C h a p t e r 2 9
Disorders of Gastrointestinal Function
719
to be one of the most common genetic diseases, with a
mean prevalence of 1% in the general population. The
disease is recognized not only in Europe and in countries
populated by persons of European ancestry, but also in
the Middle East, Asia, South America, and North Africa.
The disease results from an inappropriate T-cell–
mediated immune response against the gliadin fraction
of gluten contained in the diet. Almost all persons with
the disorder share the major histocompatibility com-
plex class II allele HLA-DQ2 or HLA-DQ8. Several
non-HLA genes that may influence susceptibility to
the disease have been identified, but their role has not
been confirmed. Persons with the disease have increased
levels of antibodies to a variety of antigens, including
transglutaminase, endomysium, and gliadin. The resul-
tant immune response produces an intense inflammatory
reaction that results in loss of absorptive villi from the
small intestine. When the resulting lesions are extensive,
they may impair absorption of macronutrients (i.e., pro-
teins, carbohydrates, fats) and micronutrients (i.e., vita-
mins and minerals). Small-bowel involvement is most
prominent in the proximal part of the small intestine,
where the exposure to gluten is greatest.
Populations at higher risk for celiac disease include
persons with type 1 diabetes mellitus, those with other
autoimmune endocrine disorders such as autoimmune
thyroid disorders or Addison disease, first- and second-
degree relatives of persons with celiac disease, and indi-
viduals with Turner syndrome. Various malignancies also
appear to be a direct result of celiac disease, in that the
increased incidence seen in persons with celiac disease
returns to that of the general population after several
years of a gluten-free diet. These malignancies include
head and neck squamous cell carcinoma, small intesti-
nal adenocarcinoma, and non-Hodgkin lymphoma.
The clinical manifestations of celiac disease vary
greatly according to age group.
55,56
Infants and young
children generally present with diarrhea, abdominal dis-
tention, failure to thrive, and, occasionally, severe mal-
nutrition. Beyond infancy, the manifestations tend to be
less dramatic. Older children may present with anemia,
constitutional short stature, dental enamel defects, and
constipation. Among adults, women constitute about
75% of newly diagnosed cases of celiac disease. The
classic presentation in adults is diarrhea, which may be
accompanied by abdominal pain or discomfort. It has
been observed that fewer persons with celiac disease are
presenting with the so-called “classic manifestations” of
the disease. While diarrhea is still the most frequent mode
of presentation, others include iron deficiency, osteoporo-
sis, and recognition of mucosal changes in persons under-
going endoscopy for esophageal reflux or dyspepsia.
55
A
prior diagnosis of irritable bowel syndrome is common.
Celiac disease is also becoming increasing recog-
nized in the elderly population.
57
Rather than symptoms
related to severe malabsorption, this age group often
presents with anemia, accelerated osteoporosis, and
osteomalacia. Although abdominal symptoms are still
common in elderly persons, these individuals tend to
present with milder symptoms such as abdominal bloat-
ing, flatulence, and abdominal discomfort, which make
diagnosis difficult.
The diagnosis of celiac disease is based on clinical
manifestations and confirmed by serologic tests and
intestinal biopsy. Based on very high sensitivities, the
best available tests are the immunoglobulin (Ig) A anti-
human tissue transglutaminase (TTG) and IgA endo-
mysial antibody (EMA) immunofluorescence tests.
56
Biopsies of the proximal small bowel are indicated in
persons with a positive celiac disease antibody test.
Usually, additional laboratory tests are done to deter-
mine if the disorder has resulted in nutritional disorders
such as iron-deficiency anemia.
The primary treatment of celiac disease consists of
removal of gluten and related proteins from the diet.
Gluten is the primary protein in wheat, barley, and rye.
Oat products, which are nontoxic, may be contaminated
with wheat during processing. Many gluten-free types of
bread, cereals, cookies, and other products are available.
56
Meats, vegetables, fruits, and dairy products are free of
gluten as long as they are not contaminated during process-
ing. Complete exclusion of dietary gluten generally results
in rapid and complete healing of the intestinal mucosa.
Colorectal Neoplasms
Adenomatous Polyps
Adenomatous polyps (adenomas) are benign neoplasms
that arise from the mucosal epithelium of the intestine.
6,7
They are composed of neoplastic cells that have prolifer-
ated in excess of those needed to replace the cells that
normally are shed from the mucosal surface. The most
common and clinically important neoplastic polyps are
colonic adenomas that are precursors in the majority of
colorectal adenocarcinomas.
Adenomas can range in size from a barely visible
nodule to a large, sessile mass. They can be classified
as tubular, villous, or tubulovillous adenomas.
Tubular
adenomas,
which constitute approximately 65% of
benign large bowel adenomas, typically are smooth-surfaced spheres, usually less than 2 cm in diameter, that
are attached to the mucosal surface by a stalk.
7
Although
most tubular adenomas display little epithelial dysplasia,
approximately 20% show a range of dysplastic changes,
from mild nuclear changes to frank invasive carcinoma.
Villous adenomas
constitute 10% of adenomas of the
colon.
7
They typically are broad-based, elevated lesions
with a shaggy, cauliflower-like surface and are found
predominantly in the rectosigmoid colon. In contrast
to tubular adenomas, villous adenomas are more likely
to contain malignant cells. When invasive carcinoma
develops, there is no stalk to isolate the tumor and inva-
sion is directly into the wall of the colon.
Tubulovillous
adenomas
manifest both tubular and villous architec-
ture. They are intermediate between tubular and villous
adenomas in terms of invasive carcinoma risk.
The pathogenesis of adenoma formation involves
neoplastic alterations in the replication of the colonic
crypt cells (Fig. 29-13). There may be diminished
apoptosis (see Chapter 2), persistence of cell replication,
and failure of cell maturation and differentiation of the
cells that migrate to the surface of the crypts. Normally,
DNA synthesis ceases as the cells reach the upper two
