Celiac Disease
Celiac disease, also known as gluten-sensitive
enteropathy or nontropical sprue, is a chronic immune-mediated
enteropathy triggered by exposure to dietary gluten. The primary target of the
disease is the small intestine; celiac disease can affect multiple systems,
however.
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| CELIAC DISEASE AND MALABSORPTION |
It is primarily seen in individuals of European descent but is increasingly recognized on almost every continent. The overall prevalence in the general population of the United States and Europe is nearly 1%; only 10% to 15% of patients have been diagnosed and treated, however. The prevalence appears to increase with age. Celiac disease develops in genetically predisposed individuals as a result of the influence of environmental factors. First-degree relatives of patients with celiac disease have a 10% to 15% risk of developing the disease. The HLA class II genes HLA-DQ2 and HLA-DQ8, which are normally expressed on the surface of antigen cells in the gut, are the most important genetic susceptibility factors in celiac disease. HLA-DQ2 is found in 90% to 95% of patients with celiac disease, with HLA-DQ8 found in most of the remaining patients. These molecules are necessary variables predisposing a patient to the disease, which means that celiac disease is unlikely if neither molecule is present. The molecules are not, however, sufficient to cause celiac disease; they occur in 30% to 40% of the general population. Gluten is a storage protein of wheat. The alcohol-soluble fraction of gluten, gliadin, is toxic in celiac disease, along with similar proteins in barley (hordeins) and rye (secalins). These proteins are rich in glutamine and proline residues that even the healthy human intestine cannot fully digest. As a result, intact gliadin peptides are left in the lumen, but few cross the intestinal barrier. In individuals with celiac disease, these fragments come into contact with tissue transglutaminase, a ubiquitous intracellular enzyme that is released by inflammatory and endothelial cells and fibroblasts in response to mechanical irritation or inflammation. Upon contact, tissue transglutaminase cross-links with these glutamine-rich proteins and deamidates them. This process modifies glutamine residues into glutamic acid residues, which are ideally suited to interact with the HLA-DQ2 or HLA-DQ8 molecules. Once bound to HLA-DQ2 or HLA-DQ8, gliadin peptides are presented to the CD4+ T cells, triggering the inflammatory reaction. The end result is an inflammatory state of the small intestine, causing a derangement in the architecture of the mucosa, with flattening of the villi, and infiltration of lymphocytes into the epithelium.
The
clinical presentation of celiac disease has been traditionally classified based
on signs and symptoms. Most patients are asymptomatic and the disease is discovered incidentally upon testing; others present with atypical extraintestinal
signs and symptoms.
Chronic
or intermittent diarrhea, often bulky and foul smelling, is one of the most
common gastrointestinal symptoms. Abdominal pain, bloating, and flatulence are
other common symptoms; however, chronic constipation has been reported.
A
variety of extraintestinal manifestations have been described in celiac disease
and are often the presenting symptom. Iron deficiency anemia, resistant to oral
iron supplementation, is the most common extraintestinal sign and is considered
the most frequent presentation among teenagers and adults. Neurologic symptoms
such as headaches as well as psychiatric issues including depression and
anxiety have been reported in association with celiac disease. Nonerosive,
polyarticular, or oligoarticular arthritis that promptly resolves with a
gluten-free diet has been documented. Metabolic bone diseases,
including osteopenia, osteoporosis, and, rarely, osteomalacia, are common in
celiac disease and can present in the absence of gastrointestinal symptoms.
Dermatitis
herpetiformis is an uncommon cutaneous manifestation of celiac
disease and presents as an intensely pruritic inflammatory papular and
vesicular skin eruption involving the extensor surfaces of the elbows,
forearms, knees, buttocks, back, and scalp. Direct immunofluorescence
microscopy of a punch biopsy is the gold standard test for the diagnosis of
dermatitis herpetiformis. Treatment consists of dietary gluten
restriction and pharmacotherapy with dapsone. Long-term treatment lasting
several years may be required to achieve complete remission.
The
diagnosis of celiac disease requires a high index of suspicion and the
identification of risk factors associated with the disease. Testing should be
carried out for those with gastrointestinal symptoms and those with unexplained
iron deficiency anemia, folate deficiency, or vitamin B12
deficiency. The presence of unexplained persistent elevation in serum
aminotransferases, short stature, delayed puberty, recurrent fetal loss, reduced
fertility, persistent aphthous stomatitis, dental enamel hypoplasia, idiopathic
peripheral neuropathy, nonhereditary cerebellar ataxia, or recurrent migraine
headaches also merits testing for celiac disease. Testing should be considered
for first-degree relatives of individuals with celiac disease and for
individuals with dis- orders known to coexist with celiac disease, such as type
1 diabetes mellitus and Down syndrome.
Testing
the serum levels of anti–tissue transglutaminase IgA is generally acknowledged
as the first choice in screening for celiac disease, displaying the highest
levels of sensitivity (98%) and specificity (96%). Anti– endomysium IgA testing
has a specificity of close to 100% and a sensitivity exceeding 90%, but this
test has high interobserver variability. Antibodies to deamidated gliadin
peptides (DGP-IgA and DGP-IgG) are also used as screening tools, and they seem
to be especially useful in very young children. In fact, DGP testing may be
more sensitive than anti–tissue transglutaminase IgA in children younger than 2
years. IgA deficiency is more common in celiac disease (2% to 5%) than in the
general population (<0.5%), leading to falsely negative IgA tissue transglutaminase
and IgA endomysium serology tests. In cases where there is a high pretest
probability, total serum IgA can be measured in addition to IgA tissue
transglutaminase and IgA endomysium. If the serum IgA is low, IgG-based assays
should be used to test for celiac disease. Negative results on testing for
HLA-DQ2 or HLA-DQ8 can also help to exclude the diagnosis in this setting.
In
addition to serologic markers, the diagnosis of celiac disease still rests on
the demonstration of histologic changes in the small intestinal mucosa as
documented by biopsy specimens from the duodenum via endoscopy. The classic
finding on endoscopy is an atrophic duodenal mucosa with loss of the folds with
or without scalloping or a nodular appearance. Such findings, however, are not
universally present and the mucosa can appear normal. Histologic findings range
from mild alteration characterized only by increased intraepithelial
lymphocytes to crypt hyperplasia and complete villous atrophy and are reported
using the Marsh-Oberhuber and Corazza classifications.
Adherence
to a strict gluten-free diet remains the only available treatment for patients
with celiac disease and typically results in a complete return to health.
Compliance with a gluten-free diet, however, is difficult at all ages but
particularly for teenagers and younger adults. Dietary counseling with a
skilled dietitian is one of the most important aspects of the treatment and
should be recommended to all patients with celiac disease. Patients should be
monitored for deficiencies of vitamins, particularly A, D, E, and B12, iron,
and folic acid, while copper and zinc should be supplemented. Deficiency of
magnesium and selenium may also occur, and signs or symptoms of a deficiency
should be sought. Constipation can occur as consequence of a gluten-free diet
because the diet is low in roughage; regular use of psyllium seed husks is
often beneficial.
If
symptoms persist or serologic and/or histologic abnormalities develop while a
patient is on a gluten-free diet, this usually indicates poor compliance with
the diet or inadvertent gluten ingestion. Alternative or concurrent disorders
such as bacterial overgrowth, pancreatic insufficiency, and microscopic colitis
should be considered and excluded appropriately. Refractory sprue is the
persistence of symptoms and villous atrophy despite a strict gluten-free diet
for at least 2 years. The cause is unknown, but the course can be severe, with
progressive malabsorption and even death. Aggressive nutritional
support is required, including parenteral nutrition if needed and
pharmacotherapy focused on immunosuppression.
In
patients unresponsive to immunosuppression, ulcerative jejunitis and lymphoma
should be considered. Patients with ulcerative jejunitis have multiple chronic,
benign-appearing ulcers, most frequently in the jejunum, which can rarely form
strictures. These can be identified on cross-sectional abdominal imaging or on
upper endoscopy and capsule endoscopy. Ulcerative jejunitis has an unfavorable
prognosis, with a 30% mortality rate. Distinction between ulcerative jejunitis
and lymphoma is challenging because both have very similar symptoms
and findings on imaging. Enteropathy-associated T-cell lymphoma is a rare but
aggressive neoplasm that arises in the gastrointestinal tract as a sequela of
untreated celiac disease. Most patients present with stage IV disease.
Treatment consists of chemotherapy with or without autologous hematopoietic
cell transplantation.
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| ENDOSCOPIC AND HISTOLOGIC FINDINGS |
Various malignant diseases are associated with celiac disease, and the gluten-free diet is considered to be protective against the development of certain malignant diseases. These include esophageal, head, and neck squamous carcinoma, small intestinal adenocarcinoma, and non-Hodgkin lymphoma.
