Angela Fabbri

Serological tests in gluten sensitivity (nonceliac gluten intolerance).

Goals: To characterize the serological pattern of gluten sensitivity (GS) and to compare it with that found in celiac disease. Background: GS has recently been identified as a new clinical entity included in the spectrum of gluten-related disorders, but it is still lacking of diagnostic markers. Study: Sera from 78 patients with GS and 80 patients with celiac disease were retrospectively assessed for immunoglobulin (Ig)G/IgA antigliadin antibodies (AGA), IgG deamidated gliadin peptide antibodies (DGP-AGA), IgA tissue transglutaminase antibodies (tTGA), and IgA endomysial antibodies (EmA). Results: IgG AGA were positive in 56.4% of GS patients and in 81.2% of celiac patients, with high antibody titers in both groups. IgA AGA were detected in 7.7% of GS patients and in 75% of celiac patients, showing lower enzyme-linked immunosorbent assay activities in GS than those found in celiac disease. Only 1 of the 78 patients with GS was positive for IgG DGP-AGA (detected in 88.7% of patients with celiac disease). IgA tTGA and IgA EmA were negative in all GS patients, whereas their positivity in celiac patients was 98.7% and 95%, respectively. Patients with GS displayed a variegated clinical picture with intestinal and extraintestinal symptoms (abdominal pain, bloating, diarrhea, constipation, foggy mind, tiredness, eczema/skin rash, headache, joint/muscle pain, numbness of legs/arms, depression, and anemia) together with normal or mildly abnormal small intestinal mucosa. Conclusions: The serological pattern of GS is characterized by IgG AGA positivity in more than half of cases associated to IgA AGA in a few patients, but without EmA, tTGA, and DGP-AGA, which are the specific markers of celiac disease.

Deamidated gliadin peptide antibodies as a routine test for celiac disease: a prospective analysis.

Goals This study was designed to establish whether deamidated gliadin peptide antibodies (DGP-AGA) could improve the serologic workup for celiac disease (CD). Background The best serologic approach for CD screening is currently based on the combined detection of tissue transglutaminase (tTGA), endomysial (EmA), and gliadin antibodies (AGA). Study One hundred forty-four consecutive patients with gastrointestinal and extraintestinal signs suggestive for CD were investigated using serologic tests, that is, IgG and IgA DGP-AGA, IgA tTGA, IgA EmA, and duodenal biopsy. Results Forty-eight out of 144 patients (33%) had CD with different severity of villous atrophy. IgA tTGA showed 93.7% sensitivity compared with 91.6% for IgA EmA, 84.3% for IgA DGP-AGA, and 82.3% for IgG DGP-AGA. Of the 3 cases negative for IgA tTGA, IgA EmA, and IgA DGP-AGA, 2 had total IgA deficiency, although both were positive for IgG DGP-AGA. IgG DGP-AGA showed a very high specificity for CD (98.9%), not only superior to IgA DGP-AGA (79.8%), but also to IgA tTGA (96.6%) and very close to IgA EmA (100%). Conclusions Our prospective study shows that the combined search for IgA tTGA and IgG DGP-AGA provides the best diagnostic accuracy for CD, allowing the identification of all CD cases---except one---with a very high specificity. The serologic workup for CD screening could be significantly improved by the routine introduction of IgG DGP-AGA together with IgA tTGA, thus reducing the number of tests and with an obvious advantage in terms of cost-efficacy.

Review article: autoimmune hepatitis -- current management and challenges.

Autoimmune hepatitis (AIH) is a disease of unknown aetiology characterised by interface hepatitis, hypergammaglobulinaemia, circulating autoantibodies and a favourable response to immunosuppression.

Fatigue and pruritus at onset identify a more aggressive subset of primary biliary cirrhosis

In recent years, primary biliary cirrhosis is mostly diagnosed in patients who are asymptomatic; however, a proportion of cases still present with typical complaints such as fatigue and/or pruritus. We compared biochemical, histological and immunological features of patients with or without fatigue and/or pruritus at onset to see whether the different clinical presentation may eventually impact on disease progression.

Old and new serological tests for celiac disease screening

Evaluation of: Lewis NR, Scott BB. Meta-analysis: deamidated gliadin peptide (DGP) antibody and tissue transglutaminase (tTG) antibody compared as screening test for celiac disease. Aliment. Pharmacol. Ther. 31(1), 73–81 (2010). In celiac disease (CD), deamidation of gliadin peptides, induced by tissue transglutaminase (tTG), generates novel antigenic epitopes evoking a specific immune response. Serological tests based on the detection of antibodies to deamidated gliadin peptides (DGP) have been developed with very promising results in terms of sensitivity and specificity for CD screening. In the present study, a meta-analysis of studies published from 1998 to 2008 was designed to compare the performance of DGP antibodies with that of tTG antibodies, the validated and routinely employed test for CD screening. The authors have limited their analysis to IgA class antibodies underlining that most of the considered studies had methodological imperfections, especially ascertainment bias. The results of this meta-analysis indicated that the pooled sensitivities for DGP and tTG antibodies were 87.8% (95% CI: 85.6–89.9) and 93% (95% CI: 91.2–94.5), respectively, and the pooled specificities were 94.1% (95%CI: 92.5–95.5) and 96.5% (95% CI: 95.2–97.5), respectively. In summary, although both tests represent a very good tool for identifying celiac patients, tTG antibodies display a higher predictive value than DGP antibodies, and must still be considered the best serological test for CD screening.

Autoimmune liver disease and concomitant extrahepatic autoimmune disease.

Aim To assess the frequency and clinical impact of associated extrahepatic autoimmune diseases (EAD) on autoimmune liver diseases (ALD). Patients and methods We investigated 608 patients with ALD (327 autoimmune hepatitis – AIH and 281 primary biliary cirrhosis – PBC) for concomitant EAD. Results In both AIH and PBC, we observed a high prevalence of EAD (29.9 and 42.3%, respectively); both diseases showed a significant association with autoimmune thyroid disease, followed by autoimmune skin disease, celiac disease, and vasculitis in AIH patients and sicca syndrome, CREST syndrome, and celiac disease in PBC patients. At diagnosis, AIH patients with concurrent EAD were more often asymptomatic than patients with isolated AIH (P<0.01). Conclusion Our study confirms the strict association between ALD and EAD, in particular with autoimmune thyroid disease. In the light of our results, all patients with an EAD should be assessed for the concomitant presence of an asymptomatic ALD.

Type 1 and type 2 autoimmune hepatitis in adults share the same clinical phenotype

Autoimmune hepatitis (AIH) is historically classified into type 1 and type 2 on the basis of the autoantibody profile, anti‐nuclear and/or anti‐smooth muscle antibodies being the serological markers of type 1 AIH, whereas anti‐liver/kidney microsomal antibody type 1 and/or anti‐liver cytosol antibody type 1 characterise type 2 AIH.

Features and Progression of Asymptomatic Autoimmune Hepatitis in Italy

BACKGROUND & AIMS Patients with autoimmune hepatitis (AIH) can present with symptoms ranging from those that are insidious and nonspecific to acute hepatitis with jaundice. However, some patients have no symptoms at diagnosis and are identified incidentally. We investigated disease progression and outcomes of these 2 groups of patients. METHODS We performed a retrospective study to compare clinical, immunologic, and histologic features and outcomes of patients with asymptomatic vs. symptomatic AIH. We analyzed data collected from 305 patients (90 asymptomatic and 215 with symptoms), diagnosed with AIH from 1994 and 2013, at the Center for the Study and Treatment of the Autoimmune Diseases of the Liver and Biliary System in Bologna, Italy. RESULTS At diagnosis, patients with asymptomatic AIH had significantly lower mean levels of alanine aminotransferase (7.0- ± 8.0-fold the upper limit of normal) than patients with symptomatic disease (23.0- ± 18.0-fold the upper limit of normal; P < .001), and lower mean levels of bilirubin (1.4 ± 1.4 mg/dL vs. 8.6 ± 10.4 mg/dL; P < .001). Asymptomatic patients also had significantly lower histologic grades (7.0 ± 2.5) than symptomatic patients (9.0 ± 2.9; P < .001). However, larger proportions of asymptomatic patients had anti-liver/kidney microsomal antibodies type 1 (26.8% vs. 13.1%; P < .006), and associated autoimmune thyroid (26.7% vs. 12.6%; P = .003) or skin (8.9% vs. 2.3%; P = .010) disorders. Age at onset, sex, response to therapy, disease progression, genetic factors, and other autoantibody markers did not differ between patients with asymptomatic vs. symptomatic disease. CONCLUSIONS Patients with asymptomatic vs. symptomatic AIH have similar courses of disease progression and responses to immunosuppressive agents, and therefore should receive the same treatment. Patients affected by thyroid or dermatologic autoimmune disorders are at increased risk of developing subclinical liver disease, and should be assessed routinely for AIH.

Sensorineural hearing loss and celiac disease: A coincidental finding

BACKGROUND Celiac disease (CD) can be associated with a variety of extraintestinal manifestations, including neurological diseases. A new neurological correlation has been found between CD and sensorineural hearing loss (SNHL). OBJECTIVE To verify the association between SNHL and CD, and to establish whether the neurological hearing impairment in CD is related to nonorgan-specific and antineuronal antibodies, as well as the presence of autoimmune disorders. METHODS A sample of 59 consecutive biopsy- and serologically proven CD patients were studied. Among CD patients, 11 were newly diagnosed and 48 were on a gluten-free diet. Hearing function was assessed by audiometric analysis in all CD patients as well as in 59 age- and sex-matched controls. Patients were tested for a panel of immune markers including nonorgan-specific autoantibodies and antineuronal antibodies. RESULTS SNHL was detected in five CD patients (8.5%) and in two controls (3.4%). In one patient, the SNHL was bilateral, whereas the remaining four had a monolateral impairment. The prevalence of SNHL was not significantly different between CD patients and controls. At least one of the antibodies tested for was positive in two of the five CD patients with SNHL and in 12 of the 54 CD patients without SNHL. Antineuronal antibodies to central nervous system antigens were consistently negative in the five CD patients with SNHL. Only one of the five CD patients with SNHL had Hashimoto thyroiditis. CONCLUSIONS SNHL and CD occur coincidentally. Hearing function should be assessed only in CD patients with clinical signs of hearing deficiency.

Non-invasive markers of inflammation in autoimmune hepatitis.

The treatment of autoimmune hepatitis (AIH) aims to downregulate the inflammatory mechanisms responsible for the appearance of the disease and to achieve sustained disease remission. Remission is conventionally considered the resolution of the clinical symptoms, when present, the complete normalization of biochemical parameters (serum aminotransferases and c-globulins levels) and the complete resolution of hepatic inflammatory activity as the ideal treatment endpoint (1). A standardized, universally accepted, definition of remission in patients with AIH exists since 1999 (2). The concept of remission in the treatment of autoimmune hepatitis has changed over the years; in the past a reduction in aminotransferases levels below twice the upper limit of normal had been considered as a satisfactory remission (3). This definition of remission associated with persistent moderate ALT abnormalities derived from ancient clinical trials (4–6) for the treatment of AIH and remained unchanged for over 40 years. Randomized controlled trials (RCTs) in the 1970s that established the efficacy of corticosteroids in the treatment of AIH included severe cases of AIH with rapidly progressive disease. The goal of therapy was to reduce both mortality and inflammatory activity; authors were not concerned with the risk that residual inflammatory activity could be the cause of a slowly progressive disease. Patients with less severe disease probably were not included in those RCTs (7). Subsequently, several reports underlined that the persistence of mildly elevated transaminases and hypergammaglobulinaemia during treatment was associated with histological evidence of ongoing hepatic inflammatory activity, and this persistent inflammatory activity was a harbinger of disease progression and reactivation. These studies also told us that normal laboratory values during treatment do not guarantee the resolution of histological inflammatory activity. Thus, a diagnosis of resolution required the assessment of a liver biopsy (8–10). This formed the basis of the AASLD guidelines 2010 (1) that defined for the first time remission as a complete normalization of aminotransferases and immunoglobulin. In a retrospective analysis of disease progression in patients who achieved complete or incomplete normalization of laboratory parameters with immunosuppressive treatment, it was demonstrated that those patients who achieved complete and persistent normalization of transaminases and immunoglobulins had a significantly lower risk of histological progression when compared with patients who did not completely normalize liver tests (11). Recent progress has made the diagnosis of AIH possible in an earlier phase of its natural history. Thus, the aim of treatment is no longer solely focused on the reduction of medium term mortality but it has shifted to achieving persistent control of inflammatory activity. This in turn reduces or abolishes the risk of disease progression with the appearance of cirrhosis and its complications (i.e. decompensation, need of liver transplant and hepatocellular carcinoma). Balancing the control of liver inflammation through close monitoring of disease activity and steroid side effects is often a difficult task. Liver biopsy is the gold standard for the fibrosis and inflammation severity assessment. It is also an invasive procedure with a limited tangible morbidity, frequently not acceptable to patients, and not suitable to be frequently repeated (12). The accuracy of the liver biopsy in assessing fibrosis is hampered by intraand interobserver discrepancies and is poorly reproducible because of sampling error. Liver biopsy in fact is based on a sample that represents one fifty thousandth of the whole liver parenchyma and should be evaluated with caution and within the broader clinical context. Therefore, transaminases and immunoglobulin levels are commonly used in clinical practice to monitor disease activity, but data supporting the close relationship between these markers and histological activity are still an open question. L€ uth et al. have approached this problem by comparing the histological activity of liver biopsies with serum parameters. They demonstrated that normal ALT and IgG were in most cases (52%) indicative of a histological activity index (HAI) <6, but often associated with HAI scores of 4 or 5. None of the patients with a HAI score of 4 or 5 showed fibrosis progression during observation for 3 years (13). It must be said that a histological activity index of 4 or 5 cannot be considered histological remission. These patients have persistent albeit mild inflammatory activity and are at high risk of reactivation after drug withdrawal. A reliable assessment of the inflammatory activity is crucial in determining progression and may