Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report.

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition.

Grand round: Autoimmune hepatitis.

Autoimmune hepatitis is a corticosteroid-responsive liver disease arising consequent to immunogenetic and environmental risk factors. The clinical course reflects relapsing and remitting, hepatocyte targeted immunologic damage, which is countered by reparative responses to cell injury. Appropriate and timely immunosuppressive therapy drives the disease into remission, albeit with inevitable side effects. Many challenges faced in the clinic reflect practice that must capture a heterogeneous disease presentation, course, and treatment response, as well as treatment tolerability. In this Grand Round we appraise the evidence supporting current treatment approaches, address the impact of autoimmune liver disease 'crossover or overlap' presentations, explore important clinical correlates to immune-serological classifiers, and discuss the factors influencing choice of alternative therapy in difficult-to-treat situations.

Palliative care in end-stage liver disease: Time to do better?

Optimal involvement of palliative care (PC) services in the management of patients with decompensated cirrhosis and end-stage liver disease (ESLD) is limited. This may result from both ignorance and the failure to recognize the spectrum and unpredictability of the underlying liver condition. Palliative care is a branch of medicine that focuses on quality of life (QoL) by optimizing symptom management and providing psychosocial, spiritual, and practical support for both patients and their caregivers. Historically, palliative care has been underutilized for patients with decompensated liver disease. This review provides an evidence-based analysis of the benefits of the integration of palliative care into the management of patients with ESLD. Liver Transplantation 24 961-968 2018 AASLD.

Liver transplantation and adolescence: The role of mental health.

Young people (YP) with chronic illness have higher rates of mental health problems than the general population, with psychosocial complexity associated with nonadherence and poorer health outcomes. This study aimed to describe the prevalence of anxiety and depression in YP after liver transplantation, with autoimmune liver disease and other chronic liver diseases, identify the factors YP attribute their distress to and the relationship between anxiety/depression, and describe YP's beliefs about their illness and treatment. An electronically administered questionnaire battery was given routinely to YP attending an outpatient liver transition clinic; 187 YP participated, of which 17.7% screened positive for anxiety or depression. There were no significant differences between disease groups. This is significantly higher than the prevalence of common mental health problems in the general adolescent population. Patients most frequently attributed their distress to fatigue, sleep difficulties, financial concerns, problems at work/school, worry, and low self-esteem. Higher levels of depression and anxiety were significantly associated with specific illness and treatment beliefs but not with perceived understanding of illness or treatment control. In conclusion, the increased prevalence of mental health problems in YP and the intertwined nature of these with their physical health outcomes provide evidence that holistic care should be delivered as standard for this age group. Liver Transplantation 22 1544-1553 2016 AASLD.

Retinoic acid stabilizes antigen-specific regulatory T-cell function in autoimmune hepatitis type 2.

Imbalance between effector and regulatory T-cells (Treg) underlies the loss of immune-tolerance to self-antigens in autoimmune disease. In autoimmune hepatitis type 2 (AIH-2), effector CD4 T-cell immune responses to cytochrome P450IID6 (CYP2D6) are permitted by numerically and functionally impaired Treg. Restoration of CYP2D6-specific Treg in AIH-2 would enable control over effectors sharing the same antigen specificity, leading to re-establishment of immune-tolerance. We have previously developed a protocol for generating antigen-specific Treg through co-culture with semi-mature dendritic cells presenting CYP2D6 peptides. In this study, we aimed to explore phenotypic and functional features of patient Treg compared to health, to test Treg stability under pro-inflammatory conditions, and to investigate the potential benefit of supplementation with all-trans-retinoic acid (RA) or rapamycin (RP), agents proven to enhance Treg function. We show that antigen-specific Treg from patients have comparable phenotypic and functional features to those from healthy controls, suppressing both proliferation and pro-inflammatory cytokine production by effector cells. Treg exposure to inflammatory challenge results in decreased suppressive function and up-regulation of Th1/Th2/Th17 transcription factors both in health and AIH-2. The increase of Th1 and Th17 transcription factors is limited by addition of RA in controls and Th1 expression is decreased by RP in patients. Importantly, inflammation-induced decrease in Treg function is also abrogated by RA/RP in health and RA in patients. Our data provide important information for the optimization of protocols aiming at generating antigen-specific Treg for treatment of autoimmune disease and for understanding their biology upon pro-inflammatory challenge and RP/RA supplementation.

Normal neurological outcome in two infants treated with exchange transfusions born to mothers with Crigler-Najjar Type 1 disorder.

Patients with Crigler-Najjar Type 1 (CN-1) disorder have an unconjugated hyperbilirubinaemia due to the complete absence in activity of uridinediphosphate glucuronosyltransferase, a bilirubin-conjugating enzyme. In pregnant women with CN-1, the foetus is at high risk of being adversely affected by the bilirubin, as unconjugated bilirubin can cross the placenta and is potentially neurotoxic. We report the long-term outcomes of two infants born to women with CN-1. These infants had exchange transfusions soon after birth and have normal neurodevelopmental outcomes at 18 months and four years of age, respectively. We propose that this intervention might have improved the neurological outcome of these infants.