Doctoral dissertation

Valma Fuchs: Earlier and Less Invasive Diagnosis of Celiac Disease

Valma Fuchs
Celiac disease is a common immune-mediated disease with a variable clinical picture. Treatment with a gluten-free diet (GFD) is simple and efficient. Due to heterogenous phenotypes, the diagnosis is often made after years of persistent symptoms. Undiagnosed celiac disease predisposes patients to impaired quality of life and risk of complications. The heterogenous clinical picture has been suggested to be a reason for the diagnostic delay, but the evidence of the causes and consequences of the delay is insufficient.

M.D. Valma Fuchs studied in her doctoral dissertation factors that predispose or result from diagnostic delay in celiac disease.

Mucosal damage established in small-intestinal biopsies has long been the gold standard of the diagnosis of celiac disease. However, similar histological lesions can also be seen in many other conditions. Moreover, pathologists vary in their interpretations, and the handling and cutting of the biopsies markedly affects the final reading.

High serum levels of transglutaminase 2 antibodies (TG2-ab) have been shown to be highly specific for celiac disease. In 2012, the first European pediatric criteria allowed omitting biopsy in the diagnostics if TG2-ab exceeds the upper limit of normal (ULN) at least 10-fold, endomysium antibodies (EMA) are positive, the disease-associate genotype is confirmed, and symptoms are present. The criteria have been shown to be accurate in clinical pediatric research and have recently been suggested for adult use only in Finland.

The aim of the dissertation was to elucidate factors that predispose or result from diagnostic delay in celiac disease. Another aim was to ascertain whether the pediatric serology-based criteria are accurate in diagnosing adults across a range of pretest probabilities of the disease.

The dissertation consists of three sub-studies. In Study I, factors associated with a long, > 10 years’, diagnostic delay of celiac disease were retrospectively investigated in 825 previously diagnosed adults. In Study II, 611 celiac disease patients diagnosed in 2007-2008 were surveyed at diagnosis and after one year on a GFD, and possible factors associated with a delay of ≥ 3 years were explored. Study III evaluated whether celiac disease can be accurately diagnosed in adults without biopsies with TG2-ab ≥ 10x ULN, positive EMA, and correct genotype. These “triple criteria” were tested in three cohorts with different pretest probability: 421 high-risk individuals with clinical suspicion, 2,358 moderate-risk family members of coeliac disease patients, and 2,722 low-risk subjects from general population.

It was observed in Study I that delayed celiac disease diagnosis of > 10 years declined over time and particularly after 1997, when the first Finnish Current Care Guidelines for celiac disease were issued. The proportion of diagnoses made in primary health care increased over time, but no association between the site of diagnosis and risk of delay was found. A long diagnostic delay was associated with classical celiac disease symptoms such as diarrhea and malabsorption, and with concomitant neurological or musculoskeletal disease, whereas the risk of the delay was reduced in screen-detected patients.

In Study II, a diagnostic delay of ≥ 3 years was associated with poorer quality of life and increased use of primary health care services and use of medications both before and one year after diagnosis. The risk due to delay was not associated with most of the socio-economic factors explored but was reduced in students and homemakers compared to employed patients.

In Study III, the positive predictive value of the “triple criteria” for biopsy- proven celiac disease was 100%. The accuracy was not affected by pretest probability for the disease or by the presence of symptoms. Genotyping did not improve the accuracy of the criteria. Of the 274 newly diagnosed celiac disease patients in Study III, the “triple criteria” were fulfilled in 33%, who thus could have been spared the biopsy.

The findings of this dissertation show that although a long diagnostic delay in celiac disease of over ten years has become rarer, it still occurs in one-fifth of patients. The presence of typical symptoms of celiac disease does not increase the probability of a prompt diagnosis. As a delay of three years is already associated with impaired quality of life and increased use of healthcare services, the delay should still be shortened. The shift in diagnostics towards primary health care has proven useful, which motivates to further educate general practitioners. This dissertation demonstrates that celiac disease can be accurately diagnosed based on high level of TGA-ab and positive EMA without biopsies, which may shorten the diagnostic delay and save the resources of the health care system.

The doctoral dissertation of M.D. Valma Fuchs in the field of Internal Medicine titled  Earlier and Less Invasive Diagnosis of Celiac Disease will be publicly examined in the Faculty of Medicine and Health Technoloy at Tampere University on Friday 6 November starting at 12 o'clock in Arvo building auditorium F114, Arvo Ylpön katu 34. The Opponent will be Docent Laura Merras-Salmio from University of Helsinki. The Custos will be Professor Katri Kaukinen.

The dissertation is available online at
http://urn.fi/URN:ISBN:978-952-03-1720-1

Photo: Aleksi Fuchs