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Item does not contain fulltext BACKGROUND & AIMS: Recently, genome wide association studies in primary sclerosing cholangitis (PSC) revealed associations with gene polymorphisms that potentially could affect the function of regulatory T cells (Treg). The aim of this study was to investigate Treg in patients with PSC and to associate their numbers with relevant gene polymorphisms. METHODS: Treg frequency in blood was assessed by staining for CD4(+)CD25(high)FOXP3(+)CD127(low) lymphocytes and determination of Treg-specific FOXP3 gene locus demethylation. Single nucleotide polymorphisms (SNP) in the interleukin-2 receptor alpha (IL2RA), the interleukin-2 (IL2) and interleukin-21 (IL21) gene locus were analysed. Liver biopsies taken at the time of diagnosis were stained for FOXP3 and CD3. Treg function was assessed in a CFSE-based suppression assay. RESULTS: The frequency of Treg in peripheral blood of PSC patients was significantly decreased. We confirmed this finding by demonstrating a reduction of non-methylated DNA in the Treg-specific demethylated FOXP3 gene region of peripheral blood cells in PSC patients. Reduced peripheral Treg numbers were significantly associated with homozygosity for the major allele of the SNP "rs10905718" in the IL2RA gene. Intrahepatic FOXP3(+) cell numbers at the time of initial diagnosis were decreased in PSC as compared to PBC. In addition to reduced numbers, the suppressive capacity of Treg isolated from PSC patients seemed to be impaired as compared to healthy controls. CONCLUSIONS: Our findings indicate that Treg impairment may play a role in the immune dysregulation observed in PSC. Reduced Treg numbers in patients with PSC are associated with polymorphisms in the IL2RA gene.

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.

Injection drug users (IDUs) constitute the largest group of HCV-infected people in the United States and account for 42% of new infections [1]. After 10 years of injection drug use, ~90% of IDUs test anti-HCV positive by means of standard EIA [2]; of these IDUs, 80% are persistently infected with HCV [2, 3]. The most common mode of HCV transmission is multiperson use of contaminated syringes and other injection-related paraphernalia [4]. More than 40,000 IDUs live in the San Francisco Bay area [5]. From 1986 through 2005, the Urban Health Study (UHS) recruited active IDUs from street settings in inner-city San Francisco Bay area neighborhoods, counseled them regarding reducing the risk of infection, tested them for HIV antibodies, and referred them to appropriate medical and social services [6-8]. Prospective, semiannual sampling revealed that the prevalence of HCV antibody increased in association with the duration of injection drug use [2, 3, 9, 10], which likely reflects an effect of cumulative exposure. Interestingly, however, the incidence of new HCV infections, as measured by seroconversion, decreased in association with longer durations of injection drug use. This reduction in the incidence of HCV infection did not appear to be a chance phenomenon and was independent of risk behavior (B.R.E., unpublished data), suggesting that seronegative IDUs with a long duration of HCV exposure may have some degree of innate or acquired immunity. In this context, 2 recent epidemiological studies demonstrated that IDUs who successfully cleared HCV in the past have a reduced risk of developing persistent HCV viremia, despite continued injection drug use and continued exposure to HCV [11, 12]. Subjects who had cleared a past HCV infection were 2 times [11] and 4 times [12] less likely to develop persistent HCV infection than were subjects without evidence of past HCV exposure. To identify potential immunological correlates of immune protection, we studied the cellular and humoral immune responses of a subgroup of IDUs in the UHS who reported injection drug use of >10 years’ duration.

To the Editor: We would like to report on a case of difficult-to-treat autoimmune hepatitis (AIH) that responded well to treatment with infliximab therapy.

Liver test abnormalities have been described in up to 60% of patients with systemic lupus erythematodes (SLE) at some point during the course of their disease. Prior treatment with potentially hepatotoxic drugs or viral hepatitis is commonly considered to be the main cause of liver disease in SLE patients. However, in rare cases elevated liver enzymes may be due to concurrent autoimmune hepatitis (AIH). To distinguish whether the patient has primary liver disease with associated autoimmune clinical and laboratory features resembling SLE - such as AIH - or the elevation of liver enzymes is a manifestation of SLE remains a difficult challenge for the treating physician. Here, we present six female patients with complex autoimmune disorders and hepatitis. Patient charts were reviewed in order to investigate the complex relationship between SLE and AIH. All patients had coexisting autoimmune disease in their medical history. At the time of diagnosis of AIH, patients presented with arthralgia, abdominal complaints, cutaneous involvement and fatigue as common symptoms. All patients fulfilled the current diagnostic criteria of both, AIH and SLE. Remission of acute hepatitis was achieved in all cases after the initiation of immunosuppressive therapy. In addition to this case study a literature review was conducted.

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.