare entities, and many clinicians and pathologists are or more, and is higher than Crohn disease and ulcerative 708
GASTRE 956 1---25

+Model
ARTICLE IN PRESS
Chronic, watery diarrhoea with functional characteristics
• Complete colonoscopy (according to Age ≥ 50 years

Dx Yes No
CRC screening protocol) with ileoscopy if possible Family history of CRC
• Colon biopsy (if frequent watery diarrhoea) Family history of IBD
No Dx
Responds to No Yes No
treatment Severe diarrhoea
Sí
Diagnostic
Functional diarrhoea
study
Specific
diagnosis
No Respuesta
Coeliac Yes Responds to Dx • Genetic testing for coeliac disease Sí Family history of coeliac tratamiento
disease treatment • ± Gastroscopy with duodenal biopsy disease
Sí
No No Dx No
Maintain
diagnosis
Dx • Lactose breath test Sí
Malabsorption of sugars Yes Responds to • Fructose-sorbitol breath test
Diarrhoea with abdominal
Bacterial overgrowth treatment • Glucose breath test distension
No No Dx No
Yes Dx • Therapeutic testing with Sí

Diarrhoea caused Responds to Diarrhoea mainly
cholestyramine
by bile acids treatment postprandial
• SeHCAT test
No No Dx No
Functional diarrhoea
No Dx
Severe chronic watery diarrhoea with
functional characteristics: • Genetic testing for coeliac disease
Diarrhoea has major impact on healthrelated quality of life, • Therapeutic testing with cholestyramine
defined as the presence of 2 or more watery bowel Diarrhoea refractory to symptomatic
• Gastroscopy with duodenal biopsies
movements per day, or at least 2 episodes per week of 3 or treatment
more bowel movements per day • Complete colonoscopy with multiple biopsies
• MR enteroscopy
Figure 6 Algorithm 6. Diagnosis of watery diarrhoea with functional characteristics

All patients with chronic diarrhoea with no signs or symptoms of alarm, no abnormal findings on laboratory tests (including serology
for coeliac disease) and no parasites in stool samples, are a priori diagnosed with functional diarrhoea. If such patients are aged
50 years or over, or have a family history of colorectal cancer (CRC), a complete colonoscopy should be performed as part of the
screening protocol for individuals at moderate risk of CRC. During colonoscopy, biopsies should be taken from various sites along
the colon to rule out microscopic colitis in patients with frequent passage of watery stools. A family history of inflammatory bowel
disease is also an indication for total colonoscopy with ileoscopy. If no pathology is found, the protocol for patients aged under 50
years with no family history should be applied; in other words, if the diarrhoea is not serious, a diagnosis of functional diarrhoea
should be established and the patient treated accordingly. In patients with severe diarrhoea, it is advisable to perform diagnostic
tests. Therefore, in patients with a family history of coeliac disease, it is advisable to perform genetic testing for coeliac disease
(HLA-DQ2/8). If positive, duodenal biopsy should be performed. In patients presenting diarrhoea with abdominal distension, it is
important to bear in mind that, although distension can be caused by various functional gastrointestinal disorders, it is advisable
to perform a hydrogen breath test to rule out intolerance to sugars (lactose or fructose and sorbital) or bacterial overgrowth. In
patients with mainly postprandial diarrhoea, it should be borne in mind that although postprandial onset is common in functional
gastrointestinal disorders, it is essential to rule out bile acid malabsorption, ideally using the SeHCAT test. If this is not available,
then therapeutic testing with cholestyramine should be performed. If these tests are not diagnostic, or if they are diagnostic but
with no therapeutic response, the diagnosis of functional diarrhoea should be maintained. All patients with undiagnosed severe
functional diarrhoea that does not respond to symptomatic treatment should undergo a comprehensive study to rule out bile acid
malabsorption, coeliac disease, microscopic colitis or inflammatory bowel disease.
709 colitis in this population. MC is a common diagnosis in this will confirm a diagnosis of MC in between 8% and 16% of 716
710 age group, and should be one of the first options in the dif- patients with chronic non-bloody watery diarrhoea referred 717
711 ferential diagnosis of chronic non-bloody watery diarrhoea. for colonoscopy,74---78 in up to 17% of women aged 50 years or 718
over, and in 23% of men aged 70 years or over.78 Histopatho- 719
logical diagnostic criteria are consistent and reproducible, 720
712 Diagnostic process with excellent inter-individual and intra-individual agree- 721
ment to discriminate between MC, normal histology and 722
713 Biopsies from different sites along a macroscopically nor- others (inter-observer agreement >90%), with slightly less 723
714 mal colon is the gold standard for diagnosis of CC and LC in agreement to discriminate between CC, LC, and incomplete 724
715 patients with chronic non-bloody watery diarrhoea.73 This MC (70---80% agreement).80 725
GASTRE 956 1---25

+Model
ARTICLE IN PRESS
726 A recent study suggests that at least 2 diagnostic biopsies Diagnosis 781
727 from 2 different segments of the colon are needed to diag-

728 nose CC and LC, with at least mild chronic inflammation of The most common diagnostic technique used in Europe (but 782
729 the lamina propiain the other biopsies and segments.81 The not available in the USA) is the 75 Se-homotaurocholic Acid 783
730 study in question showed that a diagnostic collagenous band (SeHCAT) test, which uses scintigraphy to evaluate abdomi- 784
731 (>10 ␮m) was found in 5 segments in only 47% of patients. nal retention of an orally-administered bile acid analogue 785
732 It also showed that the diagnostic yield of biopsies taken labelled with selenium (75 Se-homotaurocholic acid). The 786
733 from the ascending, transverse and descending colon was test is highly accurate, and abnormal retention values are 787
734 96.2% higher than other sampling strategies. Therefore, it predictive of good response to therapy with bile acid seques- 788
735 is recommended to take 2 biopsies each from, at least, the trants. A retention value of less than 10% at 7 days is highly 789
736 right, transverse and left colon, and store them in separate sensitive (80---90%) and specific (70---100%) for BAM.72,82,88 The 790
737 containers. drawbacks of the test are radiation exposure (equivalent to 791
a chest X-ray) and the need for special equipment. 792
Although therapeutic testing with bile acid sequestrants 793
738 Recommendations (cholestyramine) is widely used, the diagnostic accuracy 794
of the test has not been evaluated in the literature, and 795
739 1 Biopsies from different sites along a macroscopically nor- a definitive diagnosis must be established for a disorder 796
740 mal colon is the gold standard for diagnosis of CC and LC such as BAM, which often requires long-term therapy.82,88,89 797
741 in patients with chronic non-bloody watery diarrhoea (CE, If therapeutic testing is performed, it is recommended to 798
742 moderate; SR, strong). start treatment with low-dose bile acid sequestrants, and 799
743 2 It is recommended to take 2 biopsies each from, at least, gradually uptitrate while monitoring patient response. 800
744 the right, transverse and left colon, and store them in
745 separate containers (CE, moderate; SR, strong).
Recommendations 801
746 Diarrhoea caused by bile acids 1 BAM should be evaluated in patients with functional-type 802
chronic diarrhoea (functional diarrhoea, diarrhoea- 803
747 Bile acids are synthesised in the liver, secreted by the predominant irritable bowel syndrome), in intestinal 804
748 gall bladder and released in the duodenum, where they diseases associated with the ileum (Crohn disease and 805
749 facilitate absorption of liposoluble vitamins and aid in fat radiation enteritis), and in microscopic colitis (CE, mod- 806
750 digestion. They are then reabsorbed in the terminal ileum, erate; SR, strong). 807
751 from where enterohepatic circulation returns them to the 2 BAM is a ubiquitous feature of chronic diarrhoea following 808
752 liver. Less than 5% reach the colon.82 Elevated bile acid lev- cholecystectomy or ileectomy, and in these cases empir- 809
753 els in the colon increase colonic motility and the transport ical treatment is advised (CE, low; SR, strong). 810
754 of water and electrolytes in the intestinal lumen, caus- 3 The recommended test for BAM is SeHCAT (CE, moderate; 811
755 ing diarrhoea.83 Symptoms are secretory, watery diarrhoea SR, strong). 812
756 that can be associated with abdominal pain, distension, fae- 4 If SeHCAT is unavailable, the best option is therapeutic 813
757 cal urgency, incontinence, nocturnal defecation and, rarely, testing with cholestyramine (CE, very low; SR, weak). 814
758 steatorrhoea.82,83
759 Bile acid malabsorption (BAM) is a common though little-
760 known cause of chronic diarrhoea.82 Between 20% and 50% of Sugar malabsorption diarrhoea 815
761 patients with chronic functional-type diarrhoea (functional

762 diarrhoea, diarrhoea-predominant or alternating irritable Malabsorption of carbohydrates can cause digestive intol- 816
763 bowel syndrome) present BAM. BAM associated with a struc- erance symptoms, such as diarrhoea, abdominal pain, 817
764 turally normal ileum is usually called type 2, primary, or nausea and meteorism. The most common culprits are 818
765 idiopathic BAM. In contrast, BAM associated with disease or lactose, fructose and sorbitol. In a small percentage of 819
766 ileectomy is known as type 1 or secondary BAM. It is very cases, malabsorption is caused by rare congenital dis- 820
767 common in patients with Crohn disease (30%) or radiation orders that cause deficiency of disaccharidases (lactase, 821
768 enteritis (>50%), and nearly always presents after ileectomy sucrase-isomaltase, trehalase, aldolase B) or affect intesti- 822
769 (90%).84,85 BAM is also often associated with microscopic nal transport (for example, congenital glucose-galactosemal 823
770 colitis (10---60%),86 and is the primary cause of postchole- absorption caused by a mutation in the SLC5A1 gene). 824
771 cystectomy chronic diarrhoea. Finally, BAM has also been Any sugars that are not absorbed in the small intes- 825
772 associated with miscellaneous factors, such as peptic ulcer tine produce symptoms caused by osmotic imbalance and 826
773 surgery, coeliac disease, chronic pancreatitis, diabetes mel- fermentation by the intestinal microbiota, producing short- 827
774 litus, cystic fibrosis, and the use of some drugs (for example, chain fatty acids and gases (hydrogen, methane, carbon 828
775 NSAIDs, colchicine or olsalazine). When BAM presents with dioxide). Due to the rapid transit of carbohydrates through 829
776 any of the foregoing, it is known as type 3 BAM or BAM the gastrointestinal tract, symptoms will start shortly after 830
777 secondary to gastrointestinal disorders. BAM has also been sugar intake, and can persist for 6---9 h. Typically, symptoms 831
778 reported to be a common, and often under-diagnosed, only occur when the patient ingests the offending carbo- 832
779 cause of gastrointestinal symptoms associated with cancer hydrate. Symptoms are highly nonspecific, and differential 833
780 therapies.87 diagnosis with other digestive pathologies is essential. 834
GASTRE 956 1---25

+Model
ARTICLE IN PRESS
835 Lactose intolerance Fructose and sorbitol intolerance 896
836 Lactose intolerance is the body’s symptomatic response Fructose is a monosaccharide found in fruit and some veg- 897
837 to lactose ingestion caused by hypolactasia or decreased etables, and is widely used as a sweetening agent in the 898
838 ␤-galactosidase levels in intestinal villi90 ; this enzyme food industry. Fructose is absorbed by a number of pathways 899
839 hydrolises lactose into monosaccharides (glucose and galac- that facilitate transport across the intestinal epithelium. 900
840 tose) that can be absorbed by the jejunum. Hypolactasia When fructose is present in excess of glucose (also called 901
841 is classed as primary (acquired or congenital) or sec- ‘‘free fructose’’), the excess is absorbed by a low-capacity 902
842 ondary. The most common form is acquired hypolactasia, transporter (GLUT-5), so the greater the fructose overload, 903
843 which is also called primary lactase deficiency or lac- the greater the likelihood of malabsorption. Glucose facil- 904
844 tase non-persistence. Persistence or non-persistence of itates fructose absorption along a more efficient pathway 905
845 lactase is determined by autosomal-recessive inheritance which uses the GLUT-2 transport system (facilitated glucose 906
846 of polymorphisms in the regulatory region of the lactase transporter).104,105 907
847 gene.91 In lactase non-persistent individuals, the activity Sorbitol is a sugar alcohol found in some fruit that is 908
848 of the enzyme gradually declines after weaning. It is a widely used as a sugar substitute, and is found in cakes, 909
849 highly prevalent disorder that affects 70% of the world’s jams, chewing gum and low-calorie products. It is absorbed 910
850 population, although it is more predominant in certain in the small intestine by passive transport, and acts as an 911
851 regions. Most adults in Africa, Asia, Latin America and inhibitor of the GLUT-5 fructose transporter. Consumption of 912
852 the Mediterranean region are lactase non-persistent, while fructose and sorbitol together, therefore, worsens symptoms 913
853 most individuals in north and central Europe are lactase- caused by fructose malabsorption. 914
854 persistent. Fructose intolerance is defined as the onset of symp- 915
855 Lactose malabsorption is not always associated with toms following intake of <25---30 g of fructose104 . The H2 916
856 intolerance and symptoms. Only 30---50% of individuals with breath test with 25 g fructose challenge is used to diag- 917
857 lactose malabsorption are lactose intolerant. However, sub- nose fructose malabsorption, while sorbitol malabsorption 918
858 jective perception of lactose intolerance does not always is confirmed by the H2 breath test 5 g sorbitol challenge. 919
859 indicate lactose malabsorption,92---94 and therefore lactose Some authors, however, prefer to evaluate malabsorption 920
860 malabsorption and lactose intolerance are not synonymous. of a combination of fructose and sorbitol, instead of fruc- 921
861 For this reason, the patient history contributes little to a tose alone (20---25 g fructose + 3.5---5 g sorbitol),104 as these 922
862 diagnosis of lactose intolerance, and diagnostic confirma- sugars are frequently ingested together and, as already 923
863 tion is needed before imposing life-long lactose restriction. described, sorbitol obstructs absorption of fructose. Never- 924
864 The gold standard test is the determination of lactase levels theless, the main problem encountered in the diagnosis of 925
865 in samples from intestinal biopsies,95 although it is rarely both fructose and sorbitol malabsorption is uncertainty sur- 926
866 used because of its invasive nature, high cost, and limited rounding the normal absorption capacity of these sugars in 927
867 results due to the patchy distribution of lactase in the gut.96 healthy subjects.94,106 The correct dosage and concentration 928
868 The most widely used, simplest, non-invasive, inexpensive of fructose and/or sorbitol needed to differentiate between 929
869 and highly accurate diagnostic techniques are the H2 breath normal or impaired absorption remains unclear. 930
870 test with lactose challenge34 (sensitivity, 73%; specificity,

871 86%) and the gaxilose test97,98 (sensitivity, 93%; specificity, Other carbohydrates 931
872 92%). The breath test measures increased levels of H2 in
873 exhaled breath (>20 ppm) following intake of 50 g of lac-
The term ‘‘fermentable oligosaccharides, disaccharides, 932
874 tose. False positives can be caused by bacterial overgrowth
monosaccharides and polyols’’ (FODMAP) has recently been 933
875 and rapid intestinal transit. The test can trigger digestive
introduced to define a group of poorly absorbed short- 934
876 symptoms but yield false negative results in individuals with
chain carbohydrates that were previously thought to be 935
877 non-H2 -producing bacterial flora (15---20% of the population)
unrelated, but have since been found to exhibit simi- 936
878 or due to a nocebo effect (44% of individuals with a negative
lar behaviour in the small and large intestine.104,107 The 937
879 breath test).99 The gaxilose test measures the total amount
term includes malabsorbed fructose and lactose, differ- 938
880 of xylose in urine collected over 5 h following oral adminis-
ent polyalcohol sugars (sorbitol, maltitol, xylitol, etc.) that 939
881 tration of 4-galactosylxylose, with xylose levels of <37.87 mg
are usually poorly absorbed, and fructans and galactans 940
882 being diagnostic for hypolactasia.
(galacto-oligosaccharides, such as raffinose and stachyose), 941
883 Genetic testing evaluates the existence of polymor-
which are always malabsorbed. All FODMAPs exert a similar 942
884 phisms (C/T-13910, G/A-22018) associated with lactase
osmotic effect in the colon, and are rapidly fermented by the 943
885 non-persistence. CC and GG genotypes are associated with
gut microflora. The combination of fructose and fructans can 944
886 non-persistence, while CT, TT, GA and AA genotypes are asso-
aggravate symptoms in a similar way as the aforementioned 945
887 ciated with lactase persistence, although some polymorphic
dual action of fructose and sorbitol. This factor should be 946
888 variants can affect the accuracy of the test.100 The test
borne in mind when drawing up diets designed to restrict 947
889 has a high negative predictive value (98%), so the possibil-
intake of malabsorbed sugars. 948
890 ity of CT and TT-1390 genotypes presenting primary lactase
891 deficiency is extremely remote.101 Agreement with a posi-
892 tive finding in a breath test is 100%.101---103 Genetic testing, Recommendations 949
893 however, is of no use in patients with suspected secondary

894 hypolactasia, it is more costly than the gaxilose test or 1 Subjective manifestations of lactose intolerance do 950
895 breath test, and is only available in a few hospitals. not always indicate lactose malabsorption. If diarrhoea 951
GASTRE 956 1---25

+Model
ARTICLE IN PRESS
952 secondary to primary lactase deficiency is suspected, • Infiltrative diseases: amyloidosis. 1007
953 diagnostic confirmation is needed before imposing life- • After gastric surgery with vagotomy. 1008
954 long lactose restriction (CE, high; SR, strong).

955 2 The H2 breath test with lactose challenge, the gaxilose
956 test, and genetic testing are recommended to confirm
Diagnosis 1009
957 diagnosis of lactose malabsorption.

958 3 When fructose and/or sorbitol intolerance are suspected, Diagnosis is based on: (a) compatible clinical history: sug- 1010
959 a breath test using these sugars is advised (CE, low; SR, gestive symptoms, with other organic pathology ruled out 1011
960 weak). by radiographic studies. Given the rarity of intestinal neu- 1012
romuscular diseases, it is important to first rule out other, 1013
more common, causes of chronic diarrhoea. In milder cases, 1014
961 Chronic diarrhoea secondary to intestinal difficulties can be encountered in differentiating these 1015
962 motility disorders diseases from other functional pathologies (IBS/functional 1016
diarrhoea); (b) test for bacterial overgrowth (see corre- 1017
963 Motility abnormalities can be an aetiopathogenic factor sponding section above); and (c) test for motor dysfunction 1018
964 shared by several different digestive disorders in which the using small bowel manometry, which is the gold standard for 1019
965 primary symptom is chronic diarrhoea. In these entities, studying small bowel motility.110---112 1020
966 changes in motility are more a contributing factor than Small bowel manometry has high specificity but low 1021
967 the underlying mechanism causing diarrhoea. This section sensitivity. Internationally accepted manometric diagnosis 1022
968 will focus on chronic diarrhoea caused by gastrointestinal criteria are available.110 Manometry can be used to detect 1023
969 neuromuscular diseases in which the condition arises as a motor dysfunction and differentiate between myopathic 1024
970 result of changes in motor function per se (for example, and neuropathic disorders. It is a complex technique that 1025
971 diabetes mellitus), or secondary to bacterial overgrowth requires skilled interpretation, and is only available in spe- 1026
972 (for example, scleroderma). Intestinal neuromuscular dis- cialised centres. 1027
973 eases (chronic intestinal pseudo-obstruction and intestinal Motor abnormalities correlate poorly with oro-caecal 1028
974 dysmotility) are uncommon disorders that are rarely the transit time, and the latter cannot be taken as an indication 1029
975 cause of chronic diarrhoea. As such, they should only be of motor dysfunction. 1030
976 investigated when other, more common, causes of chronic

977 diarrhoea have been ruled out.108,109 Recommendations 1031
978 Classification 1 Intestinal manometry can be useful in the diagnosis of 1032
neuromuscular disorders in patients with recurrence of 1033
979 Neuromuscular diseases of the gastrointestinal tract are diarrhoea in an appropriate clinical context (CE, moder- 1034
980 divided into: ate; SR, weak). 1035
981 1 Primary neuromuscular disease. This is characterised by: Chronic diarrhoea secondary to food allergies 1036
982 • Chronic and recurrent subocclusive episodes or abdom-

983 inal distension. Adverse reactions to certain foods can be divided into 2 1037
984 • Persistent or intermittent daytime or nocturnal diar- major subgroups: (a) food allergies, which are a subgroup 1038
985 rhoea interspersed with constipation, associated with of hypersensitivity reactions caused by immune mecha- 1039
986 weight loss and laboratory test findings of malnutri- nisms derived from IgE-dependent mast cell activation, or 1040
987 tion/malabsorption. Bacterial overgrowth is a common mediated by other immune mechanisms, often type 4 or 1041
988 feature (see corresponding section above), and the delayed-type hypersensitivity reactions,113---115 and (b) food 1042
989 diarrhoea may improve or resolve after normalisation intolerance, which includes a number of reactions medi- 1043
990 of bacterial colonisation. ated by non-immune mechanisms and derived from enzyme 1044
991 • Endoscopic and radiological studies (CT, transit, MR or transport deficiencies, or the pharmacological proper- 1045
992 enterography) used to rule out other structural diseases ties of certain food components.116 Food allergies are more 1046
993 are usually unremarkable or show dilated bowel loops. common in the paediatric population, and usually decrease 1047
994 • There may also be extra intestinal symptoms due to with age; according to estimates based on diagnoses made 1048
995 involvement of other organs or systems (most often using accepted techniques, prevalence ranges between 3.5% 1049
996 the urological, cardiovascular and autonomic nervous for cow’s milk and 0.5---1.3% for other common food aller- 1050
997 systems). gies (eggs, nuts, cereals, fruit, fish and seafood).114,117 The 1051
998 2 Secondary to general disease with intestinal involvement: prevalence of food intolerance, in contrast, is estimated 1052
999 • Connective tissue diseases: scleroderma, dermato- at between 15% and 20%, and is particularly associated 1053
1000 myositis, systemic lupus erythematosus. with gastrointestinal functional diseases, such as irritable 1054
1001 • Endocrine and metabolic disorders: diabetes mellitus, bowel syndrome and functional dyspepsia.118 The subgroup 1055
1002 hyperthyroidism. of food intolerance disorders includes both common and 1056
1003 • Neurological disorders: dysautonomia, MNGIE disease, less frequent conditions that can cause diarrhoea and other 1057
1004 Parkinson disease. gastrointestinal manifestations, such as flatulence, abdom- 1058
1005 • Muscular diseases: muscular dystrophy, Steinert dis- inal distension, nausea, vomiting and abdominal and/or 1059
1006 ease. epigastric pain. Sugar malabsorption, non-coeliac gluten 1060
GASTRE 956 1---25

+Model
ARTICLE IN PRESS
1061 sensitivity and FODMAP are among the most common dis-
Table 15 Approximate diagnostic accuracy of the main
1062 orders, and have been discussed elsewhere in this report.
complementary food allergytests.
1063 Less common disorders include intolerance to salicylates,
1064 biogenic amines, caffeine and glutamate, toxic reactions to Food Technique Diagnostic accuracy
1065 microbial or fungal products, such as aflatoxins, and psycho- Egg s-IgE Se, 93% (82---98); Sp, 49% (40---58)
1066 logical reactions.116 It is important to differentiate between SPT Se, 92% (80---97); Sp, 58% (49---67)
1067 allergies and intolerance, as the gastrointestinal manifesta- Cow’s s-IgE Se, 87% (79---94); Sp, 48% (36---59)
1068 tions of food allergies are often comparable to symptoms milk SPT Se, 88% (76---94); Sp, 68% (56---77)
1069 of intolerance. Allergies, however, are commonly associ- Wheat s-IgE Se, 83% (69---92); Sp, 43% (20---69)
1070 ated with other specific extra intestinal manifestations, such SPT Se, 73% (56---85); Sp, 73% (48---89)
1071 as rash or angiooedema, which usually appear immediately Soy s-IgE Se, 83% (64---93); Sp, 38% (24---54)
1072 after exposure or intake of the offending allergen. In addi- SPT Se, 55% (33---75); Sp, 68% (52---80)
1073 tion, unlike food intolerance, in which diarrhoea can persist Nuts s-IgE Se, 96% (92---98); Sp, 59% (45---72)
1074 while the individual continues to consume, albeit unwit- SPT Se, 95% (88---98); Sp, 61% (47---74)
1075 tingly, the offending foodstuff, fool allergies can cause acute Fish s-IgE Se, ---% (67---94); Sp, ---% (65---88)
1076 diarrhoea, but are rarely the direct cause of chronic diar- SPT Se, 91%-100% (---); Sp, 57% (---)
1077 rhoea. A particular case in point is diarrhoea-predominant Seafood s-IgE Se, 100% (80---100); Sp, 45%
1078 irritable bowel syndrome, in which it can be difficult to (23---68)
1079 establish the role of food allergies and intolerance in the SPT Se, 100% (---); Sp, –% (32---50)
1080 pathogenesis of the diarrhoea, as both entities often com-
1081 bine in these patients, and can even be associated with Se: sensitivity; Sp: specificity; SPT: Skin prick test.
Source: adapted from Soares-Weiser et al.123
1082 psychological adverse food reactions. In recent years, some
1083 authors have implicated IgG- or IgG4-mediated delayed
1084 food hypersensitivity reactions119---121 in the pathogenesis and target foods.123 The double-blind, placebo-controlled oral 1120
1085 severity of clinical manifestation, including diarrhoea. The food challenge is considered the gold standard diagnostic 1121
1086 association is still under debate, and no consensus has yet test. However, it is impractical, because it is time consuming 1122
1087 been reached. and resource-intensive, and can cause anaphylaxis. 1123
Any methods that have not proved effective and safe in 1124
controlled trials should be classed as ‘‘unproven methods’’ 1125

1088 Diagnosis or ‘‘non-validated methods’’, and are therefore not recom- 1126
mended for the purpose of diagnosis.124 Such tests include: 1127

1089 The first and most important step in diagnosing food allergies (a) controversial in vivo tests: subcutaneous, sublingual and 1128
1090 and differentiating them from food intolerance is to com- intradermal provocation tests; the ricercaintolleranzeali- 1129
1091 pile a comprehensive clinical and dietary history, focussing mentaria (DRIA) test, based on the sublingual administration 1130
1092 in particular on the food consumed by the patient in the of an allergenic extract and on measurement of mus- 1131
1093 2 h prior to the onset of symptoms. It is important to take cle strength with an ergonometer; electroacupuncture and 1132
1094 into account levels of tolerance before and after ingestion electrodermal testing (Voll method); applied kinesiology 1133
1095 of the offending foodstuff: good tolerance after ingestion (manual measurement of muscle strength), and bioreso- 1134
1096 will exclude the presence of an IgE-mediated mechanism, nance; and (b) controversial in vivo tests: determination 1135
1097 except when food allergies are facilitated or aggravated by of IgG in blood samples using ELISA (A200 test, IADM test, 1136
1098 co-factors (exercise, NSAIDs, stress or alcohol). Once the and food intolerance screening [FIS]), and testing for IgG4 1137
1099 clinical suspicion has been confirmed, tests must be per- against foods (IgG4 Screen Nutritional); DNA analysis of hair 1138
1100 formed to establish whether the allergic symptoms are samples to determine food intolerance, and measurement 1139
1101 caused by an IgE-mediated hypersensitivity reaction. These of white cells using the Coulter counter, either with or with- 1140
1102 include122 : (a) skin prick tests using commercial extracts, or out incubation with food extracts (ALCAT test). There is 1141
1103 prick-prick tests using fresh foodstuffs; (b) determination currently insufficient evidence to recommend the use of 1142
1104 of food-specific IgEin serum (UniCAP100, ImmunoCAP250, detection of IgG or IgG4 against food components to guide 1143
1105 Immulite System, HYTEC-288 system); and to a lesser extent the dietary management of chronic diarrhoea. 1144
1106 (c) the use of purified or recombinant molecules (compo- A recent recommendation indicates ruling out wheat 1145
1107 nent separation) to accurately identify the allergens causing allergy before diagnosing a patient with non-coeliac gluten 1146
1108 reaction in each patient (microarray chip, ISAC; UNICAP, sensitivity.125 Nevertheless, wheat allergy is rare and usually 1147
1109 Thermofisher). These tests are mainly used to differenti- causes respiratory symptoms, above all rhinitis, particularly 1148
1110 ate between true allergic reactions or cross reactivity; (d) in association with co-factors such as exercise and stress. 1149
1111 screening tests for foods or pollens, particularly useful in Diagnosis is based on the skin prick test (whole wheat, 1150
1112 primary care, that contain a mixture of the most com- gluten and gliadin) and also by determination of IgE against 1151
1113 mon allergens (multiallergen screen IgE test, Phadiatop); ␻5-recombinant gliadin. 1152
1114 and (e) other blood tests: tryptase, eosinophil cationic pro-
1115 tein, carboxypeptidase, cathepsin G and mast cell chymase,
1116 IFN-␥, TNF-␣, FGF, IL-4, IL-5, IL-6, IL-13, histamine, chon- Recommendations 1153
1117 droitin sulphate, heparin, leukotriene C4, PGD2, total IgE

1118 and free IgE. Table 15 shows the specificity and sensitivity 1 Taking a comprehensive medical history will help differ- 1154
1119 of the most widely used complementary tests for specific entiate between diarrhoea associated with an immune 1155
GASTRE 956 1---25

+Model
ARTICLE IN PRESS
Chronic diarrhoea
Patient history
Physical examination
Basic laboratory tests
(Algorithm 1)
Signs/symptoms of
organic characteristics
(Table 2)
No Yes
Diarrhoea with organic

Diarrhoea with functional characteristics
characteristics (Algorithms 2, 3, 4
(Algorithm 6) and 5)
Indication for
Mild diarrhoea Severe diarrhoea colonoscopy?
(Table 6)
Symptomatic treatment
(Evaluate intolerance to Refer to
Colonoscopy
sugars if associated with gastroenterologist
meteorism/flatulence)
Refer to
gastroenterologist
Figure 7 Algorithm 7. Patients with chronic diarrhoea referred from primary to specialist care.
1156 reaction or with other mechanisms more typical of food

Table 16 Indications for colonoscopy in patients with
1157 intolerance.
chronic diarrhoea.
1158 2 If food allergy is suspected, the patient should be referred
1159 to an allergist for specific IgE determination and a skin Recent onset chronic diarrhoea in patients aged > 50 years
1160 prick test, both of which have good sensitivity but low Chronic diarrhoea and history of colorectal cancer in first
1161 specificity (CE, high; SR, strong). degree relatives
1162 3 The double-blind, placebo-controlled oral food challenge Chronic inflammatory diarrhoea (see definition in text)
1163 is considered the gold standard diagnostic test. How- Chronic non-bloody diarrhoea with positive faecal occult
1164 ever, it is impractical, because it is time consuming and blood
1165 resource-intensive, and can cause anaphylaxis (CE, high, Chronic non-bloody diarrhoea with calprotectin>150 mg/kg
1166 SR, strong). Chronic non-bloody diarrhoea with elevated C-reactive
protein
Chronic watery diarrhoea with severe functional diarrhoea
1167 Diagnosis and care of chronic diarrhoea criteria or signs and symptoms and test findings
suggestive of organic origin (see text)
1168 patients in primary care
1169 Primary care doctors make the initial evaluation of patients

1170 presenting with chronic diarrhoea (Algorithm 7, Fig. 7). It is
1171 important to determine whether the patient meets diagnos- In many patients presenting with recurrent but mild (less 1177
1172 tic criteria for chronic diarrhoea, to take a comprehensive than 2 episodes per week) watery diarrhoea, empirical ther- 1178
1173 medical history, and order basic blood and stool tests. It apy to treat symptoms (with loperamide or racecadotril) is 1179
1174 is essential to evaluate the presence of organic factors, to often appropriate. In these cases, it is important to evaluate 1180
1175 decide whether to refer the patient to a gastroenterologist, whether the complaint is associated mainly with symptoms 1181
1176 and whether to order a colonoscopy (Table 16). of meteorism and abdominal distension. If so, the presence 1182
GASTRE 956 1---25

+Model
ARTICLE IN PRESS
1183 of sugar malabsorption (lactose and/or fructose or sorbitol) 16. Ianiro G, Bibbò S, Montalto M, Ricci R, Gasbarrini A, Cammarota 1241
1184 must be ruled out. G. Systematic review: sprue-like enteropathy associated with 1242
olmesartan. Aliment Pharmacol Ther. 2014;40:16---23. 1243
17. Brown IS, Bettington A, Bettington M, Rosty C. Tropical sprue: 1244
1185 Conflict of interests revisiting an underrecognized disease. Am J Surg Pathol. 1245

2014;38:666---72. 1246
1186 The authors declare they have no conflicts of interest. 18. Haghighi P, Wolf PL. Tropical sprue and subclinical enteropa- 1247
thy: a vision for the nineties. Crit Rev Clin Lab Sci. 1248
1997;34:313---41. 1249
Q3
1187 Uncited reference 19. Pallav K, Leffler DA, Tariq S, Kabbani T, Hansen J, Peer A, et al. 1250
Noncoeliac enteropathy: the differential diagnosis of villous 1251
79 atrophy in contemporary clinical practice. Aliment Pharmacol 1252

1188 . Ther. 2012;35:380---90. 1253
20. Rubio-Tapia A, Murray JA. Classification and management of 1254
refractory coeliac disease. Gut. 2010;59:547---57. 1255
1189 References 21. Lagier JC, Lepidi H, Raoult D, Fenollar F. Systemic Tropheryma 1256
whipplei: clinical presentation of 142 patients with infections 1257
1190 1. Headstrom PD, Surawicz CM. Chronic diarrhea. Clin Gastroen- diagnosed or confirmed in a reference center. Medicine (Balti- 1258
1191 terol Hepatol. 2005;3:734---7. more). 2010;89:337---45. 1259
1192 2. Schiller LR, Pardi DS, Spiller R, Semrad CE, Surawicz CM, Gian- 22. Marsh MN. Gluten, major histocompatibility complex, and the 1260
1193 nella RA, et al. Gastro 2013 APDW/WCOG Shanghai working small intestine. A molecular and immunobiologic approach to 1261
1194 party report: chronic diarrhea: definition, classification, diag- the spectrum of gluten sensitivity (’celiac sprue’). Gastroen- 1262
1195 nosis. J Gastroenterol Hepatol. 2014;29:6---25. terology. 1992;102:330---54. 1263
1196 3. Sandhu DK, Surawicz C. Update on chronic diarrhea: a 23. Oberhuber G, Granditsch G, Vogelsang H. The histopath- 1264
1197 run-through for the clinician. Curr Gastroenterol Rep. ology of coeliac disease: time for a standardized report 1265
1198 2012;14:421---7. scheme for pathologists. Eur J Gastroenterol Hepatol. 1999;11: 1266
1199 4. Fine KD, Schiller LR. AGA technical review on the evalua- 1185---94. 1267
1200 tion and management of chronic diarrhea. Gastroenterology. 24. Corazza GR, Villanacci V. Coeliac disease. J Clin Pathol. 1268
1201 1999;116:1464---86. 2005;58:573---4. 1269
1202 5. Thomas PD, Forbes A, Green J, Howdle P, Long R, Playford R, 25. Ensari A. Gluten-sensitive enteropathy (celiac disease): con- 1270
1203 et al. Guidelines for the investigation of chronic diarrhoea, troversies in diagnosis and classification. Arch Pathol Lab Med. 1271
1204 2nd edition. Gut. 2003;52, v1---15. 2010;134:826---36. 1272
1205 6. Gentile NM, Khanna S, Loftus EV Jr, Smyrk TC, Tremaine WJ, 26. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray 1273
1206 Harmsen WS, et al. The epidemiology of microscopic colitis in JA. Gastroenterology ACo. ACG clinical guidelines: diagno- 1274
1207 Olmsted County from 2002 to 2010: a population-based study. sis and management of celiac disease. Am J Gastroenterol. 1275
1208 Clin Gastroenterol Hepatol. 2014;12:838---42. 2013;108:656---76, quiz 677. 1276
1209 7. Fernández-Bañares F, Esteve M, Salas A, Alsina M, Farré C, 27. Catassi C, Fasano A. Celiac disease diagnosis: simple 1277
1210 González C, et al. Systematic evaluation of the causes of rules are better than complicated algorithms. Am J Med. 1278
1211 chronic watery diarrhea with functional characteristics. Am 2010;123:691---3. 1279
1212 J Gastroenterol. 2007;102:2520---8. 28. Langenberg MC, Wismans PJ, van Genderen PJ. Distinguishing 1280
1213 8. Habba SF. Diarrhea predominant Irritable Bowel Syndrome (IBS- tropical sprue from celiac disease in returning travellers with 1281
1214 D): fact or fiction. Med Hypotheses. 2011;76:97---9. chronic diarrhoea: a diagnostic challenge? Travel Med Infect 1282
1215 9. Marzo-Castillejo M, Alonso-Coello P, Rotaeche del Campo R. Dis. 2014;12:401---5. 1283
1216 How are the quality of evidence and the strength of recom- 29. Liu H, Brais R, Lavergne-Slove A, Jeng Q, Payne K, Ye H, 1284
1217 mendations to be classified? Aten Prim. 2006;37:5---8. et al. Continual monitoring of intraepithelial lymphocyte 1285
1218 10. Waugh N, Cummins E, Royle P, Kandala NB, Shyangdan D, immunophenotype and clonality is more important than snap- 1286
1219 Arasaradnam R, et al. Faecal calprotectin testing for differ- shot analysis in the surveillance of refractory coeliac disease. 1287
1220 entiating amongst inflammatory and non-inflammatory bowel Gut. 2010;59:452---60. 1288
1221 diseases: systematic review and economic evaluation. Health 30. O’Malley DP, Goldstein NS, Banks PM. The recognition and clas- 1289
1222 Technol Assess. 2013;17, xv---xix, 1---211. sification of lymphoproliferative disorders of the gut. Hum 1290
1223 11. Van Rheenen PF, van de Vijver E, Fidler V. Faecal calprotectin Pathol. 2014;45:899---916. 1291
1224 for screening of patients with suspected inflammatory bowel 31. Gabrielli M, d’Angelo G, di Rienzo T, Scarpellini E, Ojetti 1292
1225 disease: diagnostic meta-analysis. BMJ. 2010;341, 3369. V. Diagnosis of small intestinal bacterial overgrowth in 1293
1226 12. Panes J, Bouhnik Y, Reinisch W, Stoker J, Taylor SA, Baumgart the clinical practice. Eur Rev Med Pharmacol Sci. 2013;17: 1294
1227 DC, et al. Imaging techniques for assessment of inflammatory 30---5. 1295
1228 bowel disease: joint ECCO and ESGAR evidence-based consen- 32. Miazga A, Osiński M, Cichy W, Żaba R. Current views on the 1296
1229 sus guidelines. J Crohns Colitis. 2013;7:556---85. etiopathogenesis, clinical manifestation, diagnostics, treat- 1297
1230 13. Rodríguez-Pardo D, Mirelis B, Navarro F. Infections caused ment and correlation with other nosological entities of SIBO. 1298
1231 by Clostridium difficile. Enferm Infecc Microbiol Clin. Adv Med Sci. 2015;60:118---24. 1299
1232 2013;31:254---63. 33. Saad RJ, Chey WD. Breath testing for small intestinal bacte- 1300
1233 14. Cone MM, Whitlow CB. Sexually transmitted and anorec- rial overgrowth: maximizing test accuracy. Clin Gastroenterol 1301
1234 tal infectious diseases. Gastroenterol Clin North Am. Hepatol. 2014;12:1964---72, quiz e119---20. 1302
1235 2013;42:877---92. 34. Gasbarrini A, Corazza GR, Gasbarrini G, Montalto M, Di Stefano 1303
1236 15. Koot BG, ten Kate FJ, Juffrie M, Rosalina I, Taminiau JJ, M, Basilisco G, et al. Methodology and indications of H2-breath 1304
1237 Benninga MA. Does Giardia lamblia cause villous atrophy testing in gastrointestinal diseases: the Rome Consensus Con- 1305
1238 in children? A retrospective cohort study of the histologi- ference. Aliment Pharmacol Ther. 2009;29:1---49. 1306
1239 cal abnormalities in giardiasis. J Pediatr Gastroenterol Nutr. 35. DiMagno EP. Medical treatment of pancreatic insufficiency. 1307
1240 2009;49:304---8. Mayo Clin Proc. 1979;54:435---42. 1308
GASTRE 956 1---25

+Model
ARTICLE IN PRESS
1309 36. Bollbach R, Becker M, Rotthauwe HW. Serum immunoreactive test, and histology: correlation in chronic pancreatitis. Am J 1377
1310 trypsin and pancreatic lipase in cystic fibrosis. Eur J Pediatr. Gastroenterol. 2010;105:2498---503. 1378
1311 1985;144:167---70. 55. Nakamura H, Murakami Y, Uemura K, Hayashidani Y, Sudo T, 1379
1312 37. Cleghorn G, Benjamin L, Corey M, Forstner G, Dati F, Durie Ohge H, et al. Reduced pancreatic parenchymal thickness 1380
1313 P. Serum immunoreactive pancreatic lipase and cationic indicates exocrine pancreatic insufficiency after pancreato- 1381
1314 trypsinogen for the assessment of exocrine pancreatic duodenectomy. J Surg Res. 2011;171:473---8. 1382
1315 function in older patients with cystic fibrosis. Pediatrics. 56. Leeds JS, Hopper AD, Sidhu R, Simmonette A, Azadbakht N, 1383
1316 1986;77:301---6. Hoggard N, et al. Some patients with irritable bowel syndrome 1384
1317 38. Ammann RW, Bühler H, Pei P. Comparative diagnostic accuracy may have exocrine pancreatic insufficiency. Clin Gastroenterol 1385
1318 of four tubeless pancreatic function tests in chronic pancre- Hepatol. 2010;8:433---8. 1386
1319 atitis. Scand J Gastroenterol. 1982;17:997---1002. 57. Fabian E, Kump P, Krejs GJ. Diarrhea caused by circulating 1387
1320 39. Lankisch PG, Koop H, Otto J. Estimation of serum pancreatic agents. Gastroenterol Clin North Am. 2012;41:603---10. 1388
1321 isoamylase: its role in the diagnosis of exocrine pancreatic 58. Jensen RT. Overview of chronic diarrhea caused by func- 1389
1322 insufficiency. Am J Gastroenterol. 1986;81:365---8. tional neuroendocrine neoplasms. Semin Gastrointest Dis. 1390
1323 40. Pezzilli R, Talamini G, Gullo L. Behaviour of serum pancreatic 1999;10:156---72. 1391
1324 enzymes in chronic pancreatitis. Dig Liver Dis. 2000;32:233---7. 59. Brelian D, Tenner S. Diarrhoea due to pancreatic diseases. Best 1392
1325 41. Löser C, Möllgaard A, Fölsch UR. Faecal elastase 1: a novel, Pract Res Clin Gastroenterol. 2012;26:623---31. 1393
1326 highly sensitive, and specific tubeless pancreatic function test. 60. Roerig JL, Steffen KJ, Mitchell JE, Zunker C. Laxative 1394
1327 Gut. 1996;39:580---6. abuse: epidemiology, diagnosis and management. Drugs. 1395
1328 42. Benini L, Amodio A, Campagnola P, Agugiaro F, Cristofori C, 2010;70:1487---503. 1396
1329 Micciolo R, et al. Fecal elastase-1 is useful in the detection of 61. Abraham BP, Sellin JH. Drug-induced, factitious, & idiopathic 1397
1330 steatorrhea in patients with pancreatic diseases but not after diarrhoea. Best Pract Res Clin Gastroenterol. 2012;26:633---48. 1398
1331 pancreatic resection. Pancreatology. 2013;13:38---42. 62. Schiller LR, Rivera LM, Santangelo WC, Little KH, Fordtran JS. 1399
1332 43. Halloran CM, Cox TF, Chauhan S, Raraty MG, Sutton R, Diagnostic value of fasting plasma peptide concentrations in 1400
1333 Neoptolemos JP, et al. Partial pancreatic resection for pan- patients with chronic diarrhea. Dig Dis Sci. 1994;39:2216---22. 1401
1334 creatic malignancy is associated with sustained pancreatic 63. Modlin IM, Kidd M, Bodei L, Drozdov I, Aslanian H. The clinical 1402
1335 exocrine failure and reduced quality of life: a prospective utility of a novel blood-based multi-transcriptome assay for 1403
1336 study. Pancreatology. 2011;11:535---45. the diagnosis of neuroendocrine tumors of the gastrointestinal 1404
1337 44. Goldberg DM. Proteases in the evaluation of pancreatic func- tract. Am J Gastroenterol. 2015;110:1223---32. 1405
1338 tion and pancreatic disease. Clin Chim Acta. 2000;291:201---21. 64. Marotta V, Nuzzo V, Ferrara T, Zuccoli A, Masone M, Nocerino 1406
1339 45. De Pedro C, Codoceo R, Vazquez P, Hernanz A. Fecal chy- L, et al. Limitations of Chromogranin A in clinical practice. 1407
1340 motrypsin levels in children with pancreatic insufficiency. Clin Biomarkers. 2012;17:186---91. 1408
1341 Biochem. 1986;19:338---40. 65. Van Essen M, Sundin A, Krenning EP, Kwekkeboom DJ. Neuroen- 1409
1342 46. Vantrappen GR, Rutgeerts PJ, Ghoos YF, Hiele MI. Mixed docrine tumours: the role of imaging for diagnosis and therapy. 1410
1343 triglyceride breath test: a noninvasive test of pancreatic Nat Rev Endocrinol. 2014;10:102---14. 1411
1344 lipase activity in the duodenum. Gastroenterology. 1989;96: 66. Byers RJ, Marsh P, Parkinson D, Haboubi NY. Melanosis coli is 1412
1345 1126---34. associated with an increase in colonic epithelial apoptosis and 1413
1346 47. Heikius B, Niemelä S, Lehtola J, Karttunen T, Lähde S. Pan- not with laxative use. Histopathology. 1997;30:160---4. 1414
1347 creatic duct abnormalities and pancreatic function in patients 67. Eherer AJ, Fordtran JS. Fecal osmotic gap and pH in 1415
1348 with chronic inflammatory bowel disease. Scand J Gastroen- experimental diarrhea of various causes. Gastroenterology. 1416
1349 terol. 1996;31:517---23. 1992;103:545---51. 1417
1350 48. Muniz CK, dos Santos JS, Pfrimer K, Ferrioli E, Kemp R, Marchini 68. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin 1418
1351 JS, et al. Nutritional status, fecal elastase-1, and 13C-labeled F, Spiller RC. Functional bowel disorders. Gastroenterology. 1419
1352 mixed triglyceride breath test in the long-term after pancre- 2006;130:1480---91. 1420
1353 aticoduodenectomy. Pancreas. 2014;43:445---50. 69. Money ME, Camilleri M. Review: management of postprandial 1421
1354 49. Conwell DL, Zuccaro G, Morrow JB, van Lente F, Obuchowski N, diarrhea syndrome. Am J Med. 2012;125:538---44. 1422
1355 Vargo JJ, et al. Cholecystokinin-stimulated peak lipase concen- 70. Macaigne G, Lahmek P, Locher C, Lesgourgues B, Costes L, 1423
1356 tration in duodenal drainage fluid: a new pancreatic function Nicolas MP, et al. Microscopic colitis or functional bowel dis- 1424
1357 test. Am J Gastroenterol. 2002;97:1392---7. ease with diarrhea: a French prospective multicenter study. 1425
1358 50. Erchinger F, Engjom T, Tjora E, Hoem D, Hausken T, Gilja Am J Gastroenterol. 2014;109:1461---70. 1426
1359 OH, et al. Quantification of pancreatic function using a 71. Fan X, Sellin JH. Review article: small intestinal bacterial 1427
1360 clinically feasible short endoscopic secretin test. Pancreas. overgrowth, bile acid malabsorption and gluten intolerance as 1428
1361 2013;42:1101---6. possible causes of chronic watery diarrhoea. Aliment Pharma- 1429
1362 51. Sanyal R, Stevens T, Novak E, Veniero JC. Secretin-enhanced col Ther. 2009;29:1069---77. 1430
1363 MRCP: review of technique and application with proposal for 72. Wedlake L, A’Hern R, Russell D, Thomas K, Walters JR, 1431
1364 quantification of exocrine function. AJR Am J Roentgenol. Andreyev HJ. Systematic review: the prevalence of idiopathic 1432
1365 2012;198:124---32. bile acid malabsorption as diagnosed by SeHCAT scanning 1433
1366 52. Manfredi R, Perandini S, Mantovani W, Frulloni L, in patients with diarrhoea-predominant irritable bowel syn- 1434
1367 Faccioli N, Pozzi Mucelli R. Quantitative MRCP assess- drome. Aliment Pharmacol Ther. 2009;30:707---17. 1435
1368 ment of pancreatic exocrine reserve and its correlation with 73. Magro F, Langner C, Driessen A, Ensari A, Geboes K, Mantzaris 1436
1369 faecal elastase-1 in patients with chronic pancreatitis. Radiol GJ, et al. European consensus on the histopathology of inflam- 1437
1370 Med. 2012;117:282---92. matory bowel disease. J Crohns Colitis. 2013;7:827---51. 1438
1371 53. Stevens T, Dumot JA, Parsi MA, Zuccaro G, Vargo JJ. Combined 74. Fernandez-Banares F, Salas A, Esteve M, Pardo L, Casalots J, 1439
1372 endoscopic ultrasound and secretin endoscopic pancreatic Forne M, et al. Evolution of the incidence of collagenous colitis 1440
1373 function test in patients evaluated for chronic pancreatitis. and lymphocytic colitis in Terrassa, Spain: a population-based 1441
1374 Dig Dis Sci. 2010;55:2681---7. study. Inflamm Bowel Dis. 2011;17:1015---20. 1442
1375 54. Albashir S, Bronner MP, Parsi MA, Walsh RM, Stevens T. Endo- 75. Fernandez-Banares F, Salas A, Forne M, Esteve M, Espinos 1443
1376 scopic ultrasound, secretin endoscopic pancreatic function J, Viver JM. Incidence of collagenous and lymphocytic 1444
GASTRE 956 1---25

+Model
ARTICLE IN PRESS
1445 colitis: a 5-year population-based study. Am J Gastroenterol. 95. Newcomer AD, McGill DB, Thomas PJ, Hofmann AF. Prospective 1512
1446 1999;94:418---23. comparison of indirect methods for detecting lactase defi- 1513
1447 76. Guagnozzi D, Lucendo AJ, Angueira-Lapena T, Gonzalez- ciency. N Engl J Med. 1975;293:1232---6. 1514
1448 Castillo S, Tenias Burillo JM. Prevalence and incidence of 96. Maiuri L, Rossi M, Raia V, Garipoli V, Hughes LA, Swallow D, 1515
1449 microscopic colitis in patients with diarrhoea of unknown aeti- et al. Mosaic regulation of lactase in human adult-type hypo- 1516
1450 ology in a region in central Spain. Dig Liver Dis. 2012;44:384---8. lactasia. Gastroenterology. 1994;107:54---60. 1517
1451 77. Pardi DS, Loftus EV Jr, Smyrk TC, Kammer PP, Tremaine WJ, 97. Aragón JJ, Hermida C, Martínez-Costa OH, Sánchez V, Martín 1518
1452 Schleck CD, et al. The epidemiology of microscopic colitis: a I, Sánchez JJ, et al. Noninvasive diagnosis of hypolactasia 1519
1453 population based study in Olmsted County, Minnesota. Gut. with 4-Galactosylxylose (Gaxilose): a multicentre, open- 1520
1454 2007;56:504---8. label, phase IIB-III nonrandomized trial. J Clin Gastroenterol. 1521
1455 78. Olesen M, Eriksson S, Bohr J, Jarnerot G, Tysk C. Microscopic 2014;48:29---36. 1522
1456 colitis: a common diarrhoeal disease. An epidemiological study 98. Hermida C, Martínez-Costa OH, Corrales G, Teruel C, Sánchez 1523
1457 in Orebro, Sweden, 1993---1998. Gut. 2004;53:346---50. V, Sánchez JJ, et al. Improvement and validation of d-xylose 1524
1458 79. Limsui D, Pardi DS, Smyrk TC, Abraham SC, Lewis JT, Sanderson determination in urine and serum as a new tool for the non- 1525
1459 SO, et al. Observer variability in the histologic diagnosis of invasive evaluation of lactase activity in humans. J Clin Lab 1526
1460 microscopic colitis. Inflamm Bowel Dis. 2009;15:35---8. Anal. 2014;28:478---86. 1527
1461 80. Fiehn AM, Bjornbak C, Warnecke M, Engel PJ, Munck LK. 99. Vernia P, di Camillo M, Foglietta T, Avallone VE, De Carolis A. 1528
1462 Observer variability in the histopathologic diagnosis of micro- Diagnosis of lactose intolerance and the ‘nocebo’ effect: the 1529
1463 scopic colitis and subgroups. Hum Pathol. 2013;44:2461---6. role of negative expectations. Dig Liver Dis. 2010;42:616---9. 1530
1464 81. Aust DE, Münch A, Olesen M, Vieth M, Bonderup OK, Bohr J, 100. Swallow DM. Genetics of lactase persistence and lactose intol- 1531
1465 et al. Su1183 topographical distribution of collagenous coli- erance. Annu Rev Genet. 2003;37:197---219. 1532
1466 tis --- a pooled histological analysis of 2 European prospective 101. Pohl D, Savarino E, Hersberger M, Behlis Z, Stutz B, Goetze 1533
1467 multicenter trials. Gastroenterology. 2013;144:S-421. O, et al. Excellent agreement between genetic and hydrogen 1534
1468 82. Wilcox C, Turner J, Green J. Systematic review: the manage- breath tests for lactase deficiency and the role of extended 1535
1469 ment of chronic diarrhoea due to bile acid malabsorption. symptom assessment. Br J Nutr. 2010;104:900---7. 1536
1470 Aliment Pharmacol Ther. 2014;39:923---39. 102. Krawczyk M, Wolska M, Schwartz S, Gruenhage F, Terjung B, 1537
1471 83. Khalid U, Lalji A, Stafferton R, Andreyev J. Bile acid malab- Portincasa P, et al. Concordance of genetic and breath tests 1538
1472 soption: a forgotten diagnosis? Clin Med. 2010;10:124---6. for lactose intolerance in a tertiary referral centre. J Gas- 1539
1473 84. Nyhlin H, Merrick MV, Eastwood MA. Bile acid malabsorption trointestin Liver Dis. 2008;17:135---9. 1540
1474 in Crohn’s disease and indications for its assessment using 103. Mattar R, Monteiro MS, Villares CA, dos Santos AF, 1541
1475 SeHCAT. Gut. 1994;35:90---3. Carrilho FJ. Single nucleotide polymorphism C/T(-13910), 1542
1476 85. Lenicek M, Duricova D, Komarek V, Gabrysova B, Lukas M, located upstream of the lactase gene, associated with 1543
1477 Smerhovsky Z, et al. Bile acid malabsorption in inflammatory adult-type hypolactasia: Validation for clinical practice. Clin 1544
1478 bowel disease: assessment by serum markers. Inflamm Bowel Biochem. 2008;41:628---30. 1545
1479 Dis. 2011;17:1322---7. 104. Fernández-Bañares F, Esteve M, Viver JM. Fructose-sorbitol 1546
1480 86. Ung KA, Gillberg R, Kilander A, Abrahamsson H. Role of bile malabsorption. Curr Gastroenterol Rep. 2009;11:368---74. 1547
1481 acids and bile acid binding agents in patients with collagenous 105. Frieling T, Kuhlbusch-Zicklam R, Kalde S, Heise J, Hülsdonk A, 1548
1482 colitis. Gut. 2000;46:170---5. Kreysel C. Fructose malabsorption: how much fructose can a 1549
1483 87. Phillips F, Muls AC, Lalji A, Andreyev HJ. Are bile acid healthy subject tolerate? Digestion. 2011;84:269---72. 1550
1484 malabsorption and bile acid diarrhoea an important cause 106. Kyaw MH, Mayberry JF. Fructose malabsorption: true condi- 1551
1485 of diarrhoea complicating cancer therapy? Colorectal Dis. tion or a variance from normality. J Clin Gastroenterol. 1552
1486 2015;17:730---4. 2011;45:16---21. 1553
1487 88. Vijayvargiya P, Camilleri M, Shin A, Saenger A. Methods for 107. Gibson PR, Varney J, Malakar S, Muir JG. Food components 1554
1488 diagnosis of bile acid malabsorption in clinical practice. Clin and irritable bowel syndrome. Gastroenterology. 2015;148, 1555
1489 Gastroenterol Hepatol. 2013;11:1232---9. 1158.e4---1174.e4. 1556
1490 89. Barkun AN, Love J, Gould M, Pluta H, Steinhart H. Bile acid 108. Stanghellini V, Cogliandro RF, de Giorgio R, Barbara G, 1557
1491 malabsorption in chronic diarrhea: pathophysiology and treat- Morselli-Labate AM, Cogliandro L, et al. Natural his- 1558
1492 ment. Can J Gastroenterol. 2013;27:653---9. tory of chronic idiopathic intestinal pseudo-obstruction in 1559
1493 90. Suchy FJ, Brannon PM, Carpenter TO, Fernandez JR, Gilsanz V, adults: a single center study. Clin Gastroenterol Hepatol. 1560
1494 Gould JB, et al. NIH consensus development conference state- 2005;3:449---58. 1561
1495 ment: lactose intolerance and health. NIH Consens State Sci 109. Knowles CH, Lindberg G, Panza E, de Giorgio R. New 1562
1496 Statements. 2010;27:1---27. perspectives in the diagnosis and management of enteric neu- 1563
1497 91. Enattah NS, Kuokkanen M, Forsblom C, Natah S, Oksanen ropathies. Nat Rev Gastroenterol Hepatol. 2013;10:206---18. 1564
1498 A, Jarvela I, et al. Correlation of intestinal disaccharidase 110. Camilleri M, Bharucha AE, di Lorenzo C, Hasler WL, Prather 1565
1499 activities with the C/T-13910 variant and age. World J Gas- CM, Rao SS, et al. American Neurogastroenterology and Motil- 1566
1500 troenterol. 2007;13:3508---12. ity Society consensus statement on intraluminal measurement 1567
1501 92. Casellas F, Aparici A, Casaus M, Rodríguez P, Malagelada JR. of gastrointestinal and colonic motility in clinical practice. 1568
1502 Subjective perception of lactose intolerance does not always Neurogastroenterol Motil. 2008;20:1269---82. 1569
1503 indicate lactose malabsorption. Clin Gastroenterol Hepatol. 111. Camilleri M, Hasler WL, Parkman HP, Quigley EM, Soffer E. 1570
1504 2010;8:581---6. Measurement of gastrointestinal motility in the GI laboratory. 1571
1505 93. Jellema P, Schellevis FG, van der Windt DA, Kneepkens CM. Gastroenterology. 1998;115:747---62. 1572
1506 Lactose malabsorption and intolerance: a systematic review 112. Parkman HP, Jones MP. Tests of gastric neuromuscular function. 1573
1507 on the diagnostic value of gastrointestinal symptoms and self- Gastroenterology. 2009;136:1526---43. 1574
1508 reported milk intolerance. QJM. 2010;103:555---72. 113. Johansson SG, Hourihane JO, Bousquet J, Bruijnzeel-Koomen 1575
1509 94. Fernández-Bañares F. Reliability of symptom analysis during C, Dreborg S, Haahtela T, et al. A revised nomenclature for 1576
1510 carbohydrate hydrogen-breath tests. Curr Opin Clin Nutr Metab allergy. An EAACI position statement from the EAACI nomen- 1577
1511 Care. 2012;15:494---8. clature task force. Allergy. 2001;56:813---24. 1578
GASTRE 956 1---25

+Model
ARTICLE IN PRESS
1579 114. Chafen JJ, Newberry SJ, Riedl MA, Bravata DM, Maglione M, 120. Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Food elimi- 1598
1580 Suttorp MJ, et al. Diagnosing and managing common food aller- nation based on IgG antibodies in irritable bowel syndrome: a 1599
1581 gies: a systematic review. JAMA. 2010;303:1848---56. randomised controlled trial. Gut. 2004;53:1459---64. 1600
1582 115. Turnbull JL, Adams HN, Gorard DA. Review article: the diag- 121. Ligaarden SC, Lydersen S, Farup PG. IgG and IgG4 antibodies in 1601
1583 nosis and management of food allergy and food intolerances. subjects with irritable bowel syndrome: a case control study 1602
1584 Aliment Pharmacol Ther. 2015;41:3---25. in the general population. BMC Gastroenterol. 2012;12:166. 1603
1585 116. Lomer MC. Review article: the aetiology, diagnosis, mech- 122. Hamilton RG. Clinical laboratory assessment of 1604
1586 anisms and clinical evidence for food intolerance. Aliment immediate-type hypersensitivity. J Allergy Clin Immunol. 1605
1587 Pharmacol Ther. 2015;41:262---75. 2010;125:S284---96. 1606
1588 117. Nwaru BI, Hickstein L, Panesar SS, Roberts G, Muraro A, Sheikh 123. Soares-Weiser K, Takwoingi Y, Panesar SS, Muraro A, 1607
1589 A, et al. Prevalence of common food allergies in Europe: Werfel T, Hoffmann-Sommergruber K, et al. The diagnosis of 1608
1590 a systematic review and meta-analysis. Allergy. 2014;69: food allergy: a systematic review and meta-analysis. Allergy. 1609
1591 992---1007. 2014;69:76---86. 1610
1592 118. Böhn L, Störsrud S, Törnblom H, Bengtsson U, Simrén M. 124. Ortolani C, Bruijnzeel-Koomen C, Bengtsson U, 1611
1593 Self-reported food-related gastrointestinal symptoms in IBS Bindslev-Jensen C, Björkstén B, Høst A, et al. Contro- 1612
1594 are common and associated with more severe symptoms and versial aspects of adverse reactions to food. European 1613
1595 reduced quality of life. Am J Gastroenterol. 2013;108:634---41. Academy of Allergology and Clinical Immunology (EAACI) 1614
1596 119. Aydinlar EI, Dikmen PY, Tiftikci A, Saruc M, Aksu M, Gunsoy reactions to Food Subcommittee. Allergy. 1999;54:27---45. 1615
1597 HG, et al. IgG-based elimination diet in migraine plus irritable 125. Fasano A, Sapone A, Zevallos V, Schuppan D. Nonceliac gluten 1616
bowel syndrome. Headache. 2013;53:514---25. sensitivity. Gastroenterology. 2015;148:1195---204. 1617
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3 Chronic diarrhoea: Deﬁnition, classiﬁcation and

18 Received 19 June 2015; accepted 30 September 2015

E-mail address: ffbanares@mutuaterrassa.es (F. Fernández-Bañares).

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44 Introduction the different categories used to grade certainty (or quality) 83

of the evidence (CE) and strength of recommendation (SR).9 84

45 Purpose of the consensus document

46 Chronic diarrhoea is a common complaint seen by both pri-

69 In 2014, with the aim of helping clinicians diagnose

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Table 1 Classiﬁcation of chronic diarrhoea. Table 1 (Continued)

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Patient history Physical examination Basic investigations

Basic laboratory tests

Risk markers for organic disease

Figure 1 Algorithm 1. Initial approach in patients with chronic diarrhoea.

accompanied by cramp-like pain in the umbilical area (sug- 139

Fever or pus, associated with urgent evacuation or tenesmus and 143

depression) of an origin in the left colon and/or rectum (inﬂammatory 145

Recent onset of symptoms, or change in the characteristics diarrhoea). 146

of previous symptoms The ‘‘functional’’ diarrhoea group, meanwhile, includes 147

Nocturnal diarrhoea on functional diarrhoea. These patients frequently present 150

etc.) to 10---15 movements daily. Other common symptoms are 156

calprotectin with an astringent or restrictive diet designed to prevent 161

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Figure 2 Algorithm 2. Diagnosis of chronic inﬂammatory diarrhoea

ilar in terms of diagnostic accuracy to both MR and CT, but is 189

attractive choice for a preliminary study, particularly in pae- 192

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Table 4 Causative agents of chronic infectious diarrhoea.a

Bacteraemia (rare) Protozoa Viruses

Shigella Cryptosporidium Citomegalovirus mation (CE, high; SR, strong). 239

Yersinia Blastocystishominis 2 Initial investigation in a patient with suspected chronic 240

Campylobacter Entamoebahistolytica inﬂammatory diarrhoea is colonoscopy (CE, high; SR, 241

a enterography, should be performed to evaluate the small 245

Chronic diarrhoea due to malabsorption 247

232 faecal incontinence). These infections are associated with

the most frequent cause of villous atrophy, although it 264

can also be caused by other entities (Table 6).15---20 Duo- 265

4 from the distal duodenum) will usually yield a diag- 267

available. the tissue.21 Intestinal lesions caused by coeliac disease, 272

ﬁndings of treponema in biopsy must be performed to either conﬁrm suspicion or 283

stages of infection) in the case of graft-versus-host disease, pharmaceutical 287

ing evidence. It also describes the diagnostic process for 291

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Refractory coeliac disease (RCD):

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Pathological Histopathological ﬁndings Special Other diagnostic methods CE

Consider complementary studies

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Patient with chronic diarrhoea and

1. Serum amylase and

Amylase and/or lipase < normal + Yes

Pathological faecal elastase? (C) Aetiological study of

Yes No Pancreatic imaging studies

Pancreatic imaging studies Pancreatic atrophy, signs of advanced No

Pathological? (D) Treat with pancreatic

Figure 4 Algorithm 4. Diagnosis of chronic diarrhoea due to exocrine pancreatic insufﬁciency.

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Table 7 Histopathological classiﬁcation systems in coeliac disease.

anaerobes, may be partially replaced with colic bacteria 327

diagnosis) dases, thus causing carbohydrate malabsorption. Small 335

deposits --- to Marsh 3) (stenosis, by-pass, etc.,) or functional (pseudo-obstruction, 339