Luigi Muratori

Fatigue and pruritus at onset identify a more aggressive subset of primary biliary cirrhosis

In recent years, primary biliary cirrhosis is mostly diagnosed in patients who are asymptomatic; however, a proportion of cases still present with typical complaints such as fatigue and/or pruritus. We compared biochemical, histological and immunological features of patients with or without fatigue and/or pruritus at onset to see whether the different clinical presentation may eventually impact on disease progression.

Autoimmune liver disease and concomitant extrahepatic autoimmune disease.

Aim To assess the frequency and clinical impact of associated extrahepatic autoimmune diseases (EAD) on autoimmune liver diseases (ALD). Patients and methods We investigated 608 patients with ALD (327 autoimmune hepatitis – AIH and 281 primary biliary cirrhosis – PBC) for concomitant EAD. Results In both AIH and PBC, we observed a high prevalence of EAD (29.9 and 42.3%, respectively); both diseases showed a significant association with autoimmune thyroid disease, followed by autoimmune skin disease, celiac disease, and vasculitis in AIH patients and sicca syndrome, CREST syndrome, and celiac disease in PBC patients. At diagnosis, AIH patients with concurrent EAD were more often asymptomatic than patients with isolated AIH (P<0.01). Conclusion Our study confirms the strict association between ALD and EAD, in particular with autoimmune thyroid disease. In the light of our results, all patients with an EAD should be assessed for the concomitant presence of an asymptomatic ALD.

Efficacy and Safety of Mycophenolate Mofetil and Tacrolimus as Second-line Therapy for Patients With Autoimmune Hepatitis

BACKGROUND & AIMS: Predniso(lo)ne, alone or in combination with azathioprine, is the standard‐of‐care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second‐line therapy for patients with AIH. METHODS: We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second‐line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6–190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second‐line therapy as a result of side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC. RESULTS: There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver‐related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log‐rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. CONCLUSIONS: Long‐term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.

Features and Progression of Asymptomatic Autoimmune Hepatitis in Italy

BACKGROUND & AIMSnPatients with autoimmune hepatitis (AIH) can present with symptoms ranging from those that are insidious and nonspecific to acute hepatitis with jaundice. However, some patients have no symptoms at diagnosis and are identified incidentally. We investigated disease progression and outcomes of these 2 groups of patients.nnnMETHODSnWe performed a retrospective study to compare clinical, immunologic, and histologic features and outcomes of patients with asymptomatic vs. symptomatic AIH. We analyzed data collected from 305 patients (90 asymptomatic and 215 with symptoms), diagnosed with AIH from 1994 and 2013, at the Center for the Study and Treatment of the Autoimmune Diseases of the Liver and Biliary System in Bologna, Italy.nnnRESULTSnAt diagnosis, patients with asymptomatic AIH had significantly lower mean levels of alanine aminotransferase (7.0- ± 8.0-fold the upper limit of normal) than patients with symptomatic disease (23.0- ± 18.0-fold the upper limit of normal; P < .001), and lower mean levels of bilirubin (1.4 ± 1.4 mg/dL vs. 8.6 ± 10.4 mg/dL; P < .001). Asymptomatic patients also had significantly lower histologic grades (7.0 ± 2.5) than symptomatic patients (9.0 ± 2.9; P < .001). However, larger proportions of asymptomatic patients had anti-liver/kidney microsomal antibodies type 1 (26.8% vs. 13.1%; P < .006), and associated autoimmune thyroid (26.7% vs. 12.6%; P = .003) or skin (8.9% vs. 2.3%; P = .010) disorders. Age at onset, sex, response to therapy, disease progression, genetic factors, and other autoantibody markers did not differ between patients with asymptomatic vs. symptomatic disease.nnnCONCLUSIONSnPatients with asymptomatic vs. symptomatic AIH have similar courses of disease progression and responses to immunosuppressive agents, and therefore should receive the same treatment. Patients affected by thyroid or dermatologic autoimmune disorders are at increased risk of developing subclinical liver disease, and should be assessed routinely for AIH.

Predictive factors of poor response to therapy in Autoimmune Hepatitis.

AIMnTo evaluate ex ante the predictive factors of incomplete/absent response to the standard therapy in a well characterized series of Autoimmune Hepatitis (AIH) patients from Italy.nnnMETHODSnOf 282 AIH patients screened from our database 166 (59%) had a sustained response and 116 (41%) had an incomplete/absent response to the therapy; all patients were analyzed for the clinical, serological and histological parameters at diagnosis.nnnRESULTSnThe patients with incomplete/absent response were characterized by significantly younger age (30 aa vs 42 aa p=0.001) and a significantly higher frequency of cirrhosis at diagnosis than patients who had a complete response to therapy (26% vs 3% p<0.0001); furthermore, patients with incomplete/absent response were distinguished from those with a complete response for significantly lower serum levels of both AST (7.9×upper normal limit [unl] vs 13×unl p<0.005) and ALT (10.9×unl vs 18×unl p=0.002) at diagnosis, and by an increase in IgG serum levels (1.43×unl vs 1.27×unl p=0.009). After stepwise logistic regression, cirrhosis at diagnosis (p=0.003, OR 0.12, 95% CI 0.03-0.49) and younger age (p=0.001, OR 1.03, 95% CI 1.01-1.05) represent two independent variables of incomplete/absent response.nnnCONCLUSIONSnYounger age and cirrhosis are predictive of lack of response to the standard therapy in AIH patients.

Diagnostic approach to autoimmune hepatitis

ABSTRACT Introduction: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if left without treatment, can evolve into cirrhosis and possibly liver failure. The diagnosis of AIH is hampered by the lack of specific and reliable markers of the disease and a number of clinical, biochemical, immunological, histological and genetic factors should be considered to reach a confident diagnosis Areas covered: Clinical expression of AIH, histological features, serological and genetic profiles, differential diagnosis, overlap with other autoimmune liver diseases, assessed on the basis of personal experience and review of published literature in the last 10 years through a systematic Medline search (keywords: autoimmune hepatitis, diagnosis) Expert commentary: Notwithstanding numerous efforts to identify simple and reliable markers of the disease, the diagnosis of AIH is still based on the combination of histological, immunological and biochemical features and often can represent a real challenge for the hepatologist.

Autoantibodies in Autoimmune Hepatitis

Background: The detection of diagnostic autoantibodies such as antinuclear antibodies (ANA), anti-smooth muscle antibodies (SMA), anti-liver/kidney microsomal type 1 (anti-LKM1), anti-liver cytosol type 1 (anti-LC1) and anti-soluble liver antigen (anti-SLA) is historically associated with the diagnosis of autoimmune hepatitis. Key Messages: When autoimmune hepatitis is suspected, the detection of one or any combination of diagnostic autoantibodies, by indirect immunofluorescence or immuno-enzymatic techniques with recombinant antigens, is a pivotal step to reach a diagnostic score of probable or definite autoimmune hepatitis. Conclusions: Diagnostic autoantibodies (ANA, SMA, anti-LKM1, anti-LC1, anti-SLA) are a cornerstone in the diagnosis of autoimmune hepatitis. Other ancillary autoantibodies, associated with peculiar clinical correlations, appear to be assay-dependent and institution-specific, and validation studies are needed.

Hyperferritinemia and hypergammaglobulinemia predict the treatment response to standard therapy in autoimmune hepatitis

Autoimmune hepatitis (AIH) is a chronic hepatitis with an increasing incidence. The majority of patients require life-long immunosuppression and incomplete treatment response is associated with a disease progression. An abnormal iron homeostasis or hyperferritinemia is associated with worse outcome in other chronic liver diseases and after liver transplantation. We assessed the capacity of baseline parameters including the iron status to predict the treatment response upon standard therapy in 109 patients with untreated AIH type 1 (AIH-1) in a retrospective single center study. Thereby, a hyperferritinemia (> 2.09 times upper limit of normal; Odds ratio (OR) = 8.82; 95% confidence interval (CI): 2.25–34.52) and lower immunoglobulins (<1.89 times upper limit of normal; OR = 6.78; CI: 1.87–24.59) at baseline were independently associated with the achievement of complete biochemical remission upon standard therapy. The predictive value increased when both variables were combined to a single treatment response score, when the cohort was randomly split into a training (area under the curve (AUC) = 0.749; CI 0.635–0.863) and internal validation cohort (AUC = 0.741; CI 0.558–0.924). Patients with a low treatment response score (<1) had significantly higher cumulative remission rates in the training (p<0.001) and the validation cohort (p = 0.024). The baseline hyperferritinemia was accompanied by a high serum iron, elevated transferrin saturations and mild hepatic iron depositions in the majority of patients. However, the abnormal iron status was quickly reversible under therapy. Mechanistically, the iron parameters were not stringently related to a hepatocellular damage. Ferritin rather seems deregulated from the master regulator hepcidin, which was down regulated, potentially mediated by the elevated hepatocyte growth factor. In conclusion, baseline levels of serum ferritin and immunoglobulins, which are part of the diagnostic work-up of AIH, can be used to predict the treatment response upon standard therapy in AIH-1, although confirmation from larger multicenter studies is pending.

Primary Biliary Cholangitis: advances in management and treatment of the disease

Primary Biliary Cholangitis, previously known as Primary Biliary Cirrhosis, is a rare disease, which mainly affects women in their fifth to seventh decades of life. It is a chronic autoimmune disease characterized by a progressive damage of interlobular bile ducts leading to ductopenia, chronic cholestasis and bile acids retention. Even if the disease usually presents a long asymptomatic phase and a slow progression, in many patients it may progress faster toward cirrhosis and its complications. The 10year mortality is greater than in diseases such as human immunodeficiency virus/Hepatitis C Virus coinfection and breast cancer. Ursodeoxycholic acid is the only treatment available today, but even if effective in counteracting the disease progression for the majority of patients, in approximately 40% is not able to decrease effectively the alkaline phosphatase, a surrogate marker of disease activity. Recently, obeticholic acid received the European Medicines Agency conditional approval, as add on treatment in patients non responders or intolerant to ursodeoxycholic acid. The present paper illustrates the opinion of a working group, composed by clinical pharmacologists, gastroenterologists/hepatologists with specific expertise on Primary Biliary Cholangitis and patient associations, on the state of the art and future perspectives of the disease management. The agreement on the document was reached through an Expert Meeting.

De novo autoimmune hepatitis in liver transplant: State-of-the-art review.

In the two past decades, a number of communications, case-control studies, and retrospective reports have appeared in the literature with concerns about the development of a complex set of clinical, laboratory and histological characteristics of a liver graft dysfunction that is compatible with autoimmune hepatitis. The de novo prefix was added to distinguish this entity from a pre-transplant primary autoimmune hepatitis, but the globally accepted criteria for the diagnosis of autoimmune hepatitis have been adopted in the diagnostic algorithm. Indeed, de novo autoimmune hepatitis is characterized by the typical liver necro-inflammation that is rich in plasma cells, the presence of interface hepatitis and the consequent laboratory findings of elevations in liver enzymes, increases in serum gamma globulin and the appearance of non-organ specific auto-antibodies. Still, the overall features of de novo autoimmune hepatitis appear not to be attributable to a univocal patho-physiological pathway because they can develop in the patients who have undergone liver transplantation due to different etiologies. Specifically, in subjects with hepatitis C virus recurrence, an interferon-containing antiviral treatment has been indicated as a potential inception of immune system derangement. Herein, we attempt to review the currently available knowledge about de novo liver autoimmunity and its clinical management.