Liver Kidney Microsomal Type Research Articles

MON-LB126 A Benign and Favorable Diagnosis: Glycogen Hepatopathy Causing Transient Transaminitis During Diabetic Ketoacidosis in Type 1 Diabetes Mellitus

Background: Transient transaminitis is a rarely discussed complication of uncontrolled diabetes mellitus (DM). Known as glycogenic hepatopathy (GH), it is belived to be caused by build-up of glycogen in hepatocytes. Recognized as benign and reversible, GH is associated with hepatomegaly (>90% cases) and primarily seen in patients with type 1 DM during periods of inadequate hyperglycemic control. Differential diagnoses include glycogen storage diseases, nonalcoholic fatty liver disease, hepatosclerosis, autoimmune hepatitis, hemochromatosis, Wilson disease, and acute viral hepatitis.1 Case Report: A 26-year-old African American female with type 1 DM and sickle cell presented on multiple occasions to the emergency department with abdominal pain associated with nausea, vomiting and diarrhea. Initial labs consistently included glucose levels >600 mg/dL (70-105 mg/dL), elevated anion gap ranging 20-40s mEq/L (5-15 mEq), and severe metabolic acidosis reflective of diabetic ketoacidosis (DKA). Labs were also significant for repeated mild transaminitis despite adequate fluid hydration.After several admissions, we observed a distinct pattern of mild transaminitis that directly fluctuated with her levels of blood glucose. With some minor lag, the patient’s liver enzymes normalized when her glucose levels normalized and DKA resolved.Further work-up ruled out more common etiologies of liver injury. Multiple abdominal ultrasounds and CT scans showed a normal sized liver without obvious structural abnormalities. Labs were significant for negative hepatitis B and hepatitis C; several negative anti-smooth muscle, anti-nuclear antibody, centromere antibody, and liver kidney microsomal type 1 antibody; normal levels of ceruloplasmin and alpha 1 anti-trypsin; low iron levels 23 ug/dL (60-180 ug/dL); borderline low IgG 627 mg/dL (700-1600 mg/dL).We hypothesized that the patient likely had GH by exclusion of other liver pathologies and given the context of transient transaminitis during DKA. Conclusion: GH is a benign and favorable diagnosis in diabetic patients with elevated transaminases.1 Given the small number of cases of GH reported, there is a need to record and analyze more patients with likely GH in order to better understand the condition. Appropriate clinician awareness of GH can also eliminate the need for time consuming and costly workup.

Diagnosis and Management of Pediatric Autoimmune Liver Disease: ESPGHAN Hepatology Committee Position Statement.

Paediatric autoimmune liver disease is characterized by inflammatory liver histology, circulating autoantibodies, and increased levels of IgG, in the absence of a known etiology. Three conditions have a likely autoimmune pathogenesis: autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis, and de novo AIH after liver transplantation. Two types of pediatric AIH are recognized according to seropositivity for smooth muscle and/or antinuclear antibody (AIH-1) or liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibodies (AIH-2).Pertinent issues addressing the diagnosis, treatment, and long-term follow-up were formulated by a core group of ESPGHAN members. They have commissioned the first authors with execution of this project. Initially, they have performed a systematic literature search on MEDLINE, ResearchGate, and Mendeley databases during the last 30 years and produced a document focusing on prospective and retrospective studies in children. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique.

Double Trouble Bubble: Autoimmune Overlap Syndrome Causing Portal Gastropathy, with Review of Current Literature

A 57 year old female with a past medical history of cirrhosis and high elevation of SM-Ab titer, elevated actin IGG, and anti-mitochondrial antibody significantly increased presented to the emergency department with hematemasis and bright red blood per rectum. After admission to the ICU she received 2 units packed red blood cells and was started on intravenous antibiotics, protonix, and octreotide. An esophagogastroduodenoscopy revealed esophageal and gastric varices extending into the stomach with gastropathy, not amenable to banding. A Trans-Jugular Intrahepatic Portosystemic Shunt (TIPS) was performed after resolution of bleeding. The patient was discharged with follow up for transplant evaluation while being treated with ursodiol, rifaximin, lactulose, pantoprazole, and diuretics. Autoimmune hepatitis (AIH) is a liver disease characterized by inflammatory liver histology, elevated transaminase levels, circulating autoantibodies, and increased levels of immunoglobulin G in the absence of a known etiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody (AIH type 1) and antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 (AIH type 2). There is mounting evidence that genetic susceptibility, molecular mimicry, and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4 T-cells. The histological findings of lymphocytes, plasma cells, and macrophages is non-specific but consistent with the diagnosis of AIH. A massive recruitment of activated inflammatory cells is likely to cause damage and eventually leads to portal hypertension; this prolonged elevated portal pressures then can lead to progressive congestion and eventually gastropathy. Due to large heterogeneity of the disease AIH may be unrecognized, and the clinical manifestation of AIH can range from mild or severe symptoms to fulminant hepatic failure. Growing insights into the clinical presentation of AIH highlights the importance of evaluation of the current diagnostic criteria and development of new treatment strategies to identify patients who would benefit from more efficient therapy. We present a patient in which liver transplant would be the only viable option for long term therapeutic benefit due to the untreated progression of her disease.

Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is defined by elevated serum transaminases along with the presence of one or more characteristic serum autoantibodies, including antinuclear antibody (ANA), anti–smooth muscle antibody (ASMA), and anti–liver-kidney microsomal type 1 antibody (anti-LKM-1); elevated levels of serum immunoglobulin G (IgG); interface hepatitis on histology; and responsiveness to immunosuppressive therapy. AIH has been classified into two disease subtypes based on serologic markers: type 1, which is characterized by the presence of either ANA or ASMA, and type 2, which is characterized by the presence of either anti-LKM-1 or anti–liver-cytosol antibody type 1 (anti-LC-1). This review addresses the epidemiology, natural history, pathogenesis, and management of AIH, as well as ongoing challenges. Several recent advances are highlighted, including the creation of a simplified diagnostic scoring system and the use of budesonide for AIH treatment. Figures show the pathology of AIH, treatment approach of moderate to severe AIH with combination therapy, azathioprine metabolism, and management of treatment outcomes. Tables list a comparison of type 1 and type 2 AIH, antibodies in AIH, the revised diagnostic scoring system (including a simplified version), indications for treatment in AIH, recommended treatment regimens for AIH by the American Association for the Study of Liver Diseases, and adverse effects associated with therapy for AIH. This review contains 4 highly rendered figures, 7 tables, and 146 references.

Update on Autoimmune Hepatitis.

Autoimmune hepatitis (AIH), a liver disorder affecting both children and adults, is characterized by inflammatory liver histology, elevated transaminase levels, circulating nonorganspecific autoantibodies, and increased levels of immunoglobulin G, in the absence of a known etiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody define AIH type 1 and antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2. AIH type 1 affects both adults and children, while AIH type 2 is mainly a paediatric disease, though it does occasionally affects young adults. AIH should be considered during the diagnostic workup of any patient with increased liver enzyme levels. AIH is exquisitely responsive to immunosuppressive treatment with prednisolone with or without azathioprine, with symptom free long-term survival for the majority of patients. For those who do not respond to standard treatment, or who are difficult-to-treat, mycophenolate mofetil and, in the absence of a response, calcineurin inhibitors should be tried in addition to steroids. The pathogenesis of AIH is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4 T-cells, although recent studies support the involvement of diverse populations, including Th17 cells. A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigenspecific regulatory T-cells, which ultimately aim at restoring tolerance to liver-derived antigens.

Autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a severe hepatopathy characterised by female preponderance, hypertransaminasaemia, elevated levels of immunoglobulin (IgG), presence of serum autoantibodies and, histologically, by interface hepatitis. AIH occurs both in adults and children, being particularly aggressive in the latter. According to the type of serum autoantibodies, AIH can be differentiated in two forms: one positive for smooth muscle antibody (SMA) and/or antinuclear antibody (ANA) (type 1 AIH, AIH-1) and another positive for liver kidney microsomal antibody type 1 (LKM-1) (type 2 AIH, AIH-2). These two forms differ with regard to age at onset (earlier in the case of AIH-2), mode of presentation (fulminant hepatic failure more frequently observed in AIH-2) and association with IgA deficiency (more frequent in AIH-2). AIH responds satisfactorily to immunosuppressive treatment (corticosteroids with or without azathioprine) that should be started as soon as the diagnosis is made. Despite immune suppression, some 40% of patients experience relapse and 9% undergo liver transplantation. Though the exact mechanism leading to loss of immune-tolerance in AIH is still unclear, recent evidence has pointed to a numerical and functional defect of CD4(pos)CD25(pos) regulatory T-cells as a factor permitting autoaggressive CD4 and CD8 T-cells to react against liver autoantigens. The generation and expansion of regulatory T-cells with liver autoantigen specificity in vitro represents a potential immunotherapeutic tool for the reconstitution of immune-tolerance in AIH without the drawback of pan-immunosuppression.

Localized Scleroderma and Autoimmune Hepatitis: A Unique Association

Introduction: Autoimmune hepatitis (AIH) is a rare association of systemic sclerosis. Even rarer is the association of AIH with localized scleroderma, with only two reported cases in literature up to date. We hereby report a case of AIH associated with localized scleroderma. Case description: A 39-year-old female with localized scleroderma presented to the hospital with periumbilical pain, non-bloody emesis, and jaundice. Physical exam showed normal vitals with scleral icterus, thickened skin plaques affecting all extremities, and a normal abdominal exam. Laboratory findings were significant for a Hg of 10.9 gm/dL with an MCV of 74.5 and platelets of 143 k/dL. LFTs showed a total protein of 7.3 g/dL with an albumin 3.7 of g/dL, total bilirubin of 9.5 mg/dL, AST of 1288 U/L, ALT of 775 U/L, ALP of 184 U/L, GGT of 196 U/L, LDH of 760 U/L, and an INR of 1.25. Work-up of chronic liver disease, including serologies for hepatitis A, B and C, EBV, CMV, HSV, and ferritin iron panel were unremarkable. Furthermore, autoimmune serologies, including antibodies to nuclear, mitochondrial, smooth muscle, liver cytosol, parietal cells, and liver-kidney microsome type 1 were all negative. Imaging of abdomen and pelvis with US Doppler and CT scan were unremarkable. Liver biopsy showed plasma cell infiltration, rosette formation, and interface hepatitis histology consistent with autoimmune hepatitis. The patient was started on steroids and azathioprine, with complete normalization of LFTs. Discussion: Localized scleroderma, a rare autoimmune disorder with female predominance, is associated with other autoimmune conditions. While the pathological mechanisms remain unclear, activation of the cellular and humoral immune responses may play a part. Association of AIH and scleroderma has been limited to two prior case reports. We suggest that a liver biopsy be considered in patients with localized scleroderma, with persistent elevation of liver enzymes in the setting of negative autoimmune serologies, to make a diagnosis of AIH.

Autoantibody profile in individuals with chronic hepatitis C

Autoantibodies are often produced during infection with chronic hepatitis C virus (HCV), but it remains controversial whether they influence the biochemical profile and histological features of this disease. Therefore, this current study sought to describe these autoantibodies and evaluate their impact on the clinical and histological presentation of hepatitis C. This cross-sectional analytical study assessed patients with HCV (RNA+) from October 2011 to July 2012. This study included 66 patients, with a mean age of 53.2±10.5 years. Of these patients, 60.6% were male, and 54.3% presented with genotype 1. Non-organ-specific autoantibodies (NOSA) were detected in 24% of the patients; of these, 7.6% were anti-mitochondrial antibodies (AMA+), 26.7% were anti-smooth muscle antibodies (SMA+) and 6.8% were liver kidney microsomal type 1 antibodies (LKM1+). With respect to the thyroid autoantibodies, 7.4% were anti-peroxidase (ATPO+) antibodies, and none were anti-thyroglobulin (ATG+) antibodies. Regarding celiac disease autoantibodies, 5.8% were endomysial antibodies (EMA+), and no transglutaminase (TTG+) antibodies were detected. Cryoglobulins were found in 2.1% of patients. When NOSA+ individuals were compared to patients without the presence of NOSAs, they exhibited higher median alkaline phosphatase (0.7 vs. 0.6 xULN; p=0.041), lower median platelet counts (141,500.0 vs. 180,500.0/mm 3 ; p=0.036), lower mean prothrombin activity (72.6±11.5% vs. 82.2±16.0%; p=0.012) and an increased prevalence of significant fibrosis (E≥2) (45.5% vs. 18.2%; p=0.012). There was also a tendency for a greater proportion of NOSA+ cases to have marked periportal activity (APP≥3) (44.5% vs. 15.6%; p=0.087). In addition to the high prevalence of autoantibodies associated with HCV infection, it was observed that NOSA positivity was associated with a more severe histological and biochemical profile of hepatitis C infection.

Liver kidney microsomal type 1 antibodies reduce the CYP2D6 activity in patients with chronic hepatitis C virus infection

Liver kidney microsomal type 1 (LKM-1) antibodies have been shown to decrease the CYP2D6 activity in vitro and are present in a minority of patients with chronic hepatitis C infection. We investigated whether LKM-1 antibodies might reduce the CYP2D6 activity in vivo. All patients enrolled in the Swiss Hepatitis C Cohort Study and tested for LKM-1 antibodies were assessed (n = 1723): 10 eligible patients were matched with patients without LKM-1 antibodies. Patients were genotyped for CYP2D6 variants to exclude individuals with a poor metabolizer genotype. CYP2D6 activity was measured by a specific substrate using the dextromethorphan/dextrorphan metabolic ratio to classify patients into four activity phenotypes. All patients had a CYP2D6 extensive metabolizer genotype. The observed phenotype was concordant with the CYP2D6 genotype in most LKM-negative patients, whereas only three LKM-1 positive patients had a concordant phenotype (six presented an intermediate and one a poor metabolizer phenotype). The median DEM/DOR ratio was sixfold higher in LKM-1 positive than in LKM-1 negative patients (0.096 vs. 0.016, P = 0.004), indicating that CYP2D6 metabolic function was significantly reduced in the presence of LKM-1 antibodies. In chronic hepatitis C patients with LKM-1 antibodies, the CYP2D6 metabolic activity was on average reduced by 80%. The impact of LKM-1 antibodies on CYP2D6-mediated drug metabolism pathways warrants further translational studies.

Autoimmunity and Extrahepatic Manifestations in Treatment-Naïve Children with Chronic Hepatitis C Virus Infection

Hepatitis C virus (HCV) infection has been associated with autoimmunity and extrahepatic manifestations in adults. Few data are available on these topics in children. Nonorgan specific auto-antibodies development is part of the natural course of chronic hepatitis C in children. Smooth muscle autoantibody is the most common autoantibody found, while liver-kidney microsomal type-1 antibody positivity is the most peculiar autoimmune feature of children with HCV infection. The clinical significance of non-organ specific autoantibodies in the course of paediatric chronic hepatitis C is still debated. Autoantibody positivity can be considered neutral for most patients, while it can be associated with negative connotations for others, especially those positive for liver-kidney microsomal type-1 autoantibody. Subclinical hypothyroidism but not autoimmune thyroiditis has been demonstrated in HCV infection in children, while only few cases of HCV-associated membranoproliferative glomerulonephritis have been described. Single reports are available in the literature reporting the anecdotal association between chronic hepatitis C and other extrahepatic manifestations such as myopathy and opsoclonus-myoclonus syndrome. Despite the low incidence of extrahepatic manifestations of chronic hepatitis C in children, overall, available data suggest a careful monitoring.

De Novo Autoimmune Hepatitis in Korean Children After Liver Transplantation: A Single Institution's Experience

IntroductionDe novo autoimmune hepatitis (AIH) after orthotopic liver transplantation (OLT) has been described as a new type of late graft dysfunction in children who have not undergone transplantation for previous autoimmune liver disease. The purpose of this study was to evaluate the clinical aspects of de novo AIH among children following OLT. Patients and MethodsBetween January 1994 and May 2007, 149 children underwent OLT, including 1 with recurrent AIH who was excluded from this study, whereas 4 others developed de novo AIH (2.7%; n = 4/148). We analyzed the demographics, laboratory characteristics, and response to treatment of the 4 children with de novo AIH following OLT. ResultsThe 4 patients were all girls with a median interval after OLT to presentation of 6.5 years (range, 0.7–8.8 years). The median age when de novo AIH developed was 12.4 years (range, 8.7–17.3 years). All cases were detected by abnormal liver function tests, namely, increased aspartate aminotransferase (AST; median, 322 IU/L; range, 181–919 IU/L). One patient showed elevated immunoglobulin G. Three patients displayed positive antinuclear antibodies. All were seronegative for smooth muscle antibody and liver-kidney microsomal type 1 antibody. One patient showed anti-mitochondrial antibody. All patients were treated with steroids with or without azathioprine. The liver function tests in these 4 patients, improved by at least 50% during the first month of treatment, responding to steroid treatment with or without azathioprine. ConclusionIn preadolescent or adolescent female patients with unexplained graft dysfunction after OLT, it is important to recognize de novo AIH rapidly and to develop an adequate diagnostic strategy, including evaluation of serum autoantibodies, immunoglobulin G, and liver biopsy.

Autoimmune hepatitis

Autoimmune hepatitis (AIH) is an inflammatory liver disease that mainly affects females. It is characterized histologically by interface hepatitis, biochemically by increased aspartate and alanine aminotransferase levels, and serologically by the presence of autoantibodies and increased levels of immunoglobulin G. AIH affects both adults and children, and is particularly aggressive in the latter group. It is a relatively rare but devastating disease, which progresses rapidly unless immunosuppressive treatment is started promptly. With appropriate treatment 80% of patients achieve remission and long-term survival. Those patients who progress to end-stage liver disease because they are unresponsive or nonadherent to treatment, and those with fulminant liver failure (encephalopathy grade II-IV) at diagnosis, require liver transplantation. Seropositivity for smooth muscle and/or antinuclear antibodies defines type 1 AIH, while positivity for liver kidney microsomal type 1 antibodies defines type 2 AIH. The primary cause of AIH is unknown; however, considerable knowledge about the mechanisms of liver damage involved has been gathered over the past 30 years, which is likely to provide the basis for specific modes of treatment and a possible cure.

Cutting Edge Issues in Autoimmune Hepatitis

Autoimmune hepatitis is an inflammatory liver disease affecting mainly females and characterised histologically by interface hepatitis, biochemically by elevated transaminase levels and serologically by circulating autoantibodies and increased levels of immunoglobulin G. Autoimmune hepatitis responds to immunosuppressive treatment, which should be instituted as soon as diagnosis is made. Seropositivity for smooth muscle and/or antinuclear antibody defines type 1 autoimmune hepatitis, while positivity for liver kidney microsomal type 1 antibody defines type 2 autoimmune hepatitis. The aetiology of autoimmune hepatitis is unknown, though both genetic and environmental factors are involved in its expression. The major mechanism of liver damage involves immune reactions against host liver antigens that are not adequately controlled by defective regulatory T cells. Current research aiming at potentiating regulatory T cell function in vitro to reconstitute tolerance in vivo has given promising results.

LKM-1 Sera from Autoimmune Hepatitis Patients that Recognize ERp57, Carboxylesterase 1 and CYP2D6

Liver kidney microsomal antibody type 1 (LKM-1) is a diagnostic marker for autoimmune hepatitis type 2 (AIH-2). Characterization of LKM autoantibodies of patients with AIH-2 demonstrated that a proportion of LKM sera contains autoantibodies which recognize one or more small linear epitopes on cytochrome P450, CYP2D6, an enzyme of drug metabolism pathways. The identification and epitope mapping of antigens involved in autoimmune diseases are important in understanding the mechanisms triggering autoimmunity and providing guidance for designing immunomodulatory therapy. In this study, several proteins recognized by LKM-1-positive sera in rat and human hepatic microsomes were analyzed by MALDI-TOF-MS after separation with ion-exchange chromatography or two-dimensional polyacrylamide gel electrophoresis. We identified these proteins as ERp57 and carboxylesterase 1 (CES1) as well as CYP2D6. Epitopes in ERp57 and CES1 recognized by LKM-1-positive serum were investigated by enzyme-linked immunosorbent assay (ELISA) with protease-digested peptides of ERp57 and CES1. The peptides comprising amino acids 105-129 of ERp57 and 558-566 of CES1 were specifically recognized by the serum. The epitopes in EPp57 and CES1 recognized by LKM-1-positive sera were homologous with those in hepatitis C virus (HCV). Viral infection of such as HCV may thus possibly trigger autoimmune hepatitis.

Autoantibodies and their Antigens in Autoimmune Hepatitis

Autoantibody detection assists in the diagnosis and allows differentiation of autoimmune hepatitis (AIH) type 1 (AIH-1), characterized by antinuclear antibody (ANA) and/or smooth muscle antibody (SMA), and type 2 (AIH-2), distinguished by the presence of antibodies to liver-kidney microsome type 1 (anti-LKM1) and/or antibodies to liver cytosol type 1 (anti-LC1). Detection of atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) and anti-soluble liver antigen (SLA) antibodies can act as an additional pointer toward the diagnosis of AIH, particularly in the absence of the conventional autoantibodies. Routine autoantibody testing by indirect immunofluorescence has been recently complemented by molecular assays based on purified or recombinant antigens. Although the AIH-1-specific ANA and SMA targets need better definition, those of anti-LKM1 and anti-LC1 in AIH-2 have been clearly identified; the fine specificity of antibody reactivity and its clinical relevance to disease pathogenesis are the focus of ongoing investigation. This article critically discusses the current knowledge of the diagnostic and clinical significance of AIH-related autoantibody reactivities, focusing on key issues that the physician needs to be aware of to be able to request the appropriate testing and to interpret correctly the laboratory results within the clinical context of the patient.

Autoimmune Hepatitis in Children: What is Different from Adult AIH?

Autoimmune hepatitis (AIH) is characterized by inflammatory liver histology, circulating non-organ-specific autoantibodies, and increased levels of immunoglobulin (Ig) G in the absence of a known etiology. Two types of childhood AIH are recognized according to seropositivity: smooth muscle antibody (SMA) and/or antinuclear antibody (ANA), which is AIH type 1; and antibodies to liver-kidney microsome type 1 (anti-LKM1), which is AIH type 2. There is a female predominance in both. Autoimmune hepatitis type 2 presents more acutely, at a younger age, and commonly with IgA deficiency; however, duration of symptoms before diagnosis, clinical signs, family history of autoimmunity, presence of associated autoimmune disorders, response to treatment, and long-term prognosis are similar in the two groups. Immunosuppressive treatment with steroids and azathioprine, which should be instituted promptly to avoid progression to cirrhosis, induces remission in 80% of cases. Relapses are common, often due to nonadherence. Drugs effective in refractory cases include cyclosporine and mycophenolate mofetil. Long-term treatment is usually required, with only some 20% of AIH type 1 patients able to discontinue therapy successfully. In childhood, sclerosing cholangitis with strong autoimmune features, including interface hepatitis and serological features identical to AIH type 1, is as prevalent as AIH, but it affects boys and girls equally. The differential diagnosis relies on cholangiographic studies. In autoimmune sclerosing cholangitis, liver parenchymal damage responds satisfactorily to immunosuppressive treatment, whereas bile duct disease tends to progress.

Autoimmune hepatitis

Autoimmune hepatitis (AIH) is an inflammatory liver disease affecting mainly females and characterised histologically by interface hepatitis, biochemically by elevated transaminase levels and serologically by the presence of autoantibodies and increased levels of immunoglobulin G. AIH responds to immunosuppressive treatment, which should be instituted as soon as diagnosis is made. Seropositivity for smooth muscle and/or anti-nuclear antibody defines type 1 AIH, while positivity for liver kidney microsomal type 1 antibody defines type 2 AIH. The aetiology of AIH is unknown, though both genetic and environmental factors are involved in its expression. Immune reactions against host liver antigens are believed to be the major mechanism of liver damage.

Validation of simplified diagnostic criteria for autoimmune hepatitis in Italian patients #

A simplified score for the diagnosis of autoimmune hepatitis (AIH) using only four criteria has been recently published by the International Autoimmune Hepatitis Group on Hepatology1; the included paramenters were represented by autoantibodies, immunoglobulin G, histology, and exclusion of viral hepatitis (Table 1). The authors reached 88% sensitivity and 97% specificity with a score ≥ 6 and 81% sensitivity and 99% specificity with a score ≥ 7. The aim of our study was to test this simplified score in our Italian AIH series and controls. Our study population was represented by 132 well-characterized Italian patients with AIH who were diagnosed on the basis of the revised score2 and 15 patients with a diagnosis of AIH/primary biliary cirrhosis (PBC) overlap syndrome (AIH/PBC OS) diagnosed in accordance with the reported criteria3; as pathological controls, we used 120 patients with “pure” PBC4 and 143 patients who were positive for hepatitis C virus (HCV), 38 of whom had a seropositivity for Liver Kidney Microsome type 1 (LKM1) autoantibody. A total of 121 of 132 (91.6%) Italian patients with AIH reached a score ≥ 6 and 114 of 132 (86.3%) ≥ 7. Among the 15 patients with AIH/PBC OS, 14 of them (93.3%) had a score ≥ 6 and 12 of 15 (80%) had a score ≥ 7. In the HCV series, we found six patients (all positive for LKM1) of 143 (4%) who reached a score ≥ 6 and none with ≥ 7; when we considered patients with “pure” PBC, we observed nine of 120 (8%) with a score ≥ 6 and one (1%) with a score ≥ 7. The overall sensitivity and specificity for the AIH diagnosis with a score ≥ 6 was 91.8% (95% confidence interval [CI]: 87.9-94.6) and 94.3 (95% CI: 92.1-95.9), with a positive and negative likelihood ratio of 16.1 (95% CI: 11.1-22.8) and 0.08 (95% CI: 0.05-0.13), respectively. When we considered a score ≥ 7, the overall sensitivity and specificity was 87.1% (95% CI: 84.5-87.6) and 99.6% (95% CI: 98.2-99.9), with a positive and negative likelihood ratio of 229 (95% CI: 46-1294) and 0.13 (95% CI: 0.12-0.15), respectively. The diagnosis of AIH is often difficult and needs the evaluation of several parameters not always available at the bedside of the patient. The proposed simplified score is easy to apply with high sensitivity and specificity; in particular, in our experience, a score ≥ 7 allows a raising of the specificity without a significant loss of sensitivity. Furthermore, this simplified score seems to be efficacious also in the diagnosis of AIH/PBC OS starting from patients with PBC who have signs of AIH. As expected, we found some patients (six) with the coexistence of HCV positivity and LKM1 seropositivity who satisfied the score for the diagnosis of AIH; in these cases, determining if the viral or autoimmune component is predominant or an overlap of viral/autoimmune syndrome is present is difficult. The score can help the physician, but the therapeutical approach should be tailored for each patient. Paolo Muratori*, Alessandro Granito*, Georgios Pappas*, Luigi Muratori*, * Department of Clinical Medicine, Alma Mater Studiorum University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy.

Cytochrome P450IID6‐specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2†

Autoimmune hepatitis type 2 (AIH-2) is a severe organ-specific disorder characterized by liver kidney microsomal antibody type 1 targeting cytochrome P4502D6 (CYP2D6). Growing evidence implicates the involvement of CD8 T cell immune responses in its pathogenesis. We investigated CYP2D6-specific CD8 T cell human leukocyte antigen (HLA)-A2 restricted responses in AIH-2 (20 patients, 11 HLA-A2+). Binding affinity of CYP2D6 peptides to HLA-A2 was predicted by the algorithm SYFPEITHI and assessed in vivo by T2 cell assays. CD8 T cell interferon (IFN)-gamma production was assessed via intracellular cytokine staining, cytotoxicity via chromium release assay, and frequency of circulating and intrahepatic CYP2D6-specific CD8 T cells via tetramer staining. CYP2D6-specific CD8 T cell reactivity was tested at diagnosis and during treatment and correlated with indices of disease activity. Seven CYP2D6 peptides with high HLA-A2 binding affinity colocalizing with known B cell or CD4 T cell epitopes were selected. Five sequences inducing high levels of IFN-gamma were used for HLA-A2 tetramer construction. Frequency, IFN-gamma production, and cytotoxicity of CYP2D6-specific CD8 T cells were higher at diagnosis than during treatment. Intensity of CYP2D6-specific CD8 T cell responses correlated with disease activity. Immune responses to CYP2D6(245-254) were the strongest both at diagnosis and during treatment. HLA-A2-restricted, CYP2D6-specific CD8 T cell immune responses vary according to disease stage and correlate with hepatocyte damage. CD8 T cell targets on CYP2D6-in particular CYP2D6(245-254)-may be the focus of novel immune intervention in AIH-2. (HEPATOLOGY 2007.).

Polyclonal T-Cell Responses to Cytochrome P450IID6 Are Associated With Disease Activity in Autoimmune Hepatitis Type 2

Autoimmune hepatitis type 2 (AIH-2), a severe juvenile liver disorder of unknown etiology and pathogenesis, is characterized by liver-kidney microsomal antibody type 1 targeting cytochrome P450IID6 (CYP2D6) and is associated to HLA DRB1*07. Although CYP2D6 B-cell reactivity has been extensively characterized, little is known about CYP2D6-specific T-cell responses. The aim of the present study was to characterize anti-CYP2D6 cellular immune responses and their possible pathogenic role in patients with AIH-2. We investigated T-cell reactivity against 61 overlapping peptides spanning the full CYP2D6 protein using ex vivo cultures obtained at diagnosis, remission, and relapse. Moreover, CYP2D6-specific T-cell reactivity was investigated in the context of HLA restriction, peptide-binding affinity to HLA DRB1*07, cytokine profile, disease specificity, and clinical course. Proliferative responses to CYP2D6 cluster to 7 antigenic regions in DRB1*07 and to 4 regions in non-DRB1*07 patients. Whereas distinct peptides induce production of interferon gamma, interleukin-4, or interleukin-10, peptides inducing interferon-gamma and proliferation overlap. There is also an overlap between sequences inducing T- and B-cell responses. The breadth (number of epitopes) and intensity (quantity of cytokine produced) of the T-cell response are directly correlated to disease activity (biochemical and histologic markers). These data imply that the T-cell response to CYP2D6 in AIH-2 is polyclonal, involves multiple effector types targeting different epitopes, and is associated with hepatocyte damage, knowledge that should form the basis for a more refined therapeutic approach.