++
There are a number of enteropathies associated with varying degrees
of malabsorption of nutrients. In some there is histologic evidence
of structural derangement characterized by decreased villus height
with consequent loss of intestinal absorptive surface area. In others
the mucosal architecture appears intact, and malabsorption results
from a functional defect of the enterocyte (Table
408-5). Enteropathies associated with malabsorption
can be congenital or acquired. Congenital enteropathies usually
present early in infancy, and the underlying defect is generally
not reversible. Acquired enteropathies can present at any age and
are potentially reversible, depending on the underlying cause.
+++
Congenital Enteropathies
+++
Microvillus
Inclusion Disease
++
Congenital microvillus inclusion disease has also been referred
to as congenital microvillus atrophy and familial microvillus atrophy.41 It
is believed to be inherited in an autosomal-recessive manner based
on occurrence among siblings and clustering among infants of Navajo
descent.42 The entity is characterized by watery
diarrhea, with onset within the first days after birth, although
about 20% present later over the first 2 months of life.
Stool and electrolyte losses are of such magnitude that rapid dehydration
and death will ensue unless appropriate treatment with intravenous
fluid is initiated. Massive fecal losses (50 to 800 mL/kg/day)
continue even when the infant is maintained on parenteral nutrition
and given nothing by mouth. The diarrhea is secretory, with increased
electrolyte concentrations without an anion gap. Most tests of intestinal
absorption function, such as fecal fat analysis and d-xylose uptake,
are abnormal, and stool electrolyte content is consistently high
in keeping with a secretory-type diarrhea. Nutrition cannot be maintained
via the enteral route, and parenteral nutrition is required. Without
continued intravenous nutrition and fluid-replacement therapy or
intestinal transplantation, the condition is almost always fatal.
++
Histologically, the small intestine demonstrates diffuse villus
atrophy, but without crypt hypertrophy or an inflammatory cell infiltrate.
The surface enterocytes are disorganized, with loss of brush border definition,
and there is extensive apical cytoplasmic vacuolization (eFig. 408.2). Periodic acid
Schiff staining may confirm the absence of apical brush border and
demonstrates positive staining within the apical cytoplasm of the
enterocytes.32 Electron microscopy reveals mucosal
surface enterocytes that lack microvilli completely or that have
sparse, shortened villi. The apical cytoplasm of the enterocyte
contains a marked increase in electron-dense secretory granules
of various sizes, some of which contain glycocalyx and brush border–related
material (Fig. 408-5). The hallmark of the
disease is the presence of microvilli within involutions of the
apical membrane. The crypt epithelium is usually well preserved,
as are other epithelial cells, such as goblet cells, Paneth cells,
and enteroendocrine cells. Microvillus inclusions can also be demonstrated
in colonocytes, gastric epithelial cells, renal tubules, and gallbladder.
Another characteristic feature on electron microscopy is the presence
of secretory granules within the apical cells of the surface epithelium.
These secretory granules account for the periodic acid Schiff–positive
staining of the enterocytes.
++
++
++
The differential diagnosis includes other causes of congenital
diarrhea, such as congenital chloride-losing diarrhea, congenital
sodium-losing diarrhea, primary bile acid malabsorption, and congenital short
gut. Treatment has been largely unsuccessful. Many dietary manipulations
and medications have been tried without benefit. Therapeutic agents
that have been tried include corticosteroids, antibiotics, disodium
cromoglycate, prostaglandin synthase inhibitors, and cholestyramine.
The long-acting somatostatin analog octreotide may decrease the
stool output but does not alter the course of the disease. In nearly
all cases, life can be sustained only by parenteral nutrition unless
the infant can undergo intestinal transplantation.
++
Tufting enteropathy is also known as intestinal epithelial
dysplasia. In some cases the infants may have characteristic
dysmorphic facial features.43 The condition is
characterized by chronic diarrhea beginning shortly after birth
and is associated with poor growth. In some cases nutrition cannot
be maintained via the enteral route alone, and additional parenteral
nutrition is required for normal growth.
++
Histology of the small intestine reveals varying degrees of villus
atrophy with crypt hyperplasia and a minimal increase in inflammatory
cells in the lamina propria (Fig. 408-6). The
characteristic feature is the presence of foci of closely packed
enterocytes with rounding of the apical membrane resembling “tufts” that
appear to be coming away from the epithelium. Unlike microvillus inclusion
disease, periodic acid Schiff staining in tufting enteropathy demonstrates
the presence of linear staining along the apical surface membrane
without positive staining in the enterocyte cytoplasm. Because of
the patchy nature of these findings, several intestinal biopsies
may be needed in order to make the diagnosis. Biopsies may appear
near normal early in life, showing only nonspecific signs of villous atrophy,
with characteristic tufts on later biopsy. The disorder appears
to be due to an abnormality of the basement membrane or cell-matrix
interactions. Mice in which the gene encoding the transcription factor
Elf3 is disrupted have morphologic features resembling tufting enteropathy.44
++
++
Based on occurrence in siblings and parental consanguinity, the
condition is believed to be inherited in an autosomal recessive
manner and is more common in those of Arab descent.45 The
long-term prognosis is variable. A small number of affected individuals
receive adequate nutrition via the enteral route, but most cases
require parenteral nutrition. There is a report of a successful pregnancy
in a woman with tufting enteropathy.46 In those
cases requiring long-term supplemental parenteral nutrition, the
only other therapeutic option is intestinal transplantation.
++
IPEX is characterized by immune dysregulation, polyendocrinopathy,
enteropathy, and X-linkage. It is caused by mutations in the Foxp3 gene
(also see Chapter 188) carried in the pericentric
region of the X chromosome, Xp11.23-Xp13.3.47 This gene
is involved in the control of normal regulatory T-cell development.
Mutations in the gene result in the inappropriate activation and
dissemination of activated immune cells to multiple organ systems,
including the intestinal tract (see also Chapter 188).
++
Male infants with IPEX present in infancy with chronic high-volume
diarrhea together with type-1 diabetes, autoimmune hemolytic anemia,
autoimmune thyroiditis, and a variety of skin manifestations including
eczema and psoriasis. There may be associated food allergies, peripheral
blood eosinophilia, and elevated levels of serum IgE. An exaggerated
response to viral infections is described in some cases. The condition
is associated with a high mortality.48 Supportive
therapy with parenteral nutrition and insulin, together with prolonged
immunosuppressive therapy, has been attempted with little success.
There is one report suggesting allogeneic bone marrow transplant
may offer the possibility of a cure.49
++
Histologic features in the small intestine are similar to those
seen in other immune enteropathies and include villus atrophy and
a prominent infiltration of activated T cells in the lamina propria.
The diagnosis should be suspected in any infant with chronic diarrhea
associated with autoimmune hemolytic anemia, type 1 diabetes, autoimmune
thyroiditis, or eczematous type skin manifestations. Confirmation
of IPEX requires identification of the mutation in the Foxp3 gene.
+++
Intestinal Lymphangiectasia
++
Intestinal lymphangiectasia is characterized by ectasia of the
enteric lymphatics. Congenital malformation of the lymphatic system
results in a congenital or primary form of the disorder, whereas
the acquired or secondary form is due to diseases causing obstruction
of intestinal lymphatic drainage. Most cases of the primary abnormality
are sporadic, but there are reports of occurrence in multiple siblings
from several families, suggesting in certain cases there may be
a genetic cause. Primary intestinal lymphangiectasia is often associated
with lymphatic abnormalities elsewhere in the body. These include
hypoplasia or aplasia of the peripheral lymphatic system with lymphedema,
chylous ascites, and chylothorax, or the lymphangiectasia may be
part of a syndrome such as Noonan, Klippel-Trenaunay-Weber, and
Turner. Secondary diseases causing secondary obstruction to lymph
flow include constrictive pericarditis, congestive heart failure,
retroperitoneal fibrosis, retroperitoneal neoplasms, portal hypertension,
and mesenteric tuberculosis.
++
In both the primary and secondary types of lymphangiectasia there
is usually diffuse involvement of the intestine characterized by ectatic
lymphatics located in the mucosa, submucosa or subserosa. Occasionally
the disorder is localized to one or more areas of the small bowel.
With the exception of long-chain fatty acids and fat-soluble vitamins,
small intestinal absorptive function is usually intact. However,
rupture of dilated mucosal lymphatics into the intestinal lumen
leads to loss of protein-rich lymph containing albumin, globulins, and
lymphocytes. The ensuing protein-losing enteropathy and lymphocyte
loss leads to hypoproteinemia and an absolute lymphopenia in the
peripheral blood.
++
In the primary form mean age of onset of symptoms is 11 years.
The initial presentation is often with peripheral edema and hypoproteinemia
without proteinuria or hepatic dysfunction. Gastrointestinal symptoms
vary from none or mild to severe. Symptoms include diarrhea, nausea,
vomiting, abdominal pain, and in some cases steatorrhea. Chylous
ascites and chylous pleural effusions can occur in those with longstanding
lymphangiectasia. Onset of symptoms in the first decade of life
is often associated with growth failure.
++
The diagnosis of intestinal lymphangiectasia is based on the
clinical presentation and laboratory and pathological findings.
The presence of a protein-losing enteropathy can be confirmed by demonstrating
elevated levels of fecal α1-antitrypsin. Protein-losing
enteropathy associated with peripheral blood lymphocytopenia should
suggest the possibility of intestinal lymphangiectasia. The diagnosis
is confirmed on intestinal biopsy, which demonstrates dilated lymphatic
vessels in the mucosa or submucosa of the small intestine. There
is no inflammatory cell infiltrate. The villi show no signs of atrophy
but are distorted, often appearing swollen and broad.
++
Treatment is dependent on the cause. In the small number of cases
where the abnormality is localized to a section of the intestine,
resection of this area is curative. When the lymphangiectasia is
secondary to conditions such as constrictive pericarditis, treatment
of the underlying disease will lead to resolution of the intestinal
losses. In the diffuse primary form of lymphangiectasia, treatment
requires limiting the amount of dietary long-chain fat to 5 to 10
g per day and providing a diet that is high in protein and medium-chain
triglycerides.50 The medium-chain triglycerides
are absorbed directly into the portal system, thereby minimizing
distension of the lymphatics. Additional supplementation with calcium
and water-soluble forms of fat-soluble vitamins may be required.
+++
Acquired Enteropathies
++
This malabsorption syndrome is seen in visitors or residents
of endemic tropical regions of the world. These areas include India,
parts of Asia, the Philippines, the northern part of South America,
Central America, some Caribbean countries, and central and southern
Africa. The condition occurs in children, but is more common in
adults. It is most probably infectious in origin, but no specific
pathogen has been identified.51 Damage to the intestinal
mucosa progresses from the jejunum to the ileum. On small intestinal
histology, there is flattening of the villi, crypt elongation, and
chronic inflammatory cell infiltration of the lamina propria. These
changes are similar to those found in celiac disease. Clinical symptoms
are usually insidious in onset and evolve through stages. Fatigue,
weakness, anorexia, and acute diarrhea characterize the early stage.
The acute diarrhea progresses to a more chronic form with steatorrhea
accompanied by abdominal cramps and flatulence. Signs of nutritional
deficiencies appear, including night blindness, cheilosis, glossitis,
stomatitis, and hyperkeratosis. In the final stage there is muscle
wasting, edema, abdominal distension, and a macrocytic anemia. These
changes occur over a period of several months to years. On occasion
the presentation is more acute, and the stages are accelerated over
a few months. The condition should be suspected in patients with
diarrhea and malabsorption who have lived in or recently visited
an endemic area. Differential diagnosis includes parasitic infestations
(Giardia, Strongyloides stercoralis, Isospora, Capillaria
philippinensis), celiac disease, HIV infection, tuberculous
enteritis, and small intestinal bacterial overgrowth syndromes. Once
diagnosed, tropical sprue can be treated by a course of the antibiotic
tetracycline (doxycycline) or sulfamethoxazole/trimethoprim
(cotrimoxazole), and vitamin B12 and folic acid, for at
least 6 months, which will usually lead to dramatic improvement.
++
This rare, multisystem disorder virtually always involves the
small intestine, causing a severe malabsorption syndrome.52 Other
features commonly encountered are arthritis/arthralgia, polyserositis,
fever, and central nervous system symptoms. It is caused by a gram-positive
actinomycete, Tropheryma whippelii, which is a
fastidious organism that has not yet been cultured. Small intestinal
biopsy reveals villi that are flattened and wide. The lamina propria
is extensively infiltrated with large macrophages containing periodic
acid-Schiff-positive granules representing remnants of the cell
walls of degenerated phagocytosed bacilli. Numerous tiny bacilli
are located in the upper epithelium, most abundantly beneath the
absorptive epithelium. Mucosal and submucosal lymphatics are dilated,
probably because of lymphatic obstruction by enlarged mesenteric
lymph nodes. Treatment with antibiotics produces dramatic improvement,
but long-term therapy is necessary.
++
Gastrointestinal disorders are among the most common complaints
in patients with human immunodeficiency virus (HIV) disease. These include
diarrhea, nausea, vomiting, anorexia, weight loss, and abdominal
pain. In some cases the gastrointestinal symptoms are clearly related to
one of many opportunistic bacterial, viral, or parasitic infections,
or are secondary to the effects of small intestinal bacterial overgrowth
or gastrointestinal malignancies such as intestinal lymphomas or
Kaposi sarcoma. In others there is evidence to suggest the HIV is
an intestinal pathogen capable of causing diarrhea and malabsorption.53 The
virus can be identified in macrophages within the lamina propria
and enterochromaffin cells and is believed to exert an effect on
local humoral immunity and impair motility.54,55 The
term idiopathic AIDS enteropathy has been used
to describe those patients with HIV disease who have chronic diarrhea
with no other identifiable etiology. Histologic findings are variable,
with varying degrees of villus blunting. Lamina propria cellularity
ranges from normal in some cases to a severe increase in the density
of lymphocytes and plasma cells in others.56
++
Clinically, HIV enteropathy is associated with chronic
diarrhea, and this is often accompanied by anorexia. Weight loss
and malnutrition are secondary to both inadequate nutrient intake
and malabsorption of nutrients, and growth is frequently impaired
in children. Diagnosis is dependent on careful exclusion of other
identifiable causes of diarrhea. Treatment combines strategies to
stimulate appetite using drugs such as megestrol acetate and to decrease
stool output using antidiarrheal agents. Supplemental enteral nutrition
by means of enteral tube feeding techniques may be needed in some
cases to provide sufficient caloric intake. Parenteral nutrition
may be necessary in some cases with severe diarrhea, but the decision
to use this form of therapy needs to be carefully weighed against
the potential risks that accompany central venous line placement
in an immunocompromised individual.
+++
Autoimmune Enteropathy
++
This potentially life-threatening disorder is characterized by
chronic diarrhea beginning during the first year of life but usually
after 8 weeks of age. There are rare reports of autoimmune enteropathy
occurring in older children and adults.57 The condition
is frequently associated with other autoimmune diseases, including
membranous glomerulonephritis, insulin-dependent diabetes, collagen
vascular disorders, hemolytic anemia, autoimmune hepatitis, and
hypothyroidism. Most cases are sporadic but it rarely has been associated
with a family history of unexplained chronic diarrhea in infancy.
++
Affected children present with chronic watery diarrhea. Because
of the colonic involvement, there may be associated features of
colitis with blood and mucus in the stools. Malabsorption of nutrients
leads to malnutrition and impaired growth. Chronic diarrhea associated
with other autoimmune disorders, including type-1 diabetes, autoimmune
thyroiditis, or hemolytic anemia, should always raise suspicion
for the diagnosis of autoimmune enteropathy.
++
Light microscopy of small intestinal biopsies demonstrates partial
or complete villus atrophy, crypt hyperplasia, and a mononuclear
cell infiltrate in the lamina propria. The features resemble those
of celiac disease, except there is a relative paucity of intraepithelial
lymphocytes. Furthermore, these histologic changes occur in the
absence of any gluten ingestion in the majority of cases. The microscopic changes
are not confined to the small intestine and can be seen in the colon
and stomach as well.
++
The disorder appears to be autoimmune by virtue of the presence
of autoantibodies to the enterocytes and other tissues (eg, antibodies
to pancreatic islet cells, thyroid, parietal cells, and renal tubular
epithelium). Diagnosis is dependent on (1) the clinical history
of prolonged diarrhea with histologic features of small intestinal
enteropathy, (2) lack of clinical or histologic response to an exclusion
diet or a period of complete bowel rest with parenteral nutrition,
and (3) the demonstration of circulating autoantibodies to gut and
other tissues.
++
Parenteral nutrition is often necessary to prevent progressive
malnutrition. Corticosteroids, azathioprine, cyclosporine, tacrolimus,
and infliximab have been used with some success.58 Serial
determination of enterocyte autoantibodies may be of benefit to
monitor treatment efficacy. Declining or low titers are associated
with recovery, whereas persistent high titers indicate a poorer prognosis
with worse outcome for the patient.