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CHRONIC DIARRHEA
Alfredo Guarino and David Branski
DEFINITION AND EPIDEMIOLOGY
Chronic diarrhea is defined as a diarrheal episode that lasts for 14 days or more. Its epidemiology
has two 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 the latter and chronic diarrhea. In countries with
high socio-economic conditions, chronic diarrhea is less frequent 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 may 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watery stools and persists when oral food is withdrawn.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 (Fig 1).
Secretory diarrhea is characterized by active electrolyte and water fluxes towards 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: 1.The Na-K2Cl 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 in together with Na+, to return to the extracellular fluid.
Electrogenic secretion is induced by an increase of intracellular concentration of cAMP, cGMP or
calcium in response to microbial enterotoxins, or to endogenous endocrine or non-endocrine
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-/HCO3exchangers. Defects in the genes of the Na+/H+ and the Cl-/HCO3- exchangers are responsible for
congenital Na+ and Cl- diarrhea, respectively.
Osmotic diarrhea is caused by non-absorbed nutrients in the intestinal lumen, due to one or more
of the following mechanisms: 1. Intestinal damage (such as in enteric infection), 2. Reduced
functional absorptive surface (such as in celiac disease), 3. Defective digestive enzyme or nutrient
carrier (such as in lactase deficiency), 4. Decreased intestinal transit time (such as in . functional
diarrhea) 5. Nutrient overload, exceeding the digestive capacity. Osmotic diarrhea occurs
whenever digestion or absorption are impaired. Whatever the mechanism, the osmotic force
generated by non-absorbed 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 is fermented to short-chain organic acids, generating an osmotic overload that overwhelms
the absorptive capacity.
In many children chronic diarrhea is induced by multiple mechanisms, intersecting each other and
often producing a vicious cycle. A paradigm of chronic diarrhea generated by multiple mechanisms
is provided by HIV infection, in which immune derangement, enteric infections, nutrient
malabsorption and intestinal damage, together with a direct enteropathogenic role of HIV, trigger
and maintain chronic diarrhea (Fig. 2).
ETIOLOGY
A list of the main causes of chronic diarrhea is shown in table 355.x
Enteric infections are by far the most frequent cause of chronic diarrhea, both in developing and
industrialised 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 frequently involved, whereas Cytomegalovirus and Clostridium difficile are
emerging agents of severe diarrhea in children.
Opportunistic microorganisms induce diarrhea exclusively, or more severely or for more prolonged
periods, in specific populations, such as immunocompromised children. Enteric cryptosporidiosis is
the most frequent cause of severe and protracted diarrhea in AIDS, but HIV virus may be directly
responsible for diarrhea and for the so called HIV-enteropathy.
In small intestinal bacterial overgrowth, diarrhea may be the result of either a direct interaction
between the microorganism and the enterocyte or the consequence of deconjugation and
dehydroxylation of bile salts, and hydroxylation of fatty acids due to an abnormal proliferation of
bacteria in the proximal intestine. (SEE CHAPTER XX)
Postenteritis syndrome is a clinical-pathological condition in which small intestinal mucosal
damage persists after acute gastroenteritis. Sensitization to food antigens, secondary disaccharidase
deficiency or an infection or reinfections with an enteric pathogen are responsible for postenteritis
syndrome. A change of the gut microflora due to the infectious agent and/or antibiotic therapy may
contribute to postenteritis diarrhea.
A reduction of intestinal absorptive surface is responsible for diarrhea in celiac disease, a
permanent gluten intolerance that is sustained by a genetic basis affecting as many as 1 in 100
normal people, depending on geographic origin. Gliadin induces villous atrophy leading to a
reduction of functional absorptive surface area that is reversible upon implementation of a strict
gluten free diet (see chapter XXX).
Allergy to cow’s milk protein and other foods may manifest with chronic diarrhea, especially
during infancy. Eosinophilic gastroenteritis is characterized by eosinophilic infiltration of the
intestinal wall and is strongly associated with atopy.
In older children and adolescents, inflammatory bowel disease including Crohn’s disease,
ulcerative colitis and indeterminate colitis, are major causes of chronic diarrhea.
Chronic diarrhea may be the manifestation of maldigestion due to exocrine pancreatic disorders
(see chapter xx). In most patients with cystic fibrosis, pancreatic insufficiency results in fat and
protein malabsorption. In 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 malabsorption. Familial pancreatitis,
associated with a mutation in the trypsinogen gene, may be associated with pancreatic insufficiency
and chronic diarrhea.
Liver disorders may 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’s disease or following ileal
resection. In primary bile acid malabsorption neonates and young infants present with chronic
diarrhea and fat malabsorption due to mutations of ileal bile transporter.
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 frequently a consequence of secondary lactase deficiency due to intestinal
mucosal damage. A progressive, age-related, loss of lactase activity affects about 80% of the nonCaucasian population, and may be responsible for chronic diarrhea in older children receiving
cow’s milk.
The most benign etiology is chronic non-specific diarrhea that encompasses functional diarrhea
(or toddler's diarrhea) in children below four years of age and irritable bowel syndrome in those
five years and older. The disease is the same with a slightly different age presentation, in that
abdominal pain is more frequent 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 150mL/kg/24hr, fluid intake
should be reduced to no more than 90mL/kg/24hr. The child is often irritable in the first two 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 can cause diarrhea in toddlers.
Moreover, 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 psychological
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: 1. structural enterocyte defects, 2.
disorders of intestinal motility, 3. immune-based disorders, 4. short gut and 5. multiple food
intolerance. The genetic and molecular bases of many etiologies of intractable diarrhea have been
recently identified (Table 3).
1. Structural enterocyte defects are due to specific molecular defects responsible for early onset,
severe diarrhea. In microvillus inclusion disease, microvilli are sequestered in vacuoles as a
consequence of autophagocytosis due to a defect in protein trafficking disrupting enterocyte polarity
(Fig 3). 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 α6β4 integrins has been implicated in
tufting enteropathy. These ubiquitous proteins are involved in cell-cell and cell-matrix interactions,
and play a crucial role in cell development and differentiation.
Electrolyte transport defects are a subgroup of structural enterocyte defects that include congenital
chloride diarrhea, in which a mutation in the solute carrier family 26 member 3 gene (SLC26A3)
leads to severe intestinal Cl- malabsorption due to a defect or absence of the Cl-/ HCO3- exchanger.
The consequent defect in bicarbonate secretion leads to metabolic alkalosis and acidification of the
intestinal content, with further inhibition of Na+/H+ exchanger-dependent Na+ absorption. Patients
with congenital sodium diarrhea show similar clinical features, because of a defective Na+/H+
exchanger in the small and large intestine, leading to massive Na+ fecal loss and severe acidosis.
2. Multiple food protein hypersensitivity is regarded as a causes 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.
3. Autoimmune processes may target the intestinal epithelium, alone or in association with
extraintestinal symptoms. Autoimmune enteropathy is characterized by the production of antienterocyte 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 Tcell 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
(Fig 4). Half of the patients have liver disease.
4. Disorders of intestinal motility include derangements of development and function of the
enteric nervous system, such as in Hirschsprung’s 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.
5. Short bowel syndrome (see chapter XXX) is the single most frequent etiology of diarrhea and
intestinal failure. Many intestinal abnormalities such as stenosis, segmental atresia, and malrotation
may require surgical resection. In these conditions the residual intestine may be insufficient to carry
on its digestive-absorptive functions. Alternatively, small bowel bacterial overgrowth may 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 a mitochondrial 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, Munchausen 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
Because of the wide spectrum of the etiologies, the medical approach should be based on diagnostic
algorithms that begin with the age of the child, evaluate the weight pattern, then consider clinical
and epidemiological factors, always taking into account the results of microbiological
investigations. The etiology of chronic diarrhea shows an age-related pattern and an early onset may
suggest a congenital and severe condition. In later infancy and up to two years of age, infections
and allergies are more common, whereas inflammatory diseases are more frequent in older children
and adolescents. Celiac disease on the one hand, and chronic non- specific diarrhea on the other,
should always be considered independent of age, due to their relatively high frequency (Table 4).
Specific clues in the family and personal history may provide useful indications, suggesting a
congenital, allergic or inflammatory etiology. A previous episode of acute gastroenteritis is
suggestive of postenteritis syndrome, whereas the association of diarrhea with specific foods may
indicate a nutrient basis. A history of polyhydramnion is consistent with congenital chloride or
sodium diarrhea, or conversely, cystic fibrosis. The presence of eczema or asthma is associated with
an allergic disorder, whereas specific extraintestinal manifestations (arthritis, diabetes,
thrombocytopenia, etc.) may suggest an autoimmune disease. Specific skin lesions may be
suggestive of acrodermatitis enteropathica. Typical facial abnormalities and woolly hair are
associated with phenotypic diarrhea (fig 4).
Anthropometric evaluation is essential to evaluate “if, since when, and how much” diarrhea has
impacted on 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 the evaluation of 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.
Biochemical markers assist in grading malnutrition (Table 5). The half life of serum proteins may
differentiate between short and long term malnutrition. Assessment of body composition may be
performed by measuring mid-arm circumference and triceps skinfold thickness or, more accurately,
by bioelectrical impedance analysis or dual emission x-ray absorptiometry (DEXA) scans.
Diagnosis of functional diarrhea is based on pure clinical grounds using established age-related
criteria (Table 4). Conversely a child with persistent diarrhea and suspected malabsorption, may be
inappropriately “treated” with a diluted hypocaloric diet in an effort to reduce the diarrhea, and
persistent diarrhea may be an indirect consequence of ongoing malnutrition. One such example of
this vicious cycle is exocrine pancreatic insufficiency due to protein calorie malnutrition.
The search for etiology may be based on the pathophysiology of the diarrhea. Fecal electrolyte
concentrations discriminate between secretory and osmotic diarrhea and the results may guide the
subsequent diagnostic approach. Microbiological investigation of stool samples should include a
thorough list of bacterial, viral and protozoan agents. Proximal intestinal bacterial overgrowth may
be sought using the hydrogen breath test, after an oral glucose load.
Non-invasive assessment of digestive-absorptive functions and of intestinal inflammation plays a
key role in the diagnostic work up (table 6).
Diagnostic work-up of chronic diarrhea will usually require endoscopy and histology. Small
intestinal biopsy may 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 digestiveabsorptive 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 morphological
abnormalities, inflammation and bleeding.
Biopsies should be performed at multiple sites, even in a normal appearing intestine, because
abnormalities may 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 may
help to identify specific intracellular agents, such as Cytomegalovirus, based on the presence of
large inclusion bodies in infected cells or parasites. 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 detection of gaseous distension, suggestive of intestinal obstruction. Intramural or portal gas
may be seen in necrotizing enterocolitis or intussusception. Structural abnormalities such as
diverticulae, malrotation, stenosis, blind loop, 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 may help detect liver
and pancreatic abnormalities, or an increase in intestinal wall thickness, that suggest an
inflammatory bowel disease.
Specific investigations should be carried out for specific diagnostic dilemmas. Prick and patch test
may support a diagnosis of food allergy, although definitive diagnosis requires oral challenge. Bile
malabsorption may be explored by the retention of the bile acid analogue (75)Se-homocholic acidtaurine ((75)SeHCAT) in the enterohepatic circulation. A scintigraphic examination, with radiolabelled octreotide is indicated in suspected APUD cell neoplastic proliferation. In other diseases,
specific imaging techniques such as computed tomography or nuclear magnetic resonance may have
important diagnostic value.
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
(table 7).
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 and drugs. The latter 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, and
is recommended by the WHO. Lactose is generally replaced by maltodextrin or a combination of
complex carbohydrates. A sucrose-free formula is indicated in sucrase-isomaltase deficiency. Semielemental 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, i.e. cow’s milk protein hydrolysate
to amino-acid-based formulae, depending on the child's situation. In severely compromised infants
it may be convenient to start with amino-acids-based feeding.
Clinical nutrition includes enteral or parenteral nutrition. Enteral nutrition may be performed via
nasogastric or gastrostomy tube, and is indicated in a child who is not able to 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 since it extends the time of nutrient absorption through the still functioning surface area.
In extreme wasting, enteral nutrition may 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, since it promotes ion
absorption, restores epithelial proliferation and stimulates immune response. Nutritional
rehabilitation has a general beneficial effect on the patient's general condition, intestinal function,
and immune response and may break the vicious circle shown in figure 2.
Drug therapy includes anti-infectious drugs, immune suppression, and drugs that may inhibit fluid
loss and promote cell growth. If a bacterial agent is detected, specific antibiotics should be
prescribed. Empiric antibiotic therapy may be used in children with either small bowel bacterial
overgrowth or with suspected bacterial diarrhea. Trimethoprim-sulphamethoxazole, metronidazole
or albendazole, and nitazoxanide have a broad pattern of target agents, 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 biological immune suppression can 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 somatostatin analogue octreotide may be considered. Zinc or growth
hormone promote both enterocyte growth and ion absorption and may be effective when intestinal
atrophy and ion secretion are associated.
However, when other attempts have failed, the only option may be parenteral nutrition or intestinal
transplantation.
Table 1. Infectious and non-infectious causes of diarrhea.
Infectious etiologies: Bacterial, viral and protozoan agents, small intestinal bacterial overgrowth,
postenteritis syndrome , tropical sprue, Whipple disease
Non infectious etiologies:
Diarrhea associated with exogenous substances: excessive intake of carbonated fluid, dietetic
foods containing sorbitol, mannitol or xylitol; excessive intake of antiacids or laxatives
containing lactulose or Mg(OH)2; excessive intake of methylxanthines-containing drinks (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 sucrase-isomaltase deficiency; congenital or
acquired lactase deficiency; glucose-galactose malabsorption; fructose malabsorption., congenital or
acquired short bowel
Immune/inflammatory: food allergy; celiac disease; eosinophilic gastroenteritis, inflammatory
bowel diseases, autoimmune enteropathy, primary and secondary immunodeficiencies, IPEX
syndrome.
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’s disease, chronic intestinal pseudoobstruction (neurogenic and
myopathic), thyrotoxicosis.
Neoplastic diseases: neuroendocrine hormone-secreting tumors: APUDomas such as VIPoma,
Zollinger- Ellison and mastocytosis.
Chronic non specific diarrhea: functional diarrhea, toddler's diarrhea, irritable bowel syndrome
1.
Table 3. Molecular basis of the main forms of congenital diarrheal diseases
Disease
Defects of absorption and transport of
nutrients and electrolytes
Congenital lactase deficiency
Gene
Location
Function
LCT
2q21
Lactase-phlorizin hydrolase
activity
Disaccharide intolerance
EC 3.2.1.48
3q25-q26
Isomaltase-sucrase
Maltase-glucoamylase deficiency
MGAM
7q34
Maltase-glucoamylase
activity
Glucose-galactose malabsorption
SGLT1
22q13.1
Na+/glucose cotransporter
Fructose malabsorption
GLUT5
1p36
Fructose transporter
Fanconi-Bickel syndrome
GLUT2
3q26
Basolateral glucose
transporter
Cystic fibrosis
CFTR
7q31.2
cAMP-dependent Clchannel
Acrodermatitis enteropathica
SLC39A4
8q24.3
Zn2+ transporter
Congenital chloride diarrhea
DRA
7q22q31.1
Cl-/base exchanger
Congenital sodium diarrhea
SPINT2*
Unknown
Na+/ hydrogen exchanger?
Enterokinase deficiency
Serine
protease 7
21q21
Serine-protease inhibitor
Trypsinogen deficiency
Trypsinogen 7q35
Lysinuric protein intolerance
Proenterokinase –
hydrolyzes tripsinogen
Hydrolyzes endo/exopeptidases
AA basolateral transport
Hydrolyzes triglycerides to
fatty acids
SLC7A7
14q11
Pancreatic lipase deficiency
Pancreatic
lipase
10q26
Abetalipoproteinemia
MTP
4q22
Transfer lipids to
apolipoprotein B
Hypobetalipoproteinemia
APOB
2p24
Apolipoprotein that forms
chylomicrons
Chylomicron retention disease
SARA2
5q31
Intracellular chylomicron
trafficking
Congenital bile acid diarrhea
ABAT
13q3
Ileal Na+/ bile salt
transporter
Microvillous inclusion disease
EpCAM
18q21
Myosin Vb. Intracellular
protein trafficking
Congenital Tufting Enteropathy
Unknown
2p21
Cell-cell interaction
Defects of enterocyte differentiation and
polarization
Syndromic diarrhea
Unknown
Unknown
Unknown
Enteric anendocrinosis
NEUROG3
10q21.3
Enteroendocrine cell fate
determination
Enteric dysendocrinosis
-
-
Enteroendocrine cells
function
Proprotein convertase 1 deficiency
Prohormone
convertase1
5q15-q21
Prohormone processing
Foxp3
Xp11.23q13.3
Transcription factor
IPEX-like syndrome
Unknown
Unknown
Immunodeficiency-associated
autoimmune enteropathy
Unknown
Unknown
Autoimmune polyglandular syndrome-1
(APS-1)
AIRE
21p22.3
Autoimmune regulator
protein
Autoimmune enteropathy with colitisgeneralized autoimmune gut disorder
(GAGD)
Unknown
Unknown
Unknown
Defects of enteroendocrine cell
differentiation
Defects of modulation of intestinal
immune response
IPEX (Immune dysregulation,
polyendocrinopathy, enteropathy, Xlinked)
Unknown
Unknown
Table 4. Main causes of chronic diarrhea according to the age of onset
0-30 days
All the diseases listed in table 2 and:
1-24 months
2-18 years
Autoimmune enteropathy
Congenital short bowel syndrome
Food allergy
Hirschsprung's disease
Malrotation with partial blockage
Neonatal lymphangectasia
Primary bile-salt malabsorption (PBAM)
Intestinal pseudo-obstruction
Apple juice and pear nectar
Autoimmune enteropathy
Intestinal infection
Short gut
Food allergy
Functional diarrhea*
Celiac disease
Cystic fibrosis
Post-gastroenteritis diarrhea
Apple juice or pear nectar
Antibiotic-associated C. difficile colitis
Intestinal infection
Lactose intolerance
Irritable bowel syndrome**
Celiac disease
Post-gastroenteritis diarrhea
Tufting enteropathy
Microvillus inclusion disease
Intestinal pseudo-obstruction
*Age range 0-4 years
** Age range 4-18 years
Table 5 Degree of malnutrition as estimated by visceral protein concentrations in children with
chronic diarrhea
Visceral Protein
Half-life
Normal Values
Mild
malnutrition
Moderate
malnutrition
Severe
malnutrition
Albumin
20 days
30-45 gr/l
3.0-2.9 gr/l
2.8-2.5 gr/l
<2.5 gr/l
Prealbumin
2 days
0.2-04 gr/l
0.2-0.18 gr/l
0.17-0.1 gr/l
< 0.1 gr/l
Retinol Binding
Protein
12 h
2.6-7.6 gr/l
2.5- 2.0 gr/l
1.9 -1.5 gr/l
< 1 gr/l
Transferrin
8 days
218-411 ug/dl
200-150 ug/dl
149-100 ug/dl
<100 ug/dl
Serum iron
11-19 h
16-124ug/dl
15-13 ug/dl
12-10 ug/dl
<10 ug/dl
Consider also the concentrations of the following micronutrients:
calcium, zinc, magnesium, iodine, vitamin A, vitamin C, vitamin B1
Table 6 Non-invasive tests for intestinal and pancreatic digestive-absorptive functions and
for intestinal inflammation.
Test
Normal values
Implication
Reference
α1-antitrypsin concentration
< 0.9 mg/g
increased intestinal
permeability / protein
loss
Catassi C et al. J
Pediatr
1986;109:500-502
Steatocrit
<2.5% (older
fecal fat loss
Guarino A et al. J
Pediatr
Gastroenterol
Nutr1992;14:268274
than 2 years)
Fecal reducing substances
absent
carbohydrate
malabsorption
Lindquist BL et
al. Arch Dis Child
1976;51:319-321
Elastase concentration
> 200 ug /g
stool
exocrine pancreatic
dysfunction
Carroccio A et al.
Gut 1998;43:558563
Chymotrypsin concentration
> 7.5 U/g
exocrine pancreatic
dysfunction
Carroccio A et al.
Gastroenterology
1997;112:18391844
> 375 U/24 h
Fecal occult blood
absent
fecal blood loss, distal
intestinal inflammation
Fine KD. N Engl J
Med
1996;334:11631167
Calprotectin concentration
100 ug /g
intestinal inflammation
Fagerberg UL et
al. J Pediatr
Gastroenterol
Nutr 2003;37:46872
Fecal leukocytes
<
5/microscopic
field
colonic inflammation
Harris JC et al.
1972;76:697-703
Nitric oxide in rectal dyalisate
< 5 uM of NO2/NO3-
rectal inflammation
Berni Canani R et
al. Am J
Gastroenterol
2002;97:15741576
Dual sugar (cellobiose/mannitol)
Urine excretion
Increased intestinal
Catassi C, et al. J
absorption test
ratio:
0.010+0.018
permeability
.Pediatr Gastro
Nutr 2008;46:4147
Table 7. Stepwise diagnostic workup for children with chronic diarrhea.
Step 1
Intestinal microbiology
Screening test for celiac disease




stool cultures
microscopy for parasites
viruses
H2 breath test
Transglutaminase 2 autoantibodies
Non invasive tests for:



Tests for food allergy
Step 2
Intestinal
morphology
Step 3
Special investigations
intestinal function
pancreatic function
intestinal inflammation
Prick/patch tests
 standard jejunal/colonic
histology
 morphometry
 PAS staining
 electron microscopy







intestinal immunohistochemistry
anti-enterocyte antibodies
serum chromogranin and
catecholamines
autoantibodies
75
SeHCAT measurement
brush border enzymatic
activities
motility and electrophysiological
studies
Fig. 1
Fig. 2 HIV
From Berni Canani R, Cirillo P, Mallardo G, et al . Effects of HIV-1 Tat protein on ion secretion
and on cell proliferation in Human intestinal epithelial cells. Gastroenterology 2003;124:368-376
Fig. 3
Fig. 4
Legends to figures
Fig. 1
Pathways of osmotic and secretory diarrhea.
Osmotic diarrhea is due to functional or structural damage of intestinal epithelium. Non-absorbed
osmotically active solutes drive water into the lumen. Stool osmolality and ion gap are generally
increased. Diarrhea stops in children when not eating.
In secretory diarrhea, ions are actively pumped into the intestine by the action of exogenous and
endogenous secretagogues. Usually there is no intestinal damage. Osmolality and ion gap are within
normal levels. Large volumes of stools are lost independent of food ingestion.
Fig. 2
HIV directly induces immune impairment, and intestinal dysfunction. Intestinal infections and
nutrient malabsorption contribute to malnutrition. The latter in turn contributes to immune
impairment and intestinal dysfunction. The vicious cycle is responsible for diarrhea and ultimately
results in wasting, the terminal stage of AIDS. HIV may also directly induce diarrhea through its
transactivating transfer factor Tat
Fig. 3
Fi. 3 Microvillus inclusion . From top to bottom: microvillus inclusion (a), a granule with
few microvilli (b), and a lysosome (c) detected in the same enterocyte. Inset: higher magnification
of b and c X11.000, inset X21.500 from M.Morroni et al Virchows Archiv. 2006; 448:805-810
Microvillus inclusion disease. PAS staining highlights abundant PAS-positive material (arrows) in
the apical part of the enterocyte cytoplasm
Microvillus inclusion disease. The villous enterocyte lack brush-border microvilli, whereas, their
apical cytoplasm contains a microvillus inclusion (MI) and numerous lysosomes (L) x 5.500
Fig. 4
A child with phenotypic diarrhea showing facial dysmorphism, hypertelorism and woolly hair
Etiology is unknown, but the presence of affected siblings suggests an autosomal recessive
transmission.
.
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