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Liver fibrosis regression but also progression may occur in patients with autoimmune hepatitis (AIH) under treatment. There is a need for non-invasive surrogate markers for fibrosis development in AIH to better guide immunosuppressive treatment. The aims of the study were to assess the impact of complete biochemical remission defined as normalisation of aminotransferases and IgG on histological activity and fibrosis development, and the value of repeat transient elastography (TE) measurement for monitoring disease progression in AIH.A total of 131 liver biopsies from 60 patients with AIH and more than 900 TE from 125 patients with AIH, 130 with primary biliary cholangitis (PBC) and 100 with primary sclerosing cholangitis (PSC), were evaluated. Time intervals between TE were at least 12 months. Patients with AIH were treated for at least six months at first TE.In contrast to PBC and PSC, a decrease of liver stiffness (LS) was observed in the whole group of patients with AIH (-6.2%/year; 95% CI -12.6% to -0.2%; p = 0.04). The largest decrease of LS was observed in patients with severe fibrosis at baseline (F4: -11.7%/year; 95% CI -19% to -3.5%; p = 0.006). Complete biochemical remission was strongly linked to regression of LS ("remission": -7.5%/year vs. "no remission": +1.7%/year, p 0.001). Similarly, complete biochemical remission predicted low histological disease activity and was the only independent predictor for histological fibrosis regression (relative risk3.66; 95% CI1.54-10.2; p = 0.001). Patients with F3/F4-fibrosis, who remained in biochemical remission showed a considerable decrease of fibrosis stage (3.7 ± 0.5 to 1.8 ± 1.7; p = 0.007) on histological follow-up.This study demonstrates that complete biochemical remission is a reliable predictor of a good prognosis in AIH and leads to fibrosis regression that can be monitored by TE.Autoimmune hepatitis is an inflammatory disease of the liver, which often progresses to cirrhosis if left untreated or in the case of insufficient treatment response. Current guidelines have defined biochemical remission (normalisation of biochemical markers for liver inflammation) as a major goal in the treatment of AIH. However, data on the prognostic relevance of this definition are scarce. Herein, we demonstrate that the current definition of biochemical remission is a reliable surrogate for low disease activity on histological assessment and for a beneficial long-term disease course. In addition, we establish transient elastography, a non-invasive ultrasound-based method of measuring scarring of liver tissue, as a reliable tool to monitor disease course in AIH.

Background & Aims Autoimmune hepatitis is a chronic inflammatory liver disease that leads to liver cirrhosis and corresponding complications, if left untreated. Current standard treatment with azathioprine and prednisolone induces remission in the vast majority of patients. However, for those patients not responding to standard treatment or not tolerating these drugs, few alternatives can be used and their effectiveness might be limited. We sought to analyze the safety and efficacy of off-label treatment with infliximab in a cohort of eleven patients with difficult-to-treat autoimmune hepatitis. Methods Patients with difficult-to-treat autoimmune hepatitis who could not be brought into remission with standard treatment, either due to drug intolerance or to insufficient drug impact, were treated off-label with infliximab for a minimum of six months. Patient files were reviewed retrospectively. Results Treatment with infliximab led to reduction of inflammation, evidenced by a decrease in transaminases (mean AST prior treatment 475U/L±466, mean AST during treatment 43U/L±32) as well as in immunoglobulins (pretreatment mean IgG 24.8mg/dl±10.1, mean IgG during treatment 17.38mg/dl±6). Infectious complications occurred in seven out of eleven patients and close monitoring was necessary. Conclusions Infliximab may be considered as rescue therapy in patients with difficult-to-treat autoimmune hepatitis, albeit treatment may be associated with infectious complications.

There is an unmet need for the non-invasive monitoring of fibrosis progression in patients with autoimmune hepatitis (AIH). The aim of this study was to assess the diagnostic performance of transient elastography in patients with AIH and to investigate the impact of disease activity on its diagnostic accuracy.Optimal cut-offs were defined in a prospective pilot study (n=34) and the diagnostic performance of transient elastography validated in an independent second cohort (n=60). To explore the impact of disease activity on liver stiffness, patients were stratified according to biochemical response and the time interval between start of immunosuppression and transient elastography.Liver stiffness strongly correlated with histological fibrosis stage (pilot study: ρ=0.611, p0.001; validation cohort: ρ=0.777, p0.0001). ROC curves defined an area under the receiver operating curve of 0.95 for diagnosing cirrhosis at the optimal cut-off of 16kPa. The performance of transient elastography was impaired when patients were analysed in whom transient elastography was performed within 3months from start of treatment. In this setting, liver stiffness correlated with histological grading (ρ=0.558, p=0.001), but not with staging. In contrast, using the cut-off of 16kPa, the accuracy for diagnosing cirrhosis was excellent in patients treated for 6months or longer (area under the receiver operating curve 1.0).Liver inflammation has a major impact on liver stiffness in the first months of AIH treatment. However, transient elastography has an excellent diagnostic accuracy for separating severe from non-severe fibrosis after 6months of immunosuppressive treatment.Transient elastography is a special ultrasound scan, which assesses liver stiffness as a surrogate marker for liver fibrosis/scarring. Transient elastography has been shown to be a reliable non-invasive method to assess liver fibrosis in various chronic liver diseases, it takes less than 5min and has a high patient acceptance. The current study validated for the first time this technique in a large cohort of patients with autoimmune hepatitis (AIH) and demonstrates that it is a reliable tool to detect liver fibrosis in treated AIH. For the monitoring of potential disease progression under treatment, the validation of liver stiffness as non-invasive marker of liver fibrosis will greatly improve patient care in autoimmune hepatitis.

Autoimmune hepatitis (AIH) is more variable than other liver diseases. Autoimmune hepatitis can present in young infants [1] and in octogenarians [2]. AIH can be a slowly progressive smouldering condition, or it can run an acute fluctuating course characterized by flares and spontaneous apparent remission, albeit usually associated with scarring and progressive fibrosis. AIH can present as a subclinical condition diagnosed on routine blood tests in an asymptomatic person, and it can present as acute liver failure [3]. It is the acute and hyper-acute presentation of AIH that remains the greatest challenge in this disease and at the same time has the least evidence basis to guide diagnosis and management. Key issues are the definition of diagnostic criteria, the need for prognostic parameters, and the therapeutic approach to acute AIH. The report by the King’s College group in this issue of the Journal [4] summarizing their experience in a series of 32 patients with acute severe AIH is thus an important attempt to answer some of these questions. This study only looks at patients with a severe impairment of liver function using an international normalized ratio (INR) of >1.5 as their cut-off, a limit also used as the cut-off for acute liver failure in the large American Acute Liver Failure (ALF) study group [5]. This definition is helpful to allow some comparison between the King’s data and the report of the ALF consortium looking at features of autoimmunity in patients presenting with cryptogenic acute liver failure, and it is the main reason why it was used in the study. This INR definition of liver failure does, however, have an important limitation: patients were included, if at ‘‘any time during the index presentation’’ their INR was >1.5. As jaundice leads to vitamin K deficiency through lack of resorption of this fat-soluble vitamin, substitution of vitamin K is the first measure undertaken in any patient with jaundice and elevated INR, and only those patients remaining above a limit of 1.5 can truly be considered to suffer from liver failure. On the other hand, many patients with very severe acute AIH may still have sufficient hepatic reserve to provide adequate levels of coagulation factors despite severe hepatic inflammation

Liver diseases are a major cause of morbidity and mortality worldwide. The major clinical problem is the frequent development of liver cirrhosis or liver cancer related to chronic hepatitis. A broad variety of conditions may cause chronic hepatitis, including hepatitis virus infection [1,2], toxic insult [3,4] or autoimmunity [5,6]. Hepatitis, acute or chronic, is associated with liver injury, which is largely mediated by immune effector mechanisms. In acute hepatitis, immune-mediated liver injury is usually compensated by adequate repair, and liver function is maintained. In chronic hepatitis, in contrast, continuous liver injury seems to promote aberrant repair and the development of fibrosis/cirrhosis and liver cancer. Irrespective of the cause, liver injury seems to be facilitated by similar immune effector mechanisms common to the various liver diseases. Indeed, common immune effector mechanisms may explain the high prevalence of cirrhosis and cancer common to most forms of liver injury. Improved understanding of immune-mediated liver injury may help to develop therapeutic approaches to this widespread clinical problem; so far, there is no cure for cirrhosis or liver cancer, except liver transplantation, and therapeutic options for many patients with chronic hepatitis are unsatisfactory. To approach the mechanisms of immunemediated liver injury, an EASL workshop, entitled ‘Immune-mediated liver injury: from basic science to future therapies’, was held October 9–11, 2004 in Freiburg, Germany, bringing together scientists and clinicians who study the various facets of immune-mediated liver diseases. This review is based on the presentations of the workshop and summarises some of the currently emerging answers to the old questions: Which immune effector mechanisms cause liver injury?

Prescribing medication and explaining how to take it, what side effects and benefits it may have, are core activities of every physician and hepatologist. It has been shown that straightforward review of the patients’ medication intake is not conducted routinely [1]. Physicians rarely ask their patients about their adherence to the prescribed medication [2]. At the same time, the increasing use of potent anti-infective therapy has clearly demonstrated the importance of patient adherence. Nowadays, clinical studies have proposed different means of measuring adherence as objectively as possible. However, it appears that adherence rates assessed with these measures are unsatisfactory [3,4]. Objectively measured adherence may differ quite substantially from self-reported medication adherence [5]. Many different factors may influence adherence to drug regimens [6,7] (summarized in Table 1): on the one hand, factors attributable to the patients such as psychiatric disorders, psychological distress, presence of depression or anxiety, lower formal education or communication barriers, marital status, older or younger age, poverty, geographic clustering [8] and many more have been shown to have a negative impact on drug-adherence. On the other hand, a favorable view about the goals of treatment and informed consent improve drug-adherence. In addition, there are factors having an impact on adherence attributable to the treating physician: prescription of complex therapeutic regimens containing many different pills and/or time points [7], ineffective communication about effects and possible side effects of the medication as well as incomplete information about the disease itself and the therapeutic regimen may all negatively affect adherence. Detailed education of patients has been shown to be particularly important as patients may have very different ideas of the disease’s pathogenesis and possible influencing factors [9]. These discrepancies of information level between laymen’s views and physicians’ views have a direct negative effect on adherence. In addition to factors attributable to the patient or the physician, there are disease-related factors that are specifically

Background & Aims In autoimmune hepatitis (AIH), relapse rates as high as 90% have been reported after treatment withdrawal. We therefore investigated, whether longer duration of treatment and proper patient selection could increase the long-term success rates after treatment withdrawal. Methods Following our previously published experience, treatment withdrawal was considered when biochemical remission was maintained under immunosuppressive monotherapy for at least 2years. Remission was defined as repeatedly normal serum aminotransferase levels as well as normal IgG levels. Results Out of 288 patients with well-defined AIH, 28 patients were included. Median duration of treatment was 48.5months (range 35–179) and a sustained remission was observed for 45months (range 24–111). All patients were in remission on immunosuppressive monotherapy for a minimum of 2years before treatment was withdrawn. Using this strict approach, 15 patients (54%) remained in long-term remission after a median of 28months follow-up (range 17–57) and 13 patients (46%) required reinstitution of treatment. Higher ALT and IgG levels – although within the normal range in all patients – were associated with the time to relapse. All patients who remained in remission had ALT levels less than half the ULN and IgG levels not higher than 12g/L at the time of treatment withdrawal. Conclusions Proper patient selection including a sustained complete biochemical remission on immunosuppressive monotherapy for a minimum of 2years can markedly improve the success rates of treatment withdrawal. The interpretation of aminotransferase and IgG levels within the normal range could aid in predicting the risk of relapse.

Improving health related quality of life (HrQoL) in patients with chronic diseases such as autoimmune hepatitis (AIH) should be a major treatment goal. However, little is known on the HrQoL in patients with AIH, and the topic is not given attention in current practice guidelines. We therefore conducted a single center study evaluating HrQoL in 103 consecutive outpatients with AIH.Patient-reported HrQoL data were analysed in relation to clinical disease parameters and compared to representative data of the German population as well as control patients.Based on patient-reported data, a major depressive syndrome (10.8%) was found to be five times more frequent in AIH patients compared to the general population (p0.001). The rate of severe symptoms of anxiety was also found to be significantly increased compared to the general population (p=0.006). In seven of the eleven patients who scored for a major depressive syndrome a psychiatric comorbidity had not been diagnosed before. Major factors associated with depression and anxiety were concerns with regard to the progression of the liver disease.This study identified--for the first time--a high rate of previously unrecognized severe symptoms of depression and anxiety in patients with AIH. Of importance for daily clinical practice, the factors associated with these symptoms may in part be amenable to targeted counselling and adequate treatment of the disease, thereby offering the chance to improve the care and HrQoL of AIH-patients.

Item does not contain fulltext BACKGROUND & AIMS: The pathogenesis of autoimmune hepatitis (AIH) is not understood, but it was suggested that AIH may be related to a numerical or functional impairment of CD4+CD25+FOXP3+ regulatory T cells (Treg), which are important mediators of immune tolerance to self-antigens. However, the role of Treg in AIH is not clear, since earlier studies reporting Treg impairment had used only CD25 as marker that cannot unambiguously distinguish Treg from activated effector T cells. METHODS: We assessed the frequency and suppressor function of Treg using current staining protocols that can distinguish Treg from activated effector T cells. RESULTS: The frequency of CD4+CD25(high)CD127(low)FOXP3+ Treg cells in blood of AIH patients was not reduced compared to healthy subjects, as shown by flow cytometry and confirmed by quantifying Treg-specific demethylation of the FOXP3 gene. Moreover, the suppressor function of Treg isolated from AIH patients was similar to that of Treg isolated from healthy subjects, indicating that Treg function was not impaired in AIH patients. However, we observed that the Treg frequency was significantly higher in those AIH patients with active disease than in those who were in a state of remission, suggesting that the Treg frequency may increase with the degree of inflammation. Indeed, analysis of FOXP3+ Treg in liver histology revealed that the intrahepatic Treg frequency was higher in AIH patients than in NASH patients and correlated with the inflammatory activity of the liver. CONCLUSIONS: The frequency and function of circulating Treg cells is not impaired in AIH.

Department of Medicine, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, GermanySee Article, pages 820–827Drug-induced liver injury (DILI) is a leading cause of acute liverfailure [1] and is of major importance to the pharmaceuticalindustry, as it is the most frequent reason for withdrawal of sub-stances from the market. More than 1000 different drugs and her-bal remedies have been described to cause DILI. Some drugscause a dose-dependent toxicity which can be anticipated – awell known example is acetaminophen. The vast majority of DILIcases cannot be foreseen and are, therefore, termed idiosyncratic.Oxidative stress, reactive metabolites, mitochondrial toxicity,modulation of drug metabolizing transporters, induction of apop-tosis or necrosis, as well as immunoallergic reactions to proteinadducts may all be involved in DILI, but for most of the drugsthe specific mechanisms contributing to DILI are unknown [2].A classification of hepatocellular, mixed or cholestatic liver injuryis used in the clinic to describe damage and severity of liverinjury but its value in predicting the outcome of DILI is unclear.DILI can range from asymptomatic elevation of liver enzymesto fulminant hepatic failure [1]. Its over-all mortality dependson the drug used, the timely detection of DILI including theappropriate action taken, as well as individual cofactors andcomorbidities such as the presence of diabetes mellitus [3]. Mor-tality rates of approximately 10% [1] have been reported but maybe highly overestimated since most mild drug reactions will notbe registered. In most patients, DILI leads to a complete recovery.However, up to 1% of all patients with DILI may develop liver cir-rhosis subsequently [4].DILI is a rare event with an estimated incidence of 1 per10,000 to 1 per 100,000 treated patients [5]. Some risk factorshave been identified: the daily amount of the drug causing thereaction (intake of >50 mg daily increases risk), a predominantlyhepatic metabolism of the drug (>50%) [6], and mitochondrialdysfunction that may be the underlying cause of the increasedrisk of DILI in diabetes patients [7]. Genetic polymorphismswithin genes relevant to drug metabolism [8] are being identifiedand may be used to stratify the risk of DILI to certain drugs in thefuture.A question relevant to daily clinical practice is, if re-exposureto the same or to other drugs may cause a second DILI episode.Re-exposure to the same drug generally should be avoided dueto the considerable mortality rate reported after re-exposure todrugs such as halothane (up to 50% due to a combination of mito-chondrial and immune-mediated injury) [9]. Nonetheless, fordrugs that are urgently needed in case of life threatening disease,such as in tuberculosis, careful re-exposure can be undertakenafter the resolution of the first DILI episode with acceptable risk[10]. The risk of re-exposure to a different drug that may belongto the same class of drugs or be completely unrelated is not wellstudied. To this end, the study presented by Lucena et al. in thisissue adds valuable and reassuring information[11]. In this study,the Spanish DILI registry of patients with probable or highlyprobable idiosyncratic DILI was searched for patients who suf-fered from a second DILI episode. Only a small number of patients(9 patients, 1.21%) from the cohort of patients with prior DILIdeveloped a second episode of liver injury and none of thepatients’ required liver transplantation or had a fatal outcome.Of particular interest, the majority of patients (8 out of 9) expe-riencing a second DILI episode had a similar (hepatocellular)damage pattern. The drugs responsible for the second DILI epi-sode were structurally related to the drug of the first DILI episodein 4 out of 9 cases and, in 2 cases, the target of the drug was thesame. This may point toward an immune-mediated drug injurydirected against similar protein adducts forming haptens. Indeed,4 out of the 9 patients (44%) were diagnosed with so called ‘‘auto-immune (AIH) DILI’’ since these patients fulfilled the criteria forprobable or definite AIH, according to the revised and simplifiedscore of the international autoimmune hepatitis study group[12,13]. This number was considerably higher than in patientswith a first DILI episode, where only 12/733 (1.6%) patients werediagnosed with ‘‘AIH DILI’’ [11], suggesting that immune-medi-ated reactions become the main mechanisms leading to DILI afterre-exposure to different drugs.There is no consensus on the nomenclature of immune-med-iated DILI and we will propose some definitions and respectivediagnoses at the end of this article. Until then, the diagnosesgiven in the publications cited will be used.In clinical practice, the differentiation between immune-med-iated DILI and AIH may be challenging. There are no pathogno-monic features of AIH and the diagnosis is made according to aclinical, biochemical, serological, and histological pattern whichhas to be confirmedby the response to immunosuppressive treat-ment [14]. This difficulty in differentiating between AIH and drugJournal of Hepatology 2011 vol. 55

The name primary biliary cirrhosis (PBC) was coined when the disease was mostly diagnosed in its late cirrhotic stage [1]. Today, PBC must be considered a historic misnomer, as the disease nowadays presents usually many years or decades prior to the development of cirrhosis, and with timely diagnosis and adequate treatment, the majority of patients never reach the stage of cirrhosis [2–4]. It is considered an autoimmune disease characterized by non-suppurative destructive cholangitis, and it is thus considered a disease of the small intra-hepatic bile ducts. However, there may be a second reason why PBC is a misnomer: probably the disease is not only confined to the liver, but may have extra-hepatic manifestations. In addition to the immune-mediated inflammation in the liver, patients may suffer from a number of extra-hepatic manifestations as varied as Siccasyndrome, arthralgias and, most of all, fatigue. Fatigue is a complex symptom characterized by the feeling of exhaustion, lethargy, and discomfort. Fatigue affects 40–80% of PBC patients [5,6]. Fatigue is not only common, for most patients it also constitutes the primary clinical problem, as about 50% of the patients affected describe fatigue as the most bothersome symptom of their disease [7]. In addition to this enormous impact on quality of life, new data suggest an influence on survival in PBC, as well [8]. In order to meet this highly challenging problem in PBC, effective therapeutic strategies for patients affected by fatigue would be highly desirable. However, to date there is no specific treatment for fatigue in PBC [9]. Even though different drugs have been tested in clinical trials, favorable effects have only been shown for Modafinil, such as decreased somnolence and night sleep as well as increased energy levels [10,11], and for methotrexate [12], albeit only described in small case series without adequate placebo controls. In addition to the limited effectiveness, side-effects will limit therapeutic options frustrating both patients and their treating physicians.