CHAPTER Chronic Diarhoea – An Approach 63 Swaroop Kumar Baruah, Suman Talukdar

INTRODUCTION than 4 weeks is termed as chronic diarrhoea. An acute Diarrhoea is a common human experience. The word diarrhoeal episode occurs once in every 18 months in an diarrhoea originates from the Greek terms dia (through) individual in developed countries. Chronic diarrhoea can and rhein (to flow).For many, episodes of diarrhea occur in 3–5% of the population in any given year. last a day or 2 and rapidly subside without medical Diarrhoea is defined as the passage of abnormally liquid or intervention. While for few others, diarrhoea will last unformed stools at an increased frequency, i.e. more than for more than a few days or is complicated by fever, three times in a 24 hour period. In Western populations, prostration, or rectal bleeding. Diarrhoea lasting for more Table 1: Classification of Chronic Diarrhoea 1. Osmotic 4. Inflammatory • Medications • Inflammatory bowel disease: Ulcerative colitis, Crohn’s disease,Microscopic colitis Laxatives (Mg SO4, PO4), elixirs • Undigested sugars • Malignancy: colon cancer, lymphoma Diet foods/drinks/gum (sorbitol, mannitol, others); • Radiation colitis/enteritis Enzyme dysfunction (e.g. lactose, fructose) • Mastocytosis 2. Secretory Invasive or inflammatory infections: C.difficile, • Medications Cytomegalovirus, E.histolytica, Tuberculosis Non-osmotic laxatives, antibiotics • Ischemia • Small intestinal bacterial overgrowth 5. Motility disorders • Endocrine: • Post-surgical (vagotomy, dumping) Tumors: Carcinoid, Gastrinoma, Medullary thyroid • Scleroderma cancer, VIPoma • Diabetes mellitus Systemic: adrenal insufficiency, hyperthyroidism • Hyperthyroidism • Bile salt malabsorption (ileal resection, idiopathic, 6. Miscellaneous postcholecystectomy) • Irritable bowel syndrome • Non-invasive infections: Giardiasis, • Functional diarrhoea Cryptosporidiosis • Factitious 3. Steatorrhoea • Maldigestion Decreased bile salts (cirrhosis, bile duct obstruction, ileal resection) Pancreatic dysfunction (chronic pancreatitis, cystic fibrosis, ductobstruction) • Malabsorption Celiac sprue, Tropical sprue, Giardiasis, Whipple’s disease Chronic mesenteric ischemia Short bowel syndrome Bacterial overgrowth (diabetes mellitus, scleroderma, prior bowel surgery) Lymphatic obstruction 296 Table 2: Drugs Causing Diarrhoea Motility disorders cause diarrhoea through either increased GI transit (e.g. post-vagotomy diarrhoea) or by More Common slowing transit, thereby predisposing to small intestinal Antacids, PPI bacterial overgrowth (e.g. scleroderma). Cephalosporins, Clindamycin, Ampicillin, Diabetic diarrhoea may result from abnormal gut motility Amoxycillin, Erythromycin due to autonomic neuropathy, bacterial overgrowth Colchicine and bile salt malabsorption. Irritable bowel syndrome Metformin (IBS) and functional diarrhoea are the common causes of chronic diarrhoea in Western countries. IBS is defined by Non-steroidal anti-inflammatory drugs, the Rome Committee as a chronic condition characterized 5-aminosalicylates by abdominal pain and altered bowel habits; the pain Cholesterol-lowering agents (Clofibrate, Gemfibrozil, characteristically is in association with a change in Lovastatin) stool form or frequency, and is relieved by defaecation. Anti Neoplastic drugs Functional diarrhoea is defined as recurrent or continuous passage of loose or watery stools without abdominal pain Less common or discomfort. Factitial diarrhoea accounts for up to 15%

GASTROENTEROLOGY Angiotensin converting enzyme inhibitor of unexplained diarrhoeas referred to tertiary care centers. Angiotensin receptor blocking agents It can occur as a part of Munchausen syndrome. Some Beta-adrenergic receptor antagonists, other patients may self-administer laxatives or adulterate the antiarrhythmics stool sample with water or urine to increase its volume. Carbamazepine CLINICAL APPROACH TO CHRONIC DIARRHOEA Lithium History and examination- Vitamin and mineral supplements A detailed history and thorough examination are crucial in the work up of patients with chronic diarrhoea. IBS daily faecal weight does not exceed 200g, but in Indians commonly occur in the third and fourth decade, AIDS- this figure is somewhat higher and up to 400g per day related diarrhoea is common in younger patients whereas may be acceptable. the peak incidence of microscopic colitis is in the seventh and eighth decade of life. Colon cancer should be excluded CLASSIFICATION OF CHRONIC DIARRHOEA in a patient with new onset of diarrhoea over the age of The list of differential diagnosis for chronic diarrhoea is 50 years. IBS and microscopic colitis are more common in extensive. Depending on the Patho physiology, chronic females. diarrhoea can be broadly classified into six categories. The presence of lymphadenopathy or significant weight Osmotic diarrhoea is suspected in a patient whose loss could suggest chronic infection or malignancy. diarrhoea occur after meals but resolves with fasting. Family history is important in cases of inflammatory Secretory diarrhoea is suggested in a patient with bowel disease, coeliac disease or neoplastic diseases. large-volume watery diarrhoea which is painless and History and clinical examination should exclude that persists even after fasting. It can be confirmed by systemic diseases like thyrotoxicosis, diabetes mellitus, demonstrating an increase in stool volume in absence of parathyroid and adrenal disease which may cause chronic increased osmotic gap. diarrhoea through various mechanisms. A detailed drug Steatorrhoea is suggested by the occurrence of greasy history should be obtained in all patients. History of or oily stools that have an offensive odour and float on alcohol abuse is important. Alcohol can cause diarrhoea the toilet water. Steatorrhoea can be confirmed by stool by increasing gut motility, reducing activity of intestinal analysis. Quantitatively, steatorrhoea is defined as stool disaccharidases and decreased pancreatic function. fat exceeding the normal 7 g/day. The presence of malabsorption is usually evident by steatorrhoea which include pale, bulky malodorous stool. The presence of blood or pus in the stools, pain abdomen Fat laden stools float, are sticky and difficult to flush away. and fever is suggestive of inflammatory diarrhoea. It can be confirmed by the demonstration of leukocytes in stool Patients with IBS have erratic stool pattern. Patients’ or leukocyte proteins (such as lactoferrin or calprotectin), complain of abdominal cramps accompanied by either or by the visualisation of inflammatory changes in the with diarrhoea or constipation. Abdominal pain is often colonic mucosa by endoscopy and biopsy. relieved by defaecation. The symptoms of IBS as defined by the Rome IV criteria include recurrent abdominal pain Inflammatory bowel disease, may have extra intestinal that is present at least three days per month in the last manifestation like uveitis, polyarthralgia, erythema three months, associated with a change in stool frequency nodosum etc. Microscopic colitis mostly occur in middle- or form which improves with defecation. Psychiatric aged women and those on NSAIDs, statins, PPIs and symptoms like anxiety and depression are frequently SSRIs. Biopsy of a normal appearing colon is required for associated with IBS and may be present in upto 67% cases. histologic diagnosis. CHAPTER 63 297 Dilated, esp. duodenum; delayed duodenum; delayed Dilated, esp. Table 4: Small Bowel Radiography 4: Small Bowel Table thin, fluid; increased calibre; - Dilated disease Celiac of barium (moulage), segmentation effaced folds intussusception column, painless fold calibre; thick, wild disease - Normal Whipple’s patchy micronodularity pattern; - Scleroderma peristalsis, hypomotility calibre; coarse folds; wall Lymphoma - Variable extraluminal masses; micronodularity infiltrated, stiff; caliber; symmetrical fold Normal Amyloidosis- walls; micronodularity stiff thickening, no oedema; Increased luminal fluid; thick, Lymphangiectasia- oedematous folds Stenotic (string sign); deformed/ Crohn’s disease - of walls; thickened folds; rigidity/ulceration Sometimes extraluminal mass luminal fluid; Dysgammaglobulinemia- Increased nodular lymphoid hyperplasia duodenal folds; Giardiasis- Dilated duodenum; thick spasm, rapid transit thick duodenum; Dilated - Syndrome Zollinger–Ellison pattern duodenal folds; peptic ulcer; reticulated in duodenum Cystic fibrosis - Thick folds; nodularity graininess Abetalipoproteinemia- Fine mucosal mucosal nodularity Mastocytosis- Thick gut wall; Serological tests the preferred single anti-TTG is (IgA) A Immunoglobulin the over in individuals disease celiac detection of test for at be measured IgA should serum Total 2 years. age of the same time to rule out IgA deficiency that might cause a falsely negative test. Anti- antibodies are measured to diagnose IBD. Saccharomyces cerevisiae Stool examination Fecal electrolytes can and secretory diarrhoea. It is based on calculation osmotic help to of the osmotic gap. differentiate between The stool osmotic + potassium 290 mosmol/kg) - (2 x [fecal sodium gap: serum concentration]). osmolarity (typically gap of < 50 mosmol/kg indicates a A faecal osmotic secretory diarrhoea while a gap of > 75 mOsm/kg indicates suggestive is ) pH (<7.0) fecal low diarrhoea.A osmotic an of carbohydrate malabsorption. Leucocyte enzyme, lactoferrin or calprotectin are used as surrogate markers of faecal leukocytes to diagnose mucosal inflammation. Fecal calprotectin has been found to be more sensitive. sedimentation rate, liver and kidney function tests, blood tests, function kidney and rate, liver sedimentation glucose and electrolytes. The presence of iron deficiency anaemia may indicate Coeliac disease. Implications Implications Malnutrition disease Mast cell (mastocytosis) Amyloidosis Addison’s disease Glucagonoma disease Kohlmeier-Degos Celiac disease of Medullary carcinoma the thyroid Hyperthyroidism Carcinoid syndrome Endocrine tumor, amyloidosis Inflammatory bowel disease, yersinosis lymphoma, cancer HIV, Chronic mesenteric ischemia Faecal incontinence Diarrhoea due to lactose intolerance occurs intolerance lactose to due Diarrhoea

Muscle wasting, oedema -- Muscle wasting, pigmentosa, Urticaria -- dermatographism Pinch purpura, macroglossia -- -- Hyperpigmentation Migratory necrotizing erythema -- Malignant atrophic papulosis - Dermatitis herpetiformis-- Thyroid nodule, -- lymphadenopathy Tremor, lid lag-- Right-sided murmur, wheezing,flushing -- Hepatomegaly -- Arthritis -- Lymphadenopathy-- Abdominal bruit -- Anal sphincter weakness-- Findings Table 3: Physical Finding in Some in 3: PhysicalFinding of the Causes of Chronic Table Diarrhoea LABORATORY WORK-UP TO EVALUATE CHRONIC DIARRHEA CHRONIC EVALUATE TO WORK-UP LABORATORY Routine Blood tests Routine Complete blood count, serum albumin, erythrocytes Crohn’s disease is associated with pain in the right Crohn’s disease is associated iliac complain of dull, fossa, while patients with malabsorption presence of The poorly localized abdominal discomfort. examination, usually blood in stool necessitates further by colonoscopy, although minor bleeding because of diseases. trauma is common in all diarrhoeal foods which Dietary history is important to identify of wheat may cause diarrhoea. Increased consumption fibre and certain fruits is a disaccharide cherries) can cause diarrhoea. Lactose (grapes, plums, mangos,cause of diet induced present in milk and is a common and diarrhoea. if the patient more than 12 g/day consumes (240 ml of Physical in other dairy foods). milk or its equivalent loss, signs examination should include evidence of weight of malnutrition, anaemia, clubbing, or lymphadenopathy. Rectal examination is useful to exclude local tenderness and rectal tone to rule that might suggest Crohn’s disease incontinence. cause can which sphincter defect out any Moreover, it is important to differentiate between small involvement, bowel small In diarrhoea. large bowel and 4 per day, large volume, than less usually the frequency is involvement, bulky, frothy and greasy. In large bowel the frequency is more than 4 with small volume. Blood, mucous, pus may be present. 298 Imaging tests yersinosis, and C. difficile infections are frequent causes A plain abdominal radiograph showing pancreatic of chronic diarrhoea in immunocompetent hosts. calcifications is diagnostic of chronic pancreatitis. Barium Strongyloides is occasionally seen but is quite unusual. studies have been used extensively in the past in the These five pathogens should be sought in such patients. diagnosis of chronic diarrhoea. With the introduction Giardia is most reliably detected with a stool enzyme- of abdominal CT scans, the role of barium studies has linked immunosorbent assay (ELISA) assay. Amoeba and become limited. Strongyloides are sought with serological tests and stool CT and magnetic resonance enterography examination for ova and parasites. Three stool samples CT and magnetic resonance (MR) enterography are useful should be sent for microscopic examination. C. difficile in the diagnosis of chronic diarrhoea because of small is most reliably detected with a stool DNA amplification bowel Crohn’s disease, eosinophilic gastroenteritis and in assay. the detection of small bowel tumors, such as carcinoids. Patients on immunosuppressant medications or those with Nuclear medicine imaging HIV/AIDS infection have a greater likelihood of chronic Radio ligand scintigraphy is useful in detecting infections. Enteropathogens that can cause acute, self- neuroendocrine tumors that express somatostatin limited diarrhoea in immunologically normal individuals can cause chronic diarrhoea in these patients. These GASTROENTEROLOGY receptors, such as gastrinomas and carcinoid tumors. SPECT-CT provides better localization of these tumours. pathogens are Salmonella, Shigella, Campylobacter, E. coli, Yersinia, and others. These infections can last many Endoscopy weeks in the immunosuppressed host. Traditionally, Colonoscopy with biopsy is helpful for the diagnosis these infections are detected with standard stool cultures. of IBD, neoplasia and microscopic colitis. Upper GI However, new molecular techniques may prove to be Endoscopy and duodenal biopsy can confirm a diagnosis better in time, making standard stool cultures obsolete. of celiac disease. Duodenal biopsy may also aid in Patients with HIV/AIDS suffer from potential infectious diagnosis of giardiasis and other protozoal infections aetiologies related to their degree of immunosuppression. and Whipple’s disease. Upper endoscopy also helps With lesser degrees of immunosuppression(CD4 count in collection of duodenal aspirate for quantitative for a > 200 cells/mm3),the usual pathogens predominate. diagnosis of small intestinal bacterial overgrowth. However if the CD4 count is < 200 cells/mm3, the spectrum includes mycobacterial and protozoan Colorectal and terminal ileal biopsy infections also along with the enteropathogens. These Colonoscopy and biopsy have a significant role in include MAC, cryptosporidium, cyclospora, isospora diagnosing conditions like IBD, microscopic colitis, belli and microsporidium. Viral infections, such as CMV inflammatory conditions and neoplasia. Multiple studies and Herpes simplex virus, and fungal infections, such as have evaluated the role of colonoscopy stating the yield of candidiasis and histoplasmosis, should be considered if specific diagnoses of chronic diarrhoea in 15 – 31%. other pathogens are not found. Breath tests MANAGEMENT ISSUES Hydrogen Breath Tests (HBT) The breath tests help The aetiology of chronic diarrhoea should be identified in diagnosing carbohydrate malabsorption and small and treated accordingly. Dietary measures include the intestinal overgrowth. However, the sensitivity and restriction of unabsorbed carbohydrates and sweets, specificity however varies widely. avoidance of milk and milk products in patients with Pancreatic function tests lactose intolerance, and fat restriction and supplementation The standard secretin stimulation test is rarely used of fat soluble vitamins and calcium in patients with now a days whereas the modified endoscopic secretin steatorrhoea. Empirical therapy for chronic diarrhoea stimulation test done using ERCP has limited diagnostic may be used when the diagnostic workup has failed to yield. Various other tests for pancreatic function include confirm the diagnosis, if no specific treatment is available serum trypsin, faecal chymotrypsin and faecal elastase or if the treatment has failed. Opiate anti diarrhoeal agents which again show limited utility in mild insufficiency. such as loperamide are frequently used. They are safe and Pancreatic imaging using endoscopic ultrasound and effective but should not be used in infectious diarrhoea MRI is used invariably to detect abnormal anatomy. or in severe inflammatory bowel disease. Bile acid sequestrate like cholestyramine are useful in diarrhoea Bacteriology/Microbiology caused by bile acid malabsorption. Octreotide is used In developing countries chronic bacterial, mycobacterial, to control diarrhoea occurring in carcinoid syndrome, and parasitic infections are common. Additionally some VIPomas and neuroendocrine tumors. Alpha2-adrenergic clinical situations require extensive search for a source agonist, clonidine,is used to treat diabetic diarrhoea. of infection in case of diarrhoea of chronic origin. They include diarrhoea in immigrants from endemic areas, Eluxadoline, a µ opioid receptor agonist is a new drug immunocompromised subjects, patients with HIV/ AIDS approved for use in patients with IBS. Diarrhoea in infection, men who have sex with men, and in individuals Zollinger-Ellison syndrome respond to treatment with with chronic travellers’ diarrhoea. Giardiasis, amebiasis, proton pump inhibitors. Bacterial overgrowth is treated with antibiotics. CHAPTER 63 299

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