Defective immune regulation plays a permissive role enabling effector cells to initiate and perpetuate tissue damage, eventually resulting in autoimmune disease. Numerical and functional regulatory ...T‐cell (Treg) impairment has been previously reported in autoimmune liver disease (AILD; including autoimmune hepatitis and autoimmune sclerosing cholangitis ASC). However, in these early reports, Tregs were phenotypically defined as CD4+CD25+ or CD4+CD25high cells. In the current study, we reexamined phenotypic and functional properties of Tregs by adopting a more refined definition of these cells that also includes negativity or low level of expression of CD127. We studied 43 AILD patients and 22 healthy subjects (HSs) and found that CD4+CD25+CD127− Tregs were decreased in the former. This decrease was more marked in patients with active disease than in those in remission. In AILD, Treg frequencies correlated inversely with parameters of disease activity and were not affected by immunosuppressive treatment. We also document, for the first time, that, in AILD, bona‐fide Tregs produce less interleukin (IL)−10 and are impaired in their ability to suppress CD4+CD25− target cell proliferation, a feature that in HSs, but not in AILDs, is dependent, at least in part, on IL‐10 secretion. Decreased IL‐10 production by Tregs in AILD is linked to poor responsiveness to IL‐2 and phospho signal transducer and activator of transcription 5 up‐regulation. Conclusion: Tregs are numerically impaired in AILD, this impairment being more prominent during active disease. Notably, defective IL‐10 production, resulting from low Treg responsiveness to IL‐2, contributes to Treg functional impairment. (Hepatology 2015;62:863–875)
Rates of pregnancy in women with cirrhosis are increasing. Risk of hepatic decompensation during pregnancy, therefore, merits tailored obstetric and hepatology care. Prognostic markers that determine ...pregnancy outcomes are lacking.
Medical records of women who attended hepatology clinic at King's College Hospital with chronic liver disease (CLD) who became pregnant from 1983 to 2017 were reviewed. Information on demographics, clinical history, serology, and outcome of pregnancy was collected.
In all, 165 pregnancies occurred in 100 women with CLD including 80 pregnancies in 48 women with cirrhosis. Median age of conception in cirrhotic and non-cirrhotic women were 26 years (16-44) and 28 years (16-51) respectively (p = 0.015). Whilst women with cirrhosis had similar live birth rate to non-cirrhotic women (75 vs. 85% p = 0.119), they were significantly less likely to proceed beyond 37 weeks gestation (45 vs. 58% p = 0.033). Women who received preconception counseling were more likely to have stable liver disease at conception (100 vs 86% p = 0.02). Compared with preconception MELD (model for end stage liver disease), preconception Albumin-Bilirubin score (ALBI) more accurately predicted live birth with an area under the receiver-operator curve (AUROC) of 0.741 (p < 0.001), and preconception AST to platelet ratio index (APRI) more accurately predicted ability to proceed beyond 37 weeks gestation with an AUROC of 0.700 (p < 0.001).
Most women with cirrhosis who conceived achieved a successful pregnancy outcome. ALBI and APRI scores can prognosticate pregnancy outcomes in women with CLD. Preconception counseling by a hepatologist or specialist obstetrician improved patient care in this group.
Diagnostic criteria for autoimmune hepatitis (AIH) have been created and revised by the International Autoimmune Hepatitis Group (IAIHG). Simplified criteria have been created, but remain ...independently unvalidated. We report on the diagnostic accuracy of the simplified criteria in patients across a range of diagnoses, including a subset of patients presenting with fulminant liver failure who required liver transplant. Patients with AIH and non‐AIH etiologies of liver disease were identified from dedicated patient databases. Parameters relevant to the simplified and 1999 IAIHG criteria were recorded, and sensitivity, specificity, and positive and negative predictive values for scores of ≥6 (probable AIH) and ≥7 (definite AIH) were calculated. A total of 549 patients with chronic liver disease were evaluated, (221 with AIH, 26 with variant syndromes, and 302 with non‐AIH). For scores ≥6, sensitivity was 90%, and specificity was 98% with positive and negative predictive values of 97% and 92%, respectively. For scores ≥7; sensitivity was 70%, and specificity was 100% with positive and negative predictive values of 100% and 74%, respectively. Seven false positive diagnoses of AIH occurred, all with simplified scores of 6. Concordance with 1999 criteria was 90% for probable and 61% for definite AIH. The frequency of an overall diagnosis of AIH (probable or definite AIH) among the 70 patients with fulminant liver failure was 24% for simplified criteria and 40% for 1999 criteria, respectively. Conclusion: The simplified criteria retain high specificity but exhibit lower sensitivity for scores of ≥7. The explanations for this are unclear but may relate to loss of such discriminating information as response to corticosteroids. Prospective evaluation of these criteria is required to corroborate these observations. (HEPATOLOGY 2009.)
Autoimmune hepatitis (AIH) typically responds to treatment in 90% of patients. Early prediction of treatment outcome would be advantageous in clinical practice. We evaluated whether parameters at ...initiation of therapy or changes in these parameters at day 3 and day 7 following corticosteroid initiation predicted treatment failure. Treatment‐naive, jaundiced patients presenting to our tertiary unit between 1999‐2009 were identified and mathematical models of prognosis in liver disease scores calculated at day 0, day 3, and day 7. Overall, 72 patients were identified (48 women, 24 men). Treatment failure occurred in 18% (13/72) of patients. At diagnosis, higher median bilirubin (451 μmol/L versus 262 μmol/L, P = 0.02), INR (1.62 versus 1.33, P = 0.005), model for endstage liver (MELD) score (26 versus 20, P = 0.02), MELD‐sodium (Na) score (27 versus 22, P = 0.03) and United Kingdom endstage liver disease score (UKELD) score (59 versus 57, P = 0.01) significantly correlated with treatment failure. Analysis of area under the receiver operator characteristic curve (AUROC) values at day 7 identified change (Δ) bilirubin (AUROC 0.68), Δ creatinine (0.69), Δ MELD (0.79), Δ MELD‐Na (0.83) and Δ UKELD (0.83) best predicted treatment failure. Specifically, a fall in UKELD of less than 2 points predicted treatment failure with a sensitivity of 85% and specificity of 68%. Of 13 treatment failures, nine required second‐line immunosuppression, three required emergency transplant, and one died of sepsis. In total, four patients died in the treatment failure group compared with one in the responder group (4/13 = 31% versus 1/59 = 1.7%, P = 0.003). Conclusion: Approximately 20% of icteric AIH presentations fail corticosteroid therapy. This is associated with significant mortality and the need for emergency transplantation. Treatment failure is best predicted by change in MELD‐Na and UKELD at day 7. Early identification of nonresponders may allow timely escalation of immunosuppression to prevent clinical deterioration. (HEPATOLOGY 2011;)
Abstract Introduction Optimal management during pregnancy of patients with autoimmune hepatitis (AIH) remains undefined. We therefore reviewed all patients with AIH who reported pregnancy at our ...centre to identify any pre-conception factors that might predict adverse outcomes. Results There were 81 pregnancies in 53 women. Median age at conception was 26 years (range 16–42); with 41% of pregnancies occurring in the context of cirrhosis. At conception, 61 patients (75%) were on therapy for AIH. The live birth rate (LBR) was 73% (59/81). Prematurity, occurred in 12/59 (20%) and 6 (11%) required admission to special care baby unit (SCBU). In mothers who were cirrhotic at the time of conception the LBR was lower ( p = 0.02) and need for admission to SCBU was higher. The overall maternal complication rate was 31/81 (38%) conceptions. A flare in disease activity occurred in 26/81 (33%) pregnancies. A serious maternal adverse event (death or need for liver transplant) during or within 12-months of delivery, or hepatic decompensation during or within 3-months of delivery, occurred with 9 pregnancies (11%) and was more common in women with cirrhosis ( p = 0.028). Maternal therapy had no significant impact on the LBR ( p = 0.24), termination rate ( p = 0.72), miscarriage rate ( p = 0.19) or gestational period ( p = 0.8). Flares in AIH were more likely in patients who were not on therapy ( p = 0.048) or who had a disease flare in the year prior to conception ( p = 0.03). Patients who had a flare in association with pregnancy were more likely to decompensate from a liver standpoint ( p = 0.01). Conclusions This study demonstrates that poor disease control in the year prior to pregnancy and the absence of drug therapy are associated with poor outcomes whist pregnant. These data should facilitate appropriate pre-conception counselling and appropriate pregnancy management in this cohort.
There is controversy regarding the optimal calcineurin inhibitor type after liver transplant(ation) (LT) for primary sclerosing cholangitis (PSC). We compared tacrolimus with cyclosporine in a ...propensity score-matched intention-to-treat analysis based on registries representing nearly all LTs in Europe and the US.
From the European Liver Transplant Registry (ELTR) and Scientific Registry of Transplant Recipients (SRTR), we included adult patients with PSC undergoing a primary LT between 2000-2020. Patients initially treated with cyclosporine were propensity score-matched 1:3 with those initially treated with tacrolimus. The primary outcomes were patient and graft survival rates.
The propensity score-matched sample comprised 399 cyclosporine-treated and 1,197 tacrolimus-treated patients with PSC. During a median follow-up of 7.4 years (IQR 2.3-12.8, 12,579.2 person-years), there were 480 deaths and 231 re-LTs. The initial tacrolimus treatment was superior to cyclosporine in terms of patient and graft survival, with 10-year patient survival estimates of 72.8% for tacrolimus and 65.2% for cyclosporine (p <0.001) and 10-year graft survival estimates of 62.4% and 53.8% (p <0.001), respectively. These findings were consistent in the subgroups according to age, sex, registry (ELTR vs. SRTR), time period of LT, MELD score, and diabetes status. The acute rejection rates were similar between groups. In the multivariable Cox regression analysis, tacrolimus (hazard ratio 0.72, p <0.001) and mycophenolate use (hazard ratio 0.82, p = 0.03) were associated with a reduced risk of graft loss or death, whereas steroid use was not significant.
Tacrolimus is associated with better patient and graft survival rates than cyclosporine and should be the standard calcineurin inhibitor used after LT for patients with PSC.
The optimal calcineurin inhibitor to use after liver transplantation in patients with primary sclerosing cholangitis has yet to be firmly established. Since randomized trials with long follow-up are unlikely to be performed, multicontinental long-term registry data are essential in informing clinical practices. Our study supports the practice of using tacrolimus instead of cyclosporine in the initial immunosuppressive regimen after liver transplantation for patients with primary sclerosing cholangitis. The retrospective registry-based design is a limitation.
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•Tacrolimus was associated with superior survival compared to cyclosporine after liver transplantation for PSC.•10-year patient survival estimates were 73% for tacrolimus and 65% for cyclosporine.•10-year graft survival estimates were 62% for tacrolimus and 54% for cyclosporine.•Findings were consistent across subgroups by age, sex, registry, time period of LT, MELD score, and diabetes status.•Tacrolimus emerges as the preferred calcineurin inhibitor after liver transplantation for PSC.
Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to the induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing ...cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes. We investigated the effect of Treg skewing on the phenotypic and functional properties of CD4+CD127+CD25high cells, an activated subset of Teff, in 32 patients with AIH and 20 with AISC and in 36 healthy subjects. In AIH/AISC we noted a substantial increase in peripheral blood–derived CD4+CD127+ CD25high cells that display a Th1/Th17 phenotypic profile, as reflected by heightened interferon gamma and interleukin 17 (IL‐17) production as well as by high levels of T‐bet and related orphan receptor 3 expression, which is strongly correlated with disease activity. CD4+CD127+CD25high cells are unresponsive to low‐dose IL‐2 and in patients have marked proliferative ability, further enhanced by stimulation with IL‐7. CD4+CD127+CD25high cells obtained from CD4+ cells exposed to Treg polarizing conditions display enhanced IL‐10 production; up‐regulate CD49b and LAG‐3, markers of T regulatory 1 cells; and effectively suppress responder cell proliferation in both healthy subjects and AIH/AISC patients through a mechanism which is dependent on interferon gamma and IL‐17. The suppressive function of CD4+CD127+CD25high cells is maintained upon proinflammatory challenge in healthy subjects but not in AIH/AISC. Conclusion: Treg skewing confers activated Teff phenotypic and functional properties of T regulatory 1 cells in health and in AIH/AISC, though suppressive function is lost in patients upon proinflammatory challenge; protracted modulation of the inflammatory environment is required to attenuate the effector potential while boosting immunoregulatory properties in Teff. (Hepatology 2017;66:1570–1584).
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