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  • Jefferson Adams
    Jefferson Adams

    Seronegative Celiac Disease

    Reviewed and edited by a celiac disease expert.

    Seronegative celiac disease is rare, and the little data that exist are contradictory. Some data has even indicated that seronegative enteropathies have lead to higher rates of death than standard celiac disease.

    Seronegative Celiac Disease - Image: CC--julietka and snoop
    Caption: Image: CC--julietka and snoop

    Celiac.com 08/27/2018 - Imagine the difficulty of diagnosing celiac disease without the associated blood antibodies, with seemingly normal blood tests. Seronegative celiac disease is one of the most common causes of seronegative villous atrophy, so a biopsy is crucial in such cases, but it can be hard for doctors to justify a biopsy in the face of seemingly normal blood tests. How can researchers learn more?

    Seronegative celiac disease seems like a simple enough condition. It's just the presence celiac disease without the celiac-associated blood antibodies typically found in people with the disorder. Isn't it? Well, not exactly. For one thing, seronegative celiac disease is rare, and the little data that exist are contradictory. Some data has even indicated that seronegative enteropathies have lead to higher rates of death than standard celiac disease.



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    Yet, seronegative celiac disease remains poorly defined, partly from an absence of consensus on an exact definition, and partly due to an imprecise use of specific celiac serology. Due to these factors, accurate celiac diagnosis can be extra difficult in patients with seronegative celiac disease. Even when doctors spot seronegative villous atrophy, they still need to exclude other enteropathies as a potential cause. 

    To try to shed some light on the nature of seronegative celiac disease, a team of researchers recently set out to provide a critical summary of the most recent work on this topic, along with a working definition of seronegative celiac disease. The research team included A Schiepatti, DS Sanders, and F Biagi. They are variously affiliated with the Coeliac Centre/First Department of Internal Medicine, University of Pavia, Pavia, Italy, and with the Academic Department of Gastroenterology, Royal Hallamshire Hospital & University of Sheffield, UK.

    Finding an accepted definition of seronegative celiac disease is crucial in order to ensure that patients receive a correct diagnosis, and thus avoid inappropriate treatment, and the perils associated with long-term untreated celiac disease.

    Since cases of seronegative celiac disease are commonly dealt with individually, it is important to establish strict criteria for the diagnosis of seronegative celiac disease to ensure prompt identification and treatment of these celiac patients. Doing so will require further study, along with input from the scientific community.

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  • About Me

    Jefferson Adams

    Jefferson Adams is Celiac.com's senior writer and Digital Content Director. He earned his B.A. and M.F.A. at Arizona State University, and has authored more than 2,500 articles on celiac disease. His coursework includes studies in science, scientific methodology, biology, anatomy, medicine, logic, and advanced research. He previously served as SF Health News Examiner for Examiner.com, and devised health and medical content for Sharecare.com. Jefferson has spoken about celiac disease to the media, including an appearance on the KQED radio show Forum, and is the editor of the book "Cereal Killers" by Scott Adams and Ron Hoggan, Ed.D.


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  • Related Articles

    Jefferson Adams
    Celiac.com 05/08/2007 - A recent study published in the journal Digestive Diseases and Sciences indicates that lesser degrees of villous atrophy correspond to seronegative celiac disease.
    The study was conducted by researchers J.A. Abrams, B. Diamond, H. Rotterdam, and P.H. Green, of the Department of Medicine, Columbia University College of Physicians and Surgeons in New York City. The research team set out to assess the effectiveness of various serologic tests used to diagnose celiac disease in patients with differing degrees of villous atrophy. The team evaluated 115 adult patients with biopsy-proven celiac disease. All participants met strict criteria, including serologic testing at the time of diagnosis and response to a gluten-free diet,
    71% of participants showed total villous atrophy and 29% showed partial villous atrophy. Of those with total villous atrophy, 77% tested positive for endomysial antibody, compared to 33% with partial villous atrophy (P < 0.001). No difference in sensitivity was found between those who classical presentation of celiac disease versus those with silent presentation.
    Also, patients who were endomysial positive and patients who were endomysial negative showed no difference with respect to age at diagnosis, duration of symptoms, mode of presentation, or family history of celiac disease. Endomysial antibody positivity correlated not with the mode of presentation of celiac disease, but rather, with more severe villous atrophy.
    Lastly, the study showed that, in clinical practice, serologic tests lack the sensitivity reported in the literature.
    Digestive Diseases and Sciences, 2004 Apr; 49(4):546-50.
    health writer who lives in San Francisco and is a frequent author of articles for Celiac.com.


    Jefferson Adams
    Celiac.com 11/04/2015 - A research team that conducted an analysis of the relationship between seronegative celiac disease and immunoglobulin deficiencies also conducted a literature search on the main medical databases, which revealed that seronegative celiac disease poses a diagnostic dilemma.
    The research team included F. Giorgio, M. Principi, G. Losurdo, D. Piscitelli, A. Iannone, M. Barone, A. Amoruso, E. Ierardi, and A. Di Leo. They are variously affiliated with the Section of Gastroenterology at University Hospital Policlinico, Department of Emergency and Organ Transplantation at University of Bari in Bari, Italy.
    They note that villous blunting, intraepithelial lymphocytes (IELs) count and gluten "challenge" are the most reliable markers in addressing seronegative celiac disease. They also note that immunohistochemistry/immunofluorescence tissue transglutaminase (tTG)-targeted mucosal immunoglobulin A (IgA) immune complexes in the intestinal mucosa of seronegative celiac disease patients may be useful.
    In the team's view, tTG-mRNA was similarly increased in seropositive celiac disease and suspected seronegative celiac disease, and strongly correlated with the IELs count. This increase is found even in the IELs' range of 15-25/100 enterocytes, suggesting that there may be a "grey zone" of gluten-related disorders.
    An immune deregulation, severely lacking B-cell differentiatio, underlies the association of seronegative celiac disease with immunoglobulin deficiencies. Therefore, celiac disease may be linked to autoimmune disorders and immune deficits, known as common variable immunodeficiency (CVID)/IgA selective deficiency.
    CVID is a heterogeneous group of antibody dysfunction, whose association with celiac disease revealed only by a positive response to a gluten-free diet. The research team suggests a possible familial inheritance between celiac disease and CVID.
    Selective IgA deficiency, commonly associated with celiac disease, accounts for IgA-tTG seronegativity. Selective IgM deficiency (sIgMD) is rare, with less than 300 documented cases, and is connected to celiac disease in 5% of cases.
    The team diagnosed seronegative celiac disease in a patient affected by sIgMD using the tTG-mRNA assay. One-year on a gluten-free diet restored IgM levels.
    This study data support a link between seronegative celiac disease and immunoglobulin deficiencies, and invites researchers to take a closer look at this connection.
    Source:
    Nutrients. 2015 Sep 8;7(9):7486-504. doi: 10.3390/nu7095350


    Jefferson Adams
    Celiac.com 11/10/2016 - Seronegative villous atrophy (SNVA) is commonly attributed to celiac disease. However, celiac is not the sole cause of SNVA.
    Recent reports have pointed to a connection with angiotensin-2-receptor-blockers (A2RBs), but data on such cases of SNVA was limited to centers dealing with complex case referrals, and not SNVA in general.
    A team of researchers recently completed a clinical and phenotypical assessment of SNVA over a 15-year period. The research team included I Aziz, MF Peerally, JH Barnes, V Kandasamy, JC Whiteley, D Partridge, P Vergani, SS Cross, PH Green, DS Sanders. They are variously affiliated with the Academic Department of Gastroenterology, the Department of Microbiology, the Department of Histopathology at the Royal Hallamshire Hospital in Sheffield, UK, and with the Department of Medicine, Columbia University College of Physicians and Surgeons, Celiac Disease Center, New York, New York, USA.
    Over a 15-year period (2000-2015) the team assessed 200 adult patients with SNVA. Patients were diagnosed with either seronegative celiac disease (SNCD) or seronegative non-celiac disease (SN-non-celiac disease). The team then made baseline comparisons between the groups, with 343 seropositive celiac disease patients serving as controls.
    Of the 200 SNVA cases, SNCD represented 31% (n=62) and SN-non-celiac disease 69% (n=138). The human leucocyte antigen (HLA)-DQ2 and/or DQ8 genotype was present in 61%, with a 51% positive predictive value for SNCD. The breakdown of identifiable causes in the SN-non-celiac disease group comprised infections (27%), inflammatory/immune-mediated disorders (17.5%) and drugs (6.5%; two cases related to A2RBs).
    However, the researchers found no obvious cause in 18%, while duodenal histology spontaneously normalized in 72% of SNVA patients, while those patients were consuming a gluten-enriched diet.
    Following multivariable logistic regression analysis, the only independent factor associated with SN-non-celiac disease was non-white ethnicity (OR 10.8, 95% CI 2.2 to 52.8); in fact, 66% of non-white patients showed GI infections. On immuno-histochemistry all groups stained positive for CD8-T-cytotoxic intraepithelial lymphocytes. However, additional CD4-T helper intraepithelial lymphocytes were occasionally seen in SN-non-celiac disease mimicking the changes associated with refractory celiac disease.
    Most patients with SNVA, especially non-white patients, do not have celiac disease. Furthermore, a subgroup of patients with no obvious cause for their SNVA will show spontaneous histological resolution while consuming gluten. Based on these findings, the researchers encourage doctors to investigate patient condition before prescribing a gluten-free diet.
    Source:
    Gut. 2016 Sep 7. pii: gutjnl-2016-312271. doi: 10.1136/gutjnl-2016-312271.


    Jefferson Adams
    Celiac.com 09/27/2017 - Patients who have clinical, genetic and histological signs of celiac disease, but no serological markers, present a challenge when it comes to making a diagnosis. If the patient doesn't have elevated antibodies, what signs do doctors look for? What's the best way to evaluate the patient's natural history and response to a gluten-free diet?
    A team of researchers recently set out to outline a specific profile, and to evaluate the natural history and response to a gluten-free diet of patients with seronegative celiac disease.
    The research team included Maria Pina Dore; Giovanni Mario Pes; Ivana Dettori; Vincenzo Villanacci; Alessandra Manca and Giuseppe Realdi. They are variously affiliated with the Internal Medicine Section, Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy, with the Baylor College of Medicine, Michael E. DeBakey VAMC, Houston, TX, USA, the Pathology Section, Department of Molecular and Translational Medicine, Spedali Civili and University of Brescia, Brescia, Italy, and with the Pathology Section, Department of Clinical and Experimental Medicine, University of Sassari in Sassari, Italy.
    Patients with duodenal mucosa damage Marsh I, II and III stages, HLA DQ2/DQ8 haplotype and clinical features suggestive of celiac disease, but with negative celiac serology, were defined as seronegative celiac patients.
    The team excluded other common causes of duodenal mucosa damage. They the compared HLA–DR and DQ genotype/haplotype between all Marsh stages of patients with seronegative and seropositive celiac disease. They then assessed clinical features, lab tests and histological findings after a gluten-free diet and a gluten re-challenge. The group provided the team with a long follow-up period to gather data.
    The researchers enrolled a total of 48 patients who fulfilled diagnostic criteria over a 4-year period. Patients with seronegative and seropositive celiac disease showed similar clinical phenotype and HLA−DR and DQ frequencies. However, Marsh I stage was seen in 42% of seronegative patients (42% vs 22%; p<0.05).
    After a 1-year gluten-free diet trial, clinical symptoms, histological features and laboratory testing improved in 40 patients and worsened in those who underwent a 6-months gluten challenge. Five patients with seronegative celiac disease (25%) experienced the occurrence of autoimmune diseases during an average follow-up of about 11 years.
    Patients with seronegative celiac disease did not show any specific profile, but they did see benefits from a gluten-free diet similar to seropositive patients.
    In the absence of more sensitive serological markers, diagnosing seronegative celiac disease remains an often confusing and challenging process of excluding various other possibilities.
    Source:
    BMJ Open Gastro. 2017;4(1):e000159


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