CHRONIC DIARRHEA

1. CHRONIC DIARRHEA

2. CLINICAL SCENARIO • A 50-year-old woman reported multiple loose bowel movements associated with mild, cramping abdominal pain. She had been well until 2 months earlier, when her bowel habits changed from one formed stool per day to frequent loose stools (soft) of moderate volume. The abdominal pain was variable in intensity and was slightly relieved with defecation. She had no recent dietary changes and no family history of intestinal problems, and she had not traveled outside the United States. She did not have anorexia, weight loss, hematochezia, episodes of constipation or abdominal bloating, fever, dyspnea, nausea, vomiting, pruritus, or flushing.

3. DEFINITION • More than 200 gms ? • Increased volume ? Hard to quantify • Increased frequency ? Some individuals have increased fecal weight due to fiber ingestion but do not complain of diarrhea because their stool consistency is normal. Conversely, other patients have normal stool weights but complain of diarrhea because their stools are loose or watery conceptuallyratio= water-holding capacity of insolublesolids/ total water present • Consensus statement by AGA= decrease in fecal consistency lasting for four or more wks

4. ORGANIC vs FUNCTIONAL DIARRHEA • shorter duration of diarrhea (less than 3 months), • nocturnal diarrhea, • an abrupt onset of diarrhea, • weight loss of more than 11 lb (5.0 kg), and • stool weight of more than 400 g per day. • 70 % SPECIFIC FOR FUNCTIONAL ETIOLOGY

5. Case… • The patient had a history of Graves' disease, which had been treated 8 years earlier with radioiodine, and she was receiving oral levothyroxine at a dose of 88 µg per day. • She said that she did not used alcohol, tobacco, or illicit drugs. • She appeared well. Her weight was 131 lb (59.4 kg), her height was 5 ft (1.5 m), and her body-mass index (the weight in kilograms divided by the square of the height in meters) was 26.4. • She was afebrile, with a blood pressure of 102/67 mm Hg and a heart rate of 89 beats per minute. • She had no lymphadenopathy. • The lung and cardiac examinations were normal. • Her abdomen was soft, with normal bowel sounds and no tenderness or hepatosplenomegaly. • There were no rectal masses; • A stool specimen was negative for occult blood. • Skin and neurologic examinations were normal.

6. CLUES ? • Hypothyroidism ? Underlying graves disease • Levothyroxine ? How long and any change in doses? • Think about celiac dz. ? Why ?

7. CASE CONTD: • The patient received a diagnosis of the irritable bowel syndrome, and diphenoxylate–atropine and belladonna–phenobarbital were prescribed. She noted some improvement with this regimen (e.g., the number of stools per day decreased from 10 to 7), but she reported tenesmus, and her diarrhea became watery. At a follow-up visit 1 month later, she was advised to continue these medications. One month later, the patient's gynecologist referred her to a gastroenterologist for further recommendations on management of the irritable bowel syndrome. The patient's stool was again negative for occult blood.

8. PAINFULL FUNCTIONAL DIARRHEA-IRRITABLE BOWEL SYNDROME • The irritable bowel syndrome is characterized by recurrent abdominal pain or discomfort that occurs at least 3 days per month for at least 3 months, with two or more of the following: improvement with defecation, an onset associated with a change in the frequency of bowel movements, or an onset associated with a change in the form (appearance) of stool. ABSENCE of alarm characteristics such as weight loss, nocturnal symptoms, a family history of colorectal cancer, rectal bleeding, or anemia; these would warrant further evaluation. • When measured, daily stool output is low, typically less than 400 g per 24 hours. • Consistency varies from loose to soft and rarely is water • Diarrhea does not wake patients from sleep. • Long Hx, extending back to adolescence • Labs are usually nl (hg, esr, albumin) • The irritable bowel syndrome should be a diagnosis of exclusion

9. CLUES • The new symptom of tenesmus is consistent with rectal inflammation and points away from the diagnosis of the irritable bowel syndrome. A more likely cause of her chronic diarrhea would be celiac disease, microscopic or collagenous colitis, or IBD. • Also there is change in consistency: watery

10. CLASSIFICATION • By volume (large vs. small), • By pathophysiology (secretory vs. osmotic), • By epidemiology, • By stool characteristics watery vs. fatty vs. inflammatory. • For the clinician, these classification schemes are only useful if they serve to focus the diagnostic and management approaches toward patients. In this regard, no single scheme is perfect; the experienced physician uses all of these classifications to expedite patient care

11. Laxative abuse (nonosmotic laxatives) Post-cholecystectomy (from bile salts) Congenital syndromes (chloridorrhea) Bacterial toxins Ileal bile acid malabsorption Inflammatory bowel disease Ulcerative colitis Crohn's disease Microscopic (lymphocytic) colitis Collagenous colitis Diverticulitis Vasculitis Drugs and poisons Disordered motility Postvagotomy diarrhea Postsympathectomy diarrhea Diabetic autonomic neuropathy Hyperthyroidism Irritable bowel syndrome Neuroendocrine tumors Gastrinoma VIPoma Somatostatinoma Mastocytosis Carcinoid syndrome Medullary carcinoma of thyroid Neoplasia Colon carcinoma Lymphoma Villous adenoma Addison's disease Epidemic secretory (Brainerd) diarrheaI diopathic secretory diarrhea SECRETORY DIARRHEA

12. HISTORY questioning clinical implication

13. HISTORY questioning clinical implication

14. Large-Volume Versus Small-Volume Stools • RATIONALE: that the normal rectosigmoid colon functions as a storage reservoir. When that reservoir capacity is compromised by inflammatory or motility disorders involving the left colon, frequent small-volume bowel movements ensue. (< 350 ml) If the source of the diarrhea is upstream in the right colon or small bowel and if the rectosigmoid reservoir is intact, bowel movements are fewer, but larger.( 750 ml or more) Thus, frequent, small, painful stools may point to a distal site of pathology, whereas painless large-volume stools suggest a right colon or small bowel source. • PROBLEM: it is difficult for patients to quantify volume

15. Watery diarrhea - a defect primarily in water absorption due to increased electrolyte secretion or reduced electrolyte absorption-secretory diarrhea - ingestion of a poorly absorbed substance-osmotic diarrhea). • The essential characteristic of osmotic diarrhea is that it disappears with fasting or cessation of ingestion of the offending substance. This characteristic has been used clinically to differentiate osmotic diarrhea from secretory diarrhea that typically continues with fasting • Inflammatory: diarrhea implies the presence of one of a limited number of inflammatory or neoplastic diseases involving the gut. • Fatty diarrhea: implies defective absorption of fat in the small intestine. Fatty diarrhea (steatorrhea) should be suspected in patients who report greasy, floating, and malodorous stools and those who are at risk for fat malabsorption, such as patients with chronic pancreatitis

16. PHYSICAL EXAMINATION

17. Peripheral neuropathy and orthostatic hypotension may be the only clues to a diagnosis of amyloidosis. A thyroid nodule with cervical lymphadenopathy may be the only lead to the presence of medullary carcinoma of the thyroid. Tremor and other systemic signs should lead to consideration of hyperthyroidism The perineal, anal, and rectal examinations are important. Signs of incontinence include skin changes from chronic irritation, gaping anus, and weak sphincter tone. Crohn's disease is associated with perianal skin tags, ulcers, fissures, abscesses, fistulas, and stenoses. Fecal impaction or masses might be noted. Other associated physical findings include exophthalmos (hyperthyroidism), aphthous ulcers (IBD and celiac disease), lymphadenopathy (malignancy, infection or Whipple's disease), enlarged or tender thyroid (thyroiditis, medullary carcinoma of the thyroid), arthritis (IBD, Whipple's disease), wheezing and right-sided heart murmurs (carcinoid syndrome), and clubbing (liver disease, IBD, laxative abuse, malignancy). PHYSICAL EXAMINATION

18. CASE: • Six months after the first visit to her physician, the patient consulted a general internist while she awaited her appointment with a gastroenterologist. • Her diarrhea persisted, and occasional nausea, vomiting, fever, and chills had developed. • She had no weight loss but now reported that she was awakened during the night several times each week by fecal incontinence or the need to defecate. • Tests of stool samples for ova and parasites, salmonella, shigella, and campylobacter were negative. Stool smears had no white cells or red cells. Blood tests showed a white-cell count of 4100 per cubic millimeter, with no leftward shift. The hematocrit was 35%, with a normal mean corpuscular volume, and the platelet count was 310,000 per cubic millimeter. Liver-function tests were normal, including the serum albumin level (4.3 g per deciliter). • A referral for an urgent evaluation by a gastroenterologist was made, and an appointment was scheduled for the next month. • A few days later, the patient visited her endocrinologist for a regular follow-up of Graves' disease. The free thyroxine level was normal, at 1.0 ng per deciliter, and the thyrotropin level was low, at 0.12 µU per milliliter (normal range, 0.20 to 5.39). Her dose of levothyroxine was reduced to 75 µg per day.

19. CLUES: • Absence of fecal leukocytes makes inflammatory diarrhea less likely, although the sensitivity of this test is only 70% and specificity is 50% • The test for fecal lactoferrin has higher sensitivity. • Bacterial infections are rarely a cause of chronic diarrhea. • The sensitivity of tests of three fixed, concentrated stool specimens for ova and parasites is up to 85%, although giardiasis, amebiasis, and persistent infection with microsporidia, coccidia, or cryptosporidia remain possibilities. • The low level of thyrotropin warrants a reduction in the dose of levothyroxine, although the patient's increasingly severe symptoms should not be attributed to overreplacement with levothyroxine.

20. CASE • The patient returned to her internist 1 month later. She noted a decrease in stool frequency to six bowel movements per day and a 3-lb (1.4-kg) weight loss. • The serum sodium level was 139 mmol per liter; chloride, 103 mmol per liter; potassium, 2.8 mmol per liter; bicarbonate, 21 mmol per liter; blood urea nitrogen, 10 mg per deciliter (3.6 mmol per liter); creatinine, 0.7 mg per deciliter (62 µmol per liter); and glucose, 89 mg per deciliter (4.9 mmol per liter). • Oral potassium chloride at a dose of 40 mmol per day, pantoprazole at a dose of 40 mg twice a day, and promethazine at a daily dose of 12.5 mg every 4 to 6 hours as needed for symptom relief were prescribed, with reported benefit. • Several days later, she was evaluated by a gastroenterologist and an upper endoscopy and colonoscopy were scheduled • A repeat measurement of potassium showed a level of 3.6 mmol per liter; the vitamin B12 level was 463 pg per milliliter (342 pmol per liter) (normal range, 180 to 900 pg per milliliter [133 to 665 pmol per liter]); free thyroxine, 1.1 ng per deciliter; and thyrotropin, 0.35 µU per milliliter. Stool samples were negative for giardia.

21. CLUES AND DIFFERENTIAL DX • Hypokalemia and acidosis any chronic diarrhea VIPoma rectal villous adenoma inflammatory bowel disease celiac disease neoplasm microscopic colitis • Next step ??

22. CASE: • The patient returned 2 months later (9 months after her initial presentation) for endoscopy and colonoscopy. She reported an additional 15-lb (6.8-kg) weight loss, anorexia, increased nausea, and approximately eight bowel movements per day. • Her colonoscopic examination was normal to the cecum; biopsies were not performed. • The upper endoscopic examination was normal to the fourth portion of the duodenum, with no evidence of pale, yellow, or shaggy mucosa, findings that would be suggestive of Whipple's disease. • Two small-bowel biopsy specimens obtained from the fourth portion of the duodenum showed mild chronic inflammation, with no evidence of giardia and no villous flattening. • The serum gastrin level was normal, at 15 pg per milliliter, and • stool samples were negative for Clostridium difficile. • Repeat blood chemical tests were normal except for a potassium level of 2.5 mmol per liter. The dose of potassium chloride was increased to 80 mmol per day; a follow-up potassium measurement 1 week later was 3.4 mmol per liter. • A skin test for tuberculosis was positive.

23. CLUES • Ulcerative colitis, Celiac disease and colonic neoplasm appear to be ruled out. • Positive PPD ? Intestinal TB Hx. of drinking unpasteurized milk? an unlikely diagnosis in the United States, especially in an immunocompetent patient, and it would not appear to account for this patient's persistent hypokalemia. • increases concern regarding secretory diarrhea; stool electrolyte levels should be evaluated

24. CASE • chest radiograph was normal. • One month later, the patient returned for a flexible sigmoidoscopic examination to investigate the possibility of collagenous colitis; biopsy specimens obtained during this examination were normal. • The patient had now lost a total of 27 lb (12.2 kg). • A repeat potassium measurement showed a level of 2.9 mmol per liter; the dose of potassium chloride was increased to 120 mmol per day. • The stool sodium level was 70 mmol per liter, and the stool potassium level was 82 mmol per liter

25. CLUES • fecal osmotic gap 290–[(stool sodium level+stool potassium level)x2], is less than 50 mOsm, a finding that is consistent with secretory diarrhea. • secretory diarrhea+ profound hypokalemia+weight loss = Highly suspicious for neuroendocrine tumor • Testing VIPoma and for medullary carcinoma of the thyroid, which may also cause chronic secretory diarrhea. A carcinoid tumor and mastocytosis are other potential causes of this presentation, but the patient does not report other typical symptoms such as flushing. Abuse of nonosmotic laxatives remains a possibility to be tested by means of urine and stool screening, if the results of gastrointestinal peptide hormone screening are unrevealing.

26. CASE • The serum calcitonin level was less than 1 pg per milliliter (normal range, 0 to 4). • The 5-hydroxyindoleacetic acid (5-HIAA) level in a 24-hour urine specimen was 4.4 mg (normal range, 0 to 6.0). • The VIP level was more than 400 pg per milliliter (normal value, <50).

27. elevated VIP level should be confirmed with repeat testing, this result strongly supports a diagnosis of the VIPoma syndrome. • VIPomas are rare VIP-secreting tumors that arise most often in the tail of the pancreas and classically result in watery diarrhea and hypokalemia, as well as hypochlorhydria or achlorhydria. • Abdominal computed tomography (CT) or magnetic resonance imaging should be performed to localize the tumor and look for metastases. • Treatment with a long-acting somatostatin analogue should be initiated to control the patient's diarrhea.

28. COMPLEX DIARRHEA • Most clinically significant diarrheas are complex; rather than being produced by a single pathophysiologic mechanism, they are due to several. 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)

29. PINES • Further complicating the understanding of diarrhea is that certain mediators not only affect epithelial or muscle function, but also each other. • For example, enteric nerves may stimulate mast cells and products so released from mast cells (particularly histamine) may alter enteric neuron functions A single agonist—such as prostaglandin—may have multiple, simultaneous effects on epithelial function, muscle contraction, and the paracellular pathway, leading to effects on ion transport, motility, and mucosal permeability • Thus, multiple modulators and multiple effectors contribute to the final clinical picture. A full appreciation of the pathophysiology of diarrhea requires consideration of paracrine, immune, neural, and endocrine modulators, a regulatory system that can be abbreviated by the acronym “PINES”

30. Laxative abuse (nonosmotic laxatives) Post-cholecystectomy (from bile salts) Congenital syndromes (chloridorrhea) Bacterial toxins Ileal bile acid malabsorption Inflammatory bowel disease Ulcerative colitis Crohn's disease Microscopic (lymphocytic) colitis Collagenous colitis Diverticulitis Vasculitis Drugs and poisons Disordered motility Postvagotomy diarrhea Postsympathectomy diarrhea Diabetic autonomic neuropathy Hyperthyroidism Irritable bowel syndrome Neuroendocrine tumors Gastrinoma VIPoma Somatostatinoma Mastocytosis Carcinoid syndrome Medullary carcinoma of thyroid Neoplasia Colon carcinoma Lymphoma Villous adenoma Addison's disease Epidemic secretory (Brainerd) diarrheaI diopathic secretory diarrhea SECRETORY DIARRHEA

31. OSMOTIC DIARRHEA

32. Inflammatory bowel disease Ulcerative colitis Crohn's disease Diverticulitis Ulcerative jejunoileitis Infectious diseases Pseudomembranous colitis Invasive bacterial infections Tuberculosis, yersinosis, othersUlcerating viral infections Cytomegalovirus Herpes simplex Amebiasis/other invasive parasites Ischemic colitis Radiation colitis Neoplasia Colon cancer Lymphoma INFLAMMATORY DIARRHEA

33. Fatty diarrhea Malabsorption syndromes Mucosal diseases Short bowel syndrome Postresection diarrhea Small bowel bacterial overgrowth Mesenteric ischemia Maldigestion Pancreatic exocrine insufficiency Inadequate luminal bile acid FATTY DIARRHEA