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A J Czaja

Publications and source records attributed to A J Czaja.

At least 19 recordsLinked to original sources
PubMed2005

Diverse manifestations and evolving treatments of autoimmune hepatitis.

Autoimmune hepatitis has a global occurrence and diverse manifestations. Patients are frequently asymptomatic (34%), and an acute, even fulminant, presentation is possible. Concurrent immune disorders may obscure the liver disease, and perivenular (Rappaport zone 3) necrosis is within the histological spectrum. Clinical phenotypes and outcomes vary among different ethnic groups, and genetic factors strongly affect susceptibility. Non-disease specific autoimmune modifiers include female gender and gene polymorphisms that affect immunocyte activation and differentiation. Antibodies to soluble liver antigen/liver pancreas may have prognostic importance and reflect a genetic propensity for severe disease. Subtypes based on serological profiles do not have distinctive outcomes or therapies. Variant forms include patients with bile duct injury or loss, absence of conventional serological markers, abnormal cholangiograms, or coincidental hepatitis C. Treatment is empiric and based on the predominant manifestations (hepatitic, cholestatic, or viral). New treatment strategies must be strengthened by predictive indices that accurately forecast individual differences in disease outcome. Drugs with site-specific actions on immunocyte activation and proliferation (cyclosporine, tacrolimus and myco-phenolate mofetil) must be assessed by clinical trial, and site-specific molecular interventions (blocking peptides, recombinant immune modulators, T cell vaccination, oral tolerance, gene silencing and gene therapy) require confident experimental animal models for evaluation. Better prognostic indices, new immunosuppressive agents, and site-specific molecular interventions promise to improve care.

HLA-DR Antigens↗
PubMed2004

'True' antimitochondrial antibody-negative primary biliary cirrhosis, low sensitivity of the routine assays, or both?

Anti-mitochondrial antibody (AMA) is considered the serological hallmark of primary biliary cirrhosis (PBC), but may be missing in a proportion of these patients. We assessed sensitivity and specificity of the currently available techniques for AMA detection in a large series of PBC patients and controls, and analysed their clinical and immunological features according to the AMA status. By indirect immunofluorescence on rat tissue sections and HEp-2 cells, Western immunoblot with bovine submitochondrial particles, and two ELISAs with AMA-specific recombinant proteins, we evaluated the presence of AMA in 127 PBC patients, 166 patients with type 1 autoimmune hepatitis and 100 with non alcoholic fatty liver disease. In PBC patients Western immunoblot detects AMA significantly more often than indirect immunofluorescence on HEp-2 cells (85%versus 72%, P = 0.02) or rodent tissue sections (71%, P = 0.01); both ELISAs are only slightly less sensitive than Western immunoblot (81% and 78%). Ten patients with non alcoholic fatty liver disease were AMA-positive by indirect immunofluorescence, but none recognized AMA-specific epitopes in Western immunoblot or in ELISAs. Twelve patients with type 1 autoimmune hepatitis were AMA-positive by indirect immunofluorescence, but only 6 (3.6%) reacted by Western immunoblot and ELISAs. Western immunoblot or ELISA should be regarded as first-line assay for the detection of AMA. Up to 15% of PBC patients are consistently AMA-negative, yet they share the same clinical, biochemical and histological features of AMA-positive PBC. Detection of AMA in type 1 autoimmune hepatitis might identify a subset of patients at risk of developing a hepatitic/cholestatic syndrome.

Adult↗
PubMed2002

Establishment of standardised SLA/LP immunoassays: specificity for autoimmune hepatitis, worldwide occurrence, and clinical characteristics.

BACKGROUND: Antibodies to soluble liver antigen/liver pancreas (SLA/LP) are specific markers of autoimmune hepatitis. Their target antigen has recently been cloned. AIMS: To establish standardised immunoassays using the recombinant antigen, and to assess the frequency and significance of seropositivity in patients from different countries. METHODS: An enzyme linked immunoassay was developed using purified recombinant antigen and validated by testing sera from 200 healthy blood donors and 1026 patients with various liver and non-liver diseases. The assay was then applied to 454 sera from 419 patients with autoimmune hepatitis from different countries. All sera were also tested by inhibition immunoassay and western blot. RESULTS: Antibodies were reliably detected by the recombinant immunoassay and occurred exclusively in patients with autoimmune liver disease. Twenty three of 149 patients from the USA (15%), 23/132 from Brazil (17%), 21/108 from Germany (19%), and 2/30 from Japan (7%) were seropositive. Clinical features at presentation were similar between seropositive and seronegative patients. However, relapse after corticosteroid withdrawal or during maintenance therapy occurred more commonly in seropositive patients. CONCLUSIONS: Antibodies to SLA/LP can be reliably detected by these standardised immunoassays based on recombinant antigen. Antibodies to SLA/LP occur with similar frequencies in different geographical regions, races, and age groups, and are of exquisite diagnostic specificity. Whether SLA/LP positive patients represent a clinically distinct subgroup remains to be determined; relapse during treatment reduction appeared to be more common in the SLA/LP group.

Adolescent↗
PubMed2001

Shared genetic risk factors in autoimmune liver disease.

To determine if shared genetic risk factors for autoimmune liver disease affect clinical manifestations, we evaluated 271 patients and 92 normal subjects by DNA-based techniques. Genetic risk factors were intermixed in all conditions, and frequency varied according to disease type. DR4 distinguished autoimmune hepatitis (P = 0.0002) and primary biliary cirrhosis (P = 0.004) from primary sclerosing cholangitis. DR52 distinguished primary sclerosing cholangitis from autoimmune hepatitis (P = 0.0007) and primary biliary cirrhosis (P = 0.00007) and DR3 distinguished autoimmune hepatitis (P = 0.002) and primary sclerosing cholangitis (P = 0.0005) from primary biliary cirrhosis. Only the occurrence of DR4 in primary sclerosing cholangitis was lower than in normal subjects (P = 0.02). Patients with mixed genetic risk factors did not have distinctive features or manifestations of hybrid conditions. We conclude that patients with shared genetic risk factors do not have characteristic features nor do they have overlap syndromes. DR4 may be protective against primary sclerosing cholangitis.

Adult↗
PubMed2001

Autoimmune hepatitis with incidental histologic features of bile duct injury.

Bile duct changes are atypical of autoimmune hepatitis. Our aims were to assess the frequency and significance of these changes in classical disease. Liver biopsy specimens were reviewed under code from 84 patients who satisfied international scoring criteria for autoimmune hepatitis, and the findings were correlated with clinical features and outcome. Twenty patients (24%) had biliary changes, including 6 with destructive cholangitis, 4 with ductopenia, and 10 with nondestructive cholangitis. Patients with and without bile duct changes had similar laboratory findings. Diagnostic scores for autoimmune hepatitis were lower in patients with bile duct changes (16.6 +/- 0.6 vs. 19.1 +/- 0.2, P <.0001). The frequencies of scores sufficient for a definite (80% vs. 97%, P =.03) or probable diagnosis (20% vs. 3%, P =.03) were also less in this group. Patients with destructive cholangitis and/or ductopenia responded as well to therapy as patients with nondestructive cholangitis, and outcomes in each group were similar to those of patients without biliary changes. We concluded that biliary changes can occur in classic autoimmune hepatitis, and they are not associated with distinctive clinical features or treatment response. They may be coincidental findings associated with classic disease or weak expressions of a variant syndrome. In the absence of a cholestatic clinical syndrome, they do not compel a different management strategy.

Adolescent↗
PubMed2001

Recurrent autoimmune hepatitis after orthotopic liver transplantation.

To determine the frequency, risk factors, and consequences of recurrent autoimmune hepatitis after liver transplantation, 41 patients with type 1 disease were monitored after surgery in accordance with a surveillance protocol. Tacrolimus or cyclosporine plus prednisone were administered to each patient, and liver biopsy examinations were performed at least annually according to protocol. Corticosteroid therapy was ultimately discontinued in only 2 patients. Recurrent disease was defined as the presence of lymphoplasmacytic infiltrates in liver tissue in the absence of other causes of allograft dysfunction. Autoimmune hepatitis recurred in 7 patients (17%), and the mean time to recurrence was 4.6 +/- 1 years. Recurrence was asymptomatic in 4 of 7 patients and detected only by surveillance liver biopsy assessment in 2 patients. Histological changes were mild, and there was no progression to cirrhosis during 4.9 +/- 0.9 years of observation. Five-year patient (86% v. 82%; P =.9) and graft (86% v. 67%; P =.5) survival rates were not statistically different between patients with and without recurrent disease. HLA-DR3 or HLA-DR4 occurred more commonly in patients with than without recurrence (100% v. 40%; P =.008) and healthy subjects (100% v. 49%; P =.01). Recurrent disease was unrelated to donor HLA status. In conclusion, recurrence after transplantation for type 1 autoimmune hepatitis is common. Its mild manifestations and favorable prognosis may reflect early detection by a surveillance protocol and/or continuous corticosteroid treatment. HLA-DR3- or HLA-DR4-positive recipients are at risk for recurrence regardless of donor HLA status.

Adult↗
PubMed2001

Autoimmune liver disease.

Autoimmune hepatitis in children may be associated with sclerosing cholangitis in the absence of inflammatory bowel disease. Wilson disease can have clinical and laboratory features that resemble autoimmune hepatitis, and it may respond initially to corticosteroids. Soluble HLA-DR antigens reflect clinical activity, and they may be useful markers of treatment response. Polymorphisms of the cytotoxic T lymphocyte antigen-4 gene may synergize with other autoimmune promoters or HLA risk factors to increase susceptibility and alter disease expression. DRB1*1301 distinguishes Argentine children from Argentine adults and identifies a unique subgroup. Antibodies to soluble liver antigen/liver-pancreas do not characterize a separate clinical entity. Their target antigen has been isolated, and it shares homologies with a selenocysteine-specific protecting factor (tRNP((Ser)Sec)). CYP2D6 is expressed on the hepatocyte surface, and it can be targeted by antibodies in autoimmune hepatitis and chronic hepatitis C. Perinuclear antineutrophil cytoplasmic antibodies lack sensitivity and specificity for autoimmune hepatitis, and they have diverse antigen specificities. Activation-induced cell death may be impaired in autoimmune hepatitis, and, in contrast to budesonide, mycophenolate mofetil has been effective in a small study of problematic patients.

Journal Article↗
PubMed2001

Understanding the pathogenesis of autoimmune hepatitis.

OBJECTIVES: The aim of this study was to review the pathogenic mechanisms of autoimmune hepatitis, identify gaps in knowledge, and focus future investigative efforts. METHODS: The study was based on a review of all relevant articles on the mechanisms of autoimmunity in autoimmune liver disease from 1980 to 2000, extraction of pertinent concepts from the medical literature; and integration of evolving paradigms of pathogenesis with personal experiences and investigations. RESULTS: Autoimmune hepatitis is a consequence of autoantigen exposure, genetic predisposition, and defective immunoregulatory mechanisms. Autoantigen is optimally presented by class II molecules of the major histocompatibility complex that have lysine residues at position DRbeta71 of the antigen-binding groove. Cytokines and non-disease-specific autoimmune promoters modulate immune reactivity. Cell-mediated and antibody-dependent mechanisms contribute to hepatocyte injury. CONCLUSIONS: Multiple disturbances in the homeostatic mechanisms that preserve self-tolerance are likely in autoimmune hepatitis. Future investigations must focus on individual determinants of autoantigen presentation, immunocyte activation, and liver cell destruction. Findings can then be integrated into a comprehensive knowledge base that may be applicable to other autoimmune diseases.

Autoantigens↗
PubMed2001

Current concepts in the diagnosis, pathogenesis, and treatment of autoimmune hepatitis.

Autoimmune hepatitis has a global distribution and affects all ages. Genetic factors strongly influence susceptibility, clinical expression, and treatment response. The diagnosis of autoimmune hepatitis has been codified by an international panel. An acute or fulminant presentation is recognized but not a cholestatic form. Subclassifications by predominant autoantibody profile have been proposed, but they lack etiologic and prognostic differences. Autoantibodies continue to be characterized to improve diagnostic specificity, predict outcome, and identify pertinent antigenic targets. Cytosolic enzymes are prime candidates as autoantigens. DRB1*0301 and DRB1*0401 are the susceptibility alleles in Caucasoid Northern Europeans and North Americans, and they also affect clinical expression and treatment outcome. Other autoimmune promoters affecting cytokine production and immunocyte activation may act in synergy with the susceptibility alleles to affect disease behavior. Cell-mediated and antibody-dependent forms of cytotoxicity are probably interactive pathogenic mechanisms, and novel site-specific therapies are feasible because these mechanisms are defined. Potent new immunosuppressive agents are emerging from the transplantation arena, but prednisone alone or in combination with azathioprine remains the mainstay of treatment. Corticosteroid therapy is effective but not ideal.

Age Distribution↗
PubMed2000

Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis.

Genetic susceptibility to type 1 autoimmune hepatitis is indicated by a preponderance of female subjects and strong associations with human leukocyte antigens (HLA) DRB1*0301 and DRB1*0401. The gene encoding cytotoxic T-lymphocyte antigen-4 (CTLA-4) on chromosome 2q33 may also influence autoimmunity. To determine the frequency and significance of the exon 1 adenine (A)-guanine (G) base-exchange polymorphism for CTLA-4 in patients with type 1 autoimmune hepatitis, 155 northern European Caucasoid patients and 102 ethnically-matched control subjects were tested by polymerase chain reaction. The genotype distribution was significantly different in patients compared to controls (AA = 50/155 patients vs. 51/102 controls; AG = 84/155 patients vs. 38/102 controls; GG = 21/155 patients vs. 13/102 controls, chi(2) = 8.94, P =.011). This difference was caused by a significant over-representation of the G allele in patients compared to controls (105/155 patients vs. 51/102 controls, chi(2) = 8.34, P =.004, odds ratio = 2.12). The GG genotype was associated with a significantly higher mean serum aspartate transaminase level (P =. 03), greater frequency of antibodies to thyroid microsomal antigens (P =.004) and was found more commonly in patients with HLA DRB1*0301 (P =.02). Treatment outcomes, however, were not affected by the genotype. The CTLA-4 G allele is more common in patients with type 1 autoimmune hepatitis and may represent a second susceptibility allele. Furthermore, there may be synergy between the HLA-DRB1*0301 and the GG genotype in terms of disease risk.

Abatacept↗
PubMed2000

Nature and behavior of serum cytokines in type 1 autoimmune hepatitis.

To assess the relationship between serum cytokine behavior and treatment outcome in type 1 autoimmune hepatitis, serum levels of interferon-gamma, interleukin-2, interleukin-4, and interleukin-10 were measured by enzyme immunoassay in 43 patients and 20 normal subjects. Serum samples were similarly tested in 38 patients after corticosteroid treatment. Serum levels of interleukin-2 and interleukin-4 were significantly lower in patients than in normal subjects. Interleukin-2 was the least common cytokine detected before (3%), during (0%), or after treatment (0%). Serum levels of interleukin-10 at presentation did not differ from those of normal subjects but they did decrease during therapy, especially in patients who entered remission. Changes in these levels, however, did not always parallel treatment outcome or histological activity. We conclude that serum levels of interleukin-2 and interleukin-4 are lower than normal in type 1 autoimmune hepatitis. Serum concentrations of interleukin-10 diminish during corticosteroid therapy but changes do not closely reflect outcome. The rarity of interleukin-2 in serum may be a distinguishing feature.

Adolescent↗
PubMed2000

Hepatocellular carcinoma in autoimmune hepatitis.

To determine if hepatocellular carcinoma can develop in autoimmune hepatitis in the absence of viral infection and to assess its frequency, liver tissue removed at hepatectomy was tested for HBV DNA and HCV RNA in one patient and the frequency of hepatocellular carcinoma was determined in 212 other uniformly followed individuals. The liver tissue from the propositus was uninfected and only one patient (0.5%) in the cohort undergoing routine follow-up developed malignancy during 1,732 patient-years of observation. Only one of 88 patients with cirrhosis (1%) developed hepatocellular carcinoma during 1,002 patient-years of observation after cirrhosis (mean, 123 +/- 9 months) and of the 65 patients with histological cirrhosis for at least five years, only one developed carcinoma during 162 +/- 8 months (incidence, 1 per 965 patient-years). We conclude that hepatocellular carcinoma can develop in autoimmune hepatitis in the absence of viral infection. Its occurrence is rare and only in long-standing cirrhosis.

Adult↗
PubMed2000

Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis.

Genetic susceptibility to type 1 autoimmune hepatitis in white northern Europeans is related to female sex, HLA alleles encoding the six amino acid sequence LLEQKR at positions 67-72 of the DRB1 polypeptide, and CTLA-4 gene polymorphism. The principal HLA alleles associated with type 1 autoimmune hepatitis in Britain and North America are DRB1*0301 and DRB1*0401. In this model of susceptibility, lysine at position 71 of the expressed DR molecule is the critical amino acid. In Japan, Argentina and Mexico, susceptibility is linked to DRB1*0405 and DRB1*0404. These two alleles encode arginine at position 71 rather than lysine, but they share the motif LLEQ-R with DRB1*0401 and DRB1*0301. Thus, K or R at position 71 in the context of LLEQ-R may be critical for susceptibility. This "shared motif" or "epitope" may optimize T-cell recognition of autoantigen, and other alleles that encode lysine at DRbeta71 may also affect susceptibility and outcome, possibly by increasing the density of lysine or arginine 71 molecules on the surface of antigen-presenting cells. Since the DRB1*0301 allele is part of the extended ancestral 8.1 haplotype, it carries with it additional risk factors for autoimmunity, including TNFA*2 and C4A*Q0. Type 1 autoimmune hepatitis is a polygenic disorder and other yet undefined polymorphic genes may be non-specific immunoregulators. These additional MHC encoded genes and other non-MHC encoded genes may be important determinants of disease susceptibility and severity in type 1 autoimmune hepatitis.

Abatacept↗
PubMed2000

Isolation and characterization of cDNA encoding the antigenic protein of the human tRNP(Ser)Sec complex recognized by autoantibodies from patients withtype-1 autoimmune hepatitis.

We previously described autoantibodies against a UGA serine tRNA-protein complex (tRNP(Ser)Sec) in patients with type-1 autoimmune hepatitis [1] and now define the specificity and frequency of this autoantibody and the DNA sequence encoding the tRNA(Ser)Sec-associated antigenic protein. The presence of anti-tRNP(Ser)Sec antibodies was highly specific for type-1 autoimmune hepatitis, as 47.5% of patients were positive compared with none of the control subjects. To characterize the antigenic protein(s), we immunoscreened a human cDNA library with anti-tRNP(Ser)Sec-positive sera. Two clones (19 and 13) were isolated. Clone 19 encodes a protein with a predicted molecular mass of 48.8 kD. Clone 13 is a shorter cDNA, almost identical to clone 19, which encodes a 35.9-kD protein. Expression of both cDNAs was accomplished in Escherichia coli as His-tagged recombinant proteins. Antibodies eluted from both purified recombinant proteins were able to immunoprecipitate the tRNA(Ser)Sec from a HeLa S3 cell extract, demonstrating their cross-reactivity with the mammalian antigenic complex. Recent cloning data relating to the target antigen(s) of autoantibodies in autoimmune hepatitis patients that react with a soluble liver antigen (SLA) and a liver-pancreas antigen (LP) have revealed that these two autoantibodies are identical and that the cloned antigen shows 99% amino acid sequence homology with tRNP(Ser)Sec.

Adolescent↗
PubMed2000

Failure of budesonide in a pilot study of treatment-dependent autoimmune hepatitis.

BACKGROUND & AIMS: Budesonide has a high hepatic first-pass clearance and metabolites virtually devoid of glucocorticoid activity. Our goals were to assess budesonide in patients with treatment-dependent autoimmune hepatitis and to determine if efficacy and safety justified a controlled trial. METHODS: Ten patients who were dependent on continuous treatment to prevent exacerbation of their disease were treated with budesonide, 3 mg thrice daily. RESULTS: Laboratory indices did not improve significantly during 5 +/- 1 months of therapy (range, 2-12 months). Three patients entered clinical and biochemical remission; 2 of them achieved histologic remission. Seven patients either deteriorated during therapy or became drug intolerant. Withdrawal symptoms complicated conversion from prednisone to budesonide treatment, and every patient developed at least 1 side effect. Lumbar spine density decreased in 2 patients, and femur density decreased in 2 patients, including 1 with lumbar spine changes. However, mean bone densities actually increased slightly in the entire group. CONCLUSIONS: Budesonide therapy was associated with a low frequency of remission and high occurrence of treatment failure and side effects in treatment-dependent autoimmune hepatitis. Findings did not support the need for a controlled treatment trial in this select population.

Adult↗