Transcript Malabsorption Syndromes

Malabsorption Syndromes
Department of pediatrics
Background
• Malabsorption syndromes encompass a
number of different clinical entities that result
in chronic diarrhea, abdominal distention, and
failure to thrive. Clinical malabsorption can be
broken down into several distinct conditions,
both congenital and acquired, that affect one
or more of the different steps in the intestinal
hydrolysis and subsequent transport of
nutrients.
Pathophysiology
• Carbohydrate, fat, or protein malabsorption is
caused by a disorder in the intestinal
processes of digestion, transport, or both of
these nutrients across the intestinal mucosa
into the systemic circulation. Either a
congenital abnormality in the digestive or
absorptive processes or, more commonly, a
secondarily acquired disorder of such
processes may result in malabsorption.
Carbohydrates
• Of the carbohydrates most commonly present in the diet (starches,
sucrose, lactose), only starches require preliminary luminal digestion by
salivary and, more importantly, pancreatic amylases. However, note that
the development of pancreatic amylase is slow and is not complete until
the second semester of life.
• The final products of amylase digestion include maltose, maltotriose, and
higher residues of glucose polymers. The final hydrolysis of disaccharides
and oligosaccharides occurs at the brush border of the enterocytes, where
sucrase-isomaltase breaks down maltose, isomaltose (to glucose), and
sucrose (to glucose and fructose); glucoamylase releases glucose from
glucose polymers; and lactase splits lactose into glucose and galactose.
Subsequent entry of the final monosaccharides (glucose, galactose,
fructose) into the enterocytes through the brush border occurs via carrier
molecules. Glucose and galactose share the same carrier, named SGLT-1,
which transports 1 molecule of the monosaccharide and 1 sodium (Na)
molecule in a secondarily active transport, energized by sodium- and
potassium-activated adenosine triphosphatase (NaK ATPase. On the other
hand, fructose uses a carrier that allows its entry only down a
concentration gradient (facilitated diffusion).
• Disorders of these processes can be congenital
(cystic fibrosis and Shwachman-Diamond
syndrome, which cause amylase deficiency;
the extremely rare congenital lactase
deficiency; glucose-galactose malabsorption;
sucrase-isomaltase deficiency; adult-type
hypolactasia) or acquired (the most common
being lactose intolerance, typically secondary
to a damage of the mucosa, such as a viral
enteritis or conditions that cause mucosal
atrophy, such as celiac disease).
Protein
• Proteins are first digested in the stomach, where
pepsinogens, which are activated to pepsins by a pH
of less than 4, hydrolyze them in large molecular
weight peptides. Upon entering the duodenum, the
pancreatic proteases (activated by trypsin, which has
a proenzyme trypsinogen that is activated by the
brush border–bound enterokinase) further split
them into low molecular weight peptides and free
amino acids.
• Interestingly, the final breakdown products of
intraluminal digestion of protein are composed of low
molecular weight peptides (2-6 amino acid residues) in
70% of cases and of only free amino acids in 30% of
cases. Subsequently, brush border–bound peptidases
further hydrolyze peptides to release a mixture of free
amino acids and small peptides (2-3 amino acid
residues). Finally, free amino acids are taken up by
enterocytes through specific Na-linked carrier systems
(5 carriers with selective affinities for groups of amino
acids are described), while the small peptides are
translocated into the absorptive epithelial cells by a
system with a broad specificity. Of interest, in the first
few months of life, the latter system is much more
active than those that transport amino acids and is
thought to play a bigger physiological role.
• Congenital disorders of protein digestion include
conditions such as cystic fibrosis, ShwachmanDiamond syndrome, and enterokinase deficiency,
which cause inadequate intraluminal digestion.
No congenital defects have been described in any
of the brush border–bound peptidases or in the
peptide carrier.
• Acquired disorders of protein digestion and/or
absorption are nonspecific (ie, they also affect
the absorption of carbohydrates and lipids) and
are found in conditions that result in damage to
the absorptive intestinal surface, such as
extensive viral enteritis, milk protein allergy
enteropathy, and celiac disease.
Lipids
• A lingual lipase is responsible for the first partial
hydrolysis of triglycerides; this enzyme becomes active
in persons with low gastric pH levels and is active even
in premature infants. However, the largest part of
triglyceride digestion is accomplished in the
duodenojejunal lumen because of a complex of
pancreatic enzymes, the most important of which is
the lipase-colipase complex. Like amylase, these
enzymes also develop slowly, and this accounts for the
known low capacity of babies to absorb lipids, termed
physiologic steatorrhea of the newborn. Additionally,
adequate concentrations of intraluminal conjugated
bile salts are needed to form micelles, and the
secretion of bile acids may also be partially inadequate
in very young patients.
• Disorders of these processes can be congenital
(cystic fibrosis and Shwachman-Diamond
syndrome, which cause lipase and colipase
deficiency; the uncommon isolated deficiency of
lipase and colipase; the extremely rare congenital
primary bile acid malabsorption, which results in
low bile acids concentrations) or acquired
(secondary mostly to disorders of the liver and
the biliary tract or to chronic pancreatitis).
Clearly, any condition that results in the loss of
small intestinal absorptive surface also causes
steatorrhea.
Frequency
• If celiac disease in its entirety (ie, including the forms without overt
malabsorption) is considered among the malabsorption syndromes,
this condition should be considered the most common inherited
malabsorption syndrome because the documented prevalence is
close to 1%.
• Cystic fibrosis is the second most common malabsorption
syndrome.
• Other congenital disorders are rare, with the exception of adulttype hypolactasia, which has a prevalence that varies greatly among
different ethnic groups.
• Among acquired conditions, cow's (and soy) milk protein allergic
enteropathy is very common. The prevalence of milk protein allergy,
of which enteropathy is one of the presenting clinical symptoms, is
estimated to be around 3%.
• A transient and common form of malabsorption in
infants results from acute-onset enteritis (mostly viral,
specifically rotaviral), which causes transient lactose
intolerance.
• Although toddler's (or unspecific) diarrhea accounts for
approximately 7.5% of referrals to pediatric
gastroenterologists, it should not be considered a
malabsorption syndrome because, by definition, no
digestive or absorptive processes are impaired.
• Secondary malabsorption syndromes that result from
liver, pancreas, and intestinal diseases are uncommon.
The manifestations vary according to the severity of
each disease and the extent of intestinal mucosal
injury.
Mortality/Morbidity
Although the morbidity can be severe, and
aside from the single entity of cystic fibrosis,
common malabsorption syndromes carry low
mortality rates.
• Neonates and young infants, especially those
with signs of malnutrition, are particularly at
risk.
• In many of the congenital syndromes,
morbidity varies with the particular syndrome
and may be associated with systemic
manifestations of the disease.
Race
• Congenital sucrase-isomaltase deficiency is
most common in Canadian Eskimos and
natives of Greenland.
• Trehalase (a sugar found almost exclusively in
mushrooms) deficiency is rare, except in
natives of Greenland.
• Adult-onset lactase deficiency is most
common in persons of Asian, African, and
Mediterranean descent.
Sex
• Celiac disease is slightly more common in
females.
• Autoimmune enteropathy is an X-linked
disorder that only affects males in familial
cases.
Age
• Neonates and young infants with malabsorption
syndromes are at particularly high risk for chronic
diarrhea and malnutrition.
• Symptoms of a congenital disease are usually apparent
shortly after birth (the exception being adult-onset
lactase deficiency, which appears only after age 6-8 y)
or after a short hiatus once a particular substance is
ingested in substantial amounts.
• Protein sensitivity syndromes to milk or soy protein
usually present in infants younger than 3 months, but
solid food protein sensitivity syndromes are also known
to occur in older patients.
CLINICAL
History
• Diet history: Obtain a complete history of the patient's diet,
including the amount and type of fluids, solid foods, and
formula ingested. Caregivers should keep a detailed journal
of the patient's diet and symptoms for a minimum of 1
week.
– The proper amount of fluid for most young children is around
100 mL/kg/d. Fluid intake that exceeds this amount may result
in looser stools, which causes a referral for a suspected but
nonexistent malabsorption.
– Fat is important for slowing the movement of food through the
intestine via hormonal mechanisms. Fat intake of less than 3
g/kg/d may contribute to toddler's diarrhea, especially in the
setting of excessive free fluid and carbohydrate intake (eg, as
occurs with large amounts of fruit juice intake). Thus, history is
important in differentiating the common toddler's diarrhea from
the rarer malabsorption syndromes.
– In the United States, juice is commonly introduced
into the diet in the latter portion of the first year of
life. Purple grape juice has a high osmolarity, which
can cause osmotic diarrhea. The transport of fructose
into enterocytes is not active and relatively inefficient.
Apple and pear juice contain a high fructose-toglucose ratio, and consumption of these juices can
result in fructose malabsorption and diarrhea. Since
sorbitol and fructose compete for the same intestinal
transporter, ingesting them together may result in the
malabsorption of these sugars.
• Gastrointestinal tract symptoms: Gastrointestinal
tract symptoms are common in patients with
malabsorption syndromes, and symptoms range
from mild abdominal gaseous distention to
severe abdominal pain and vomiting. Chronic or
recurrent diarrhea is by far the most common
symptom.
– Abdominal distention and watery diarrhea, with or
without mild abdominal pain, associated with skin
irritation in the perianal area due to acidic stools are
characteristic of carbohydrate malabsorption
syndromes.
– Periodic nausea, abdominal distention and pain, and
diarrhea are common in patients with chronic Giardia
infections.
– Vomiting, with moderate-to-severe abdominal pain and bloody
stools, is characteristic of protein sensitivity syndromes or other
causes of intestinal injury (eg, inflammatory bowel disease).
– Recurrent abdominal pain has been implicated as a symptom of
dietary disorders, although psychological variables that relate to
an elevated anxiety level have clouded the certainty of this
relationship. Malabsorption syndromes can definitely cause
abdominal pain or irritability (particularly seen in celiac disease).
– Failure to identify the cause of malabsorption can result in the
misdiagnosis of a physiologic syndrome as a behavioral disorder.
Some dietary items may cause symptoms only when they are
taken alone or with other specific dietary items.
– Poor appetite is common in food sensitivity syndromes. The
child becomes conditioned to refuse foods that cause
inflammatory reactions of the intestine. However, this is not
typically obvious in celiac disease. Malabsorption syndromes
not associated with inflammatory reactions typically cause an
increase in appetite (eg, cystic fibrosis) unless the associated
abdominal gaseous distention hampers intake and induces early
satiety.
Stool characteristics
– Patients with Toddler's diarrhea often have loose
stools with undigested food particles. This should not
be taken to imply the presence of true malabsorption.
– Frequent loose watery stools may indicate
carbohydrate intolerance.
– Pasty or loose foul-smelling stools indicate fat
malabsorption, also termed steatorrhea. This
symptom is commonly seen in Giardia infections,
enterokinase deficiency, hepatic and pancreatic
dysfunction, and protein sensitivity syndromes.
– Bloody stools are seen in patients with protein
sensitivity syndromes and not in disaccharidase and
pancreatic enzyme deficiencies or in patients with
giardiasis.
Other symptoms
– Systemic symptoms, including weakness, fatigue,
and failure to thrive, are systemic consequences of
chronically poor nutrient absorption.
Malabsorption of carbohydrates, fats, or proteins
can cause failure to thrive, while folate and B-12
malabsorption result in macrocytic anemia.
– Patients with abetalipoproteinemia develop
retinitis pigmentosa and ataxia because of chronic
fat-soluble vitamin malabsorption and deficiency
(vitamins A and E).
Physical
• In the absence of gastrointestinal tract symptoms, malabsorption
syndromes should be considered during the workup for failure to thrive,
malnutrition, poor weight gain, or delayed puberty. Signs of malnutrition
discovered during physical examination, such as reduced muscle and fat
mass, atrophic tongue changes, or enlarged liver or spleen, have been
reported in children with chronic malabsorption. Malabsorption
syndromes should be suspected in infants with weight loss or little weight
gain since birth and in infants with low weight and weight-for-height
percentiles. By definition, toddler's diarrhea does not cause failure to
thrive, unless anxious parents intervene by imposing unnecessary dietary
restrictions that result in lower caloric intake.
• Dehydration caused by a diarrhea that is induced by a malabsorption
syndrome is not common, but, when it occurs, dehydration can cause
serious morbidity and mortality. Assess each patient for signs, symptoms,
and severity of dehydration. Lethargy, depressed consciousness, sunken
anterior fontanel, dry mucous membranes, sunken eyes, poor skin turgor,
and delayed capillary refill are all signs of dehydration.
A significant increase in peristaltic activity can be detected audibly and
with tactile palpation. This is associated with decreased intestinal
transient time.
• Large numbers of stools result in a constant
wet diaper in young children. Failure to
properly dry the buttocks and perianal area
results in erythema, skin irritation, and skin
breakdown, with evidence of bleeding seen in
the diaper or in stool.
• Protein sensitivity may be associated with an
eczematous rash.
Causes
• Carbohydrate malabsorption: Starch molecules
are primarily digested by salivary and pancreatic
amylase, but glucoamylase in the intestinal brush
boarder also assists in digestion.
– Pancreatic insufficiency impedes the digestion of large
starch molecules.
– Absence or reduction of the brush border
disaccharidases causes selective carbohydrate
malabsorption.
– Transient reduction of these enzymes is common after
an infection in the intestine, particularly a viral
infection, because intestinal villi and microvilli may be
damaged.
Causes
– Glucoamylase and maltase are most resistant to the depleting
effects of mucosal injury that result from infection, while lactase
is the most sensitive because of its predominant distribution
near the tips of the villi.
– Lack of sucrase and isomaltase is, by far, the most frequent
congenital enzyme deficiency. This enzyme deficiency is
inherited in an autosomal recessive manner.
– Congenital lactase deficiency is exceedingly rare, but adult-type
lactase deficiency is very common in some ethnic groups.
– Glucose and galactose are actively transported from the
intestinal lumen into the cytoplasm of the enterocyte, while
fructose (carrier mediated) and mannose are passively
transported.
– A congenital deficiency in the glucose galactose transporter
(SGLT-1) is inherited in an autosomal recessive manner.
– Take care when diagnosing lactose or another complex
carbohydrate intolerance because many complex carbohydrates
are broken down into glucose.
Causes
– Both bacterial overgrowth of normal flora and growth of abnormal flora alter
the intraluminal metabolism of carbohydrates. Bacteria ferment carbohydrates
into smaller osmotically active molecules and organic acids. Increased
osmolarity causes fluid from systemic circulation to enter the intestinal lumen,
resulting in diarrhea. Organic acids stimulate motility and may directly injure
the intestinal mucosa. Fermentation eliminates the reducing substances and
lowers the pH of the stool. The production of lactate and short-chain fatty
acids in the human colon can result in systemic acidosis. In particular, a
syndrome of D-lactic acidosis may develop when specific bacteria that are
capable of producing this uncommon and poorly cleared D isomer of lactate
exist in the intestinal flora.
– Bile acids are usually recycled by enterohepatic circulation. Many factors can
prevent this recirculation. Bacterial overgrowth of normal flora and growth of
abnormal flora are the most common causes of altered intraluminal
metabolism of bile acids. Anaerobes and Staphylococcus aureus deconjugate
bile acids, which impedes their active reabsorption by the terminal ileum into
the portal circulation for reuptake by the liver. A congenital deficiency in the
sodium–bile acid cotransporter results in primary bile acid malabsorption. The
resulting diminished transport of bile acids from the intestinal lumen allows
intestinal flora to deconjugate bile acids.
– Deconjugated bile acids directly inhibit the carbohydrate transporters, reduce
intraluminal pH levels, and damage the enterocyte. They may also directly
stimulate the colon to secrete fluid, contributing to diarrhea.
Fat malabsorption
– Increased delivery of fat to the colon results in diarrhea and
soft, pasty, foul-smelling stools. However, the gas causes stools
to float. Consequences include the malabsorption of fat-soluble
vitamins A, D, E, and K and insufficient energy intake due to the
high energy value of dietary lipids.
– Digestion of fat begins in the stomach with gastric lipase;
however, the major source of lipase is the pancreas.
– Exocrine pancreatic insufficiency is the principal condition that
results in severe fat malabsorption. Pancreatitis, pancreatic
cancer, pancreatic resection, cystic fibrosis, ShwachmanDiamond syndrome, Johnson-Blizzard syndrome, and Pearson
syndrome can all result in pancreatic insufficiency. Significant
obstructive biliary or cholestatic liver disease or extensive
intestinal mucosal disease, such as occurs in celiac disease, may
also result in severe steatorrhea.
– Impaired bile production or secretion is seen in liver
or biliary tract disease. Inflammation or resection of
the ileum impedes enterohepatic circulation, which
results in a reduced bile acid pool. Bacterial
overgrowth in the small bowel deconjugates bile
acids, thereby inactivating their ability to help lipids
form a micelle. These syndromes result in moderate
lipid malabsorption.
– Abetalipoproteinemia is a rare disorder with
autosomal recessive inheritance. Absence of the
lipoproteins results in cytoplasmic lipid accumulation
in the enterocyte. Lymphatic transport of long-chain
fats is impaired in patients with abetalipoproteinemia,
lymphangiectasia, and protein-losing enteropathy,
resulting in moderate fat malabsorption.
Protein malabsorption
– Protein malabsorption is a fairly common result of
exocrine pancreatic enzyme deficiency, as occurs in
patients with cystic fibrosis.
– Protein malabsorption that results from congenital
enterokinase deficiency is well described but rare.
– Creatorrhea, loss of protein in the stool (ie, proteinlosing enteropathy), is often caused by the leakage of
protein from the serum due to inflammation of the
mucosa, as in Crohn disease, celiac disease, and
protein sensitivity syndromes. Congenital
lymphangiectasia, a developmental disorder in which
dilation and dysfunction of intestinal lymphatics
occurs, often in association with limb edema (Milroy
disease), may present with severe protein-losing
enteropathy without mucosal injury.
Vitamin malabsorption
– Malabsorption of vitamin B-12 and folate is
associated with tropical spruce, a disorder that is
acquired after travel to tropical areas.
– Vitamin B-12 is absorbed in the ileum, and
absorption requires an intrinsic factor made in the
gastric parietal cell. Intrinsic factor deficiency that
results from atrophic gastritis or absence (from
resection) or disease of the terminal ileum (the
predominant site of active B-12) results in vitamin
B-12 malabsorption.
DIFFERENTIALS
• Congenital Microvillus Atrophy
Constitutional Growth Delay
Crohn Disease
Cystic Fibrosis
Diarrhea
Failure to Thrive
Gastroenteritis
Giardiasis
Growth Failure
Irritable Bowel Syndrome
Lactose Intolerance
Other Problems to be Considered
Enterokinase deficiency
Hypobetalipoproteinemia
Pancreatic enzyme deficiencies
Pancreatic insufficiency
• Stool analysis
WORKUP
Lab Studies
– The presence of reducing substances indicates that carbohydrates
have not been properly absorbed. One common mistake, especially
with the use of superabsorbent diapers, is to test the solid portion of
the stool instead of the liquid portion. Furthermore, in stools that are
not fresh, bacterial hydrolysis, removal of the reducing substances,
and artifactual reduction of pH occur.
– Acidic stool has a pH level of less than 5.5. This indicates carbohydrate
malabsorption, even in the absence of reducing substances.
– Normally, stool bile acids should not be detected. If bile acid
malabsorption is suspected, quantitative conjugated and
unconjugated bile acids may be measured in stool, although this test is
not routinely available and is not used in routine clinical practice.
– The level of quantitative stool fat and the amount of fat intake should
be measured and monitored for 3 days. Normal fat absorption
depends on age (lower in the neonate) and improves throughout the
first year of life to the reference range levels of 95% or higher.
Moderate fat malabsorption ranges from 60-80%. Fat absorption of
less than 50% indicates severe malabsorption.
– The presence of large serum proteins in the stool,
such as a1-antitrypsin, indicates leakage of serum
protein and serves as a screening test for proteinlosing enteropathy.
– Examination of the stool for ova and parasites or
testing for the stool antigen may reveal the presence
of Giardia species, a known cause of acquired
malabsorption syndromes in children who are usually
older than 2 years.
– Testing for other chronic intestinal infections that
cause malabsorption, such as Clostridium difficile
(assays for toxins A and B) or Cryptosporidium species
(modified acid-fast examination of stool), may be
performed.
Urinalysis
– Urine examination may reveal an unusually high
concentration of the malabsorbed substance,
since, in many cases, the kidney and the gut use
the same transporter.
– In glucose-galactose malabsorption, the urinary
glucose level is typically elevated when the serum
glucose level is within reference range because of
congenital malfunction of SGLT-1.
– Levels of urinary 4-hydroxyphenylacetic acid have
been demonstrated to be elevated in the urine of
children with bacterial overgrowth syndrome.
Other laboratory studies
– A CBC count may reveal megaloblastic anemia in patients with
folate and vitamin B-12 malabsorption or neutropenia in
patients with Shwachman-Diamond syndrome (associated with
pancreatic insufficiency). In patients with abetalipoproteinemia,
blood smears may reveal acanthocytosis.
– Total serum protein and albumin levels may be lower than
reference range in syndromes in which protein is lost or is not
absorbed, particularly in protein-losing enteropathy and
pancreatic insufficiency or enterokinase deficiency, respectively.
– With fat malabsorption or ileal resection, fat-soluble vitamin
levels in the serum are lower than reference range.
– With bile acid malabsorption, levels of the low-density
lipoprotein (LDL) cholesterol may be lower than reference
range.
– With inflammatory bowel diseases, the erythrocyte
sedimentation rate, C-reactive protein level, or both
are commonly elevated.
– In patients with liver or biliary disease, the results of
liver function tests may be higher than reference
range levels. These tests include assays for alanine
aminotransferase (ALT), aspartate aminotransferase
(AST) (in hepatitis), g-glutamyltransferase (GGT),
alkaline phosphatase, and bilirubin (in cholestatic liver
disease).
– Immunoglobulin G (IgG) and immunoglobulin A (IgA)
antigliadin and IgA antiendomysial antibodies, or
especially tissue transglutaminase antibodies, are
useful in the diagnosis of gluten-sensitive enteropathy.
– Enterocyte, smooth muscle, thyroid, and islet cell
serum antibodies are revealed in patients with
autoimmune enteropathy.
Imaging Studies
• Although upper gastrointestinal radiography
with small bowel follow-through
demonstrates a pattern of thickened folds and
increased fluid content in the jejunal loops in
celiac disease and conditions characterized by
protein-losing enteropathies, this test is no
longer used because it is unspecific and not
sensitive enough, especially when compared
with other diagnostic tests.
Procedures
• Substance tolerance test
– Attempt to isolate the substance that is causing the
malabsorption. Resolution of diarrhea after the suspected
substance is removed from the diet and resumption of the
diarrhea when the substance is reintroduced are specific signs
that the particular substance is not adequately absorbed.
– If diarrhea does not resolve when the particular substance is
removed from the diet, this does not necessarily indicate
intolerance to the substance.
– Malabsorption of certain nutrients can result in secondary
intestinal damage and secondary malabsorption, which may no
longer be related to the malabsorbed substance. Thus, this
technique has low sensitivity until mucosal injury has had a
chance to heal.
– Challenging the patient with the suspected malabsorbed
substance once the diarrhea has resolved provides a more
sensitive test.
• Carbohydrate malabsorption tolerance test
– Carbohydrate malabsorption results in bacterial fermentation.
This biochemical process releases hydrogen gas that is absorbed
into the blood and excreted by the lungs.
– Under normal conditions, fermenting bacteria reside in the large
intestine. When the bacteria in the large intestine ferment the
carbohydrate load, an increase in the level of exhaled hydrogen
is detected.
– The amount of carbohydrate administered is typically 2 g/kg,
with a maximum dose of 50 g. When testing for lactose
tolerance, using a more physiologic amount (eg, 12.5-25 g) may
be preferable.
– An increase in the exhaled hydrogen concentration following
ingestion of an oral carbohydrate load (>20 ppm) indicates
carbohydrate malabsorption. Bacterial overgrowth in the small
intestine results in an additional early rise in the exhaled
hydrogen concentration.
– Antibiotic administration within the 2 weeks prior to the test
may cause false-negative results in this test.
• D-xylose absorption test
– Another time-honored test for carbohydrate
malabsorption is the D-xylose absorption test. Xylose
is a pentose that is passively absorbed by the jejunal
mucosa.
– A standard dose of 5 g or, alternatively, 14.5 g/m2
(maximum dose of 25 g) of D-xylose is orally
administered as a 10% solution in water. The test
result is positive in the following instances:
• Children who weigh less than 30 kg - Serum level at 1 hour
after ingestion is less than 25 mg/dL.
• Children who weigh more than 30 kg - The 5-hour urinary
excretion is less than 15%.
• A positive test result suggests malabsorption due to
proximal small bowel mucosal lesion (enteropathy).
• Beware of false-positive results (eg, from delayed gastric
emptying, small bowel bacterial overgrowth, accelerated
transit time).
• Mucosal biopsy
– This test is fundamental in obtaining a definitive diagnosis
in many circumstances, such as common celiac disease.
Almost all pediatric gastroenterology centers obtain
biopsies of the duodenal mucosa during an upper
endoscopy.
– Moderate villous atrophy may be seen in protein-sensitive
enteropathies, Giardia infection, or bile acid
malabsorption.
– Histologic examination of the biopsy tissue may reveal the
mucosal inclusions seen in abetalipoproteinemia,
eosinophilic gastroenteritis, Wolman disease, or congenital
microvillous atrophy, for which electron microscopy is
needed.
– Functional assays of the biopsy tissue assess carbohydrate
disaccharidase enzymes.
Histologic Findings
• Biopsy of the small intestine remains the
criterion standard for the diagnosis of celiac
disease. The classic features include villous
atrophy, infiltration of the epithelium by
cytotoxic intraepithelial T lymphocytes, and
crypt hyperplasia. However, the spectrum can
range from intraepithelial lymphocytosis and
crypt hyperplasia without villous atrophy to
severe villous atrophy with crypt hypoplasia.
TREATMENT
Medical Care
• Because the intestine heals slowly, chronic diarrhea may require a
long course of treatment. Treating diarrhea with oral gentamicin or
another suitable broad-spectrum antibiotic, particularly one with
anaerobic coverage (eg, metronidazole), diminishes bacterial
overgrowth. In children with chronic diarrhea secondary to bile acid
malabsorption, the use of cholestyramine (Questran) to bind bile
acids may help to reduce the duration and severity of the diarrhea.
• Any loss of pancreatic enzymes can be replaced with oral
supplements.
• Immunosuppressive medications can be used to control
autoimmune enteropathy and should be prescribed only by a
specialist.
• Eliminate allergenic or malabsorbed substances. In patients with
celiac disease, strict adherence to a diet completely devoid of
wheat, barley, and rye is necessary
Surgical Care
• Most children with short gut syndrome are
eventually weaned off parenteral nutrition
and do not require surgery. However, in some
children, disease is refractory to enteral
feeding, and other children develop end-stage
liver disease from the prolonged
supplementation of parenteral nutrition.
Consider liver, gut, or multivisceral
transplantation in these children.
Consultations
• In children in whom a malabsorption
syndrome is suspected to cause growth failure
or is associated with high morbidity, prompt
referral to a pediatric gastroenterologist is
recommended.
Diet
• Carbohydrate intolerance
– Initiate treatment in patients with severe acquired
carbohydrate intolerance by eliminating all dietary
carbohydrates until the diarrhea is resolved. Then,
slowly reintroduce carbohydrates.
– In infants, use a glucose polymer (Polycose)–based
formula (eg, Pregestimil). In patients with the most
severe carbohydrate intolerance, use MJ3232A, a
casein-based formula that contains essential amino
acids and medium-chain triglyceride (MCT) oil and no
carbohydrates. If MJ3232A is used, parenteral
dextrose must be supplied.
– Once the diarrhea has resolved, slowly reintroduce
fructose into the diet as the only enteral carbohydrate
source.
– Begin with 14 g fructose/L formula, and gradually
advance in 14-g increments to a maximum of 56 g
fructose/L formula. Once this goal is reached, slowly
replace fructose with Polycose until 56 g Polycose/L
formula is tolerated. Once 56 g Polycose/L formula is
tolerated, begin introducing Pregestimil, a lactose-free
formula.
– For older children, eliminate simple carbohydrates
and lactose from the diet until the diarrhea is
resolved. Simple sugars, including fruit juices, should
be avoided for several weeks.
– If after several weeks of a relatively carbohydrate-free
diet symptoms return when carbohydrates are
reintroduced, the child most likely has a congenital
defect in carbohydrate transport or digestion.
• Fat intolerance
– MCT oil is used to treat patients with poor weight gain that
results from fat malabsorption. MCT oil does not require
traditional fat metabolism and, thus, is more easily
absorbed directly into the enterocyte and is transported
through the portal vein to the liver.
– Fat-soluble vitamin supplements are required for patients
with fat malabsorption or short gut syndrome.
– Supplements in patients with fat malabsorption should
also include linoleic and linolenic fatty acids.
– Patients with short gut syndrome may not be able to
effectively absorb formula until mucosal hyperplasia has
increased the mucosal absorption area. During this period
of adaptation, appropriate parenteral nutrition may be
needed to maintain optimal nutritional status.
• Alternative formulas
– Currently, soy formulas are not considered
effective for the prevention or treatment of
nutritional allergies. Instead, use hydrolyzed
protein formulas.
– High-degree protein hydrolysate formulas are
used to treat infants with a cow's milk allergy, but
these formulas may contain residual epitopes
capable of provoking a severe allergic reaction. In
these infants, use formulas with crystalline amino
acids (eg, Neocate, EleCare, EO28) as the protein
source.
MEDICATION
Drug Category: Antibiotics
• These agents are used to treat bacterial
overgrowth. Empiric antimicrobial therapy
must be comprehensive and should cover all
likely pathogens in the context of the clinical
setting.
• Drug Name
Gentamicin (Garamycin)
• Description
Aminoglycoside antibiotic for gram-negative coverage. Used in
combination both with an agent against gram-positive organisms
and with an agent that covers anaerobes. Poor oral absorption
allows gentamicin to target normal and abnormal gut flora while
maintaining high intraintestinal bioavailability.
• Pediatric Dose
50 mg/kg/d PO divided qid for 5 d
• Contraindications
Documented hypersensitivity
• Interactions
Unknown with oral administration
• Pregnancy
C - Safety for use during pregnancy has not been established.
• Precautions
Unless renal failure exists, serum level monitoring is not required
because only small amount of gentamicin is orally absorbed
Drug Category: Bile acid&;binding agents
• These agents are used in combination with
antibiotics for bile acid malabsorption
syndromes. Bacteria overgrowth may cause
diarrhea by deconjugation and
dehydroxylation of bile acids. Primary bile acid
malabsorption may also occur.
•
•
•
•
•
•
•
Drug Name
Cholestyramine (Questran)
Description
Binds bile acids, thus reducing damage to the intestinal mucosa. Also reduces induction of
colonic fluid secretion. Forms a nonabsorbable complex with bile acids in the intestine, which
in turn inhibits enterohepatic reuptake of intestinal bile salts.
Pediatric Dose
2-4 g/d PO divided bid/qid for 8-10 d
Contraindications
Documented hypersensitivity; biliary obstruction; neonates with history of structural
intestinal abnormalities, abdominal surgery, or necrotizing enterocolitis
Interactions
Inhibits absorption of numerous drugs including warfarin, thyroid hormone, amiodarone,
NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, phenobarbital, imipramine,
niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, penicillin G, and fat-soluble
vitamins
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Caution if constipation exists; avoid aspartame-containing cholestyramine with
phenylketonuria; cholestyramine products containing added carbohydrates (ie, fructose,
sorbitol) for flavoring (eg, LoCholest) may exacerbate diarrhea and should be avoided
Drug Category: Digestive enzymes
• Pancreatic enzyme deficiency may occur
because of steatorrhea secondary to
malabsorption.
• Drug Name
Pancrelipase (Cotazym, Zymase, Ultrase, Pancrease, Creon)
• Description
Assists in digestion of protein, starch, and fat. Contains lipase, protease,
and amylase.
• Pediatric Dose
Adjust dose according to severity of pancreatic enzyme deficiency and fat
content of stools 500-1500 U/kg (based on lipase content) enteric-coated
tab per meal; not to exceed 2500 IU/kg/dose, because colitis with
strictures (fibrosing colonopathy) may occur at higher doses
• Contraindications
Documented hypersensitivity; history of pork protein allergy
• Interactions
Drugs that increase gastric pH (eg, H2 antagonists) may increase effects of
pancreatic enzymes by inhibiting destruction of ingested pancreatic
enzymes
• Pregnancy
C - Safety for use during pregnancy has not been established.
• Precautions
High doses may be associated with fibrosing colonopathy, which has been
evident in patients with cystic fibrosis who developed ascending colon
strictures; high degree of variability between enzyme products (do not
interchange once stabilized)
FOLLOW-UP
Further Inpatient Care
• If the patient shows any symptoms of
dehydration or malnutrition, admit the patient
to a medical care facility and immediately
initiate treatment with parenteral fluid and
nutrition supplements.
• Treatment for severe acquired carbohydrate
malabsorption requires admission to a
medical care facility for enteral nutrition with
a low-carbohydrate formula and
administration of parenteral dextrose.
Further Outpatient Care
• Strict follow-up monitoring with the primary
care pediatrician is necessary to reevaluate
diet therapy efficacy and compliance.
Prognosis
•
•
•
Mucosal atrophy caused by infectious gastroenteritis, food-sensitivity
enteropathies, or malnutrition can result in an 80% reduction of intestinal surface
area. Once the causative agent is removed, the repair of the small bowel is usually
rapid (4-6 days). In some patients, repair may be slow, and after 2 months, the villi
surface area is 63% normal and the microvillous surface area is only 38% normal.
Some malabsorption syndromes are transient, while others simply require a
change in diet. Most disorders that cause secondary malabsorption are progressive
and, because of systemic complications, result in a limited lifespan in patients. For
example, patients with abetalipoproteinemia can die in early adulthood because of
cardiac abnormalities, while patients with severe autoimmune enteropathies or
microvillus inclusion disease have a very poor prognosis without intestinal
transplantation.
Outcome in patients with short gut syndrome is variable. The long-term prognosis
depends primarily on the amount of time parenteral nutrition is required. The
complications of parenteral nutrition and the lack of trophic stimulation of
intestinal mucosal growth impede recovery. Delayed intestinal autonomy depends
on the characteristics of the residual intestine length, presence of the ileocecal
valve and colon, and motor function. Bacterial overgrowth compromises intestinal
adaptation and increases the risk of liver disorders