Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if untreated, often leads to cirrhosis, liver failure and death. Major advances were made in its management based on ...controlled trials performed in England and the USA in the 1970s and 1980s. Unfortunately, in recent decades there has been a dearth of controlled clinical trials and, thus, many questions regarding the optimal management of this disease remain unanswered. Many promising newer immunosuppressive therapies await formal comparison with standard therapies and also many important details in relation to the application of standard therapies remain unclear. These guidelines describe the optimal management strategies in adults based on available published evidence, including the American Association for the Study of Liver Diseases practice guidelines for the diagnosis and treatment of AIH published in 2002 and recently updated.
Patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid remain at risk of disease progression. We investigated the safety and efficacy of elafibranor, ...a dual PPARα/δ agonist, in patients with PBC.
This 12-week, double-blind phase II trial enrolled 45 adults with PBC who had incomplete response to ursodeoxycholic acid (alkaline phosphatase levels ≥1.67-fold the upper limit of normal (ULN). Patients were randomly assigned to elafibranor 80 mg, elafibranor 120 mg or placebo. The primary endpoint was the relative change of ALP at 12 weeks (NCT03124108).
At 12 weeks, ALP was reduced by -48.3±14.8% in the elafibranor 80 mg group (p <0.001 vs. placebo) and by -40.6±17.4% in the elafibranor 120 mg group (p <0.001) compared to a +3.2±14.8% increase in the placebo group. The composite endpoint of ALP ≤1.67-fold the ULN, decrease of ALP >15% and total bilirubin below the ULN was achieved in 67% patients in the elafibranor 80 mg group and 79% patients in the elafibranor 120 mg group, vs. 6.7% patients in the placebo group. Levels of gamma-glutamyltransferase decreased by 37.0±25.5% in the elafibranor 80 mg group (p <0.001) and 40.0±24.1% in the elafibranor 120 mg group (p <0.01) compared to no change (+0.2±26.0%) in the placebo group. Levels of disease markers such as IgM, 5’-nucleotidase or high-sensitivity C-reactive protein were likewise reduced by elafibranor. Pruritus was not induced or exacerbated by elafibranor and patients with pruritus at baseline reported less pruritic symptoms at the end of treatment. All possibly drug-related non-serious adverse events were mild to moderate.
In this randomized phase II trial, elafibranor was generally safe and well tolerated and significantly reduced levels of ALP, composite endpoints of bilirubin and ALP, as well as other markers of disease activity in patients with PBC and an incomplete response to ursodeoxycholic acid.
Patients with primary biliary cholangitis (a rare chronic liver disease) that do not respond to standard therapy remain at risk of disease progression toward cirrhosis and impaired quality of life. Elafibranor is a nuclear receptor agonist that we tested in a randomized clinical trial over 12 weeks. It successfully decreased levels of disease activity markers, including alkaline phosphatase. Thus, this study is the foundation for a larger prospective study that will determine the efficacy and safety of this drug as a second-line therapy.
Clinical Trials.gov NCT03124108
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•In a phase II trial in PBC, the dual PPARα and δ agonist elafibranor achieved the primary endpoint of reducing ALP.•Compared to placebo, the 80 mg and 120 mg dose had positive effects on prognostically important composite endpoints.•In patients with pruritus at baseline, an improvement was noted in both elafibranor arms.•Elafibranor was generally well-tolerated over the duration of treatment.
Acute severe presentations of autoimmune hepatitis (AIH) represent a challenge for the transplant community. As a disease, it is poorly characterized, and there is a weak evidence base to guide ...diagnosis and treatment. Early identification of acute severe AIH is key because it determines the initiation of corticosteroids, which can be lifesaving. However, their use in this setting remains controversial. The Model for End‐Stage Liver Disease score, severity of coagulopathy, and grade of encephalopathy may be predictors of outcome with corticosteroid therapy. The optimal timing of liver transplantation (LT) can be difficult to determine and, as such, the decision to proceed to transplantation should not be delayed by protracted courses of corticosteroids. The aim of this review is to better characterize this subset of patients; to differentiate them clinically, serologically, and histologically from chronic AIH and other causes of acute liver failure; and to present the role, predictors, and optimal timings of corticosteroid therapy and LT. Although this review is specific to adults, many principles hold true for the pediatric population.
Autoimmune hepatitis Heneghan, Michael A, Dr; Yeoman, Andrew D, MB; Verma, Sumita, MD ...
The Lancet (British edition),
10/2013, Letnik:
382, Številka:
9902
Journal Article
Recenzirano
Summary Autoimmune hepatitis is a disease of the hepatic parenchyma that can present in acute or chronic forms. In common with many autoimmune diseases, autoimmune hepatitis is associated with ...non-organ-specific antibodies in the context of hepatic autoimmunity. This dichotomy has made definition of a unifying hypothesis in the pathophysiology of the disease difficult, although data from the past 8 years have drawn attention to the role of regulatory T cells. Several triggers have been identified, and the disease arises in genetically susceptible individuals. Clinical and biochemical remission is achievable in up to 85% of cases. For the remaining patients, alternative immunosuppression strategies are an option. Liver transplantation provides an excellent outcome for patients with acute liver failure or complications of end-stage liver disease, including hepatocellular carcinoma. Variant or overlapping syndromes are worthy of consideration when unexpected disease features arise.
Summary Severe liver disease in pregnancy is rare. Pregnancy-related liver disease is the most frequent cause of liver dysfunction in pregnancy and provides a real threat to fetal and maternal ...survival. A rapid diagnosis differentiating between liver disease related and unrelated to pregnancy is required in women who present with liver dysfunction during pregnancy. Research has improved our understanding of the pathogenesis of pregnancy-related liver disease, which has translated into improved maternal and fetal outcomes. Here, we provide an overview of liver diseases that occur in pregnancy, an update on the key mechanisms involved in their pathogenesis, and assessment of available treatment options.
Background, & Aims Studies of primary biliary cirrhosis (PBC) phenotypes largely have been performed using small and selected populations. Study size has precluded investigation of important disease ...subgroups, such as men and young patients. We used a national patient cohort to obtain a better picture of PBC phenotypes. Methods We performed a cross-sectional study using the United Kingdom-PBC, patient cohort. Comprehensive data were collected for 2353 patients on diagnosis reports, response to therapy with ursodeoxycholic acid (UDCA), laboratory results, and symptom impact (assessed using the PBC-40 and other related measures). Results Seventy-nine percent of the patients reported current UDCA, therapy, with 80% meeting Paris response criteria. Men were significantly less likely to have responded to UDCA than women (72% vs 80% response rate; P < .05); male sex was an independent predictor of nonresponse on multivariate analysis. Age at diagnosis was associated strongly and independently with response to UDCA; response rates ranged from 90% among patients who presented with PBC when they were older than age 70, to less than 50% for those younger than age 30 ( P < .0001). Patients who presented at younger ages also were significantly more likely not to respond to UDCA therapy, based on alanine aminotransferase and aspartate aminotransferase response criteria, and more likely to report fatigue and pruritus. Women had mean fatigue scores 32% higher than men's ( P < .0001). The increase in fatigue severity in women was related strongly (r = 0.58; P < .0001) to higher levels of autonomic symptoms ( P < .0001). Conclusions Among patients with PBC, response to UDCA, treatment and symptoms are related to sex and age at presentation, with the lowest response rates and highest levels of symptoms in women presenting at younger than age 50. Increased severity of fatigue in women is related to increased autonomic symptoms, making dysautonomia a plausible therapeutic target.
Autoimmune hepatitis (AIH) in pregnancy has many unique considerations. Evidence provided from single center studies with patient level data and nationwide population studies provide valuable insight ...into this complex situation. Because a planned pregnancy is a safer pregnancy, preconception counseling is a crucial opportunity to optimize care and risk stratify women with AIH. Women with chronic liver disease who receive preconception advice and counseling are more likely to achieve stable liver disease at conception and undergo appropriate variceal surveillance. Loss of biochemical response in pregnancy is associated with adverse outcomes in unstable disease. New onset AIH in pregnancy should be managed with classical treatment regimens. The continued use of immunosuppression in pregnancy, with the exception of mycophenolate mofetil, has not shown to adversely affect the rates of stillbirth or congenital malformation. Previously adopted immunosuppression withdrawal paradigms in pregnancy should no longer be considered advantageous, because remission loss postdelivery is likely (12%–86%). Population studies, report improved outcomes with preterm birth rates falling from 20% to 9%–13% in AIH pregnancies over a 20‐year period. Newer data have also demonstrated an increased risk of gestational diabetes and hypertensive complications in AIH pregnancy, which has implications for management and preeclampsia prevention with aspirin use. This review aims to provide the framework to guide and manage pregnancy in AIH outlining pearls and pitfalls to ensure optimal outcomes for mother, baby and to reduce variation in practice.
Background
Autoimmune hepatitis (AIH) is common in females of childbearing age. Although some studies have provided information about the outcomes of pregnancy, there remains uncertainty regarding ...conclusions.
Aim
To comprehensively explore the interactions between pregnancy and AIH.
Methods
Databases including PubMed, Embase, Cochrane Library and Science Citation Index Expanded were searched to collect available studies in relation to pregnancy in AIH patients (from inception to 28 August 2021). Pooled data were calculated using a random effects model with standardised mean difference (SMD), or risk ratio (RR), and 95% confidence intervals (CI).
Results
Twelve studies were considered eligible for meta‐analysis. Data from 26 case reports/series were extracted for systematic review. AST level in AIH patients was significantly lower during pregnancy (SMD = −0.41, 95% CI = −0.70, −0.12; SMD = −1.60, 95% CI = −2.76, −0.44) and loss of biochemical remission occurred more frequently in post‐partum (RR = 0.31, 95% CI = 0.19, 0.52). Patients with portal hypertension or without established remission before conception presented as high‐risk subgroups and the incidence of pre‐term delivery was higher in these groups compared to other AIH patients (RR = 9, 95% CI = 1.22, 51.1; RR = 0.05, 95% CI = 0.004, 0.38). In population‐based comparison, pre‐term birth (RR = 2.45, 95% CI = 1.66, 3.62) also occurred more often in AIH patients compared with the general population.
Conclusions
Successful pregnancy is a reasonable expectation in AIH. However, hepatic biochemistry should be monitored closely in both the puerperium and the post‐partum period. Though some patients may present higher risk, with carefully selected therapeutic manipulation and multi‐disciplinary care, the majority of mothers and infants should achieve uneventful outcomes.
Pregnancy presents the maternal immune system with a unique immunological challenge since it has to defend against pathogens while tolerating paternal allo-antigens expressed by fetal tissues. T ...helper (Th) cells play a central role in modulating immune responses and recent advances have defined distinct contributions of various Th cell subsets throughout each phase of human pregnancy, while dysregulation in Th responses show association with multiple obstetrical complications. In addition to localized decidual mechanisms, modulation of Th cell immunity during gestation is mediated largely by oscillations in sex hormone concentrations. Aberrant Th cell responses also underlie several autoimmune disorders while pregnancy-induced changes in the balance of Th cell immunity has been shown to exert favorable outcomes in the progression Th1 and Th17 driven autoimmune conditions only to be followed by post-partal exacerbations in disease.
•Dynamic adaptations in T helper cell immunity are vital for successful pregnancy•Aberrant T helper cell responses are associated with adverse pregnancy outcomes•Sex hormone fluctuations exert profound systemic changes in maternal T helper cell immunity during pregnancy•Pregnancy can induce spontaneous remission followed by post-partal disease flares in Th1 and Th17 driven autoimmune disorders
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