Identifying, Managing Comorbidity of Celiac, IBD

Q: How Often Does Celiac Disease Coexist With Inflammatory Bowel Disease?

Issue: October 2016

ByCiaran Kelly, MD

ByToufic Kabbani, MD

A: Celiac disease and inflammatory bowel disease (IBD) can coexist, and studies suggest that there is an increased risk of celiac disease in IBD patients. In a small study of 27 patients with newly diagnosed Crohn’s disease (CD), 5 patients (18.5%) were found to have biopsy-proven celiac disease. Similarly, celiac disease patients are at increased risk for both ulcerative colitis (UC) and CD. However, the association between celiac disease and UC is stronger (5-fold increased risk). Recent genome-wide association studies in celiac disease and UC showed overlap between genes implicated in the inflammatory cytokine response in the IL2/IL21 region. This suggests that the link between celiac disease and IBD might be genetically derived.

When Do I Suspect Celiac Disease in Patients With Inflammatory Bowel Disease?

Celiac disease should be suspected in IBD patients who do not respond as expected to anti-inflammatory or immunosuppressive therapy. Celiac disease and IBD symptoms can overlap. Therefore, it is challenging to diagnose celiac disease based on symptoms alone. Celiac disease typically presents with gastrointestinal symptoms. However, it can have extra-intestinal manifestations that include nutritional deficiencies, and skin, liver, psychiatric, and metabolic findings.

One skin finding that should direct attention to possible celiac disease is dermatitis herpetiformis (DH), which is a papulovesicular pruritic symmetrical rash that predominantly affects extensor body surfaces and is associated with IgA deposits in the dermal papillae. It is pathognomonic of celiac disease but only affects a minority of celiac disease patients (10%). Sometimes DH might be difficult to differentiate from other skin disorders, and a dermatological consultation with skin biopsies is often necessary. For the biopsies to be sufficient, they should be taken from an area of unaffected skin adjacent to the blisters.

Nutritional deficiencies, including iron deficiency with anemia, are not uncommon in IBD but are a hallmark finding of celiac disease. One should also suspect celiac disease in patients who have persistent elevation of hepatic transaminases. Moreover, testing for celiac disease should occur in patients who have spontaneous fractures, osteopenia, or osteoporosis. Finally, it should be noted that celiac disease is associated with several autoimmune conditions. Therefore, celiac disease should be considered in patients who require unusually high doses of thyroid replacement or have suggestive gastrointestinal symptoms in the setting of insulin-dependent diabetes mellitus or autoimmune rheumatologic and thyroid diseases.

Figure 1. Medium-power image of duodenal mucosa from a Crohn’s disease patient demonstrating shortening and widening of villi, hyperplastic crypts, and surface intraepithelial lymphocytosis, all histologic features that are commonly associated with celiac disease (hematoxylin-eosin stain, original magnification x200).

Figure 2. Lower-power image of a separate biopsy fragment in the same patient in Figure 1 demonstrating more classic histologic features of CD with multifocal active inflammation, ulceration, and centrally located, well-formed, non-necrotizing granuloma (hematoxylin-eosin stain, original magnification x100).

Finally, CD and celiac disease can share similar histologic features such as widened villi, hyperplastic crypts, and surface intraepithelial lymphocytosis (Figure 1). However, multifocal active inflammation, ulceration, and centrally-located, well-formed non-necrotizing granuloma remain the more classic histologic features of CD (Figure 2).

What Should I Do if I Suspect Celiac Disease in a Patient With Inflammatory Bowel Disease?

Serologic testing is the first step in approaching celiac disease diagnosis in IBD patients. Several serologic tests are available with variable specificities. IgA tissue transglutaminase antibodies (IgA-tTG) and immunoglobulin G deaminated glidan peptide antibodies (IgG-DGP) have specificities higher than 95%. IgA-tTG is more widely used than DGP, but it can be normal in IgA-deficient patients. On the other hand, IgG-DGP is more expensive and less widely available but is not affected by IgA levels. Less specific serologic tests including IgA- and IgG-anti–glidan antibodies are falling out of favor due to high rates of false positivity.

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If IgA-tTG or IgG-DGP are positive, or if your index of suspicion for celiac disease is high despite normal serology, the next step should be an upper endoscopy with multiple (6 to 8) duodenal biopsies. The Marsh classification is used for assessing intestinal inflammation and damage in celiac disease and falls into 4 categories (0 to III). Marsh 0 is normal appearing small intestinal mucosa and villi. Marsh I involves increased intra-epithelial lymphocytes (IELs) of > 30 per 100 enterocytes. However, this finding is nonspecific and can be caused by many other conditions including peptic injury, Helicobacter pylori infection, nonsteroidal anti-inflammatory drug use, other autoimmune conditions, and small intestinal bacterial overgrowth. Marsh II is rare and involves increased IELs with crypt hyperplasia, but intact villous architecture. Villous blunting or atrophy is the hallmark of Marsh III and is often diagnostic of active celiac disease. Multiple biopsies from the duodenum are necessary since celiac disease can be patchy in nature. Moreover, normal duodenal bulb biopsies can sometimes be misinterpreted as celiac disease due to distortion of the villous architecture by underlying Brunner’s glands and the presence of changes in peptic duodenitis. Finally, changes of duodenal CD may be mistaken for those of celiac disease and vice versa. However, the nature of the inflammatory infiltrate will usually allow for correct differentiation by an experienced GI pathologist.

Some patients will start the gluten-free diet (GFD) before any specific testing for celiac disease is performed. In such cases, the negative predictive value of serologic testing significantly drops after a few weeks of GFD. Human leukocyte antigen (HLA) testing for DQ2 and DQ8 can be useful in reliably excluding celiac disease if negative. However, a positive result for either HLA type carries a low positive predictive value. Definitive diagnosis often requires gluten challenge with duodenal biopsy if the patient is willing and able to tolerate it. A detailed approach to gluten challenge is provided in Figure 3.

Figure 3. Proposed modified gluten challenge algorithm. (Reproduced from Leffler D, Schuppan D, Pallav K, et al. Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease. *Gut*. 2013;62(7):996-1004 with permission from BMJ Publishing Group Ltd.)

Figure 4. Workup of nonresponsive celiac disease (NRCD). Abbreviations: CD, Celiac Disease; Ttg, Tissue transglutaminase antibody; DGP, Deamidated Gliadin Peptide; IgA, Immunoglobulin A; IgG, Immunoglobulin G. (Reproduced from Pallav K, Leffler DA, Tariq S, et al. Noncoeliac enteropathy: the differential diagnosis of villous atrophy in contemporary clinical practice. *Alimentary Pharmacology & Therapeutics.* 2012;35:380–390 with permission from John Wiley and Sons.)

How Should I Treat and Follow IBD Once Celiac Disease is Confirmed?

The cornerstone treatment of celiac disease is life-long GFD. Over 90% of celiac disease patients improve with the GFD alone. Clinical improvement usually occurs within 1 to 2 weeks of starting the diet and precedes serologic improvement and intestinal healing. Once diagnosed, patients should be referred for education on the GFD by a specialized dietician. Serologic follow-up is recommended every 3 to 6 months until normal, after which annual surveillance is sufficient. The need for follow-up endoscopy and biopsy is controversial and is not mandatory as long as the patient is clinically improving. Many patients will continue to have abnormalities on biopsy despite a lack of symptoms and normal serology. This is expected, and no therapeutic changes are recommended other than ensuring that the patient understands and adheres to the GFD.

A daily gluten-free multivitamin is generally recommended to patients with celiac disease on a GFD. Vitamin D supplements are reserved for patients with vitamin D deficiency. Bone mass densitometry is recommended 1 year after starting the GFD in celiac patients with IBD; long-standing symptoms; or a history of osteopenia, osteoporosis, or use of systemic steroid therapy.

What if the Gluten-Free Diet Does Not Work for My Patient?

Nonresponsive celiac disease (NRCD) may be defined as continued symptoms or clinical manifestations suggestive of active celiac disease despite treatment with a GFD. Many conditions can mimic or complicate celiac disease. The first step is to assess the patient’s adherence to the GFD, as dietary noncompliance is the most common reason for persistent symptoms in celiac disease. Another important step is to reconfirm the initial diagnosis of celiac disease, especially the serology and histology findings prior to the GFD. If any doubt remains, the initial pathology slides should be re-evaluated by an experienced gastrointestinal pathologist. Other conditions that can lead to NRCD include small intestinal bacterial overgrowth, disaccharide and other food intolerances, microscopic colitis, pancreatic insufficiency, and coexisting IBD. Repeating small bowel biopsy and comparing it to the biopsies obtained prior to starting the GFD will determine if there is continued celiac disease activity. Figure 4 illustrates an approach to the workup of NRCD.

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Refractory celiac disease accounts for only 2% of celiac disease cases and 10% of NRCD. In refractory celiac disease, severe villous atrophy and inflammation persist despite the GFD. T-cell studies done by immunohistochemical staining of small intestinal biopsy tissue and/or intestinal T-cell receptor analyses can determine whether the refractory celiac disease is Type I (absence of abnormal T-cells) or Type II (presence of abnormal T cells). Type I refractory celiac disease is a less severe condition and often responds to treatment with enteric-coated budesonide or small intestine release mesalamine. Type II refractory celiac disease carries a high mortality rate as a result of severe malabsorption or transition to enteropathy-associated T-cell lymphoma. It may be treated with systemic steroids and immunosuppressive agents, but treatment is often ineffective.

Which Conditions can Mimic Celiac Disease and Crohn’s Disease of the Small Intestine?

Several small intestinal disorders can mimic the symptoms and features of celiac disease or CD. This will lead to apparent NRCD because patients will not respond to the GFD. Patients will also be less likely to respond to standard treatments for CD. Combined variable immune deficiency (CVID) can clinically and histologically mimic CD and celiac disease. It is easily identified by measuring total serum immunoglobulin concentrations (IgA, IgG, immunoglobulin M and IgG subclasses). Microscopic colitis can present with persistent diarrhea and is strongly associated with coexisting celiac disease. Other conditions include eosinophilic gastroenteritis, peptic duodenitis (a common reason for histologic misdiagnosis), collagenous sprue, and tropical sprue. Nonceliac enteropathies that cause villous atrophy include autoimmune enteropathy (where anti-enterocyte antibodies are sometimes helpful in diagnosis), postviral enteropathy, and immune-mediated enteropathy. Negative serologies for tissue transglutaminase and for deamidated gliadin peptide at presentation and prior to the GFD are a definite indication to consider causes other than celiac disease in patients with malabsorption and villous atrophy. Human leukocyte antigen testing for DQ2 and DQ8 may be helpful in excluding a diagnosis of celiac disease in this circumstance.

What Risk Does Celiac Disease Add to Inflammatory Bowel Disease Patients?

The main implication for patients with both celiac disease and IBD is that the diagnoses may be delayed due to overlap in the signs and symptoms of the two conditions. Celiac disease puts IBD patients at higher risk for nutrient deficiencies including iron, fat-soluble vitamins like vitamin D, and water-soluble vitamins including B12 and B6. Untreated celiac disease increases the risk of intestinal lymphoma (8 cases per 10,000 patient-years). However, this risk decreases after 1 year of treatment with a reported odds ratio of 1.22 (95% confidence interval, 1.13 to 1.32). The lifelong risk for celiac disease in first- and second-degree relatives of celiac patients is around 8% and 4%, respectively. Young children in high-risk groups (eg, a first- or second-degree relative of someone with celiac disease) are recommended to have serologic testing regardless of symptoms. Further testing will be required if suggestive symptoms occur later in life. Screening of adult relatives is more controversial but is certainly indicated in symptomatic subjects or in subjects with possible manifestations of celiac disease such as iron deficiency.

Excerpted from:

References:
Casella G, et al. Dig Liver Dis. 2010;42(3):175-178.
Green PH, Cellier C. N Engl J Med. 2007;357(17):1731-1743.
Leffler DA, Kelly CP. Curr Opin Allergy Clin Immunol. 2006;6(3):191-196.
Leffler D. JAMA. 2011;306(14):1582-1592.
Leffler D, et al. Gut. 2013;62(7):996-1004.
Pallav K, et al. Aliment Pharmacol Ther. 2012;35(3):380-390.

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