Investigation of chronic diarrhoea British Society of Gastroenterology Guidelines 2 nd Edition 2003 Dr. P.D. Thomas Consultant Gastroenterologist Taunton and Somerset Hospital

Outline l Definitions l Initial assessment l Factitious diarrhoea l Functional bowel problems l Colonic investigations l Small bowel investigations l Investigation of fat and carbohydrate malabsorption l Investigation of malabsorption due to pancreatic insufficiency l Specific conditions small bowel bacterial overgrowth, bile salt malabsorption, hormone secreting tumours

Mechanisms Intestinal secretions and food- 7l per day 5L absorbed in small intestine 1.5-2L absorbed by colon Stool mL water 10% decrease in fluid absorbed by colon will double stool volume Considerable reserve capacity of colon to absorb increased ileal effluent

Approaches to the classification of diarrhoea Mechanistic Osmotic - eg carbohydrate/ fat malabsorption Secretory- mucosal disease, defects of ion absorption, stimulant laxatives Gut hormone Deranged motility- post vagtomy, IBS carcinoid

Distinguishing osmotic from secretory diarrhoea - fasting - osmotic diarrhoea should stop - osmotic gap low stool osmolality 125mosmol/kg osmotic diarrhoea <50 in secretory diarrhoea

Anatomical …...

Causes of diarrhoea Colonic Colonic neoplasia Endocrine Ulcerative and Crohn's colitisHyperthyroidism Microscopic colitis Diabetes Small bowel Hypoparathyroidism Coeliac disease Addison's disease Crohn's disease Hormone secreting tumours (VIPoma, Other small bowel enteropathies, gastrinoma, carcinoid) (e.g. Whipples disease, tropical sprue, amyloid, intestinal lymphangiectasia ) Bile Acid malabsorption Disaccharidase deficiency Small bowel bacterial overgrowth Mesenteric ischaemia Radiation enteritis Other Lymphoma Factitious diarrhoea GiardiasisSurgical' causes (e.g. small bowel Pancreatic resections) Chronic pancreatitis Autonomic neuropathy Pancreatic carcinomaDrugs Cystic fibrosisAlcohol

Definitions l>200g stool/24 hours lMore than three loose stools/day lChronic > 4 weeks lLayman’s definition

Initial assessment Organic vs functional <3 months, continuous, nocturnal, alarm symptoms Malabsorptive or colonic/inflammatory Specific Drugs, family history, surgery, systemic disease, alcohol, infective

Initial investigations Blood tests FBC, UE, LFT, B12, folate, fe studies, ESR, CRP, TFT Serological tests for coeliac disease Prevalence of 1:200 in asymptomatic western pops.IgA anti-endomysium antibodies anti-tissue transglutaminase antibodies

Stool tests Stool microscopy culture Protozoal eg Giardia, amobae, cryptosporidia Non specific Stool osmolality stool fat Specific stool elastase other..

Stool markers of intestinal inflammation e.g. lactoferrin Stool calprotectin cytosolic protein in monocytes, neutrophils stable for 1 week at RT Use of surrogate markers of inflammtion and Rome criteria to distinguish organic from non- organic disease Tibble et al Gastroenetrology 2002

N=602 all patients underwent invasive imaging Ix Rome criteria, Intestinal permeability Results 263 organic disease, 339 IBS Sensitivityspecificity stool calprotectin8979 intestinal permeability6387 Rome criteria8571

Factitious diarrhoea l 4% of patients attending district gastroenterology clinic l 20-33% attending tertiary referral centres l Association with medical training/eating disorder l In patient assessment/monitoring - stool collections hour fast l ‘Laxative screen’ - anthraquinones, biascodyl, phenolphthaleins, oils, Mg, PO 4.

Case 1 50 year old female 6 months watery diarrhoea up 6 x day Normal baseline investigations including TFT, coeliac serology Normal flexible sigmoidoscopy with bx 2 years ago Next investigation?

Microscopic colitis Lymphocytic or collagenous colitis Rectosigmoid biopsies alone may miss up to 40% of cases (Offner1999)

Frequency Age Malignancy

Overlap between functional and organic disease Irritable Bowel syndrome Rome criteria (II)> 3 months abdominal pain or discomfort with 2 or more - altered stool frequency - altered stool consistency - relieved by defecation bloating or distention or mucous supportive

Discriminant factors >45 Family history <45 Female sex Other ‘functional’ Sx Irritable bowelColonic pathology

Chronic diarrhoea in patients <45yrs Flexible sigmoidoscopy Fine et al patients studied Microscopic colitis 10% >Crohn’s >UC 99.7% of pathology accessible with FS

Chronic diarrhoea in patients >45yrs Rationale for total colonic examination Neoplasia 37% asymptomatic individuals have adenomas 8% adenomas>1cm (Lieberman 2000) Prevalence in symptomatic? Higher prevalence of proximal non-neoplastic pathology e.g microscopic colitis, IBD 7-31% Colonoscopy or barium enema and flexi sigmoidoscopy

Case 2 40 year old male Loose offensive stools 4x/day ? ½ stone weight loss 1 year FBC, LFT, CRP etc normal IgA Antiendomysial antibodies negative Flexible sigmoidoscopy normal

Selective IgA deficiency 0.14% population 2.6% coeliac disease IgG antiendomysium Ab or IgG anti-tTG Ab are suitable alternative serological tests Check IgA levels

Endoscopic distal duodenal biopsies Little information on diagnostic yield Serological tests have replaced D2 biopsies as the initial investigation for coeliac disease Coeliac disease is (by far) the most common small bowel enteropathy in western european populations BUT other small bowel enteropathies should be considered. ‘D2 biopsies where small bowel malabsorption is clinically suspected’

Case 3 55 year old male RIF pain and diarrhoea Tenderness RIF Baseline Ix NAD except CRP 32 Colonoscopy incomplete (histology normal) Next step?

Terminal ileal disease How to assess?

Small bowel imaging Barium follow through Enteroclysis -yield low, equivalent role -small bowel malabsorption suspected (distal duodenal histology normal) Structural abnormalities

Small bowel imaging (2) Tc- HMPAO labelled white cell scanning Enteroscopy diagnostic yield up to 31% ( 20% if gastroscopically accessible lesions excluded)

Small bowel imaging (3) Capsule endoscopy? Established role in the investigation of iron deficiency anaemia ? Suspected small bowel malabsorption or diarrhoea of unknown cause Superior to small bowel barium XR 70% vs 40% diagnostic yield

Capsule Endoscopy: Detection of inflammatory lesions in the small intestine Thickened infiltrated folds (Jejunum) Villous erosion Linear ulcerationsApthous ulcerations (ileum)

Capsule endoscopic diagnosis of Crohn’s Disease Jejunal Crohn's Disease

CELIAC DISEASE

INVESTIGATION OF CHRONIC DIARRHOEA

Malabsorption and ‘difficult diarrhoea’

‘‘Malabsorption’’ Malabsorption - mucosal disease carbohydrate>fat Maldigestion - pancreatic disease fat> carbohydrate (protein quantification difficult)

Tests related to fat malabsorption (1) Stool tests l 3 day faecal fat (poorly reproducible) patients with steatorrhoea reduce fat intake no assessment of completeness of collection no quality control l faecal fat concentration (not widely available) l Stool steatocrit and Sudan III (semi-quantitative) all are non-specific

Tests of fat malabsorption (2) Breath tests l 14 C-triolein l 13 C-hiolein Lembke hr, 30 min breath samples sensitivity 92% in severe, 46% in mild/mod pancreatic insufficiency l 13 C- mixed chain triglyceride l Only sensitive if moderate or severe steatorrhoea

Tests related to carbohydrate malabsorption l D-xylose - used in assessment of mucosal disease for 30 years - High sensitivity (98%) and specificity (95%) reported (although controvercial) - 5 hour urine collection and/or 1 hour serum sample l D-xylose breath test Both have been largely replaced by endoscopic distal duodenal biopsies

Chronic pancreatitis Usually obvious Previous episodes of pancreatitis History of XS alcohol Weight loss Steatorrhoea Coincident diabetes?

Investigation of pancreatic malabsorption: Imaging USS 50-60% sensitive CT 74-90% sensitive ERCP ‘Gold standard’ MRI ?equivalent to ERCP

Investigation of pancreatic malabsorption Invasive l Pancreatic function tests - Secretin/cholecystokinin stimulation - ‘Lundh’ test Sensitivity 90% l ERCP secretin-cholecystokininERCP 26/30 abnormal21/30

Investigation of pancreatic malabsorption Non-invasive (1) l (all tests related to fat malabsorption) l (Serum enzymes) l Faecal tests - chymotrypsin (Sens 80% Spec 84%) - lipase (sensitivity 46%) - elastase mildmoderate severe sensitivity % (Loser 1996) % (Lankisch 1998)

Investigation of pancreatic malabsorption Non-invasive (2) ‘Tubeless’ oral pancreatic function tests l NBTP/PABA - N-benzoyl-L-tyrosyl-p-aminobenzoic acid - hydrolysed by chymotrypsin - 6 hour urine collection - Sensitivity 64-83% Specificity 89% l Fluorescein dilaurate (Pancreolauryl) test - Pancreatic esterase - 10 hour urine collection - variable sensitivities reported

Investigation of pancreatic malabsorption (summary) Faecal elastase is the non-invasive investigation of choice May complement with Urine test such as pancreolauryl or NBTP-PABA but - specificity influenced by small bowel disease - technically more demanding

Miscellaneous causes and ‘difficult diarrhoea’ Small bowel bacterial overgrowth Bile acid malabsorption Hormone secreting tumours

Small bowel bacterial overgrowth l Underdiagnosed -few data on prevalence - Up to 50% of patients with gastrojejeunostomy - Resection of ileo-caecal valve eg pouch patients - 14% asymptomatic elderly by glucose HBT l Small bowel aspirate and culture - ‘Gold standard’ >10^6 cfu/mL - Culture of anaerobes difficult - May overestimate -contamination and ‘normal’ small bowel colonisation by bacteria.

Investigation of small bowel bacterial overgrowth l Breath tests - 14 C-cholylglycine - now abandoned - Hydrogen breath tests (glucose or lactulose) Sensitivity: % Specificity: 70-83% - 14 C-D xylose – not available in UK Proximally absorbed No reliance on H 2 production

Bile acid malabsorption Causes terminal ileal disease, surgical resection primary defect, post cholecystectomy rapid transport 75Se homotaurocholate (75SeHCAT) synthetic analogue of taurocholic acid retained fraction assessed by gamma camera 7 days after oral administration <15% suggest BAM 7alphahydroxy-4-cholestone-3-one Therapeutic trial of cholestyramine

Hormone secreting tumours Rare! Incidence approx. 1 per million VIPoma, gastrinoma, carcinoid, somatostatinoma Large volumes (>1 litre) of watery diarrhoea VIPoma 90% are pancreatic, large tumours Diarrhoea primary symptom (100%) Can be episodic. Secretory diarrhoea Fasting VIP level >170pg/mL

Summary

Conclusions l Baseline investigations (primary care) l lower GI endoscopy with biopsy l Consider factitious diarrhoea l Small bowel malabsorption - Distal duodenal biopsies - small bowel imaging l Pancreatic insufficiency - faecal elastase, Pancreolauryl test, pancreatic imaging l Other – SB bacterial overgrowth, BAM etc In 1/3 patients no diagnosis made: ‘chronic idiopathic diarrhoea’