Chronic diarrhoea update

1- Understand the pathophysiologic mechanisms involved in chronic diarrhea.
2. Classification the causes of chronic diarrhea in resource-rich and resource-limited countries
3- Know how to evaluate a child who has chronic diarrhea
4. Know the therapies for the many causes of chronic diarrhea

1. Chronic diarrhoea Dr Mohamed Adan Ahmed ( Marwan ) University of Nairobi Master of paediatric and Child health d [email protected]

2. Objectives: 1- Understand the pathophysiologic mechanisms involved in chronic diarrhea. 2. Classification the causes of chronic diarrhea in resource-rich and resource-limited countries 3- Know how to evaluate a child who has chronic diarrhea 4. Know the therapies for the many causes of chronic diarrhea.

3. Chronic diarrhoea Diarrhea is defined as stool volume of more than 20 grams/kg/day in young infants, 10 grams/kg/day in older infants and toddlers, or more than 200 grams/day in older children for more than 14 days. This typically translates to persistent loose or watery stools occurring at least three times a day, where the change in stool consistency is more important than stool frequency Some authors make a distinction between chronic diarrhoea, which they define as having a gradual onset, from persistent diarrhoea , which they define as having a sudden onset . Functional Diarrhea , ROME III criteria: daytime painless diarrhea > 3months.

4. Prevalence and morbidity   A common condition. According to one review, diarrhea lasting more than two to four weeks occurs in up to 3 to 5 percent of the population worldwide ( uptodate ) It is generally more frequent in males, with a male-to-female ratio of 1.2 to 2.6:1 in the age range of 6 to 24 months.( uptodate )

5. The major causes and the prevalence of chronic diarrhea differ between resource-rich and resource-limited countries: ●In the resource-limited countries, chronic diarrhea is typically associated with serial enteric infections and malnutrition; it is manifested by a chronic enteropathy, with impaired mucosal healing and diminished digestive and absorptive capacity. ●In resource-rich countries, children are less likely to be exposed to serial enteric infections and malnutrition. In these populations, chronic diarrhea is more likely to be induced by underlying disease that causes malabsorption or maldigestion . However, enteric infections (particularly in immunocompromised patients), malnutrition, and dietary factors ( eg , excessive consumption of juice) can play a role in some cases.

6. Pathophysiology-mechanisms The basic pathophysiology of all diarrheas is incomplete absorption of water from the intestinal lumen either because of a reduced rate of net water absorption (related to impaired electrolyte absorption or excessive electrolyte secretion) or because of osmotic retention of water within the lumen . Osmotic Secretory Motility-related Inflammatory

7. A)osmotic Caused by non absorbed nutrients in the intestinal lumen from either 1 or > of following mechanism: 1)Intestinal damage e.g Enteric infections that cause damage to intestinal epithelial cells leading to malabsorption may cause diarrhea with an osmotic component. 2)reduced absorptive surface area e.g active celiac disease. 3)defective digestive enzyme or nutrient or nutrient carrier ( e.g lactase deficiency )

8. 4)decreased intestinal transit e.g functional diarrhea 5)nutrient overload ,exceeding the digestive capacity e.g overfeeding ,sorbitol in fruit juice. Examples of osmotic diarrhea : Lactose intolerence Glucose-galactose malabsorption Lactulose use Laxative abuse Polyethylene glycol ( Miralax ) use

9. B)Secretory is characterized by active electrolyte and water fluxes toward the intestinal lumen, resulting from either : inhibition of neutral NaCl absorption in villous enterocytes or increase in electrogenic chloride secretion in secretory crypt cells as a result of the opening of the cystic fibrosis transmembrane regulator (CFTR) chloride channel or both. The result is more secretion from the crypts than absorption in the villous that persists during fasting.

10. The other components of the enterocyte ion secretory machinery : (1) the Na-K 2Cl cotransporter for the electroneutral chloride entrance into the enterocyte (2) the Na-K pump, which decreases the intracellular Na+ concentration, determining the driving gradient for further Na+ influx (3) the K+ selective channel, that enables K+, once it has entered the cell together with Na+, to return to the extracellular fluid.

11. Electrogenic secretion is induced by an increase of intracellular concentration cAMP,cGMP , or calcium in response to microbial enterotoxins, or to endogenous endocrine or nonendocrine moieties, including inflammatory cytokines. Another mechanism of secretory diarrhea is the inhibition of the electroneutral NaCl -coupled pathway that involves the Na+/H+ and the Cl −/HCO3− exchangers. Defects in the genes of the Na+/H+ and the Cl−/HCO3− exchangers are responsible for congenital Na+ and Cl− diarrhea, respectively. Examples of secretory diarrhea : 1. Carcinoid 2 . VIP 3 . Neuroblastoma 4 . Congenital chloride diarrhea

12. osmotic Secretory Stool volume Moderately increased Very large Response to fasting Diarrhea stops Diarrhea continues Stool osmolaity Normal to increased Normal Ion gap >/100mosm/kg <100mosm/kg

13. C)Motility related  — Motility disorders Changes in gastrointestinal motility can influence absorption. Hypomotility , or the severe impairment of intestinal peristalsis(Defect in neuromuscular units) results in stasis, with subsequent inflammation, bacterial overgrowth, and secondary bile acid deconjugation and malabsorption. E.g Blind loop syndrome Decreased surface area ( osmotic and motility) Decreased functional capacity eg : Short bowel syndrome Celiac disease Rotavirus enteritis hypermotility , such as in irritable colon of infancy, can lead to diarrhea secondary to inadequate time for absorption . E.g : Irritable bowel syndrome , Thyrotoxicosis .

14. D)Inflammatory Inflammatory processes causes destruction of villous cells and/or dysfunction of the transporters, leading to loss of fluids and electrolytes, as well as exudation of mucus, proteins and blood into the intestinal lumen. This can be caused by infectious processes ( eg , shigella), inflammatory bowel disease immune-mediated processes ( eg , celiac disease)

15. ETIOLOGY Infectious and Non- infectious

16. Enteric infections are by far the most frequent cause of chronic diarrhea, both in developing and industrialized countries but, outcomes are often very different. In developing countries, enteroadherent Escherichia coli and Giardia lamblia have been implicated in chronic diarrhea, whereas, in developed countries, chronic infectious diarrhea usually runs a more benign course and the etiology is often viral, with a major role of rotavirus and norovirus . Opportunistic microorganisms induce diarrhea exclusively, more severely or for more prolonged periods, in specific populations, such as immunocompromised children. Specific agents cause chronic diarrhea or exacerbate diarrhea in many chronic diseases. Clostridium difficile or cytomegalovirus act as opportunistic agents in oncologic patients as well as in patients with inflammatory bowel diseases. Cryptosporidium may induce severe and protracted diarrhea in AIDS patients

17. HIV disease  — Persistent diarrhea is commonly associated with HIV, and provides a paradigm for the complex interactions between the immunocompromised host, malnutrition, and enteric infection. Malnutrition is often an early manifestation of HIV disease, and is associated with a rapid decrease in the CD4+ cell number and an increased rate of opportunistic infections . Combined dysfunctions of the digestive-absorptive processes are common in children with HIV infection and may involve the intestine, the liver, and the pancreas. Iron and lactose malabsorption are particularly common

18. Postenteritis syndrome - Most enteric infections in otherwise healthy children resolve within 14 days and do not develop into a chronic diarrhea illness. However, in a minority of patients, an acute gastroenteritis can trigger persistent diarrhea by causing mucosal damage to the small intestine . The mechanisms underlying this syndrome are not fully understood. sensitization to food antigens and secondary disaccharidase deficiency , persistent infections, reinfection with an enteric pathogen, or side effects of medication may be responsible for causing postenteritis diarrhea syndrome

19. Malnutrition  — Chronic and acute under-nutrition impair the development and function of the immune system [55]. This leads to suboptimal immune responses that are also associated with a generalized increase in inflammatory mediators, which can contribute to the tissue damage caused by enteric infection. Malnutrition also impairs tissue repair mechanisms so that infections tend to be more severe and of longer duration. Specific nutrient deficiencies, such as Vitam A  and zinc deficiencies, are associated with persistent diarrhea

20. IMMUNE-MEDIATED RESPONSE Inflammatory bowel disease  — Ulcerative colitis and Crohn disease are idiopathic chronic inflammatory diseases (IBD) of the bowel. These disorders typically present with gradual onset of chronic diarrhea, with or without blood, from mid-childhood through adulthood. Ulcerative colitis can occasionally present with acute colonic inflammation that resembles bacterial colitis ( eg , Salmonella). Allergic enteropathy  — An abnormal immune response to food proteins can cause a proctitis /colitis or an enteropathy. Proctocolitis tends to present as streaks of blood mixed with mucus and is frequently triggered by cow milk protein in formula or in breastmilk. Eosinophilic gastroenteritis  —

21. MALABSORPTION,MALDIGESTION AND FATTY DIARRHOEA Malabsorption refers to impaired absorption of nutrients . It can result from congenital defects in the membrane transport systems of the small intestinal epithelium ( primary malabsorption ) or from acquired defects in the epithelial absorptive surface ( secondary malabsorption ). Another factor that can interfere with nutrient absorption is maldigestion , which is due to impaired digestion of nutrients within the intestinal lumen or at the terminal digestive site of the brush border membrane of mucosal epithelial cells . Three steps are required for normal nutrient absorption [ 1 ]: ●Luminal and brush border processing ●Absorption into the intestinal mucosa ●Transport into the circulation

22. Celiac disease  — Celiac disease (also known as gluten-sensitive enteropathy or nontropical sprue) is an immune-mediated inflammation of the small intestine caused by sensitivity to dietary gluten and related proteins in genetically sensitive individuals . Autoimmune response to gliadin and prolamin peptide fragments However , the classic presentation of celiac disease in children with the triad of failure to thrive, diarrhea, and abdominal distension is being seen less frequently. Diagnosis should begin with establishing the presence of antiendomysial IgA antibodies, which have near 100% specificity , or employing newer and less expensive techniques for measuring enzyme-linked immunosorbent assay-based anti-TTG IgA antibodies. Diagnosis is confirmed by particular histologic findings in the duodenum, gastrointestinal disorders chronic diarrhea villous blunting and prominent intraepithelial lymphocytosis .

23. Celiac disease Presumed pathophysiology: Gliadin is absorbed into the lamina propria and presented to T cells by antigen presenting cells in conjunction with HLA-DQ2 or DQ8. Tissue transglutaminase deamidates gliadin peptides which generates acidic, negatively charged residues binds the T cell receptor more strongly. This leads to a more pronounced T cell response. These activated lymphocytes generate a cytokine response (TNF- α, interleukin-4, interferon- γ), which lead to damaged villi and inflammation . I ncreased risk of Small intestinal lymphoma in patients with Celiac Sprue . R isk may be lessened with adherence to gluten free diet

24. Disaccharide Intolerance Lactose malabsorption is, by far, the most common type of disaccharide intolerance. Approximately 70% of the world’s adult population has primary acquired lactase deficiency , resulting in lactose intolerance. Secondary lactase deficiency results from small intestinal mucosal injury when lactase enzyme is lost from the tips of the villi. Causes include rotaviral infection, parasitic infection, celiac disease, Crohn disease, and other enteropathies . Incompletely digested lactose reaches the dense colonic microbial population, which ferments the sugar to hydrogen and other gases, thereby causing gassy discomfort and flatulence. The non absorbed lactose serves as an osmotic agent, resulting in an osmotic diarrhea .

25. Diagnosis can be made by a successful lactose-free diet trial of 2 weeks or by hydrogen breath-testing. Treatment entails minimizing lactose intake because the symptoms are dose dependent and may not require complete removal of dietary lactose. Artificial lactase enzyme may be taken once the diagnosis has been made . Fructose intolerance  — Up to one-half of the population cannot completely absorb a load of 25 g of fructose while daily intake varies from about 11 to 54 g per day

26. MALDIGESTION OF FAT Congenital defects in pancreatic enzyme activity and lipid trafficking tend to present with chronic fatty diarrhea (steatorrhea) due to fat malabsorption, often with failure to thrive during infancy. Cystic fibrosis  — Cystic fibrosis is the most common cause of pancreatic exocrine insufficiency in children. The disease may present at birth with meconium ileus, or may be suggested later by gastrointestinal symptoms of fat malabsorption, failure to thrive, rectal prolapse (particularly in the setting of diarrhea), or pulmonary symptoms . Other causes of pancreatic exocrine insufficiency   —include Shwachman -Diamond syndrome (associated with bone marrow failure and skeletal abnormalities), and four rare disorders (Pearson syndrome , Johanson -Blizzard syndrome , pancreatic lipase deficiency and colipase deficiency) . Disorders of fat metabolism  — Disorders of fat metabolism that may present with chronic diarrhea during infancy include abetalipoproteinemia , primary bile acid diarrhea , chylomicron retention disease (also known as Anderson disease , and diacylglycerol acyltransferase 1 deficiency

27. Diarrhea from neuroendocrine Tumors Neuroendocrine tumors affecting the gastrointestinal tract in children are rare. These tumors produce symptoms by the systemic effect of their secretory products. The neuroendocrine tumors produce secretory diarrhea and include vasoactive intestinal polypeptide-secreting tumor , or VIPoma ; Zollinger -Ellison syndrome ( ZES) tumors secreting prostaglandin E2; and carcinoid syndrome . VIP stimulates cyclic adenosine monophosphate activity, eventually resulting in intestinal secretion, similar to the effects of the cholera toxin. Therefore, the classic presentation of VIPoma is with profuse watery diarrhea (usually >20 cc/kg per day), hypokalemia, and achlorhydria (WDHA syndrome). ZES causes diarrhea because of high intestinal gastrin levels. Carcinoid tumors may secrete serotonin, bradykinin, and histamine, also leading to gastric acid hypersecretion and diarrhea. Once secretory diarrhea is established, the evaluation may include measuring the concentrations of serum VIP, fasting gastrin, and prostaglandin E2 levels, along with 24-hour urine 5-hydroxyindoleacetic acid for carcinoid tumor. Most VIPomas in children are ganglioneuromas or ganglioneuroblastomas , which can be identified radiographically. Operative resection is imperative but not always curative if the tumor has

28. Chronic Nonspecific Diarrhea (CNSD) Also termed functional diarrhoea or toddler's diarrhoea. CNSD is the most common form of persistent diarrhea in the first 3 years after birth. The typical time of onset may range from 1 to 3 years of age and can last from infancy until age 5 years. Affected children may pass 4 to 10 loose bowel movements per day without blood or mucus . Specific to CNSD is the pattern that these patients pass stools only during waking hours, typically beginning with a large formed or semiformed stool after awakening. T ransit time of enteral contents may be especially short, and parents frequently describe undigested food remnants in the stool. By definition, children with CNSD maintain their weights and heights In some cases, the diarrhea is associated with excessive intake of fruit juice, sorbitol or other osmotically active carbohydrates, and will improve when the intake of these foods is moderated Mgt : Diet based on ‘4F’ principles: reduce Fructose and Fluids, increase Fat and Fiber .

29. BOWEL OBSTRUCTION OR DYSMOTILITY Disorders of intestinal motility include abnormal development and function of the enteric nervous system, such as in Hirschsprung disease and chronic idiopathic intestinal pseudoobstruction (which encompass both the neurogenic and the myogenic forms). Other motility disorders may be secondary to extraintestinal disorders, such as in hyperthyroidism and scleroderma. Motility disorders are associated with either constipation or diarrhea or both, with the former usually dominating the clinical picture.

30. Congenital diarrheas and enteropathies (CODEs) are a group of rare genetic disorders that are characterized by chronic diarrhea, which typically presents within days of birth, and is often severe and associated with impaired growth . Two very rare causes of secretory diarrhea in early infancy are Congenital chloride diarrhea ( CCD) and congenital sodium diarrhea (CSD). At birth, high-volume secretory diarrhea continues despite bowel rest and may cause life-threatening dehydration and electrolyte disturbances. CCD causes severe hypochloremia and a unique metabolic alkalosis, whereas CSD causes hyponatremia with alkaline stools resulting in metabolic acidosis.

31. Factitious Diarrhea When inconsistencies arise among a patient’s history, physical signs, and laboratory findings, the practitioner should consider the possibility of a factitious disorder. Many cases of factitious diarrhea induced by either the patient or patients’ parents have been reported in the literature. Although laxative ingestion is the most common cause of factitious diarrhea, the ingestion of osmotic agents or even feces may induce diarrhea. Patients also may dilute stool to create the appearance of diarrhea

32. Evaluation of chronic diarrhoea Detailed history and physical examination: Timing of onset Stool characteristics Other symptoms – A history of failure to thrive or weight loss suggests the possibility of malabsorptive disease (celiac disease, cystic fibrosis, or other cause of pancreatic exocrine insufficiency), hyperthyroidism, or anorexia nervosa in the school-age child or Family history :rule out hereditary diseases Abdominal examination – Severe abdominal pain or abdominal distension may be caused by intestinal obstruction or enterocolitis, particularly if blood is present in the stools

33. Diagnostic approach

34. treatment Optimize nutritional support :adequate caloric intake ,micronutrient , vitamin ,Zn, Medications  : directed at the specific cause. Diet : Total food abstinence is unnecessary and not recommended. Foods providing calories are necessary to facilitate renewal of enterocytes Dairy products should be avoided, because transient lactase deficiency can be caused by enteric, viral, and bacterial infections Caffeinated beverages and alcohol, which can enhance intestinal motility and secretions, should be avoided . When lactose intolerance, sucrase deficiency, and/or food allergy or food-protein-induced enteropathy/ proctocolitis is suspected, we suggest excluding the suspected offending food from the diet for 7 to 10 days

35. P robiotics   - Many diarrheal diseases are associated with alterations in the intestinal microbiota , however, t here is limited evidence, that probiotics are effective in treating chronic pediatric diarrhea Antidiarrheal drugs  —  Loperamide and diphenoxylate / atropine may improve symptoms in children with severe and protracted diarrhea - These agents inhibit intestinal peristalsis, facilitating intestinal absorption, and have antisecretory properties but these agents have important side effects, including sedation and risk for toxic megacolon . We do not recommend the use of these or other antimotility drugs for children with chronic diarrhea, except in unusual circumstances to facilitate fluid management, when the cause of the diarrhea has been established ( eg , irritable bowel syndrome), and the medication is administered under careful supervision Somatostatin  — Treatment may be directed at modifying specific pathophysiologic processes. In severe secretory diarrheas for instance (such as in neuroendocrine tumors , microvillous inclusion disease, and enterotoxin-induced severe diarrhea )

36. At the end of this presentation Chronic diarrhea is a great challenge which needs extensive history, examination and investigations, however, good pediatrician should minimize the DD so as to reach a diagnosis as soon as possible. Although most cases are benign, there are some dangerous causes. Pediatric gastroenterologist has a major role in diagnosis of most cases.

37. references Uptodate21.2 Persistent diarrhea in children in resource-limited countries Overview of the causes of chronic diarrhea in children in resource-rich countries Nelsons 20 th edition Medscape Chronic Diarrhea in Children American Academy of paediatrics https ://pedsinreview.aappublications.org/content/pedsinreview/33/5/207.full.pdf WHO –DIARRHEAL DISEASES