The Landscape of Celiac Disease Testing and Treatment

What is Celiac Disease?

Celiac disease is a clinically heterogeneous condition caused by an autoimmune response with exposure to gluten that may be found in cereals such as wheat, rye, barley, spelt, and kamut. It is estimated that celiac disease affects approximately 1% of the global population. There has been a recent increase in the diagnosis of celiac disease, partly due to the development of newer tests with high sensitivity and specificity. Many people remained undiagnosed before these tests were clinically available.  Celiac disease diagnoses have increased 500% in the United States between 1975 and 2000. Indeed, such a drastic change cannot be explained by advances in testing alone and is not completely understood. Other factors that are likely to contribute in this upsurge is the increased consumption of wheat with high gluten content, and preparation methods using Baker’s yeast.

Celiac disease is multifactorial, having both genetic and environmental influences. The genetic component of celiac disease is compelling, as there is a high concordance in monozygotic twins (75-80%) and high familial recurrence (10-15%).  The presence of DQ2 and DQ8 variants of the HLA gene increases the risk for celiac disease above the general population. Furthermore, when two copies of the HLA-DQ2 variant are present, there may be a 25-30% increased risk for celiac disease especially when there is also an affected first-degree relative.

The clinical presentation of celiac disease is variable, and symptoms are classified as intestinal or extra-intestinal. Intestinal symptoms may include chronic diarrhea, nutritional malabsorption, bloating, constipation, abdominal pain, weight loss, and fatty stool. Extra-intestinal symptoms may include anemia (microcytic or macrocytic), bone mineral density changes, hair loss, growth retardation and delayed puberty in children, headache, anxiety, fatigue, depression, and even infertility in adults. Immunological factors, age of diagnosis, duration of disease, gender, and family history are factors that may impact symptomatic differences among patients.

Diagnosing Celiac Disease

Prior to reliable testing, the diagnosis was dependent upon the patient’s symptoms. This was challenging given their wide range and severity, and the overlap with other health conditions. Celiac disease is diagnosed by a combination of positive serological tests and duodenal biopsy results. There are three antibody tests commonly used to diagnose celiac disease. Anti-tissue transglutaminase (TTG) is often the first line of testing, which has a 93-95% sensitivity and 91-95% specificity for celiac disease. It uses ELISA laboratory technique. Anti-endomysial antibody(EMA) is another highly accurate serological test. However, it is more expensive and technically challenging compared to TTG testing since it uses immunofluorescence. Deaminated gliadin peptide (DGP) is especially valuable in screening young children (< 2 years old). It is important to note that these serological tests must be performed while the patient is on a gluten diet, or there is a risk for a false negative result. Characteristic histologic features in small intestinal biopsy is considered the “gold standard” for diagnosis. Intestinal changes due to celiac disease can be patchy, so multiple biopsies are taken from the duodenum. Usually, 1-2 specimens are taken from the duodenal bulb (which is closest to the stomach), and at least four specimens are taken from the post-bulbar section. The duodenum has finger-like protrusions in the lining called villi that assist in nutrient absorption. Celiac disease will cause the villi to be blunted or flattened, and there may be fissuring of the mucosal folds. Histological changes of the duodenal mucosa reflect disease progression; therefore, mild cases may not be easy to interpret. Fortunately, there are different classification guides to assist in rating subtle morphological changes. Genetic testing for the DQ2 and DQ8 HLA genetic variants may be incorporated into a testing algorithm when celiac disease is suspected but serological testing results are conflicting. Genetic testing is also informative when there is a known affected family member who tests positive for the genetic markers.

Celiac Disease Treatment

Treatment for celiac disease is a gluten-free diet (GFD), which may eliminate intestinal and extra-intestinal symptoms, including regrowth of duodenal villi. However, GFD is not without some adverse effects, including negative impact on quality of life, vitamin and mineral deficiencies, constipation, and increased risk for cardiovascular disease. Nutrition can be managed by a dietician, and counseling may be helpful to patients navigating the emotional impact of a GFD for life. Based on patient demand for treatments outside of GFD, other therapies are being investigated. Two promising treatments are larazotide acetate and latiglutenase, a gluten-specific protease. Larazotide acetate is a peptide consisting of 8 amino acids. It blocks the intestinal tight junction from opening, thus impeding the absorption of gluten, which triggers the immune response. Perhaps this therapy could help patients tolerate some minimal gluten exposure. Latiglutenase breaks down gluten in the stomach prior to reaching the intestine. Studies have shown an improvement in patient-reported abdominal pain, bloating, tiredness and constipation with latiglutenase use. Both therapies are still in clinical trials and are not clinically available as treatments.

Celiac disease continues to increase around the world. Physicians have multiple testing technologies available to diagnose celiac disease including serological, histological, and genetic tests. Furthermore, there are different testing algorithms available which may assist physicians in their assessment of patients who present with symptoms of celiac disease. The only definitive treatment is a gluten-free diet for life. However, going gluten-free has its own set of nutritional and quality of life challenges. Fortunately, there are therapies being researched that may assist patients in treatment and management that can increase their quality of life. Perhaps in the near future, there will be different therapeutic options for those diagnosed with celiac disease.

References

Cecilio LA, Bonatto MW. The prevalence of HLA DQ2 and DQ8 in patients with celiac disease, in family and in general population. Arq Bras Cir Dig. 2015 Jul-Sep;28(3):183-5. doi: 10.1590/S0102-67202015000300009. PMID: 26537142; PMCID: PMC4737358.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737358/

Caio G, Volta U, Sapone A, Leffler DA, De Giorgio R, Catassi C, Fasano A. Celiac disease: a comprehensive current review. BMC Med. 2019 Jul 23;17(1):142. doi: 10.1186/s12916-019-1380-z. PMID: 31331324; PMCID: PMC6647104.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647104/

Kowalski K, Mulak A, Jasińska M, Paradowski L. Diagnostic challenges in celiac disease. Adv Clin Exp Med. 2017 Jul;26(4):729-737. doi: 10.17219/acem/62452. PMID: 28691413.

https://www.advances.umed.wroc.pl/pdf/2017/26/4/729.pdf

Singh A, Pramanik A, Acharya P, Makharia GK. Non-Invasive Biomarkers for Celiac Disease. J Clin Med. 2019 Jun 21;8(6):885. doi: 10.3390/jcm8060885. PMID: 31234270; PMCID: PMC6616864.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616864/

Taraghikhah N, Ashtari S, Asri N, Shahbazkhani B, Al-Dulaimi D, Rostami-Nejad M, Rezaei-Tavirani M, Razzaghi MR, Zali MR. An updated overview of spectrum of gluten-related disorders: clinical and diagnostic aspects. BMC Gastroenterol. 2020 Aug 6;20(1):258. doi: 10.1186/s12876-020-01390-0. PMID: 32762724; PMCID: PMC7409416.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409416/

Syage JA, Green PHR, Khosla C, Adelman DC, Sealey-Voyksner JA, Murray JA. Latiglutenase Treatment for Celiac Disease: Symptom and Quality of Life Improvement for Seropositive Patients on a Gluten-Free Diet. GastroHep. 2019 Nov;1(6):293-301. doi: 10.1002/ygh2.371. Epub 2019 Oct 8. PMID: 32313451; PMCID: PMC7169937.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169937/

Yoosuf S, Makharia GK. Evolving Therapy for Celiac Disease. Front Pediatr. 2019 May 14;7:193. doi: 10.3389/fped.2019.00193. PMID: 31157194; PMCID: PMC6530343.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530343/