From the Guidelines
Seronegative celiac disease is a condition where patients have villous atrophy and compatible HLA genetics, but test negative for celiac disease antibodies, and show clinical and histologic response to a gluten-free diet.
Definition and Diagnosis
- It is defined as patients with or without gastrointestinal signs and symptoms of celiac disease, with villous atrophy and compatible HLA genetics, and without IgA/IgG tTG and IgA/IgG DGP and IgA/IgG EMA antibodies 1.
- The diagnosis of seronegative celiac disease can be established by a clinical and histologic response to the gluten-free diet in patients with consistent pathology and compatible HLA haplotypes 1.
Prevalence and Characteristics
- Seronegative celiac disease comprises approximately 1.7%–5% of patients with celiac disease 1.
- It is the most common etiology of seronegative enteropathy, representing up to one-third of cases in White patients 1.
Challenges in Diagnosis
- The differential diagnosis for seronegative enteropathy is broad and includes immune-mediated, infectious, and iatrogenic causes, among others 1.
- An accurate diagnosis of seronegative enteropathy may be complicated by challenges such as poorly oriented duodenal mucosa leading to misinterpretation of histologic findings, use of immunosuppressive agents masking serologic findings, or inadequate or incorrect use of serology testing 1.
From the Research
Definition and Characteristics of Seronegative Celiac Disease
- Seronegative celiac disease is a poorly defined form of celiac disease that poses a diagnostic challenge due to the lack of a consensus on its definition and incorrect use of specific celiac serology 2.
- It is characterized by the absence of anti-tissue transglutaminase antibodies and endomysial antibodies, despite clinical signs of celiac disease and an abnormal duodenal biopsy 3.
- Seronegative celiac disease is rare, accounting for a small percentage of cases in the large population of celiac patients, and strict criteria for diagnosis need to be fulfilled 2.
Diagnostic Criteria and Challenges
- The diagnostic workup of seronegative villous atrophy must ensure exclusion of other enteropathies before starting patients on a lifelong gluten-free diet 2.
- The diagnosis of seronegative celiac disease can be confirmed by clinical and histologic improvements after 1 year of a gluten-free diet, in the presence of flat villi, positive HLA-DQ2 and/or HLA-DQ8, and the absence of celiac disease antibodies 4.
- The management of seronegative celiac disease is still debated, and the treatment option may be represented by a gluten-free diet, but its usefulness and appropriateness are controversial 5.
Clinical and Histological Features
- Seronegative celiac disease is often characterized by a higher median age at diagnosis, a higher prevalence of classical phenotype, autoimmune disorders, and severe villous atrophy compared to seropositive celiac disease 6.
- The condition is also associated with mucosal deposits of tissue transglutaminase (tTG)/anti-tTG immuno-complexes, which may counteract the passage of anti-tTG into the bloodstream, explaining seronegativity 5.
- Flow cytometry-determined duodenal immunophenotypes and rates of refractory celiac disease are similar in seronegative and seropositive celiac disease 3.
Epidemiology and Outcome
- Seronegative celiac disease is uncommon, and epidemiological data are scarce and contrasting 2.
- There is some data to suggest that seronegative enteropathies have a higher mortality than conventional celiac disease 2.
- Further cooperative studies are highly desirable to improve the knowledge of seronegative celiac disease and its outcome 4.