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
dr.awies02@gmail.com

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. Copyrights apply

5. 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)

6. 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.

7. 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

8. 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 )

9. 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

10. B)Secretory
• is characterized by active electrolyte and water fluxes toward
the intestinal lumen, resulting from either :
o inhibition of neutral NaCl absorption in villous enterocytes
o 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.

11. 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.

12. • 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

13. 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

14. 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 .

15. 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)

16. Copyrights apply

19. ETIOLOGY
• Infectious and Non- infectious

20. 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

21. • 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

22. • 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

23. 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

25. 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 —

26. 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

27. Copyrights apply

28. 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.

29. 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 .
Increased risk of Small intestinal lymphoma in patients with Celiac Sprue .
Risk may be lessened with adherence to gluten free diet

30. 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 .

31. 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

32. 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

33. 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

34. 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.
Transit 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.

35. 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.

36. 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.

37. 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

38. 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

39. Copyrights apply

40. Diagnostic approach

44. 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

45. Probiotics - Many diarrheal diseases are associated with alterations in the
intestinal microbiota , however, there 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)

46. 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.

47. 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 20th edition
• Medscape
• Chronic Diarrhea in Children American Academy of paediatrics
https://pedsinreview.aappublications.org/content/pedsinreview/3
3/5/207.full.pdf
• WHO –DIARRHEAL DISEASES