Approach to Diagnosis & Management of Celiac Disease

Introduction

Celiac disease (CD) is an autoimmune disorder associated with malabsorption caused by permanent intolerance to gluten. It occurs in genetically susceptible individuals¹Ivor H, Martha D, Gregory L, et al. J Pediatr Gastroenterol Nutr 2005; 40(1): 1-19.    ²Wolfgang H, Wolfgang C. Celiac disease. Orphanet Journal of Rare Diseases; 2006,1:3.   and is characterised by villous atrophy and inflammation of the duodenum or jejunum.³Ludvigsson J. F, Green P. H. Clinical management of coeliac disease. J Intern Med 2011;269:560-571.   Gluten is the rubbery mass that remains when wheat dough is washed to eradicate starch granules and other soluble components.⁴Kumar Y, Ujja P. Clinical management of coeliac disease. Indian J Gastroenterol. 2007;26(5):2307.  

The key step of gluten intolerance mainly involves the alteration of the gliadin peptides in gluten by tissue transglutaminase. The altered gliadin peptides are recognised as foreign when presented to local intestinal T cells. Thus, an immune response is stimulated. The gliadin peptides are preferentially presented by a limited number of human leucocyte antigen (HLA) haplotypes, with more than 90% of patients with CD sharing the HLA DQ2 haplotype (DQA1*0501, DQB1*0201 heterodimer) and most of the remainder carrying DQ (alpha 1*0301, beta 1*0302) (Dq8).⁵Daniel L, Sumona S, Richard F. Am J Manag Care 2003;9:825-831.  

The prevalence of CD in children between 2.5 years to 15 years of age is 3 to 13/1000 children in the USA and Europe. The delay between the onset of symptoms and diagnosis of the disease leads to under diagnosis of this disease.¹Ivor H, Martha D, Gregory L, et al. J Pediatr Gastroenterol Nutr 2005; 40(1): 1-19.    CD in children typically presents with gastrointestinal symptoms like diarrhoea, abdominal distentio, or symptoms of malnutrition such as short stature, anaemia, defects in dentition, failure to thrive, or developmental delay. Non specific symptoms like abdominal pain, flatulence, diarrhoea may also be present.⁵Daniel L, Sumona S, Richard F. Am J Manag Care 2003;9:825-831.   The symptoms of CD however, differ from case to case and can range from asymptomatic (silent) to full blown (symptomatic, clinically overt) CD. The definition of different states of CD is shown in Table 1.

Some autoimmune diseases such as type 1 diabetes, Sjogren syndrome, thyroid diseases (Hashimoto’s thyroiditis and Graves’s disease), autoimmune hepatitis and primary biliary cirrhosis, Selective IgA deficiency, Turner’s syndrome and Down’s syndrome may also be associated with CD.²Wolfgang H, Wolfgang C. Celiac disease. Orphanet Journal of Rare Diseases; 2006,1:3.   Table 2 shows features and conditions associated with CD.

Diagnosis

Owing to high percentage of under diagnosed patients and the broad spectrum of clinical manifestations, it is necessary to follow appropriate and reliable diagnostic steps to reach a proper diagnosis of CD.⁶Markus H, Alexander H, Simon H, et al. Modern diagnosis of coeliac disease and relevant differential diagnoses in
the case of cereal intolerance. Allergo J Int 2014; 23: 67-77.   Figure 1 shows the diagnostic testing algorithm for CD.

Who to diagnose?

It is recommended that CD must be considered in the differential diagnosis of children with:

• Failure to thrive and persistent diarrhoea
• Other persisting GI symptoms, including recurrent abdominal pain, constipation and vomiting.
• Non-gastrointestinal symptoms of CD (dermatitis herpetiformis, dental enamel hypoplasia of permanent teeth, osteoporosis, short stature,delayed puberty and iron-deficient anaemia resistant to oral iron).
• Asymptomatic conditions associated with CD (type 1 diabetes mellitus, autoimmune thyroiditis, Down syndrome, Turner syndrome, Williams’s syndrome, selective IgA deficiency and first-degree relatives of celiac patients).

The testing for asymptomatic children belonging to high risk should begin around 3 years of age, provided that they have had atleast 1 year of adequate gluten containing diet before testing. It is also observed that some individual groups show a negative serological test but subsequently test positive after some years and have biopsies compatible with CD. Thus it is recommended that repeat testing be performed on symptomatic individuals with negative test.¹Ivor H, Martha D, Gregory L, et al. J Pediatr Gastroenterol Nutr 2005; 40(1): 1-19.   

How to diagnose?

Serological tests

In patients with low to moderate probability of CD, serological tests are very helpful.⁷Abdulkarim A.S, Murray J.A. Review article: the diagnosis of coeliac disease. Aliment
Pharmacol Ther 2003; 17: 987-995.   They also play an important role in monitoring the adherence of the patient for gluten free diet. The 3 most commonly available serological tests for diagnosis of CD are:

• Anti-gliadin antibody (AGA)
• Anti-endomysial antibody (EMA)
• Anti-tissue transglutaminase antibody (TTG)

The 3 tests however, differ in sensitivity and accuracy⁵Daniel L, Sumona S, Richard F. Am J Manag Care 2003;9:825-831.   as shown in Table 3.

Gliadin antibodies

Gliadin is water soluble portion of gluten. In CD, gliadins elicit a strong humoral response that originates from the submucosa. The IgA and the IgG subclasses are used as adjuvant diagnostic techniques in the management of CD. However, due to the advent of newer tests with higher sensitivity and specificity, they are not very widely used.⁷Abdulkarim A.S, Murray J.A. Review article: the diagnosis of coeliac disease. Aliment
Pharmacol Ther 2003; 17: 987-995.   The positive predictive value of the test is also higher⁵Daniel L, Sumona S, Richard F. Am J Manag Care 2003;9:825-831.   as compared with other tests, as false positives are frequently observed in conditions like inflammatory bowel disease, peptic ulcer disease, gastro-oesophageal reflux disease and gastroenteritis.⁷Abdulkarim A.S, Murray J.A. Review article: the diagnosis of coeliac disease. Aliment
Pharmacol Ther 2003; 17: 987-995.  

Endomysial antibodies

Endomysium is a connective tissue protein found in the collagenous matrix of human and monkey tissue. It is an immunoflourescence test and mainly involves binding of EMA to Endomysium which produces a characteristic staining pattern. Human umbilical cord or monkey oesophagus is used as substrates.⁵Daniel L, Sumona S, Richard F. Am J Manag Care 2003;9:825-831.   This qualitative test has a high specificity (~ 100%), but is expensive and burdensome.

tTG antibodies

tTG is a cytosolic protein that is released by the damaged epithelium and serves as a cross-linker of different extracellular matrix proteins, resulting in the formation of an -(c-glutamyl)-lysin bond. tTG has advantages over EMA like:

• Enzyme-linked immunosorbent assay (ELISA) based
• Inexpensive
• Lesser time consuming
• No use of substrates
• NO subjective interference of immunoflourescence test

tTG antibody tests are equivalent to EMA with respect to sensitivity. However, in conditions like Downs Syndrome or disorders, there is loss of specificity observed and diagnosis by biopsy becomes essential⁷Abdulkarim A.S, Murray J.A. Review article: the diagnosis of coeliac disease. Aliment
Pharmacol Ther 2003; 17: 987-995.  

Intestinal Biopsy

The gold standard to confirm the diagnosis of CD is intestinal biopsy⁵Daniel L, Sumona S, Richard F. Am J Manag Care 2003;9:825-831.   during the upper endoscopy.⁷Abdulkarim A.S, Murray J.A. Review article: the diagnosis of coeliac disease. Aliment
Pharmacol Ther 2003; 17: 987-995.   Multiple biopsies taken from the second or third part of the duodenum are also important for a definitive diagnosis of CD. Enteroscope is rarely used and on some occasion a small bowel biopsy may also be obtained if the mucous is suspicious of CD.⁷Abdulkarim A.S, Murray J.A. Review article: the diagnosis of coeliac disease. Aliment
Pharmacol Ther 2003; 17: 987-995.   A confirmed CD would display a flat jejunal mucosa with absence of normal intestinal villi.²Wolfgang H, Wolfgang C. Celiac disease. Orphanet Journal of Rare Diseases; 2006,1:3.   The 3 main important characteristics of a biopsy confirming CD are:

1. Partial or complete villous atrophy
2. Crypt hyperplasia
3. Increased intra-epithelial lymphocytes or plasma cells (>40 IEL/100 epithelial cells)⁷Abdulkarim A.S, Murray J.A. Review article: the diagnosis of coeliac disease. Aliment
   Pharmacol Ther 2003; 17: 987-995.  

The typical histological characteristics that pathologists observe to report the stage of CD are shown in Table 4.

In patients with minor histological changes, a 6-week gluten challenge followed by endoscopy can be done. Patients with negative serological results should be out ruled for other conditions, which can cause villous flattening (Table 5). Thus the diagnosis of CD should be confirmed on the basis of a combination of serological tests and intestinal biopsy.²Wolfgang H, Wolfgang C. Celiac disease. Orphanet Journal of Rare Diseases; 2006,1:3.  

Management of CD

The only effective treatment option for the management of CD is lifetime commitment to gluten-free diet (GFD).⁵Daniel L, Sumona S, Richard F. Am J Manag Care 2003;9:825-831.   The exact term “gluten-free” implies a diet that has very low levels of gluten to cause any likely damage. Although the exact quantity below which gluten is harmless is unclear, a review article suggests that gluten below 10mg per day is unlikely to cause any damage to the patients.⁸Tapia A, Ivor H, Ciarán K, et al. ACG Clinical Guidelines: Diagnosis and Management
of Celiac Disease. Am J Gastroenterol 2013; 108:656-676.  

It is recommended that a registered dietician must counsel all patients about their diet. It is very important to educate the patient about the commercial and processed food that is rich sources of gluten. Patients should also be counseled about carefully reading the labels of various food products. Wheat, barley and rye proteins are rich sources of gluten. Wheat flour is generally used as a thickener in the processing of some meat, vegetable, fruit, and dairy products.

Patients should also be screened for iron, folate, Vitamin B₁₂,calcium, and vitamin D and must be treated for deficiency, if any. It is important that patients on GFD should be thoroughly supplemented with multivitamin, iron, calcium and Vitamin D.

The role of oats as a part of GFD is controversial as it is processed from wheat and there are chances of contamination. The American Dietician Association does not recommend oats as a part of GFD.⁵Daniel L, Sumona S, Richard F. Am J Manag Care 2003;9:825-831.   The American College of Gastroenterology guidelines also recommends that “oats should be introduced into the diet with caution and patients should be monitored closely for evidence of adverse reaction”.⁸Tapia A, Ivor H, Ciarán K, et al. ACG Clinical Guidelines: Diagnosis and Management
of Celiac Disease. Am J Gastroenterol 2013; 108:656-676.  

In certain cases, I.V corticosteroid therapy may be used in critically ill patients with acute celiac crisis manifested by severe diarrhoea, dehydration, weight loss, acidosis, hypocalcaemia, and hypoproteinaemia. It is also used rarely in patients presenting with a gliadin shock after gluten challenge. Drugs like corticosteroids and immunosuppressants like azathioprine and cyclosporine may be required in refractory CD. If immunosuppresants fail, total parenteral nutrition may also become essential.⁵Daniel L, Sumona S, Richard F. Am J Manag Care 2003;9:825-831.  

Monitoring of CD

It is necessary to regularly monitor patients for any complications. It is also recommended to monitor the normal growth and development of children. Adherence to GFD should be checked periodically by a combination of history and serological testing. Development of any symptoms should be regularly checked. In patients not showing any clinical response in spite of GFD, upper endoscopy with intestinal biopsies is recommended. Regular follow up with the health care practitioner and dietician is necessary. In case of any gluten contamination, the dietician should be contacted. Figure 2 depicts the approach to manage and monitor CD.

Conclusion

CD is an untreated autoimmune disorder and is often under diagnosed. The symptoms of CD coincide with other conditions; hence differential diagnosis of CD is essential. The diagnosis of CD involves a combination of serological tests with a confirmatory test of intestinal biopsy. The management involves a GFD and proper counseling and education of the patients. Pharmacological agents may also be used in some conditions associated with CD. Thus a multidisciplinary approach for diagnosis, management, and monitoring is essential for proper prognosis in children with CD.

References

1. Ivor H, Martha D, Gregory L, et al. J Pediatr Gastroenterol Nutr 2005; 40(1): 1-19.
2. Wolfgang H, Wolfgang C. Celiac disease. Orphanet Journal of Rare Diseases; 2006,1:3.
3. Ludvigsson J. F, Green P. H. Clinical management of coeliac disease. J Intern Med 2011;269:560-571.
4. Kumar Y, Ujja P. Clinical management of coeliac disease. Indian J Gastroenterol. 2007;26(5):2307.
5. Daniel L, Sumona S, Richard F. Am J Manag Care 2003;9:825-831.
6. Markus H, Alexander H, Simon H, et al. Modern diagnosis of coeliac disease and relevant differential diagnoses in the case of cereal intolerance. Allergo J Int 2014; 23: 67-77.
7. Abdulkarim A.S, Murray J.A. Review article: the diagnosis of coeliac disease. Aliment Pharmacol Ther 2003; 17: 987-995.
8. Tapia A, Ivor H, Ciarán K, et al. ACG Clinical Guidelines: Diagnosis and Management of Celiac Disease. Am J Gastroenterol 2013; 108:656-676.