Infection and Autoimmune Liver Diseases

Autoimmune liver diseases (AiLDs) are heterogeneous disorders affecting either the hepatocytes (autoimmune hepatitis, AIH) or the biliary epithelial cells (primary biliary cirrhosis, PBC, and primary sclerosing cholangitis, PSC). Genetic, immunological and environmental factors appear to be involved in the pathogenesis of these conditions. Studies have linked several infectious agents to the development of these diseases and, in particular, to the development of PBC and AIH. The connection between infections and PSC remains largely obscure, however. The most common hypothesis linking infections with AiLDs is based on molecular mimicry and immunological cross reactivity between infectious agents and self-antigens. This chapter discusses those infectious agents investigated in relation to PBC and AIH. We do not discuss PSC because the data are scarce. Notably, the paucity of data is largely due to a lack of studies as opposed to negative findings. © 2015 Elsevier B.V. All rights reserved

Ascites in a patient with episodic angio-oedema and eosinophilia: Thinking outside the box

Episodic angio-oedema with eosinophilia (EAE) or Gleich's syndrome is a rare condition characterised by recurrent episodes of oedema and eosinophilia, accompanied by urticaria, fever and weight gain. The presence of ascites has not been reported so far. We report a 21-year-old Caucasian woman who presented with marked ocular oedema and ascites. Laboratory evaluation revealed marked eosinophilia. During the last 3 months, three episodes of facial and neck oedema were reported, which resolved spontaneously over a period of 3-5 days. The diagnosis of EAE was established after exclusion of secondary causes (infections, allergic reactions, collagen diseases, neoplasms) and clonal disorders associated with marked eosinophilia. Low-dose steroids resulted in eosinophil decrease and complete resolution of symptoms, including ascites. This case highlights that ascites can be a very rare manifestation of EAE particularly if other more frequent causes of ascites have been excluded and the clinical and laboratory findings are supportive of EAE. © BMJ Publishing Group Ltd

p38 mitogen-activated protein kinase impairment of innate immune cells is a characteristic feature of HBeAg-negative chronic hepatitis B

The mitogen-activated protein kinase p38 (MAPK) is implicated in the induction of immune responses by regulating the differentiation of T lymphocytes and production of cytokines. Our aim was to investigate p38MAPK phosphorylation in different stages of the natural history of hepatitis B virus (HBV) infection. Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll-Hypaque density-based centrifugation from 10 patients with HBeAg-negative chronic hepatitis B [HBeAg(−) CHB;HBV-DNA>2000IU/mL], eight patients with HBeAg-negative chronic HBV infection [HBeAg(−) CI;undetectable HBV-DNA] and 8 healthy controls (HCs). p38MAPK phosphorylation was assessed by phospho-specific flow cytometry in PBMCs and cell subsets (CD3+,CD3−,CD56+,CD56−) after stimulation with cytokines (IL-12+IL-2 and IL-12+IL-18) or nonspecific stimuli [arsenite, phorbol 12-myristate 13-acetate (PMA) and ionomycin] at 0,30,60,120 and 240 minutes using p38 phospho-specific conjugated antibodies. ΙFN-γ was determined by ELISA in PBMCs culture supernatants after stimulation with rhIL-2, rhIL-12 and rhIL-18, with and without pre-treatment with the p38 MAPK inhibitor, SB203580. HBeAg(−) CI patients showed the highest expression of phosphor-p38 MAPK in total PBMCs and subpopulations compared to HBeAg(−) CHB and HCs. A striking impairment in p38 phosphorylation was noted in CD56+ cells and in especially in NK cells (CD3-CD56+). SB203580-induced inhibition of p38MAPK phosphorylation was associated with suppression of IFN-γ production in all groups. The universal lack of p38 MAPK activation in CD56+ and in particular in NK cells from HBeAg(−) CHB patients during viremia suggests a potential cell-dependent implication of this pathway in the natural history of HBV infection. © 2019 John Wiley & Sons Lt

Alcoholic liver disease and autoimmune hepatitis: Sometimes a closer look under the surface is needed

Aims: Differential diagnosis of autoimmune hepatitis (AIH) incorporates various liver diseases, including alcoholic liver disease (ALD). We report on clinical, laboratory and outcome characteristics of AIH patients who were initially referred as ALD based on increased alcohol consumption (AIH/ALD). Methods: From 2000-2019, we retrospectively identified 12 AIH/ALD patients [9 males, age: 61 (30-73) years] in our prospective data base of 317 AIH patients. Results: AIH diagnosis was based on aminotransferases elevation in 10 patients, high IgG in 8, compatible autoantibody profile in all and typical/compatible histology in all 9 with available biopsy. There were no significant differences of baseline demographics, presentation, cirrhosis at diagnosis, response to treatment and simplified score compared to 45 age- and sex-matched AIH patients without alcohol consumption and 44 age- and sex-matched ALD patients. However, the AIH/ALD cohort was characterized by more frequent progression to cirrhosis, higher liver-related deaths and overall mortality compared to AIH, though similar to the ALD group. AST/ALT ratio>1 seems to bear a good positive (0.84) and negative predictive value (0.88) for ALD and AIH diagnosis, respectively, but cannot help in discriminating the AIH/ALD variant. Conclusions: AIH should not be forgotten in patients with alcohol use when clinical and laboratory features hint towards the diagnosis of AIH/ALD variant as this group seems to have worse outcome compared to those with AIH alone suggesting the need for closer follow-up and surveillance. Reliable autoantibody testing and cautious interpretation of liver histology appear mandatory for AIH diagnosis in these difficult to diagnose cases. © 202

Autoimmune hepatitis in patients with multiple sclerosis: The role of immunomodulatory treatment

Background: Development of autoimmune hepatitis (AIH) has been sporadically reported in patients with multiple sclerosis (MS) either concurrently or after treatment with immunomodulatory drugs, including interferon-beta (IFN-β) and steroids. Aim: To report a large cohort of 14 patients with MS diagnosed with AIH during an assessment of deranged liver function tests (LFTs). Patients and methods: From 2005 to 2017, we prospectively identified 14 (13 women) patients with MS who suffered also from AIH after investigation in our department for the presence of deranged LFTs. Age at diagnosis of MS was 36.7 ± 9.3 years while at diagnosis of AIH 43.1 ± 12 years. Results: AIH diagnosis was based on elevation of aminotransferases in all patients [alanine aminotransferase: 520 IU/L (range: 115–1219)], elevation of IgG in 6, compatible autoantibody profile in all, including 5 patients with liver-specific autoantibodies and typical or compatible histological features in 11 patients. 5 patients were under treatment with IFN-β plus methylprednisolone pulses, 3 with IFN-β plus oral steroids, 1 with IFN-β, 4 with methylprednisolone pulses whereas 1 patient was free of treatment. The median time from IFN-β initiation to the development of hepatitis was 12 months (range:1–120). Treatment for AIH was initiated in 13 patients with prednisolone (0.5–1 mg/kg/day) plus mycophenolate myfetil (2 g/day) in 10 and prednisolone plus azathioprine in 3 with complete and partial response in 11 and 2 patients, respectively. Conclusions: The differential diagnosis of hepatitis in MS patients should include AIH and in particular when immunomodulatory treatment has been preceded. Autoantibody testing and liver histology play fundamental role in establishing a prompt diagnosis of AIH in these patients. Treatment of AIH in patients with MS seems safe and efficient as complete or partial response was recorded in all of our patients. © 2018 Elsevier Masson SA

Efficacy of n-3 fatty acid supplementation on rheumatoid arthritis’ disease activity indicators: a systematic review and meta-analysis of randomized placebo-controlled trials

Theoretical evidence and previous studies suggest that oralnutrient supplementation (ONS) with n-3 fatty acids for rheumatoid arthritis (RA) has the potential to lower disease activity indicators and non-steroidal anti-inflammatory drug (NSAID) uptake. A systematic search was conducted on five databases/registries from inception until May 23, 2021 with the aim to identify randomized placebo-controlled trials comparing n-3 supplements to placebo on disease-specific outcomes. A total of 23 studies matched the criteria (PROSPERO: CRD42019137041). Pooled analyses revealed that n-3 ONS provided a small effect in reducing pain [standardized mean difference (SMD): −0.16, 95% confidence intervals (CI): −0.40 to 0.09], and tender (SMD: −0.20, 95% CI: −0.46 to 0.05) and swollen joint count (SMD: −0.10, 95% CI: −0.28 to 0.07). In sensitivity analyses, there was a small effect in the reduction of NSAIDs intake (SMD: −0.22, 95% CI: −0.90 to 0.46), and c-reactive protein was reduced only by 0.21 mg/dL (95% CI: −0.75 to 0.33). Similar findings were observed regarding other objective/subjective outcomes. The certainty of the evidence was mostly of “very low/low” quality. Overall, n-3 ONS in RA might have a limited clinical benefit. Previous findings suggesting a reduction in NSAID intake may have been biased from the inadequate blinding of interventions. © 2022 Taylor & Francis Group, LLC

A real-world study focused on the long-term efficacy of mycophenolate mofetil as first-line treatment of autoimmune hepatitis

Background Front-line therapy with mycophenolate mofetil (MMF) in autoimmune hepatitis (AIH) has shown high on-treatment remission rates. Aim To study prospectively in a real-world fashion the long-term outcome of a large group of consecutive treatment-naïve AIH patients. Methods Between 2000 and 2014, 158 patients were recruited but only 131 were eligible for treatment (109 MMF/prednisolone; 22 prednisolone ± azathioprine). Long-term data on outcome after drug withdrawal were evaluated. Patients stopped treatment after having achieved complete response (normal transaminases and IgG) for at least the last 2 years. Results At diagnosis, 31.6% of patients had cirrhosis and 72.8% insidious presentation. A total of 102 of 109 (93.6%) responded initially to MMF within 2 (1-18) months. A total of 78 of 109 (71.6%) had complete response on treatment and 61 of 78 (78.2%) maintained remission off prednisolone. MMF-treated patients had increased probability of complete response compared to those receiving azathioprine (P = 0.03). Independent predictors of complete response were lower ALT at 6 months (P = 0.001) and acute presentation (P = 0.03). So far, treatment withdrawal was feasible in 40/109 patients and 30 (75%) are still in remission after 24 (2-129) months. Remission maintenance was associated with longer MMF treatment (P = 0.005), higher baseline ALT (P < 0.02), lower IgG on 6 months (P = 0.004) and histological improvement. Conclusions Mycophenolate mofetil proved to be an efficient first-line treatment for AIH, achieving so far the highest rates of remission maintenance off treatment (75%) ever published for at least a median of 2 years, although the remission criteria used were strict. However, the risk of potential bias and overestimation of intervention benefits from MMF cannot be completely excluded as this is a real world and not a randomised controlled trial. © 2016 John Wiley & Sons Ltd

Polymorphisms of IL12RB2 may affect the natural history of primary biliary cholangitis: A single centre study

Background. Recent GWAS in primary biliary cholangitis (PBC) showed strong associations with SNPs located within interleukin-12 receptor (IL12R) beta-2 (IL12RB2) gene. Aims.We assessedwhether genetic variation of IL12RB2 is associatedwith laboratory and clinical features of PBC. Methods. Genomic DNA was isolated from 306 patients with PBC and 258 age/gender-matched controls. PBC-specific anti-mitochondrial antibodies (AMA) were tested in all subjects by ELISA. Two SNPs, rs3790567 and rs6679356, of IL12RB2 were genotyped using the MGB-TaqMan SNP assay. Results. Despite comparable age at diagnosis of cirrhotic and noncirrhotic PBC patients, allele A of rs3790567 and allele C of rs6679356 were overrepresented in the former rather than the latter group (P = 0.0009 and P = 0.002, resp.). The risk of cirrhosis at presentation increased when allele A and allele C coexisted. AMA-M2 titres were significantly higher in AA homozygotes of rs3790567 compared to GG homozygotes (132±54 versus 103±62, P = 0.02) and in rs6679356 when C allele was present (P = 0.038). There were no other significant associations between IL12RB2 polymorphisms and laboratory or clinical features. Conclusion. In this first study analyzing phenotypic features of PBC carriers of the IL12RB2 polymorphisms, we found that carriers are more frequently cirrhotic at diagnosis and have significantly higher titres of AMA. Copyright © 2017 Urszula Wasik et al

Assessment of health related quality of life in polish patients with primary biliary cirrhosis

Background Most patients with primary biliary cirrhosis (PBC) have impaired health related quality of life (HRQoL), as assessed by PBC-specific HRQoL (PBC-40) and generic (SF-36) questionnaires. Data on the applicability of PBC-27, a shorter version of PBC-40, have been limited. Aims To assess HRQoL in Polish PBC patients, applying PBC-40, PBC-27 and SF-36 and to associate clinical or laboratory parameters with HRQoL factors. Methods A total of 205 PBC patients (188 females) were analyzed using PBC-40, PBC-27 and SF-36; 85 disease-free demographically matched (in terms of age, gender, ethnicity) individuals were used as normal controls. Results When compared to controls, PBC patients had significantly impaired HRQoL across all the domains of SF-36. HRQoL impairment by PBC-40 and PBC-27 was comparable between cirrhotics and non-cirrhotics, except for significantly worse Itch in cirrhotics (6.5 ± 4.9 vs 5.1 ± 4.3; P = 0.03). In PBC-40/27, alkaline phosphatase (ALP) levels correlated with itch (P = 0.0003). Female patients had marginally impaired cognitive function compared to males by PBC-40 (P = 0.06). Other gender-related differences were not found. Anti-gp210 positive, as well as AMA negative PBC patients, had worse HRQoL features in itch and social/emotional domains of PBC-40/PBC-27 questionnaires. Very strong correlations (P < 0.0001) between PBC-40/PBC-27 and SF-36 were seen for several domains. Conclusions HRQoL is significantly impaired in Polish patients with PBC, independently of gender and disease severity. PBC-40 and PBC-27 questionnaires are efficient in detecting HRQoL impairment in Polish PBC patients. The striking correlation between PBC-40/PBC-27 and SF-36 confirms the usefulness of the former HRQoL measures in PBC patients from Central-Eastern Europe. © 2015 Elsevier Masson SA

Diagnostic and clinical significance of antigen-specific pancreatic antibodies in inflammatory bowel diseases: A meta-analysis

BACKGROUND Non-invasive criteria are needed for Crohn’s disease (CD) diagnosis, with several biomarkers being tested. Results of individual diagnostic test accuracy studies assessing the diagnostic value of pancreatic autoantibodies-to-glycoprotein-2 (anti-GP2) tests for the diagnosis of CD appear promising. AIM To systematically review and meta-analyze evidence on the diagnostic accuracy of anti-GP2 tests in patients with suspected/confirmed CD. METHODS An electronic search was conducted on PubMed, Cochrane-CENTRAL and grey literature (CRD42019125947). The structured research question in PICPTR format was “Population” including patients with symptoms akin to CD, the “Index test” being anti-GP2 testing, the “Comparator” involved standard CD diagnosis, the “Purpose of test” being diagnostic, “Target disorder” was CD, and the “Reference standard” included standard clinical, radiological, endoscopical, and histological CD diagnostic criteria. Quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool and hierarchical models were employed to synthesize the data. RESULTS Out of 722 studies retrieved, 15 were meta-analyzed. Thirteen studies had industry-related conflicts-of-interest, and most included healthy donors as controls (spectrum bias). For the combination of IgA and/or IgG anti-GP2 test, the summary sensitivity was 20% (95% confidence interval: 10%-29%) at a median specificity of 97%. If the test was applied in 10000 suspected patients, 9669 would be true negatives and in 26, the diagnosis would be missed. In this hypothetical cohort, the anti-GP2 would fail to produce a diagnosis for 81.3% of the positive cases. Low summary points of sensitivity and high specificity were estimated for the IgG or IgA anti-GP2 test. Analogous results were observed when the analyses were restricted using specific cut-offs, or when ulcerative colitis patients were used as comparators. CONCLUSION Anti-GP2 tests demonstrate low sensitivity and high specificity. These results indicate that caution is required before relying on its diagnostic value. Additionally, the need for improving the methodology of diagnostic test accuracy studies is evident. © The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved