chronic diarrhea-an approach.,etiology,diagnosis and management

chronic diarrhea-an approach.,etiology,diagnosis and management

1. An Approach to Chronic Diarrhea D r . V ijay k.c. DM Resident

2. Introduction Derived from the Greek words meaning “flowing through” Defined as stool weight greater than 200 g per day Limited value in clinical practice WHO: Passage of 3 or more loose or liquid stools per 24 hours, or more frequently than is normal for an individual person Over 3.5 million outpatient visits for diarrhea occur each year in the USA. M ore than 180,000 hospital admissions and 3000 deaths each year in US.

3. Clinical Classification Acute vs Chronic Diarrhea Large volume vs Small Volume Diarrhea Osmotic vs Secretory Diarrhea Watery vs Fatty vs Inflammatory Diarrhea

4. Acute vs Chronic Diarrhea Acute: less than or equal to 14 days in duration Persistent: more than 14 days in duration Chronic: more than 30 days in duration Fine KD , Schiller LR . AGA technical review on the evaluation and management of chronic diarrhea. Gastroenterology1999; 116 :1464–86

5. Persistence of an acute diarrheal episode beyond 7 days makes the possibility of a protozoal cause—such as giardiasis or crypto- sporidiosis . Few infectious agents (e.g., Aeromonas or Yersinia spp.) cause prolonged diarrhea in an immunocompetent person. chronic diarrhea is usually not caused by an infectious agent. chronic diarrhea: consider possibility of noninfectious causes first.

6. Large volume vs Small Volume Diarrhea Inflammatory or motility disorder involving the left colon Frequent small-volume bowel movements Painful Source of diarrhea in the right colon or small bowel with intact rectosigmoid reservoir Less frequent and larger bowel movements Mostly painless Stool weights > 1000 g produces dehydration (in the absence of vomiting or limited oral intake)

7. Osmotic vs Secretory Diarrhea Osmotic diarrhea Due to intestinal malabsorption of ingested non-electrolytes Abates with fasting Large osmotic gap (>100 mOsm/kg) and low stool sodium level (<60 mmol/L) Secretory diarrhea Due to malabsorption or secretion of electrolytes Continues during fasting Small osmotic gap (<50 mOsm/kg) and stool sodium concentration > 90 mmol/L

8. Watery vs Fatty vs Inflammatory Diarrhea Watery diarrhea implies either secretory or osmotic diarrhea. Fatty diarrhea implies defective absorption of fat and perhaps other nutrients in the small intestine. Inflammatory diarrhea implies the presence of one of a limited number of inflammatory or neoplastic diseases involving the GI tract.

9. Watery diarrhea Osmotic diarrhea Carbohydrate malabsorption Celiac disease Osmotic laxatives (e.g., Mg+2, PO4−3, SO4−2) Sugar alcohol ( mannitol , sorbitol, xylitol) Functional Irritable bowel syndrome

10. Fatty Diarrhea Malabsorption syndromes Mesenteric ischemia Mucosal diseases (e.g., celiac disease, Whipple's disease) Short bowel syndrome Small intestinal bacterial overgrowth Maldigestion Inadequate luminal bile acid concentration Pancreatic exocrine insufficiency

11. Inflammatory Diarrhea Infectious diseases Invasive bacterial infections (e.g., tuberculosis, yersiniosis) Invasive parasitic infections (e.g., amebiasis, strongyloidiasis) Pseudomembranous colitis (Clostridium difficile infection) Ulcerating viral infections (e.g., cytomegalovirus, herpes simplex virus) Inflammatory bowel diseases Crohn's disease Ulcerative colitis Ulcerative jejunoileitis Ischemic colitis Neoplasia Colon cancer Lymphoma Radiation colitis

12. Chronic diarhhea

13. Likely Causes of Diarrhea in Well-Defined Patient Groups or Settings

14. Pathophysiology Normally, the small intestine and colon absorb 99% of both oral intake and endogenous secretions from the salivary glands, stomach, liver, and pancreas—a total fluid load of approximately 9 to 10 L daily . Fluid loads along the gastrointestinal tract

15. P rotective response to a variety of intestinal insults and assaults. I nfectious agents, toxins, or other noxious substances are present in the intestine. Increase fluid secretion and motility it is inappropriate and non adaptive purpose in chronic diarhhea . Excess of stool water due to abnormal net intestinal water and electrolyte transport . Reduced net water absorption change in the composition of stool solids that may alter stool consistency.

16. Interplay of many factors: epithelial function, motor function, and luminal composition. Decrease in absorption or an increase in secretion leads to additional fluid within the lumen . Disruption of epithelial electrolyte transport or its regulatory system by toxins, drugs, hormones, and cytokines. I ngestion of some poorly absorbed osmotically active substance (e.g., magnesium ion, lactulose)

17. COMPLEX DIARRHEA Most clinically significant diarrheas are complex; rather than being produced by a single pathophysiologic mechanism. These may include the effects of substances released by enteric endocrine cells, cytokines released by local and remote immunologically reactive cells, by the activity of the enteric nervous system, and by peripherally released peptides and hormones (paracrine, immune, neural, and endocrine systems).

18. ALPINES regulatory system in the intestine.

19. Evaluation History Physical examination Laboratory Examination Radiological Endoscopy

20. A pproach in patients with chronic Diarrhoea

21. History Features suggestive of an organic disease History of diarrhoea of < 3months’ duration Predominantly nocturnal or continuous (as opposed to intermittent) diarrhoea Significant weight loss Family history: particularly of neoplastic, IBD or coeliac disease

22. History Previous surgery Extensive resections of the ileum and right colon Bypass operations such as in gastric surgery and jejunoileal bypass procedures Shorter resections of the terminal ileum Post cholecystectomy Previous pancreatic disease Systemic disease: thyrotoxicosis and hypoparathyroid disease, DM, adrenal disease or systemic sclerosis

23. History Alcohol Diet Excessive intake of caffeine (eg, coffee, energy drinks) Milk in patients with lactase deficiency, Food additives (eg,sorbitol), fructose and other FODMAPs (fermentable oligo-,di-, mono-saccharides and polyols) Drugs and Toxins

24. History Recent overseas travel or other potential sources of infectious gastrointestinal pathogens. Recent antibiotic therapy and Clostridium difficile infection

25. Physical Examination

26. Investigations Screening for evidence of malabsorption should include CBC Urea and electrolytes Liver function tests Vitamin B12, folate Calcium Ferritin ESR and CRP TFT Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology,3rd edition 2018

27. Stool tests Stool Osmolality Stool pH Stool FOBT Stool WBC , Lactoferrin, Calprotectin Stool Fat content Others

28. Stool Osmotic Gap and Osmolality Stool Osmotic gap 290 - 2 × (stool Na + stool K) Negative osmotic gap Multivalent anions e.g. Phophate, sulphate Stool osmolality Useful only in detecting samples that have been contaminated by the addition of water or hypotonic urine which have an osmolality < 290 mOsm/kg Osmotic Gap < 50 Osmotic Gap >100

29. Stool pH pH < 6 suggestive of Carbohydrate malabsorption Indirectly indicates excess carbohydrate fermentation in the colon

30. Faecal occult blood test (FOBT) Two types of tests: FOBT Faecal immunochemical technique (FIT) Emerging studies indicate that,in those with lower GI symptoms suggestive of colorectal cancer,FIT testing has a high negative predictive value (0.99) with the optimal cut-off between 7 and 10 μ g/g faeces 1,2,3 1.Mowat C, Digby J, Strachan JA, et al. Faecal haemoglobin and faecal calprotectin as indicators of bowel disease in patients presenting to primary care with bowel symptoms. Gut 2016;65:1463–9. 2. Quyn AJ, Steele RJ, Digby J, et al. Application of NICE guideline NG12 to the initial assessment of patients with lower gastrointestinal symptoms: not FIT for purpose? Ann Clin Biochem 2018;55:69–76. 3. Widlak MM, Thomas CL, Thomas MG, et al. Diagnostic accuracy of faecal biomarkers in detecting colorectal cancer and adenoma in symptomatic patients. Aliment Pharmacol Ther 2017;45:354–63

31. FOBT Colitis Malignancy Lymphoma of the small intestine Celiac disease (fecal occult blood in 50% of cases) Refractory sprue (fecal occult blood in 70% of cases)

32. Faecal calprotectin 50μ g/g faeces as the decision level above which IBD is more likely other causes of raised calprotectin include CRC,infectious gastroenteritis and NSAIDs Calprotectin levels >250 μ g/g faeces suggest active inflammation. 1. Kawashima K, Ishihara S, Yuki T, et al. Fecal calprotectin more accurately predicts endoscopic remission of Crohnʼs disease than serological biomarkers evaluated using balloon-assisted enteroscopy. Inflamm Bowel Dis 2017;23:2027–34

33. Fecal lactoferrin assay Collected fecal specimens were labeled, stored at –80 C, and batched for subsequent analysis. Fecal lactoferrin was quantified by use of a commercially available polyclonal-based enzyme-linked immunosorbent assay ( IBD-SCAN ; TECHLAB, Inc) A cutoff point of 7.25 m g/mL for indicating elevated FLA has been previously established and validated for use in patients with IBD (10,21). Fecal lactoferrin is stable at room temperature for as long as 5 days

34. Stool Fat Output Qualitative : Sudan stain Quantitative: Total fat content in 24 Hrs stool >7gm / >9% of intake Fat excretion over 14 g/24 hr strongly indicates a problem with fat absorption Semiquantitative No and size of fat globules

35. Faecal elastase Three-day faecal fat estimation unpleasant and time consuming test. Stool chymotrypsin assays have been replaced by faecal elastase because of its greater stability and sensitivity. Human elastase-1 is an anionic protease belonging to the family of serine proteases along with other digestive enzymes such as chymotrypsin and trypsin. This stool test has emerged as a preferred test of pancreatic function. Normal values are 200–500 μ g/g, with 100–200 μ g/g in mild to moderate insufficiency The test is unaffected by simultaneous enzyme therapy or diet and requires only a single 100mg stool sample. Sensitive biomarker for moderate to severe pancreatic insufficiency with sensitivities of 73–100% and specificities of 80–100%. However, faecal elastase is not useful in cases of mild pancreatic insufficiency with sensitivities of <60%.

36. Others Stool culture C difficile antigen (glutamate dehydrogenase [GDH]) EIA Real-time PCR assay to detect  C.difficile  gene toxin EIA for detecting toxins A and B Stool cytotoxin test 

37. Others Stools for ova, cysts and parasites Stool ELISA for Giardia (92% sensitivity and 98% specificity) Fecal elastase Faecal bile acid measurement

38. Implications of Stool Characteristics in Patients with Chronic Diarrhea

39. Vitamin/mineral defciencies in chronic diarrhea

40. Secretory diarrhea: Classical findings Frequent, watery, voluminous, bowel movements Night-time awakening Dehydration Altered serum electrolytes Lack of response to fasting

41. Carcinoid tumors Arise from enterochromaffin cells involved in the primary production and release of serotonin (5-HT) along with other bioactive hormones Excessive levels of 5-HT are converted systemically to 5-HIAA Symptoms include Cutaneous flushing of the chest and superior thorax, respiratory wheezing, right heart failure from pulmonic and tricuspid valve disease, and pellagra Frequent watery diarrhea occurs in up to 80% of patients with carcinoid syndrome

42. VIPoma Pancreatic non- β islet cell tumors that express VIP in an unregulated fashion Constellation of watery diarrhea and hypokalemia associated with elevated VIP levels Presenting along with dehydration, achlorhydria, metabolic acidosis, flushing, hypercalcemia, and hyperglycemia

43. Gastrinomas Ectopic secretion of gastrin by a NET (gastrinoma), which causes excessive gastric acid secretion. characteristically causing peptic disease (often severe) and/or GERD

44. Bile acid diarrhoea Dihydroxy bile salts stimulate colonic secretion of fluid and electrolytes clinically manifesting as secretory diarrhea Empirical trial of a bile acid–sequestering resin A 7-day SeHCAT ( 75 selenium homotaurocholic acid test) retention value less than 15% 0–15%: mild bile acid loss 5–10% as moderate 0–5% as severely abnormal Fecal bile acid >2300 µmol/48hours indicative of bile acid diarrhea

45. Villous adenoma Account for 5%–10% of all adenomatous polyps Majority remain asymptomatic A rare subset can cause severe secretory diarrhea leading to hypovolemia with acute renal failure, hyponatremia, hypokalemia, metabolic acidosis, and confusion Secretory villous adenomas are typically large and located in the rectosigmoid colon

46. Villous adenoma Management Fluid and electrolyte resuscitation Adenoma removal by either endoscopic polypectomy, EMR, or surgery Medical management with indomethacin

47. Osmotic diarrhea Classically, patients sufering from osmotic diarrhea have Loose stools that improve or resolve with fasting Nighttime symptoms are rare

48. Hydrogen Breath Test J Neurogastroenterol Motil 2011;17:312~317 Rise in Hydrogen by 20 ppm above basal after lactose ingestion is considered as positive lactose HBT

49. Malabsorptive diarrhea Malabsorption is the lack of uptake of intraluminal nutrients across the intestinal epithelium and transport into the bloodstream Steatorrhea is defined physiologically as stool fat exceeding 7 g per 24 h and clinically by the presence of gross fat in stool Typically described as greasy, foating, foul smelling, and with or without fat droplets

50. Pancreatic insufficiency Occurs upon destruction of > 90% of acinar cells and pancreatic lipase production of < 10% of normal Clinical findings Weight loss Fat-soluble vitamin deficiencies Steatorrhea Investigations Fecal elastase < 100µg/g Secretin stimulation test Imaging

51. Small intestine bacterial overgrowth Common symptoms Bloating, fatulence, and abdominal pain Diarrhea may be secondary to fat malabsorption or maldigestion of carbohydrates Diagnosis Indirect measures such as carbohydrate or [14C]-d-xylose breath testing Technical limitations with jejunal aspirate cultures Commonly associated findings Megaloblastic anemia (vitamin B-12 def) with elevated serum folate levels

52. Infammatory diarrhea Results from the activation of intestinal inflammatory mediators leading to excessive cytokine production that disrupts epithelial function and integrity Presentation Wide array of symptoms ranging from bloody diarrhea in colonic infammatory bowel disease, to chronic malabsorption from celiac disease

53. IBD ulcerative colitis Continuous infammatory disease confined to the colon involving the mucosa and submucosa Extraintestinal manifestations: anterior uveitis,diffuse scleirits,erythema nodosum,pyoderma gangerosum . Diarrhea: typically bloody with or without abdominal pain Tenensmus Crohn’s disease Transmural infammation that can involve any site along the GIT while sparing the rectum Extraintestinal manifestations same as ulcerative colitis. Variable GI symptoms

54. Intestinal tuberculosis Two types of bowel lesions are seen: ulcerative and ulcerohypertrophic . The ulcerative form has been described in malnourished individuals T he ulcerohypertrophic form has been described in relatively well-nourished individuals. Ulcerative and stricturous forms are usually observed in the small intestine. C olonic and ileocecal lesions are usually ulcerohypertrophic . And most common site is ileocecal area A palpable right lower quadrant abdominal mass is present in 25 to 50 percent of patients  . Clinical manifestations in ulceroconstrictive disease; include intestinal colic, abdominal distension, chronic diarrhea, nausea, vomiting, constipation, and bleeding.

55. Celiac disease A chronic disorder of the digestive tract that results in an inability to tolerate gliadin, the alcohol-soluble fraction of gluten gluten, a protein found in products containing wheat, barley, and rye. Gluten contains an undigestible gliadin component that is responsible for an inflammatory immune reaction at intestinal epithelial cells. Endoscopic findings are scalloped mucosa, decreased epithelial folds, a mosaic mucosal pattern, and mucosal nodularity Clinical manifestations Diarrheal syndromes (<50 %) May present only with extraintestinal manifestations of the disease such as dermatitis herpetiformis, arthropathy, peripheral neuropathy,IDA, and elevated LFTs

56. Celiac disease (CD) diagnostic testing algorithm ACG Guideline 2013

57. Whipple's disease , due to the bacillus Tropheryma whipplei histiocytic infiltration of the small-bowel mucosa, typically occurs in young or middle-aged men; frequently associated with arthralgias , fever, lymphadenopathy , and extreme fatigue, and it may affect the CNS and endocardium

58. Tropical Sprue Tropical sprue is a chronic diarrheal disease, possibly of infectious origin, that involves the small intestine. C haracterized by malabsorption of nutrients, especially  folic acid and vitamin B12. Most patients with tropical sprue have overgrowth of toxigenic coliform bacteria ( Klebsiella, E. coli , and  Enterobacter ) in the proximal small intestine . Treatment with broad spectrum antibiotics is usually curative .

59. Microscopic colitis Lymphocytic colitis denotes the presence of a lymphocyte-predominant mixed infammatory condition with intraepithelial lymphocyte counts > 20/HPF Collagenous colitis includes histological features of lymphocytic colitis accompanied by the formation of a subepithelial collagen band greater the 7µm in size (normal 1–7µm) Biopsies from different sites along a macroscopically normal colon is the gold standard for diagnosis of CC and LC in patients with chronic non-bloody watery diarrhoea (CE, moderate; SR, strong). It is recommended to take 2 biopsies each from, at least, the right, transverse and left colon, and store them in separate containers (CE, moderate; SR, strong).

60. Prolonged infectious diarrhea

61. I rritable bowel syndrome-Diarrhea variant Diarrhea is usually characterized as frequent loose stools of small to moderate volume. Bowel movements generally occur during waking hours, most often in the morning or after meals. Most bowel movements are preceded by lower abdominal cramping pain, urgency, and a sensation of incomplete evacuation or tenesmus. Approximately one-half of all patients with IBS complain of mucus discharge with stools 

62. Ford AC et al. N Engl J Med 2017;376:2566-2578. Rome IV Criteria for the IBS ome IV Criteria for the Irritable Bowel Syndrome.

63. Post-surgical diarrhoea Patients develop diarrhoea as a result of surgical intervention. The underlying aetiology leads to pyloric dysfunction, bile salt malabsorption, bacterial overgrowth or gut bypass reducing absorptive capacity. Upper GI surgery may result in damage to vagus nerve and reduction in capacity of the stomach after gastrectomy. Rapid gastric emptying (osmotic diarrhoea ) is associated symptoms of ‘dumping’ syndrome. Surgery provides an ideal environment for bacterial colonization. GI tract surgeries that create a blind loop ( eg , a Billroth II procedure or a Roux-en-Y anastomosis) may predispose to stasis and overgrowth of microbes.

64. Diarrhea in Hospitalized Patients Diarrhea frequently develops during hospitalization, particularly in severely ill patients hospitalized for protracted periods. Common causes of diarrhea in this setting include medications (especially antibiotics), tube feedings, intestinal ischemia, and fecal impaction. Antibiotic therapy is particularly likely to cause diarrhea by at least 2 mechanisms: (1) impairing carbohydrate metabolism by the colonic bacterial flora, thereby producing an osmotic diarrhea. (2) facilitating overgrowth of C. difficile and production of its toxins, thereby producing an inflammatory and/or secretory diarrhea. E rythromycin may produce diarrhea by its motilin-like effect on GI transit.

65. Factitious diarrhea Factitious diarrhea may be characterized by a true increase in stool volume, which is self-induced, or the creation of an apparent increase in stool volume by the addition of various substances to the stool. Surreptitious laxative abuse is the most frequent cause of factitious diarrhea. Laxative abuse often presents as watery diarrhea that is high in frequency and volume. The diarrhea is often associated with crampy abdominal pain, lethargy and generalized weakness, malnutrition, dehydration, and electrolyte abnormalities may result.

66. In addition to the history, evaluation of the patient with suspected factitious diarrhea consists of stool analysis and attempted detection of chemical laxatives. Stool analysis consists of measurement of stool osmolality, and sodium, potassium, and magnesium concentrations. An osmolal gap indicates the presence of an unmeasured solute which can be due to laxatives containing magnesium, sorbitol, lactose, lactulose, or polyethylene glycol as the active ingredients. Colonoscopy may reveal melanosis coli and a cathartic colon may be seen on barium enema

67. Evaluation of suspected laxative abuse

68. IDIOPATHIC SECRETORY DIARRHEA When an exhaustive evaluation fails to reveal a cause of chronic diarrhea and stool analysis suggests a secretory diarrhea,the diagnosis of idiopathic secretory diarrhea should be made. It occurs in two forms: 1)Epidemic form: Brainerd diarrhea 2)Sporadic form. Self limited forms of diarrhea.

69. Diarrhea of Obscure Origin Physicians sometimes fail to make a specific diagnosis in patients with chronic diarrhea, despite an elaborate evaluation.

70. Empirical therapy for chronic diarrhea Empirical therapy is used in three situations: as a temporizing or initial treatment before diagnostic testing, after diagnostic testing has failed to confirm a diagnosis, and when a diagnosis has been made, but no specific treatment is available or specific treatment fails to effect a cure

71. Empirical trials of antimicrobial therapy may be justified if the prevalence of bacterial or protozoal infection is high in a specific community or situation. An empirical trial of bile acid–binding resins, such as cholestyramine , may be the least expensive way to diagnose bile acid–induced diarrhea. Opiates are the most effective nonspecific antidiarrheal agents. Octreotide should be reserved as a secondary agent. Enkephalinase inhibitor (delta opiate receptor effect)- Racecadotril .

72. Adequate hydration is an essential part of the treatment of diarrheal diseases, and oral rehydration solutions may be necessary in some instances. Some patients, particularly those with post- resection diarrhea, may need long-term intravenous fluid administration. Parenteral nutrition should be reserved for patients who are unable to maintain an adequate nutritional status because of the diarrheal disease.

73. ADVENT TRIAL A predominant type of diarrhea that develops in HIV patients has secretory characteristics, including increased secretion of chloride ions and water into the intestinal lumen. One proposed mechanism that may lead to this type of secretory diarrhea is explained by the activation of the cystic fibrosis transmembrane conductance regulator and calcium-activated chloride channels. CROFELEMER is a novel antidiarrheal agent that works by inhibiting both of these channels. More recently, crofelemer was approved by the US Food and Drug Administration for the symptomatic relief of noninfectious diarrhea in adult patients with HIV/AIDS on antiretroviral therapy.

74. OBADIAH TRIAL OBADIAH, an ongoing Phase 2a trial of obeticholic acid (OCA) as a treatment for primary bile acid diarrhea (PBAD) presented at the Digestive Diseases Week conference. The initial results from the OBADIAH trial demonstrate that treatment with OCA is associated with statistically significant increased levels of fibroblast growth factor 19 (FGF19) and improvement in clinical symptoms in patients with PBAD

75. FODMAP FODMAP is an acronym for Fermentable Oligosaccharides, Disaccharides, Monosaccharides , and Polyols It is an elimination diet which attempts to improve symptoms in functional gastrointestinal disorders. FODMAPs are osmotically active and ferment rapidly, thereby causing gastrointestinal symptoms in some individuals. Currently there are no official published guidelines recommending specific dietary treatment of functional gastrointestinal disorders, but multiple studies have looked into this topic and there is increasing evidence suggesting that this diet benefits certain patients.

76. References Sleisenger and fordtran’s gastrointestinal and liver disease, 11th Edition Chronic diarrhoea : Definition, classification and diagnosis Fernando Fernández-Banares et all.( Gastroenterol Hepatol. 2016; 39(8) :535-559) British Society of Gastroenterology,3rd edition 2018 . Upto Date

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