Clinical Immunology

4th class

Lec. 7

Gastrointestinal and liver diseases

Gluten-Sensitive Enteropathy
Introduction
Gluten-sensitive enteropathy (GSE), also known as celiac disease (CD) or
celiac sprue, is characterized by inflammatory injury to the mucosa of the
small intestine after ingestion of gluten in genetically predisposed

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individuals. The inciting agent is gluten, a storage protein commonly
found in wheat, barely and rye. More specifically, GSE is caused by T-

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cell-mediated recognition of gliadin, an alcohol-soluble fraction of
gluten.
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Removal of gluten from the diet has been found to result in significant
regression of the inflammatory lesion and symptoms seen with the
disease.
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This disease either limited to intestine or associated with a vesicular skin

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disease -DH]
Epidemiology:
1. Currently, it is thought to affect as many as 1 in 100 to 250
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individuals worldwide.
2. Predominantly affecting Caucasians and people mainly in North
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America, Europe, and South America.

3. GSE has also been observed among populations in North Africa,
Iran, and India, which attests to the widespread occurrence of the
disease.
4. It was once thought to occur only in childhood, but GSE can
manifest at any age.
5. Celiac disease is associated with other autoimmune syndromes. For
example, about 7 % of patients with type I diabetes have GSE.
Clinical Immunology
4th class

Etiology:
1. Genetics plays a major role in the pathogenesis of GSE.
2. Individuals expressing the MHC haplotypes -DR3, -DR5, -DR7,
and, more importantly, -DQ2 or -DQ8 are at increased risk of
developing GSE.
3. The disease tends to cluster in families, and the monozygotic twin
concordance rate of 75 percent further emphasizes the strong

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genetic component.
4. GSE has been associated with a region on the long arm of

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chromosome 5 (5q31 33), which is where other candidate

and asthma are also located.

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5. It has been speculated that there is some involvement of the gene
that encodes the negative co-stimulatory molecule, cytotoxic T-
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lymphocyte antigen-4 (CTLA-4).

Clinical features:
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1. The myriad of symptoms associated with GSE has made detection

of disease especially difficult. Patients commonly present with
malabsorption, steatorrhea, and weight loss relating to the
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flattening of proximal small intestinal villi.

2. Diarrhea is not usually present unless the distal small bowel, in
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addition to the proximal portion, is affected.

3. Some patients do not present with any gastrointestinal symptoms,
but with effects secondary to malabsorption of vitamins such as
iron, folate, and calcium. These patients may only present with
anemia and osteoporosis, respectively.
Clinical Immunology
4th class

4. In addition, there is a strong association between GSE and

autoimmune disease. Some individuals with GSE also present with
Dermatitis Herpetiformis (DH), Fewer than 10 percent of adults
with gluten-sensitive enteropathy present with dermatitis
herpetiformis. This skin condition may be misdiagnosed as atypical
psoriasis or nonspecific dermatitis. The rash of dermatitis
herpetiformis is intensely pruritic and typically occurs on the back,

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buttocks, knees, and elbows. Unexcoriated lesions are remarkably

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Granular IgA deposition on immunofluorescence of a skin biopsy
specimen is diagnostic. Most DH patients have GSE, whereas all
individuals with GSE do not have DH.
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Symptoms of Celiac Disease and Possible Causes
SYMPTOMS POSSIBLE CAUSES
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Fatigue, malaise Anemia, general immune system activation

Weight loss Nutrient malabsorption
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Diarrhea, abdominal pain Accelerated gastrointestinal tract transit time,

steatorrhea, malabsorption
Anemia Most commonly, iron deficiency; less commonly,
vitamin B12 and/or folate deficiency
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Bone pain Osteoporosis

Aphthous oral ulcers, glossitis,
stomatitis
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Infertility Postulated cause: iron, folate, and/or zinc deficiency

Male impotence, decreased libido Peripheral insensitivity to circulating testosterone

Alopecia areata
Dental enamel defects
Hypoglycemia
Gas, flatus, borborygmus
Seizures, gluten ataxia, central
nervous system symptoms
Immunologic attack on hair follicles
Demineralization during tooth bud development in
children
Delayed absorption of glucose
Secondary digestion of sugars by intestinal flora
Increased affinity of celiac antibodies for brain
vasculature
Clinical Immunology
4th class

Pathophysiology (immune mechanism):

1. A strong association exists between celiac disease and two human
leukocyte antigens (HLA) haplotypes (DQ2 and DQ8).
2. GSE is due to an immune reactivity to certain cereal storage protein
peptides.
3. Endogenous tissue transglutaminase deamidates gliadin into a
negatively charged protein, increasing its immunogenicity.
4. Damage to the intestinal mucosa is seen whene APC present gliadin

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peptide, that consist of 33 amino acids, by the MHC molecules to helper
T cells that mediate the inflammatory response.

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5. TH1 cells producing IFN- -
macrophages to produce pro-inflammatory cytokines such as IL-1 and
TNF-
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6. More lymphocytes infiltrate the epithelium (intraepithelial
lymphocytes), and B-cell specific for gliadin will produce IgA
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antibodies. In addition, other antibodies against transglutaminase

enzymes are also produced.
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7. Absence of intestinal villi and lengthening of intestinal crypts

characterize mucosal lesions in untreated celiac disease.
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Clinical Immunology
4th class

Diagnosis
Abnormal Laboratory Findings in Celiac Disease
LABORATORY FINDING PATHOPHYSIOLOGY

Anemia Iron deficiency; vitamin B12 and/or folate deficiency

Elevated alkaline phosphatase level Osteoporosis, osteomalacia

Elevated aspartate transaminase and alanine Minimal elevation common in celiac disease;
transaminase levels presumably autoimmune

Decreased albumin level Malnutrition

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Elevated calcium level, decreased phosphate Vitamin D deficiency, secondary
level hyperparathyroidism

Thrombocytosis, leukocytosis General inflammatory reaction

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Coagulopathy Decreased vitamin K absorption

Low high-density and low-density lipoprotein Decreased fat absorption, decreased hepatic
cholesterol levels lipoprotein production
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Serological test:
1. Tissue transglutaminase antibody (TtG), IgA class: the primary
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test ordered to screen for celiac disease. It is the

mostsensitive and specific blood test for celiac disease.
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The IgG class of anti-tTG may be ordered as an alternative in those

who have a deficiency of IgA.
2. Deamidated gliadin peptide (DGP) antibodies (anti-DGP), IgA or
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IgG: may be positive in some people with celiac disease who are
negative for anti-tTG, especially children less than 2 years old.
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3. Anti-endomysial antibodies (EMA): antibodies developed in

reaction to the ongoing damage to the intestinal lining.
4. Anti-reticulin antibody (ARA) test: not as specific or sensitive as
the other autoantibodies; it is found in about 60% of people with
celiac disease and about 25% of those with dermatitis
herpetiformis; it is rarely ordered.
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4th class

5. Other tests include:

CBC (complete blood count) to look for anemia.
ESR (erythrocyte sedimentation rate) to evaluate inflammation.
CRP (C-Reactive protein) to evaluate inflammation.
CMP (comprehensive metabolic panel) to determine electrolyte,
protein, and calcium levels, and to verify the status of the kidney
and liver function tests.

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Vitamin D and B12 and folate to measure vitamin deficiencies
Iron, iron binding capacity or transferrin, and ferritin to detect iron

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deficiency.
Stool fat, to help evaluate malabsorption.
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To confirm a diagnosis of celiac disease, a four biopsies were
taken from the seconed portion of duodenum, are examined to
detect damage to the intestinal villi.
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Distal duodenal biopsy is the gold standard for the diagnosis of

celiac disease. Biopsy should be performed in most patients with
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suspected gluten-sensitive enteropathy. In determining the need for

biopsy, family physicians should consult a gastroenterologist who
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is experienced in the diagnosis and management of celiac disease

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