Diarrhea

Diarrhoea, a pathophysiology perspective

1. Diarrhea Professor. Amnia Diaz

2. Objectives Examine concepts of the different types of diarrhea. Analyze Pathophysiology, epidemiology, and etiology of different types of diarrhea.

3. Summary Diarrhea. Concept. Classification: Osmotic diarrhea/malabsorption . Secretory diarrhea. Altered motility. Inflammatory diarrhea. Pathophysiology.

4. Diarrhea It is an increase in the volume of stool or frequency of defecation. Excess water, electrolytes, fat, other substances in intestinal lumen More than 200 grams stool in 24 hours It is one of the most common clinical signs of gastrointestinal diseases but also can reflect primary disorders outside of the digestive system

5. General considerations 10 liters of ingested fluid and secretions enter the intestine daily. 90% absorbed in small intestine. 90% of remaining fluid(~800- 1000 ml) absorbed in colon 80-100 ml fluid in stool daily Normal stool output: 200grams/24h

6. General considerations

7. Classification of diarrhea according duration. Acute Diarrhea: Diarrhea last less than 14days . Persistent diarrhea: more than 14 days Chronic diarrhea: Diarrhea last longer than 4 weeks .

8. Other concepts Pseudodiarrhea : More frequent bowel movement but <200g/24hrs Incontinence: Involuntary loss of stool Anal sphincter dysfunction Neurologic impairment

9. Classification of diarrhea according pathophysiologicol mechanism. Osmotic Malabsorption / Maldigestion /Fatty . Inflammatory Secretory Altered motility

10. Osmotic diarrhea

11. Osmotic diarrhea Excess amounts of poorly absorbed substances that remain in intestinal lumen. Substances exert osmotic effect. Obligate water retention in intestinal lumen Lactose, lactulose , magnesium, polyethylene glycol(PEG).

12. Osmotic diarrhea Ingestion of a poorly absorbed substrate : The offending molecule is usually a carbohydrate or divalent ion, examples: mannitol or sorbitol , epson salt (MgSO 4 ) and some antacids (MgOH 2 ). Malabsorption : Inability to absorb (carbohydrates), Example: lactose intolerance

13. Lactose intolerance

14. Malabsorption / Maldigestion /Fatty.

15. Malabsorption Luminal phase - Intraluminal maldigestion Mucosal phase Mucosal loss (surgical resection) Mucosal disease Transport phase

16. Malabsorption . Luminal phase 1- Reduced nutrient availability Cofactor deficiency(pernicious anemia, gastric surgery) Nutient consumption (bacteria overgrowth)

17. Malabsorption . Luminal phase 2- Impaired fat solubilization Reduce bile salt synthesis: Hepatocellular diseases Impaired bile salt secretion: chronic cholestasis Bile salt inactivation: bacterial overgrowth Increase bile salt losses: terminal ileal disease or resection

18. Malabsorption.Luminal phase 3- Defective nutrient hydrolysis Lipase inactivation: ZE syndrome Enzyme deficiency : pancreatic insufficiency or cancer Improper mixing or rapid transit: resection, bypass, hyperthyroidism

19. Malabsorption . Mucosal phase 1- Extensive mucosal loss: reserction or infarction 2- Diffuse mucosal disease: gluten, tropical, Chrohn’s , infection, drugs, infiltration, radiation. 3- Enterocyte defects: microvillous inclusion disease, brush border hydrolase deficiency

20. Malabsorption . Transport phase 1- Vascular: vasculitis , atheroma 2- Lymphatic: lymphangiectasia , ratiation , nodal tumor, infiltration

21. Fat malabsorption Steatorrhea , “ oily”stool Possible deficiences of fat soluble vitamins:A,D,E,K Causes: Bacterial overgrowth, pancreatic insufficiency, mucosal diseases. Diag : Suden stain of stool; 72hours stool collection and measurement of fecal fat

22. Bile salt inactivation: small intestinal bacterial overgrowth syndrome Normal concentration of bacteria in proximal small intestine:<10 4 organisms Conditions that predispose to bacterial overgrowth cause: Intestinal stasis Abnormal connections between proximal and distal bowel

23. Conditions predisposing to bacterial overgrowth Intestinal stasis Anatomic Intestinal strictures Small intestinal diverticulosis Surgical procedures Motility disorders Sclerodermia Diabetes Mellitus

24. Conditions predisposing to bacterial overgrowth Abnormal connections between proximal and distal bowel Resection of ileocecal valve Fistulas

25. Pathophysiology of malabsorption in bacterial overgrowth Reduce nutrient availability - Bacteria consume nutrients Bile salt inactivation - Excess bacteria deconjugate bile salts - Unconjugated bile salts unable to solubilize micelles Fat malabsorption

26. Diagnosis of small intestinal bacterial overgrowth syndrome Direct aspiration of jejunal contents. Breath tests 14C glycocholate 14c xylose Glucose or lactulose : measure expire H2 ( brekdown product of bacterrial fermentation)

27. Treatment Correct predisposing condition Correct nutritional deficiencies Antibiotics

28. Increased bile salt losses Mucosal disease in terminal ileum: Crohn’s disease Surgical resection or bypass of ileum. Mechanism of diarrhea : Cholerrheic diarrhea, bile acid diarrhea. Bile acids that reach colon cause colonic secretion of electrolytes and water. Fat malabsorption

29. Defective nutrient hydrolisis Lipase inactivation by excess of HCL: Zollinger Ellison syndrome Pancreatic enzyme deficiency : Chronic pancreatitis or pancreatic cancer-obstruction of pancreatic duct Improper mixing or rapid transit of nutrients: resection,bypass , hyperthyroidism

30. Malabsorption. Mucosa loss Extensive surgical resection - Short bowel syndrome Extensive infarction

31. Malabsorption Mucosal disease Complication of radiation treatment Infections Vascular insufficiency ( ischemia) Inflammatory conditions Crohn’s disease Celiac sprue

32. Celiac sprue Gluten sensitive enteropathy Reaction against gluten in diet Epidemiology: whites(highest in northern European descent)

33. Celiac sprue . Pathogenesis Genetic Enveronmental Autoimmune

34. Celiac sprue.Pathogenesis Ingestion of Gliadins , Hordeins , and secalins : protein found in wheat, barley and rye. Infiltartion of intestinal mucosa with intraepithelial CD8+ lymphocytes and CD4+ lymphocytes in lamina propria villous atrophy CD4+ T cells mediate disease process Genetic: Very close association with HLA-DQ2(presents peptides to and binds CD4+) - Lesser associated with HLA-DQ8

35. Celiac sprue . Pathology Villous atrophy: flattening of mucosa, loss of villi . Increased lamina propria lymphocytes

36. Celiac sprue . Clinical presentation Varied- depends on extent of mucosal disease Typical: crampy , abdominal pain, chronic diarrhea, bloating, weight loss, steatorrhea . Iron deficiency Osteoporosis (vitamin D, Ca 2+ ) Easy bruising (vitamin K) Peripheral neuropathy(vitamin B 12 )

37. Celiac sprue . Associated diseases Dermatitis herpetiformis - IgA deposits in skin - Pruritic , blistering Small intestinal lymphoma - Risk may be less with adherence to gluten free diet

38. Celiac sprue . Diagnosis Biopsy of small intestine during endoscopy Blood tests. Anti- gliadin antibodies( IgA and IgG ) Anti- endomysial antibodies Tissue transglutamine antibodies

39. Drugs causing malabsorption Luminal effect Neomycin Cholestyramine Alcohol Mucosal effect Villous flattening Colchicine Methotrexate

40. Drugs causing malabsorption Stricture Non-steroidal antiinflammatories Enterocyte damage Direct toxicity Alcohol Brush border enzyme effect Neomycin Alcohol

41. Drugs causing malabsorption Intracellular effect Laxatives Colchicine Biguanides

42. Secretory diarrhea

43. Secretory diarrhea Abnormal ion transport in intestinal epithelial cells Decreased absorption of electrolytes. Electrolytes: major solutes in intestinal lumen. Electrolytes account for most of luminal osmolarity .

44. Causes of secretory diarrhea Congenital defect in ion absorption Intestinal resection Diffuse mucosal diseases Abnormal mediators

45. Abnormal mediator Changes in cAMP , cGMP , intracellular Ca 2+ , protein kinases - Bacterial toxins E, Coli ( cAMP ) Cholera( cAMP ) Endogenous secretagogues Non osmotic laxatives: senna , anthraquinones

46. Abnormal mediator Fatty acids: stimulate colon secretion Bile acids: stimulate fluids and electrolyte secretion in colon Circulating agents released by neuroendocrine tumors

47. Diarrhea by altered intestinal motility

48. Diarrhea by altered intestinal motility Autonomic diabetic neuropathy. Hyperthyroidism After vagotomy ( peptic ulcer surgery) Irritable bowel syndrome(IBS)

49. Irritable bowel syndrome Chronic or recurrent Lowe abdominal pain Disturbed defecation Bloating Not explained by structural or unknown biochemical abnormalities

50. IBS. Symptoms Abdominal pain with constipation or diarrhea Bloating, gas Abdominal distention

51. IBS. Epidemiology Prevalence in North America is 10%-20% Equally divided between IBS with diarrhea, IBS with constipation and IBS alternating between diarrhea and constipation Prevalence of each subtype is ~5% 2:1 female predominance in north America population-based studies

52. Pathophysiology IBS is a condition associated with altered brain-gut communication resulting in: Disturbed gut function and sensation Disturbed CNS function IBS patients display Altered CNS responsiveness to visceral stimuli Viscera hyper responsiveness to environmental and luminal events(gut)

53. Role of the enteric nervous ENS contains many neurotransmitters including 5-HT, substance P, VIP and C GRP ENS controls motility and secretory functions of the intestine ENS functions autonomously but may be modified by the parasympathetic and sympathetic nervous systems

54. Selected mediators of motility and visceral hypersensitivity Motility Serotonin ACH ATP Motilin Nitric oxide Somatostatin Substance P Vasoactive intestinal polypeptide (VIP)

55. Selected mediators of motility and visceral hypersensitivity Visceral hypersensitivity Serotonin Bradykinin Tachykinins Calcitonin gene-related peptide (C GRP) Neurotropins

56. Inflammatory diarrhea

57. Inflammatory diarrhea Disruption of the epithelium of the intestine due to microbial or viral pathogens It is a very common cause of diarrhea in all species. Destruction of the epithelium results not only in exudation of serum and blood into the lumen but often is associated with widespread destruction of absorptive epithelium.

58. Causes Bacteria: Salmonella, E. coli, Campylobacter Viruses: rotaviruses, coronaviruses , parvoviruses (canine and feline), norovirus Protozoa: coccidia species, Cryptosporium , Giardia

59. Pathophysiology The immune response to inflammatory conditions in the bowel contributes substantively to development of diarrhea. Activation of white blood cells leads them to secrete inflammatory mediators and cytokines which can stimulate secretion, in effect imposing a secretory component on top of an inflammatory diarrhea.

60. Pathophysiology Reactive oxygen species from leukocytes can damage or kill intestinal epithelial cells, which are replaced with immature cells that typically are deficient in the brush border enzymes and transporters necessary for absorption of nutrients and water. In this way, components of an osmotic (malabsorption) diarrhea are added to the problem.

61. Reference Harrison’s Principles of Internal Medicine, 17th Edition , Robbins and Cotran PATHOLOGIC BASIS OF DISEASE. 7 th edition, chapter 17