Coeliac disease is characterised by small intestinal malabsorption of nutrients after the ingestion of wheat gluten or related proteins from rye and barley, villous atrophy of the small intestinal mucosa, prompt clinical and histologic improvement following strict adherence to a gluten-free diet, and relapse when gluten is reintroduced. 

It shows a marked geographic variation, with the highest incidence in western Europe. The condition is more common in Scandinavian and Celtic populations, where the prevalence has been reported to be as high as one in 99 and one in 122, respectively. These patients often have a genetic predisposition to coeliac disease, especially human leukocyte antigen class II DQ (HLA-DQ2) in 90-95% of patients, while the rest are (HLA-DQ8), (compared with approximately 35% of the general white population).^1,2,3,4

Coeliac disease exhibits a spectrum of clinical presentations (see Table 1). Non-classical coeliac disease (atypical coeliac disease) is fully expressed gluten sensitive enteropathy manifested only by extra intestinal symptoms and signs, including short stature, anaemia, osteoporosis, and infertility. 

Silent coeliac disease is fully expressed gluten-sensitive enteropathy usually found after serologic screening in asymptomatic patients. The atypical and silent variants are more common than classic or typical coeliac disease, which is fully expressed gluten-sensitive enteropathy found in association with the classic gastrointestinal symptoms of malabsorption. Patients with latent coeliac disease have normal villous architecture on a gluten-containing diet but, at another time, have had or will have gluten-sensitive villous atrophy. Patients with potential coeliac disease have never had a biopsy consistent with the disease but show characteristic immunologic abnormalities. 

Refractory coeliac disease is defined as symptomatic, severe small intestinal villous atrophy that mimics coeliac disease but does not respond to at least six months of a strict gluten-free diet. This is a diagnosis of exclusion that is not accounted for by inadvertent gluten ingestion, other causes of villous atrophy, or overt intestinal lymphoma.³

Adapted from Farrell RJ, Kelly CP. Diagnosis of coeliac sprue. Am J Gastroenterol 2001 (Dec): 96(12): 3237-46(click to enlarge)

Diagnosis of coeliac disease

There are numerous disorders associated with coeliac disease (see Table 2). The diagnosis of coeliac disease can be made on the basis of the following: 

• The presence of a clinical feature or features compatible with the disease
• Supportive serologic studies
• Characteristic small-bowel biopsy findings
• Clinical response to a gluten-free diet.
• The available serologic tests include: 
• Anti-gliadin antibodies 
• Endomysial antibodies (EMAs)
• Tissue transglutaminase antibodies (tTG)
• Deamidated gliadin peptides (DGPs).

IgA-based tTG test is considered the single best screening test for coeliac disease in patients older than two years of age and has a sensitivity of about 95% and a specificity greater than 95%. The native anti-gliadin antibody test has less sensitivity and specificity than other serologic markers and should be avoided in practice. EMA testing may be more expensive and subjective than tTG testing. IgA deficiency affects 2-3% of patients who have coeliac disease. In patients with known IgA deficiency, an IgG-based test (Ig G tTG or Ig G DGP) should be performed. In patients with suspected IgA deficiency, an IgA level can be checked first, with IgA- or IgG-based serologies checked thereafter according to the IgA level. In children younger than two years, EMA and tTG testing may be less sensitive, so a combination of both tTG and DGP testing is recommended in this age group.

Before patients are tested, they need to be eating a gluten-containing diet. While a six- to eight-week gluten challenge has been recommended in the past, diagnostic changes may be seen as early as two weeks after consuming gluten. Testing could be done after two weeks on a gluten-containing diet if the patient cannot tolerate a longer interval on the diet. In symptomatic patients, biopsy of the small bowel is needed regardless of the results of serologic testing. Also, any positive serologic study needs to be confirmed with small-bowel biopsy studies.¹

From Farrell RJ, Kelly CP. Diagnosis of coeliac sprue. Am J Gastroenterol. 2001 Dec: 96(12):3237-46(click to enlarge)

Figure 1. Small-bowel histopathologic findings in coeliac disease (from Mayo Clinic Gastroenterology and Hepatology Board Review 5th edition) (4) A - Normal findings (haematoxylin-eosin)(click to enlarge)

B - Intraepithelial lymphocytes alone as seen in an early March lesion of coeliac disease (haematoxyln-eosin)(click to enlarge)

C - Classic histologic findings of coeliac disease, with marked villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis with a chronic inflammatory cell infiltrate in the lamina proporia (haematoxylin-eosin)(click to enlarge)

Pathology

Coeliac disease affects the mucosa of the small intestine; the submucosa, muscularis propria, and serosa usually are not involved. The mucosal lesion of the small intestine can vary considerably in severity and extent. This spectrum of pathological involvement might contribute to the striking variations in the clinical manifestations of the disease. 

Histological examination of tissue sections confirms loss of normal villous structure, with crypts markedly elongated (crypt hyperplasia) and open on to a flat absorptive surface. These architectural changes decrease the amount of epithelial surface available for digestion and absorption (see Table 3).

The cellularity of the lamina propria is increased in the involved small intestine. The cellular infiltrate consists largely of plasma cells and lymphocytes. Polymorphonuclear leukocytes, eosinophils, and mast cells also can contribute substantially to the increased cellularity of the lamina propria. The number of intraepithelial lymphocytes (IELs) per unit area of absorptive epithelium (often reported as the number of IELs per 100 enterocytes) is increased in untreated coeliac disease. In the normal small intestinal mucosa, lamina propria T cells are predominantly CD4+ (helper/inducer) cells, whereas the IELs are mainly CD8+ (cytotoxic/suppressor) cells.

Conditions that mimic coeliac disease

Causes of small-bowel biopsy findings that may mimic coeliac disease include:⁴

• Small intestinal bacterial overgrowth
• Nonsteroidal anti-inflammatory drugs
• Helicobacter pylori infection
• Giardiasis
• Crohn’s disease
• Viral gastroenteritis
• Combined variable immunodeficiency
• Tropical sprue
• Lymphoma
• Zollinger-Ellison syndrome
• Hypersensitivity to non-gluten protein
• Medications (olmesartan).

Treatment with a gluten-free diet results in significant improvement in intestinal structure. The cytologic appearance of the surface absorptive cells improves first, often within a few days. Tall, columnar absorptive cells with basal nuclei and well-developed brush borders replace the abnormal, immature cuboidal surface cells; the ratio of IELs to absorptive cells decreases. Subsequently, villous architecture reverts toward normal, with lengthening of the villi and shortening of the crypts; the lamina propria decreases in cellularity. The mucosa of the distal small intestine improves more rapidly than that of the more severely involved proximal bowel.

In the debilitated patient with severe untreated coeliac disease and associated nutritional deficiency states, pathological changes may be present in many other organ systems besides the digestive tract. The mucosal lesion of coeliac disease can be identical histologically to the mucosal response to injury typical of a wide range of other enteropathies.^1,2,3,4

 (click to enlarge)

References

1. Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association [AGA] Institute technical review on the diagnosis and management of coeliac disease. Gastroenterology 2006(Dec); 131[6]: 1981-2002
2. Farrell RJ, Kelly CP. Diagnosis of coeliac sprue. Am J Gastroenterology 2001(Dec); 96(12): 3237-46
3. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease - 2 Volume Set: Pathophysiology, Diagnosis, Management, 10 edition (March 2015)
4. Hauser SC. Mayo Clinic Gastroenterology and Hepatology Board review 5TH edition
5. World Gastroenterology Organisation Global Guidelines, Coeliac disease April 2012