Chronic Diarrhea

Submitted to: Dr. Gerrard Dennis Uy

Submitted by: Allaine Marie Daral

Definition and Epidemiology

Chronic diarrhea is defined as a diarrheal episode that lasts for ≥14 days. Its epidemiology has 2

distinct patterns. In developing countries, chronic diarrhea is often the result of an intestinal

infection that lasts longer than expected. This syndrome is often defined as protracted diarrhea,

and there is no clear distinction between protracted and chronic diarrhea. In countries with

high socioeconomic conditions, chronic diarrhea is less common and its etiology is more

diverse, showing an age-related pattern. The outcome of diarrhea depends on its cause and

ranges from benign conditions such as toddler's diarrhea, to severe congenital diseases such as

microvillus inclusion disease that can lead to irreversible intestinal failure and ultimately death.

Pathophysiology

The mechanisms of diarrhea are generally divided into secretory and osmotic, but often

diarrhea is the result of both mechanisms. Secretory diarrhea is usually associated with large

volumes of watery stools and persists when oral food is withdrawn. Osmotic diarrhea is

dependent on oral feeding, and stool volumes are usually not as massive as in secretory

diarrhea

Secretory diarrhea is characterized by active electrolyte and water fluxes toward the intestinal

lumen, resulting from either the inhibition of neutral NaCl absorption in villous enterocytes or

an increase in electrogenic chloride secretion in secretory crypt cells due to the opening of the

cystic fibrosis transmembrane regulator (CFTR) chloride channel. The other components of the

enterocyte ion secretory machinery are the Na-K-2Cl cotransporter for the electroneutral

chloride entrance into the enterocyte; the Na-K pump, which decreases the intracellular

Na+concentration, determining the driving gradient for further Na+ influx; and the K+ selective

channel, which enables K+, once it has entered the cell in together with Na+, to return to the

extracellular fluid.

Osmotic diarrhea is caused by nonabsorbed nutrients in the intestinal lumen due to one or

more of the following mechanisms: intestinal damage (such as in enteric infection), reduced

functional absorptive surface (such as in celiac disease), defective digestive enzyme or nutrient

carrier (such as in lactase deficiency), decreased intestinal transit time (such as in functional

diarrhea), and nutrient overload exceeding the digestive capacity. Osmotic diarrhea occurs

whenever digestion or absorption is impaired. Whatever the mechanism, the osmotic force

generated by nonabsorbed solutes drives water into the intestinal lumen. An example of

osmotic diarrhea is lactose intolerance. Lactose, if not absorbed in the small intestine, reaches

the colon, where it is fermented to short-chain organic acids, generating an osmotic overload

that overwhelms the absorptive capacity.

Etiology INFECTIOUS AND NONINFECTIOUS CAUSES OF CHRONIC DIARRHEA

INFECTIOUS ETIOLOGIES

Bacterial

Viral and protozoan agents

Small intestinal bacterial overgrowth

Postenteritis syndrome

Tropical sprue

Whipple disease

DIARRHEA ASSOCIATED WITH EXOGENOUS SUBSTANCES

Excessive intake of carbonated fluid

Dietetic foods containing sorbitol, mannitol, or xylitol

Excessive intake of antacids or laxatives containing lactulose or Mg(OH)2

Excessive intake of drinks containing methylxanthines (cola, tea, coffee)

ABNORMAL DIGESTIVE PROCESSES

Cystic fibrosis

Shwachman-Diamond syndrome

Isolated pancreatic enzyme deficiency

Chronic pancreatitis

Johanson-Blizzard syndrome

Pearson syndrome

Trypsinogen and enterokinase deficiency

Chronic cholestasis

Use of bile acids sequestrants

Primary bile acid malabsorption

Terminal ileum resection

NUTRIENT MALABSORPTION

Congenital or acquired lactase deficiency

Congenital or acquired sucrase-isomaltase deficiency

Glucose-galactose malabsorption

Fructose malabsorption

Congenital or acquired short bowel

IMMUNE AND INFLAMMATORY

Food allergy (cow's milk or soy proteins, others)

Celiac disease

Eosinophilic gastroenteritis

Inflammatory bowel disease

Autoimmune enteropathy

IPEX syndrome

Primary and secondary immunodeficiencies

STRUCTURAL DEFECTS

Microvillus inclusion disease

Tufting enteropathy

Phenotypic diarrhea

Heparan-sulphate deficiency

α2β1 and α6β4 integrin deficiency

Lymphangiectasia

Enteric anendocrinosis (neorogenin-3 mutation)

DEFECTS OF ELECTROLYTE AND METABOLITE TRANSPORT

Congenital chloride diarrhea

Congenital sodium diarrhea

Acrodermatitis enteropathica

Selective folate deficiency

Abetalipoproteinemia

MOTILITY DISORDERS

Hirschsprung disease

Chronic intestinal pseudo-obstruction (neurogenic and myopathic)

Thyrotoxicosis

NEOPLASTIC DISEASES

Neuroendocrine hormone-secreting tumors (APUDomas such as VIPoma)

Zollinger-Ellison

Mastocytosis

Pheochromocytoma

Lymphoma

CHRONIC NONSPECIFIC DIARRHEA

Functional diarrhea

Toddler's diarrhea

Irritable bowel syndrome

Enteric infections are by far the most common cause of chronic diarrhea in developing and

industrialized countries, and sequential infections with the same or a different pathogen may

be responsible for prolonged symptoms. Entero-adherent Escherichia coli and Cryptosporidium

parvum have been implicated in chronic diarrhea in developing countries. In developed

countries chronic infectious diarrhea usually runs a benign course and the etiology is often viral.

Rotavirus and Norovirus are often involved, whereas cytomegalovirus and Clostridium difficile

are emerging agents of severe diarrhea in children.

Small intestinal bacterial overgrowth diarrhea may be the result of either a direct interaction

between the microorganism and the enterocyte or the consequence of the deconjugation and

dehydroxylation of bile salts and the hydroxylation of fatty acids due to an abnormal

proliferation of bacteria in the proximal intestine.

Postenteritis syndrome is a clinical-pathologic condition in which small intestinal mucosal

damage persists after acute gastroenteritis. Sensitization to food antigens, secondary

disaccharidase deficiency, or an infection or reinfection with an enteric pathogen is responsible

for postenteritis syndrome. A change of the gut microflora due to the infectious agent and/or

antibiotic therapy can contribute to postenteritis diarrhea.

Allergy to cow's milk protein and other foods can manifest with chronic diarrhea, especially

during infancy.

Eosinophilic gastroenteritis is characterized by eosinophilic infiltration of the intestinal wall and

is strongly associated with atopy.

Shwachman-Diamond syndrome, exocrine pancreatic hypoplasia may be associated with

neutropenia, bone changes, and intestinal protein loss. Specific isolated pancreatic enzyme

defects result in fat and/or protein mal absorption.

Familial pancreatitis, associated with a mutation in the trypsinogen gene, may be associated

with pancreatic insufficiency and chronic diarrhea.

Liver disorders can lead to a reduction in the bile salts, resulting in fat malabsorption. Bile acid

loss may be associated with terminal ileum diseases, such as Crohn disease or disease following

ileal resection.

Carbohydrate malabsorption and lactose intolerance may be due to a molecular deficiency of

lactase or sucrase-isomaltase, or to congenital glucose-galactose malabsorption. Lactose

intolerance is more commonly a consequence of secondary lactase deficiency due to intestinal

mucosal damage. A progressive, age-related loss of lactase activity affects about 80% of the

nonwhite population and may be responsible for chronic diarrhea in older children receiving

cow's milk.

The most benign etiology is chronic nonspecific diarrhea that encompasses functional

diarrhea (or toddler's diarrhea) in children <4 yr of age and irritable bowel syndrome in those

≥5 yr. The disease is the same with a slightly different age presentation, in that abdominal pain

is more common and clearly associated with the diarrhea in older children.

The hallmark of the syndrome is diarrhea associated with normal weight growth in well-

appearing subjects.

In younger children diarrhea is often watery, at times containing undigested food particles. It is

usually more severe in the morning. If the child's fluid intake is >150 mL/kg/24 hr, fluid intake

should be reduced to no more than 90 mL/kg/24 hr.

The child is often irritable in the first 2 days after the fluid restriction; however, persistence

with this approach for several more days results in a decrease in the stool frequency and

volume. If the dietary history suggests that the child is ingesting significant amounts of fruit

juices, then the offending juices should be decreased.

Sorbitol, which is a nonabsorbable sugar, is found in apple, pear, and prune juices and it can

cause diarrhea in toddlers. Apple and pear juices contain higher amounts of fructose than

glucose, a feature postulated to cause diarrhea in toddlers. In older children, irritable bowel

syndrome is often associated with abdominal pain and may be related to anxiety, depression,

and other psychologic disturbances.

The most severe etiology includes a number of heterogeneous conditions leading to

the intractable diarrhea syndrome, which is often the result of a permanent defect in the

structure or function of intestine, leading to progressive, often irreversible intestinal failure,

requiring parenteral nutrition for survival. The main etiologies of intractable diarrhea include

structural enterocyte defects, disorders of intestinal motility, immune-based disorders, short

gut, and multiple food intolerance.

Structural enterocyte defects are due to specific molecular defects responsible for early-onset

severe diarrhea. Inmicrovillus inclusion disease, microvilli are sequestered in vacuoles as a

consequence of autophagocytosis due to a mutation in myosin that impairs apical protein

trafficking leading to aberrant brush border development.

Intestinal epithelial dysplasia (or tufting enteropathy) is characterized by disorganization of

surface enterocytes with focal crowding and formation of tufts. Abnormal deposition of laminin

and heparan sulfate proteoglycan on the basement membrane has been detected in intestinal

epithelia. An abnormal intestinal distribution of α2β1 and α6β4integrins has been implicated in

tufting enteropathy. These ubiquitous proteins are involved in cell-cell and cell-matrix

interactions, and they play a crucial role in cell development and differentiation.

Multiple food protein hypersensitivity is regarded as a cause of intractable diarrhea

syndrome. However, this is usually a diagnosis of exclusion and is based on a relationship

between any ingested food and diarrhea. In most cases, multiple food intolerance is not

ultimately confirmed by oral challenge, and most children are eventually able to return to a free

diet.

Autoimmune processes can target the intestinal epithelium, alone or in association with

extraintestinal symptoms.Autoimmune enteropathy is characterized by the production of anti-

enterocyte and anti-goblet cell antibodies, primarily IgG, directed against components of the

enterocyte brush border or cytoplasm and by a cell-mediated autoimmune response with

mucosal T-cell activation. An X-linked immune dysregulation, polyendocrinopathy and

enteropathy (IPEX) syndrome is associated with variable phenotypes of chronic diarrhea.

Abnormal immune function, as seen in patients with agammaglobulinemia, isolated

immunoglobulin A deficiency, and combined immunodeficiency disorders, can result in

persistent infectious diarrhea.

Phenotypic diarrhea, also defined as syndromic diarrhea or tricho-hepato-enteric syndrome,

is a rare disease presenting with facial dysmorphism, woolly hair, severe diarrhea, and

malabsorption . Half of the patients have liver disease.

Disorders of intestinal motility include derangements of development and function of the

enteric nervous system, such as in Hirschsprung disease and chronic idiopathic intestinal

pseudo-obstruction (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.

Short bowel syndrome is the single most common etiology of diarrhea and intestinal failure.

Many intestinal abnormalities such as stenosis, segmental atresia, and malrotation can require

surgical resection. In these conditions the residual intestine may be insufficient to carry on its

digestive-absorptive functions. Alternatively, small bowel bacterial overgrowth can cause

diarrhea, such as in the blind loop syndrome.

In rare cases of severe chronic diarrhea, the gastrointestinal symptoms may be the initial

manifestation of amitochondrial disease or another metabolic disorder, namely carbohydrate-

deficient glycoproteins. Finally, when the cause of the diarrhea is undetermined and the clinical

course is inconsistent with organic disorders,factitious disorder by proxy (formerly

Munchausen syndrome by proxy) should be considered.

The natural history of intractable diarrhea is related to the primary intestinal disease. Food

intolerances generally resolve in a few weeks or months, as does autoimmune enteropathy

when appropriate immune suppression is started. Children with motility disorders have long-

lasting stable symptoms that are rarely fatal, whereas those with structural enterocyte defects

never recover, undergoing a more-severe course and often becoming candidates for intestinal

transplantation.

Evaluation of Patients

The medical approach should be based on diagnostic algorithms that begin with the age of the

child, evaluate the weight pattern, and then consider clinical and epidemiologic factors, always

taking into account the results of microbiologic investigations. The etiology of chronic diarrhea

shows an age-related pattern, and an early onset might suggest a congenital and severe

condition. In later infancy and up to 2 yr of age, infections and allergies are more common,

whereas inflammatory diseases are more common in older children and adolescents.

MAIN CAUSES OF CHRONIC DIARRHEA ACCORDING TO THE AGE OF ONSET

0-30 DAYS 1-24 MONTHS 2-18 YEARS

Microvillus inclusion disease

Apple juice and pear nectar Apple juice or pear nectar

Autoimmune enteropathy

Antibiotic-associated Clostridium difficile colitis

Intestinal infection Intestinal infection

Congenital short bowel syndrome Short gut

Food allergy

Food allergy Lactose intolerance

Functional diarrhea[†] Irritable bowel syndrome[‡]

Celiac disease Celiac disease

Hirschsprung's disease Cystic fibrosis

Malrotation with partial blockage

Post-gastroenteritis diarrhea Post-gastroenteritis diarrhea

Neonatal lymphangectasia

Tufting enteropathy

Primary bile-salt malabsorption

Intestinal pseudo-obstruction

Intestinal pseudo-obstruction

0-30 DAYS 1-24 MONTHS 2-18 YEARS

† Age range 0-4 years.

‡ Age range 5-18 years.

Anthropometric evaluation is an essential step to evaluate “if, since when, and how much”

diarrhea has affected body weight. The combined evaluation of the duration and amount of

weight loss provides an estimate of the severity of diarrhea.

Initial clinical examination should include evaluating general and nutritional status.

Dehydration, marasmus, or kwashiorkor requires prompt supportive interventions to stabilize

the patient. Nutritional evaluation is crucial to establish the need for rapid intervention. It

should start with the evaluation of the weight and height curves and of the weight for height

index to determine the impact of diarrhea on growth. Weight is generally impaired before

height, but with time linear growth also becomes affected, and both parameters may be

equally abnormal in the long term. Assessment of nutritional status includes the dietary

history and biochemical and nutritional investigations. Caloric intake should be quantitatively

determined and the relationship between weight modifications and energy intake should be

carefully considered.

Diagnostic work-up Chronic diarrhea usually requires endoscopy and histology. Small intestinal biopsy can

detect a primary intestinal etiology in the majority of cases of chronic diarrhea and

malabsorption. Colonoscopy should be performed in all cases of chronic diarrhea in which

gross blood or leukocytes are detected in the stools or when an increased frequency of

mucoid stools and abdominal pain suggest colonic involvement. Abnormalities in the

digestive-absorptive function tests suggest small bowel involvement, whereas intestinal

inflammation, as demonstrated by increased calprotectin and rectal nitric oxide, supports a

distal intestinal localization. Capsule endoscopy allows exploration of the entire intestine

looking for morphologic abnormalities, inflammation, and bleeding.

Biopsies should be performed at multiple sites, even in a normal-appearing intestine,

because abnormalities can have a patchy distribution. Histology is important to establish

the degree of mucosal involvement through grading of intestinal damage and the

evaluation of associated abnormalities, such as inflammatory infiltration of the lamina

propria. Morphometry provides additional quantitative information of epithelial changes.

In selected cases, light microscopy can help to identify specific intracellular agents, such as

cytomegalovirus, based on the presence of parasites or of large inclusion bodies in infected

cells. Electron microscopy is essential to detect cellular structural abnormalities such as

microvillous inclusion disease. Immunohistochemistry allows the study of mucosal immune

activation as well as of other cell types (smooth muscle cells and enteric neuronal cells),

and the components of the basal membrane.

Imaging has a major role in the diagnostic approach. A preliminary plain abdominal x-ray is

useful for detecting gaseous distention that suggests intestinal obstruction. Intramural or

portal gas may be seen in necrotizing enterocolitis or intussusception. Structural

abnormalities such as diverticula, malrotation, stenosis, blind loop, and inflammatory

bowel disease, as well as motility disorders, may be appreciated after a barium meal and an

entire bowel follow-through examination. The latter also provides information on transit

time. Abdominal ultrasound can help detect liver and pancreatic abnormalities or an

increase in intestinal wall thickness that suggests an inflammatory bowel disease.

Once infectious agents have been excluded and nutritional assessment performed, a

stepwise approach to the child with chronic diarrhea may be applied. The main etiologies

of chronic diarrhea should be investigated based on the features of diarrhea and their

predominant or selective intestinal dysfunction. A step-by-step diagnostic approach is

important to minimize the unnecessary use of invasive procedures and overall costs, while

optimizing the yield of the diagnostic work-up.

STEPWISE DIAGNOSTIC WORK-UP FOR CHILDREN WITH CHRONIC DIARRHEA

STEP 1

• Stool cultures

• Microscopy for parasites

• Viruses

• Stool electrolytes

• H2 breath test

Screening test for celiac disease (transglutaminase 2 autoantibodies)

Noninvasive tests for: • Intestinal function

• Pancreatic function and sweat test

• Intestinal inflammation

Tests for food allergy • Prick/patch tests

STEP 2

Intestinal morphology • Standard jejunal/colonic histology

• Morphometry

• PAS staining

• Electron microscopy

STEP 3

Special investigations • Intestinal immunohistochemistry

• Anti-enterocyte antibodies

• Serum chromogranin and catecholamines

• Autoantibodies

• 75SeHCAT measurement

• Brush border enzymatic activities

• Motility and electrophysiological studies

Treatment

Chronic diarrhea associated with impaired nutritional status should always be considered a

serious disease, and therapy should be started promptly.

Treatment Includes

General Supportive Measures

Nutritional Rehabilitation

Elimination Diet

Drugs

Drug treatment includes therapies for specific etiologies as well as interventions aimed at

counteracting fluid secretion and/or promoting restoration of disrupted intestinal

epithelium. Because death in most instances is caused by dehydration, replacement of fluid

and electrolyte losses is the most important early intervention.

Nutritional rehabilitation is often essential and is based on clinical and biochemical

assessment. In moderate to severe malnutrition, caloric intake may be progressively

increased to 50% or more above the recommended dietary allowances. The intestinal

absorptive capacity should be monitored by digestive function tests. In children with

steatorrhea, medium chain triglycerides may be the main source of lipids. A lactose-free diet

should be started in all children with chronic diarrhea, as is recommended by the World

Health Organization (WHO). Lactose is generally replaced by maltodextrin or a combination

of complex carbohydrates. A sucrose-free formula is indicated in sucrase-isomaltase

deficiency. Semi-elemental or elemental diets have the double purpose of overcoming food

intolerance, which may be the primary cause of chronic diarrhea, and facilitating nutrient

absorption. The sequence of elimination should be graded from less to more restricted diets,

such as cow's milk protein hydrolysate to amino-acid–based formula, depending on the

child's situation. In severely compromised infants it may be convenient to start with amino-

acid–based feeding.

Clinical nutrition includes enteral or parenteral nutrition. Enteral nutrition may be delivered

via nasogastric or gastrostomy tube and is indicated in a child who cannot be fed through

the oral route, either because of primary intestinal diseases or because of extreme

weakness. Continuous enteral nutrition is effective in children with a reduced absorptive

function, such as short bowel syndrome, because it extends the time of nutrient absorption

through the still-functioning surface area. In extreme wasting, enteral nutrition might not be

sufficient, and parenteral nutrition is required.

Micronutrient and vitamin supplementation are part of nutritional rehabilitation and

prevent further problems, especially in malnourished children from developing countries.

Zinc supplementation is an important factor in both prevention and therapy of chronic

diarrhea, because it promotes ion absorption, restores epithelial proliferation, and

stimulates immune response.

Drug therapy includes anti-infectious drugs, immune suppression, and drugs that can inhibit

fluid loss and promote cell growth. If a bacterial agent is detected, specific antibiotics should

be prescribed. Empirical antibiotic therapy may be used in children with small bowel

bacterial overgrowth or with suspected bacterial diarrhea. Trimethoprim-sulfamethoxazole,

metronidazole or albendazole, and nitazoxanide have a broad pattern of targets, including

parasites. In Rotavirus-induced severe and protracted diarrhea, oral administration of

human immunoglobulins (300 mg/kg) should be considered.

Immune suppression should be considered in selected conditions such as autoimmune

enteropathy. In selected cases, biologic immune suppression may be considered.

Treatment may be also directed at modifying specific pathophysiologic processes. Severe ion

secretion may be reduced by pro-absorptive agents, such as the enkephalinase inhibitor

racecadotril. In diarrhea due to neuroendocrine tumors, microvillus inclusion disease, and

enterotoxin-induced severe diarrhea, a trial with the somatostatin analog octreotide may be

considered. Zinc or growth hormone promote enterocyte growth and ion absorption and

may be effective when intestinal atrophy and ion secretion are associated.

When other attempts have failed, the only option may be parenteral nutrition or intestinal

transplantation.