Celiac disease: A review

Introduction

In 1888, Samuel Gee described the clinical features of childhood celiac disease.[1] After the Second World War, Dicke and colleagues from Holland noted that certain cereal grains, particularly wheat and rye, were harmful to children with celiac disease. Later studies showed that gliadin, the alcohol-soluble component of gluten, a water-insoluble protein from wheat, could cause impaired fat absorption in these patients.[2,3] Between 1954 and 1960, the intestinal histopathological features of celiac disease were described [4-6] based on peroral small intestinal biopsy—refining earlier descriptions based on surgical specimens. During the last 40 years, the clinical and pathological spectrum of celiac disease has become further appreciated, especially in recent studies that have implicated genetic, immunologic, and environmental factors in the etiology and pathogenesis of this most intriguing disorder.

Definition

Celiac disease (also known as celiac sprue, gluten-sensitive enteropathy, nontropical sprue) has been defined [7] as a chronic disorder with a characteristic but nonspecific small intestinal mucosal biopsy lesion that is associated with nutrient malabsorption. Following removal of dietary wheat gliadins (the toxic alcohol-soluble gluten fractions) and equivalent dietary prolamines in barley, rye, and oats, prompt improvement in the small intestinal biopsy appearance results, along with improved nutrient absorption. Biopsy changes found in untreated celiac disease include a “flat” mucosal surface with absence of villi, striking hyperplasia of the crypts, and extensive infiltration of the lamina propria by lymphocytes and plasma cells (Figure 1). Absorptive cells in untreated celiac disease appear cuboidal and vacuolated, while the surface epithelium is infiltrated with increased numbers of intra-epithelial lymphocytes (Figure 2).[7]

A number of small intestinal disorders may have a similar small intestinal biopsy appearance. These disorders must be excluded (Table 1) before celiac disease can be diagnosed.[7,8] Demonstrated improvement as a result of a gluten-free diet is also essential for a diagnosis of celiac disease. In most patients, improved bowel function, weight gain, or normalization of abnormal laboratory blood tests occurs with a gluten-free diet; operationally, it is usually sufficient to confirm the diagnosis of celiac disease. In some patients, however, particularly those with few symptoms (e.g., iron deficiency anemia without diarrhea or evident weight loss), additional small intestinal biopsies may be necessary.

The biopsy appearance in treated celiac disease (Figure 3) includes re-appearance of the villi, a reduction in crypt height and mitotic activity, and normalization of the small intestinal villus-to-crypt ratio. The lamina propria region appears less cellular, as the number of plasma cells and lymphocytes are reduced. Absorptive cells of the normal villus appear as tall columnar cells without vacuolization, and fewer intra-epithelial lymphocytes are seen.[7]

A number of studies have shown that in celiac disease the most severe small intestinal histological changes occur in the proximal small intestine. These changes may extend into the more distal small intestine if the disease is more severe; studies with small intestinal biopsies (along the length of the small intestine) indicate improvement in a distal-to-proximal direction with dietary restriction of gluten. Thus, histological improvement may be very difficult to show in some patients if the same proximal small intestinal site is biopsied again within a short period of the institution of a gluten-free diet. Although clinical recovery may occur, objective evidence of histological improvement in the proximal small intestine may require several weeks or even months.[7,9]

Epidemiology

Celiac disease is a disorder that occurs primarily in white people, particularly from countries of Western Europe and those countries to which Europeans have emigrated, specifically North America and Australia.[10] In Asia, the disorder is observed primarily in India and Pakistan but is rare in China and Japan. Celiac disease is rare in Africa, but more common in South Africa. In British Columbia, in addition to cases among white people, cases have also been documented in the Coast Salish. The highest recorded prevalence rates worldwide of well-documented disease approximate l:300 in western Ireland. Others[10] have speculated that the high incidence of celiac disease in Ireland may be related to the past Irish reliance on the potato as a staple food rather than wheat; on this diet, those with celiac disease could remain well and have children. Interestingly, seriologically based studies from several countries suggest that celiac disease may be present in up to 1% of adults. Although precise Canadian data (including British Columbia) are not available, these results suggest that celiac disease, particularly subclinical forms of the disorder, may be far more common than is currently appreciated.

Celiac disease may be diagnosed for the first time at any age, even in the elderly. In British Columbia, it is far more commonly diagnosed between ages 20 and 50 years than in any other age group, including children. Celiac disease is reported in most series more often in women than men—this is reflected in the author’s own experience in British Columbia of almost 200 patients, except those initially diagnosed over the age of 60 years. In this elderly group, males and females have a similar rate of recognition. Indeed, there is an apparent bimodal distribution in adults with an early peak in the fourth decade primarily in women, and a later peak in the sixth and seventh decades primarily in men.[11]

Celiac disease occurs more often in families. An early landmark study on the familial incidence was done in 1965 by MacDonald and colleagues,[12] who studied the results of small intestinal biopsy in 96 relatives of 17 index patients. Of 32 siblings, 4 had celiac disease. Five of 26 children of the index cases had celiac disease. Subsequent studies have generally confirmed this prevalence of celiac disease in first-degree relatives as from 8% to 12%.

Etiology and pathogenesis

Although gluten interacts with and damages the small intestinal mucosa, the primary host defect requires definition. Moreover, the critical amino acid sequence or sequences in gluten, as well as the precise molecular interaction with the enterocyte, remains unclear and must still be elucidated. At least four major mechanisms have been implicated but, to date, none has been proven.

First, some hypothesize that an enzyme deficiency leads to incomplete gluten digestion in patients with celiac disease. As a result of this deficiency, a toxic peptide accumulates; it may then damage the susceptible small intestinal mucosa. Evidence to date suggests that the reduced enzyme activities observed in celiac disease are a result of the disease per se and not specific to celiac disease.

Second, others believe that abnormal glycosylation of apical membrane glycoproteins on the enterocyte facilitates a lectin-like interaction between gluten and small intestinal absorptive cells. Although lectins (proteins largely derived from plants with a specificity for certain sugar residues) may bind to the damaged small intestinal mucosa of celiac disease, there is no published evidence that such differences persist with mucosal healing and treatment with a gluten-free diet.

Third, genetic factors, that is, associations with selected class II HLA antigens, may play a role in celiac disease. They may predispose some individuals to an immune response that results in small intestinal mucosal damage.

Finally, in addition to exposure to cereal grains, other factors may trigger the immune response. One hypothesis suggested that exposure of susceptible patients to a specific environmental factor may be necessary. Kagnoff and colleagues[13] described the high degree of sequence homology as well as cross-reactivity of a 12-amino acid alpha-gliadin fragment and a fragment of the E1b protein of the type 12 adenovirus. Although later studies provided contradictory evidence of a specific role for an adenovirus infection in celiac disease,[14] it has been hypothesized that a genetically predisposed host may be sensitized to gluten by molecular mimicry due to an earlier adenovirus infection. While it is well known that both humoral and cellular immunological events may be substantially altered in celiac disease, no specific immunological abnormality has been defined.

Clinical features

The essential elements for the diagnosis of celiac disease include the characteristic small intestinal biopsy coupled with a response to a gluten-free diet. The clinical features of classical celiac disease include diarrhea, weight loss, and malabsorption of various nutrients leading to various deficiencies, which may be the most clinically prominent finding. Other more subtle presentations of celiac disease also occur (Table 2).

Celiac disease may be clinically occult in some patients, particularly if the extent of small intestinal involvement is limited, especially to the proximal small intestine. Isolated deficiency of iron with anemia in the absence of bleeding, unexplained folic acid deficiency, and osteopenic bone disease have all been reported in this setting in the absence of other overt gastrointestinal symptoms.

A number of other diseases may co-exist with celiac disease—perhaps best exemplified by the skin disorder dermatitis herpetiformis.[15] A common clinical triumvirate includes celiac disease, dermatitis herpetiformis, and abdominal lymphoma.[9] Published data from Vancouver[16] documented the overall incidence of lymphoma was 8%, but the incidence in patients with celiac disease diagnosed after age 60 years was over 20%. In some patients, including those with dermatitis herpetiformis[17] or lymphoma,[18] celiac disease may not be diagnosed until the patient is treated with a diet containing excessive quantities of gluten—a sign of latent celiac disease. Recent studies from British Columbia have also documented a strong association of celiac disease with autoimmune thyroid disorders[19] and insulin-dependent diabetes in children.[20]

Treatment

The cornerstone of treatment in celiac disease is the gluten-free diet. Patients must avoid all offending cereal grains. The clinical response to gluten withdrawal occurs rapidly, usually within the first month. Normalization of the small intestinal mucosal lesion may require longer periods. A failure to improve suggests refractory celiac disease and usually indicates that there is an unidentified or ubiquitous source of dietary gluten. If compliance has been meticulous, the initial diagnosis may be incorrect or a second or superimposed cause for clinical symptoms may be present. In some patients, especially those who have an initial clinical response to a gluten-free diet, recurrent symptoms may reflect an associated disorder (i.e., collagenous or lymphocytic colitis)[21,22] or a complication (i.e., lymphoma).[9,23,24]

The Canadian Celiac Association has chapters in Vancouver, Victoria, Kelowna, and Kamloops. This organization is dedicated to providing service and support to persons with celiac disease through programs of awareness, advocacy, education, and research. See the resources for contact information.

Table 1. Differential diagnosis of the flat lesion of celiac sprue.*

*Defined by the presence of a flat lesion that improves with dietary gluten restriction.

Table 2. Classification of celiac sprue.*

*Defined by the presence of a flat lesion that improves with dietary gluten restriction.

Hugh Freeman, MD, FRCPC, FACP, FACG

Dr Freeman is a professor of gastroenterology in the Department of Medicine at the University of British Columbia