Definite Autoimmune Hepatitis Research Articles

Diagnosis and presenting features of autoimmune hepatitis at a central referral hospital in South Africa

Introduction Autoimmune hepatitis (AIH) has scarcely been reported on in patients of black African descent. Similarly, few studies have focused on the relationship between AIH and Human-Immunodeficiency Virus (HIV) infection. Aim We aim to describe the presenting features of AIH from a single referral centre in a Sub-Sahara African setting. We also compare the presenting features of HIV-infected and HIV-uninfected patients. Methods This study was a retrospective chart review. Patients were included if they fulfilled criteria for the International AIH Group simplified score for probable or definite AIH, were 18 years or older at inclusion, and attended the adult Gastroenterology clinic at Inkosi Albert Luthuli Central Hospital (IALCH) for the period 1/1/2015 to 31/12/2020 on at least 2 occasions. Results Forty cases were included, of which 33 (82.5%) were female and 33 (82.5%) were black African. Median age at diagnosis was 26 years. A diagnosis of a coexistent autoimmune disease was made in 22.5% of patients, with Systemic Lupus Erythematosus (SLE) being the most common (12.5%). Sixteen patients were HIV-infected, all of whom were female (p =0.03), with a significantly older age of disease onset as compared to their HIV-uninfected counterparts (median age 38 vs 17.5 years, p <0.001). Conclusion AIH is a disease most commonly affecting young females. Female sex and older age of onset is associated with AIH in HIV-infected individuals.

Presence of ectopic germinal center structures in autoimmune hepatitis

Autoimmune tissues may contain ectopic germinal centers (EGCs). However, these structures have never been described in the liver of patients suffering from autoimmune hepatitis (AIH). We retrospectively reviewed histological features of 120 definite AIH cases, and found 10 cases harboring markers of EGCs. In these cases, CD21+ follicular dendritic cells were intermixed with CD3+ T and CD20+ B lymphocytes. The latter expressed the GC-specific marker bcl6, and some were proliferative as assessed by Ki67 expression. Antibody-secreting cells (ASCs) defined by expression of the mum-1 transcription factor and presence of cytoplasmic IgMs were usually present in the periphery of these structures, but some were also present within the EGCs. Notably, some ASCs were IgG-switched. Common treatment applied to AIH patients achieved biochemical normalization as efficiently as in patients without EGCs. In the present study, we provide the proof for the occurrence of functional EGCs enabling differentiation of B cells into ASCs and occurrence of immunoglobulin switch in AIH livers.

S2954 COVID-19 Infection as a Trigger for Seronegative Autoimmune Hepatitis: A Case Report

Introduction: Autoimmune hepatitis (AIH) is an immune-mediated liver disease that commonly develops in a genetically predisposed patient after exposure to an environmental trigger. These triggers include viruses, immunization and drugs. Both COVID-19 infection and vaccination have been linked to the development of AIH. Case Description/Methods: A 58-year-old male patient, known to have vitiligo and mild rheumatic mitral stenosis presented to our hospital complaining of flu-like symptoms. The patient denied any history of alcohol intake, substance abuse, over-the-counter or herbal medications, or family history of liver or autoimmune disease. His chronic medications included aspirin and bisoprolol. He tested positive for COVID-19 PCR, so he was admitted for observation. Chest X-ray showed no abnormality, and he was not started on any medication. His laboratory investigations (Table 1) were remarkable for ALT of 271 and AST of 175 U/L. During hospitalization, liver enzymes were trending down but remained elevated. The hepatitis workup (Table 1) was notable for an elevated IgG level of 16.9 g/l (normal range 7-16). His radiological investigations included US abdomen that revealed mildly increased echotexture, MRI liver that was only remarkable for tiny cyst 2 mm, and liver elastography that showed a stiffness average of 5.77 kPa indicating mild stiffness. The patient was offered a liver biopsy, but he was reluctant. During follow-up, his LFTs remained elevated but were fluctuating (Figure 1a). On week 31, he finally agreed for liver biopsy that showed moderate interface and portal tract inflammatory cell infiltrate composed mainly of lymphocytes with occasional eosinophils (Figure 1b,c). The histopathological findings were suggestive of AIH. On week 34, he was started on prednisone 40 mg. LFTs on week 36 were completely normal. The prednisone was tapered over the following two months. Six months later, repeat LFTs were also normal. Discussion: Our patient had an elevation of LFTs after COVID-19 infection that persisted for weeks and promptly responded to steroids therapy. Drug-induced liver injury was less likely as he didn’t receive any hepatotoxic medications prior to or during his hospitalization. In our patient, the Revised Original Score for Autoimmune Hepatitis (AIH) was 17, indicating definite AIH. The proposed mechanism of AIH development after COVID-19 infection is the molecular mimicry between spike protein S1 and multiple human tissue proteins. More studies are needed to examine this association.Figure 1.: a: Trend of LFTs over time. b,c: histopathological images showing interface and portal tract inflammation. Abbreviations alphabetically: Bx: biopsy - d/c: discharge - Dx: diagnosis - f/u: followup - Rx: treatment Table 1. - shows extensive hepatitis workup Laboratory test result Reference ALT 271 0-40 U/L AST 175 0-37 U/L ALP 38.9 40-129 U/L Antinuclear ab Negative Negative Anti Mitochondrial ab Negative Negative Anti Mitochondrial M2 ab Negative Negative Anti Smooth Muscle ab Negative Negative Anti Liver Kidney Microsomes Negative Negative Hepatitis B Core ab Reactive non-reactive Hepatitis B Core Ab IgM non-reactive non-reactive Hepatitis B Surface Antigen Non-reactive Non-reactive Hepatitis B e Ab Non-reactive Non-reactive Hepatitis B e Antigen Non-reactive Non-reactive Hepatitis A Ab IgM Non-reactive Non-reactive Hepatitis C Ab Non-reactive Non-reactive Hepatitis E IgG Reactive Non-reactive Hepatitis E IgM Non-reactive Non-reactive Herpes Simplex virus Ab IgM Non-reactive Non-reactive Parvovirus Ab IgM Non-reactive Non-reactive Alpha-1 anti-trypsin 37 20-53 µmol/L Ceruloplasmin 33 14 to 40 mg/dL CMV PCR Negative Negative EBV PCR Negative Negative HBV PCR Negative Negative

Validating a novel algorithm to identify patients with autoimmune hepatitis in an administrative database.

Population-level studies on the treatment practices and comparative effectiveness of therapies in autoimmune hepatitis (AIH) are lacking due to the absence of validated methods to identify patients with AIH in large databases, such as administrative claims or electronic health records. This study ascertained the performance of International Classification of Diseases (ICD) codes for AIH, and developed and validated a novel algorithm that reliably identifies patients with AIH in health administrative data and claims. This was a cross-sectional study of patients with ≥1 inpatient or ≥2 outpatient ICD codes for AIH between 2008 and 2019 at a single health system. In a random sample of 250 patients, definite or probable AIH was determined using the Simplified AIH score, Revised AIH score or expert adjudication. The positive predictive value (PPV) was obtained. Variations of this base algorithm were evaluated using additional criteria to increase its performance. Of the 250 patients, 143 (57.2%) patients had sufficient records available for review. The PPV of the base algorithm was 77.6% (95% CI: 69.9-84.2%). Exclusion of patients with ≥1 ICD code for primary biliary cholangitis or primary sclerosing cholangitis yielded a PPV of 89.7% (95% CI: 82.8-94.6%). Further exclusion of patients with recent immune checkpoint inhibitor therapy increased the PPV to 92.9% (95% CI: 86.5-96.9%). The use of ICD codes for AIH alone are insufficient to reliably identify patients with AIH in health administrative data and claims. Our proposed algorithm that includes additional diagnostic and medication-related coding criteria demonstrates excellent performance.

Prognosis of probable autoimmune hepatitis patients: a single-center study in Japan.

Autoimmune hepatitis (AIH) is an idiopathic inflammatory liver disease with genetic susceptibility and unknown environmental triggers. The gold standard for diagnosis, International Autoimmune Hepatitis Group (IAIHG) scoring system, classifies AIH as definite or probable. Conventional research on probable AIH has focused on the Caucasian population and there is little data pertaining to the Asian population. This study aimed to assess and compare the prognosis of Japanese patients with probable and definite AIH. In the current study, patients with probable and definite AIH diagnosed based on IAIHG scores between 1987 and 2018 were enrolled. As a result, 72 patients with definite AIH and 49 patients with probable AIH were evaluated. Univariate analysis revealed age, fibrosis stage 4, and the fibrosis-4 index were prognostic factors for overall survival. Multivariate analysis indicated that age and liver cirrhosis significantly affected the overall survival. When the cut off albumin-bilirubin score was set appropriately, cirrhosis was differentially diagnosed using albumin-bilirubin score with 100% sensitivity and 70.5% specificity. Classification of probable or definite disease did not alter overall survival with statistical significance. In conclusion, our findings suggest that probable AIH should be managed as definite AIH is managed in Japanese population. The albumin-bilirubin score helps identify liver cirrhosis and is a prognostic biomarker for overall survival.

A249 FREQUENCY AND CLINICAL SIGNIFICANCE OF INFLAMMATORY BOWEL DISEASE IN PATIENTS WITH AUTOIMMUNE HEPATITIS

Abstract Background Previous studies suggested that patients with autoimmune hepatitis (AIH) and inflammatory bowel disease (IBD) have poorer outcomes; however, the significance of this association is limited. Aims To describe the phenotype of AIH-associated IBD and assess the impact of IBD on the response to treatment and risk of adverse liver outcomes in patients with AIH. Methods In our retrospective cohorts, we identified patients with concomitant diagnoses of IBD and a definite AIH. The comparison cohort consisted of AIH patients matched by gender, age at diagnosis, ethnicity, and time to follow-up. Chi-square and Mann-Whitney tests were used to assess differences. Univariate analysis was performed using the Cox proportional hazards model. Results We identified a total of 16 patients (9 males, 56.3%) with AIH-associated IBD from a cohort of 6006 IBD patients (0.27%) and 357 AIH patients (4.5%). All patients were Caucasians. Twelve patients (75.0%) had ulcerative colitis with a pancolonic extent; 4 (25.0%) – Crohn’s disease: one patient had ileitis, three – ileocolitis with one having stricturing and fistulising gastroduodenal, ileocolonic and perianal disease. The median age at IBD diagnosis was 26.5 years old and varied from 2 to 53. The age at AIH diagnosis ranged from 7 to 59 years old (median 21.1) and median follow-up time was 11.1 years ranging from 11 days to 35.2 years. The matching cohort of 113 AIH-IBD- patients was comparable to the AIH-IBD+ cohort by gender (44 males, 38.9%; p=0.188), age at diagnosis (median 28.4, IQR 32; p=0.442), ethnicity, and the follow-up time (median 8.7 years, IQR 10.2; p=0.764). There was no difference in AST, ALT and ALP at diagnosis. Complete response rates were similar in AIH-IBD+ and AIH-IBD- groups (50.0% vs. 53.1%; p=0.816). The risk of developing cirrhosis and a median time to its onset did not differ significantly: 28.6% vs. 31.0% (p=0.853) and 11.8 vs. 8.2 years (p=0.359), respectively. In univariate Cox regression, IBD was not a predictor of progression to cirrhosis (HR 0.45; 95% CI 0.13–1.50; p=0.192). The risk of developing decompensation and a median time was also comparable between groups: 21.4% vs. 33.0% (p=0.384) and 18.4 vs. 9.8 years (p=0.053), supported by the Cox regression analysis (HR 0.44; 95% CI 0.13–1.48; p=0.187). The presence of IBD was not associated with higher need in liver transplant (18.8% vs. 30.1%; p=0.348), median time was slightly shorter (1.48 vs. 4.73 years; p=0.542), also evidenced by Cox regression (HR 1.40; 95% CI 0.42–4.65; p=0.578). The risk of liver-related death was also not different among the two groups (6.3% vs. 4.4%; p=0.746), and IBD was not a predictor of it (HR 1.94; 95% CI 0.17–21.69; p=0.589). Conclusions The presence of IBD in patients with AIH is rare and do not identify a subgroup of patients with worse response to treatment or poor clinical outcomes. Funding Agencies AbbVie

Role of age in presentation, response to therapy and outcome of autoimmune hepatitis

BackgroundFew studies with diverging results and a small sample size have compared autoimmune hepatitis (AIH) in the elderly to younger patients.AimTo unbiasedly investigate the role of age in behaviour and treatment outcome of AIH.MethodsAll patients with probable or definite AIH type 1 in four tertiary academic centres were included in this retrospective—and since 2006 prospective—cohort study. Influence of age on presentation, remission and outcome of AIH were investigated.Results359 patients were included. Presence of cirrhosis at AIH diagnosis around 30% was independent of age. ALAT was higher at age 30–60 years on AIH diagnosis, and above age 60 there were less acute onset, less jaundice and more concurrent autoimmune disease. Remission was reached in 80.2%, incomplete remission in 18.7%, only 1.1% (all aged 50–65) was treatment-refractory. Age was not an independent predictor of remission, while cirrhosis was. Above age 45 there was more diabetes, above age 60 more loss of remission. Rate of progression to cirrhosis was 10% in the 10 years after diagnosis and unrelated to age at AIH diagnosis. With onset below age 30, there was more development of decompensated cirrhosis over time. With higher age at AIH diagnosis there was a lower survival free of liver-related death or liver transplantation.ConclusionsAIH presents at all ages. Age influences features at diagnosis, but not response to treatment, while survival without liver-related death or liver transplantation decreases with higher age at diagnosis.

Suitability of the simplified autoimmune hepatitis score for the diagnosis of autoimmune hepatitis in a German cohort.

Several years ago the International Autoimmune Hepatitis Group simplified the previous revised original scoring system for diagnosis of autoimmune hepatitis (AIH) into a scoring system based on only four instead of 13 parameters. We aimed to evaluate the suitability of the simplified AIH score for diagnosis of AIH in a German cohort with chronic liver diseases. In this retrospective single-center study, we compared the accuracy of both AIH scores in 70 patients with AIH and 211 patients with chronic liver diseases (PBC (n = 52), PSC (n = 27), NASH (n = 67), DILI (n = 15), CHB/C (n = 50)). Sensitivity, specificity and predictability of each scoring system were calculated. Using the simplified AIH score, the sensitivity and specificity of detecting a probable AIH (scores ≥ 6) were 96% and 97% with a positive and negative predictive value of 92% and 99%, respectively. For diagnosis of definite AIH (scores ≥ 7), the sensitivity and specificity were 43% and 100% with a positive and negative predictive value of 97% and 84%, respectively. The concordance with the revised original criteria was 63%. The specificity for excluding AIH was excellent in both scoring system. The simplified diagnostic criteria allow a reliable diagnosis of AIH in a German cohort.

Transient Exacerbation After Infections in Patients With Autoimmune Hepatitis

Aims Although the pathogenesis of autoimmune hepatitis (AIH) is unknown, many recent studies have demonstrated that infection can act as a trigger for the onset of AIH. The existence of a pathogenetic link between AIH and infections has not been confirmed. If AIH is triggered by infections, it is possible that infections may transitorily worsen liver function in patients with AIH. We investigated the association between the effects of infections and the exacerbation of liver dysfunction in patients with AIH. Methods We determined the changes in liver function before and after infections in 20 patients with definite AIH, 33 with probable AIH, 24 with primary biliary cholangitis (PBC), 30 with chronic hepatitis C (CH(C)), and 23 control subjects. Results During the study period, 19 of the 20 patients (95%) with AIH experienced one or more signs of liver dysfunction after infection. Seventy-three (59%) out of the 124 total occurrences of infectionsin 19 patients met the criteria for transient exacerbation of liver dysfunction. The incidence of liver dysfunction and the serum IgG levels after infection were significantly higher in the patients with definite AIH than in the patients with probable AIH, PBC and CH(C), and in the control subjects. Serum IgG level was a significant independent predictor of liver dysfunction. Conclusion The present study results suggested that infection was one cause of exacerbation of liver dysfunction in patients with AIH, and that serum IgG level was a significant independent predictor of exacerbation of liver dysfunction after infection.

HLA-DRB1 and DQB1 alleles in Japanese type 1 autoimmune hepatitis: The predisposing role of the DR4/DR8 heterozygous genotype.

ObjectiveAutoimmune hepatitis (AIH) is a chronic progressive liver disease. AIH is composed predominantly of type 1 in Japanese populations. The genetic and environmental factors are associated with the pathogenesis of AIH. HLA-DRB1*03:01 and *04:01 are associated with type 1 AIH in European and *04:05 in Japanese populations. Here, we conducted an HLA association study in order to find HLA alleles or haplotypes predisposing or protective for Japanese AIH.MethodsHLA-DRB1 and DQB1 genotyping of 360 type 1 AIH patients and 1026 healthy controls was performed.ResultsThe predisposing association of DRB1*04:01 (P = 0.0006, corrected P [Pc] = 0.0193, odds ratio [OR] 2.97, 95% confidence interval [CI] 1.62–5.43), DRB1*04:05 (P = 1.89×10−21, Pc = 5.86×10−20, OR 3.41, 95% CI 2.65–4.38), and DQB1*04:01 (P = 4.66×10−18, Pc = 6.99×10−17, OR 3.89, 95% CI 2.84–5.33) and the protective association of DRB1*13:02 (P = 0.0003, Pc = 0.0080, OR 0.48, 95% CI 0.32–0.72) with Japanese type 1 AIH were observed. An association of the DR4/DR8 heterozygous genotype with Japanese AIH was identified for the first time (P = 3.12×10−9, OR 3.52, 95% CI 2.34–5.29). Susceptible diplotypes were DRB1*04:05-DQB1*04:01/DRB1*08:02-DQB1*03:02 (P = 0.0004, OR 24.77, 95% CI 1.45–424.31) and DRB1*04:05-DQB1*04:01/DRB1*08:03-DQB1*06:01 (P = 1.18×10−6, OR 10.64, 95% CI 3.19–35.46). Serum levels of Immunoglobulin G and Immunoglobulin M, International Autoimmune Hepatitis Group score, positive rate of anti-smooth muscle antibodies, and the rate of definite AIH were higher in AIH patients with DRB1*04:05 than without.ConclusionsThe important roles of specific combinations of DRB1 and DQB1 alleles or haplotypes in the pathogenesis of type 1 AIH were suggested. The association of DR4/DR8 heterozygous genotype suggested the pathologic importance of trans-complementing DQα-β heterodimer molecules encoded by DQA1 allele of one haplotype and the DQB1 allele of the other haplotype, as it was proposed in the HLA association studies of Type 1 diabetes.

Comparative Analysis of the Clinical Outcomes of Liver Transplantation for Probable and Definite Auto-immune Hepatitis by International Diagnostic Scoring Criteria

BackgroundLiver transplantation (LT) is an effective treatment for patients with end-stage liver disease caused by auto-immune hepatitis (AIH). However, diagnosis of AIH can be challenging for patients with end-stage liver disease at the time of transplantation. We classified patients into “probable” or “definite” AIH groups, using the diagnostic criteria of the International Autoimmune Hepatitis Group, and compared the clinical outcomes of AIH after LT in these 2 groups. MethodsWe performed a retrospective study of 18 patients who were diagnosed with AIH and underwent LT from March 2003 to March 2015 at a single institute. Of the 18 patients, 8 were diagnosed with definite AIH and 10 were diagnosed with probable AIH, according to the international scoring criteria. We evaluated the patient characteristics, recurrence rate, graft loss, and survival rates after LT. ResultsThe mean follow-up duration was 59.3 months. Age, sex, medical condition at transplantation, warm ischemic time, cold ischemic time, and Model for End-Stage Liver Disease score did not differ significantly between the 2 groups. No patient died after LT in either group, but 1 patient in the definite AIH group had graft failure. In Kaplan-Meier analysis, the 5-year recurrence rates of the definite and probable groups were 14.3% and 0%, respectively (P = .992). ConclusionsThe recurrence of definite AIH appeared to be higher than that of probable AIH. However, careful immunosuppressive therapy allowed the long-term survival of both definite and probable AIH patients after LT.

Autoimmune hepatitis: review of histologic features included in the simplified criteria proposed by the international autoimmune hepatitis group and proposal for new histologic criteria

Simplified criteria for diagnosis of autoimmune hepatitis are based on autoantibodies, serum immunoglobulin G, histologic features, and negative viral serology. A score of 6 points is necessary for the designation of probable autoimmune hepatitis and 7 points or more for definite autoimmune hepatitis. The presence of three histologic features is required for categorizing a case as typical (2 points): interface hepatitis with portal lymphocytic/lymphoplasmacytic cells extending into lobule, emperipolesis, and rosettes. In the absence of all three features, a chronic hepatitis picture is considered compatible with autoimmune hepatitis (1 point). This study examines the validity of these histologic features for the diagnosis of autoimmune hepatitis. Clinical data and liver biopsies were reviewed for 88 autoimmune hepatitis, 20 primary biliary cholangitis, and 13 non-autoimmune acute hepatitis cases. Interface/lobular activity, number of plasma cells, copper/CK7 stains, and presence/absence of biliary features were assessed in autoimmune hepatitis and primary biliary cholangitis cases. The simplified criteria score was calculated. Modified histologic criteria were formulated on the basis of interface/lobular activity, number of plasma cells, and presence/absence of biliary features. Using the proposed histologic features, histologic score of 2 increased from 8 to 77%, while total simplified score of >6 increased from 69 to 86%. There was no increase in total simplified score for primary biliary cholangitis or non-autoimmune acute hepatitis. Rosettes and emperipolesis are difficult to interpret, and lack sensitivity and sensitivity for autoimmune hepatitis diagnosis. The current histologic criteria used in the current simplified score lead to underscoring of autoimmune hepatitis cases. The modified histologic criteria based on the inflammatory activity, extent of plasma cells, and results of copper/CK7 staining increased the histologic score in autoimmune hepatitis and led to a probable/definite diagnosis of autoimmune hepatitis in 17% of cases that would have otherwise been classified as non- autoimmune hepatitis by simplified score.

Association of a single nucleotide polymorphism upstream of ICOS with Japanese autoimmune hepatitis type 1.

Autoimmune hepatitis (AIH) is an uncommon chronic autoimmune liver disease. Several studies reported the association of polymorphisms between CD28, CTLA4 and ICOS gene cluster in 2q33.2 with autoimmune or inflammatory diseases. The previous genome-wide association study on type 1 AIH in a European population has reported a risk G allele of a single nucleotide polymorphism (SNP), rs4325730, in this region. Here, we conducted an association study of this SNP with type 1 AIH in a Japanese population, as a replication study.An association study of rs4325730 was conducted in 343 Japanese AIH patients and 315 controls.We found that rs4325730 is associated with AIH (P=0.0173, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.05-1.62, under the allele model for G allele, P=0.0070, OR 1.62, 95% CI 1.14-2.31, under the dominant model for G allele). This SNP was strongly associated with definite AIH (P=0.0134, OR 1.36, 95% CI 1.07-1.74; under allele model for G, P=0.0035, OR 1.85, 95% CI 1.22-2.81, under dominant model for G).This is the first replication association study of rs4325730 upstream of ICOS with AIH in the Japanese population and rs4325730G is a risk allele.

Long-term follow-up of children and adolescents with primary sclerosing cholangitis and autoimmune sclerosing cholangitis

Sclerosing cholangitis (SC) is a chronic cholestatic hepatobiliary disease with uncertain long-term prognosis in pediatric patients. This study aimed to evaluate long-term results in children with SC according to the types of SC. We retrospectively followed up 25 children with SC over a period of 4-17 years (median 12). The diagnosis of SC was based on biochemical, histological and cholangiographic findings. Patients fulfilling diagnostic criteria for probable or definite autoimmune hepatitis at the time of diagnosis were defined as having autoimmune sclerosing cholangitis (ASC); other patients were included in a group of primary sclerosing cholangitis (PSC). The incidence of the following complications was studied: obstructive cholangitis, portal hypertension, advanced liver disease and death associated with the primary disease. Fourteen (56%) patients had PSC and 11 (44%) had ASC. Patients with ASC were significantly younger at the time of diagnosis (12.3 vs 15.4 years, P=0.032) and had higher IgG levels (22.7 vs 17.2 g/L, P=0.003). The mentioned complications occurred in 4 (16%) patients with SC, exclusively in the PSC group: one patient died from colorectal cancer, one patient underwent liver transplantation and two patients, in whom severe bile duct stenosis was present at diagnosis, were endoscopically treated for acute cholangitis. Furthermore, two other children with ASC and 2 children with PSC had elevated aminotransferase levels. The 10-year overall survival was 95.8% in all patients, 100% in patients without complicated liver disease, and 75.0% in patients with complications. In children, ASC is a frequent type of SC, whose prognosis may be better than that in patients with PSC.

PTU-083 Long-Term Follow-Up of Patients with Autoimmune Hepatitis after Withdrawal of Immunosuppressant Therapy

Introduction If immunosuppressant therapy (IST) is withdrawn in patients with autoimmune hepatitis (AIH) when remission is achieved, 50–70% will have a disease relapse within 12 months. Thus, many patients receive long-term maintenance IST. However, IST has potential side effects, including an increased cancer risk. Recent studies suggest a lower AIH relapse rate if IST is withdrawn at a later stage in the disease. Data are lacking in regard to long-term outcome following IST withdrawal. Methods Retrospective audit of long-term outcome of AIH following withdrawal of IST. A total of 282 patients with definite or probable AIH by International AIH Group criteria, had presented to our Unit between 1971–2015 and had achieved normalisation of serum ALT within 12 months of starting IST (prednisolone plus azathioprine, or mycophenolate if azathioprine intolerant). From these, we found 25 patients in whom all IST was subsequently discontinued. We assessed outcome in these patients, in comparison to those who continued IST. Follow-up was until last serum ALT for calculating relapse rate and until death or last known to be alive for calculating survival rates. Results The 25 patients (21 female, age at diagnosis 50 (8–68) years) had been on IST before withdrawal for 3.9 (0.1–22.4) years. Five had cirrhosis at presentation. All patients had normal serum ALT and globulins at time of withdrawal except one patient with acute pancreatitis. Reasons for IS withdrawal were: cancer (6), infections (3), side effects (4), frailty (6) patient choice (6), doubt about diagnosis (subsequently resolved) (1). Relapses occurred in 7 patients (28%) after 1.6 (0.5–9.6) years. Relapse rates were 15%, 20% and 28% after 2, 5 and 10 years respectively. All patients achieved re-normalisation of serum ALT within 3 months of re-starting therapy (prednisolone 10–40 mg/day) plus (in 5 patients) azathioprine or mycophenolate, subsequently continued as maintenance therapy. Over follow up (from IST withdrawal) of 4.2 (1.2–25.1 years), no patient developed liver decompensation, variceal bleeding or hepatocellular carcinoma. Six patients died after 4 (3.3–15.9) years; none due to liver disease or following AIH relapse. Patients stopping IST (n = 25) had, compared to those who continued IST (n = 257) higher 10- and 20 year survival (99±4% and 79±9% respectively vs 78±3% and 48±4% p = 0.021). Conclusion In patients with AIH who achieve remission a trial of withdrawal of IS therapy is associated with (a) a lower disease relapse rate than previously reported, (b) no liver adverse events and (c) no reduction in long-term survival compared with patients who continue on long-term IS therapy. Disclosure of Interest None Declared

Autoimmune Hepatitis as an Initial Presentation of SLE

: An 11-year-old female patient with autoimmune hepatitis (AIH) was referred to our rheumatology clinic due to her current musculoskeletal manifestations. The patient had been diagnosed with AIH 3 months previously, based on jaundice and impaired liver function tests, and she had been treated with low-dose prednisolone and azathioprine. She presented with malaise, arthritis, a malar rash on the face, and oral ulcers. Laboratory tests revealed a positive ANA/anti-dsDNA test. Liver biopsy showed chronic hepatitis with severe inflammatory activity, in favor of a diagnosis of definite AIH. She fulfilled the international criteria for both SLE and AIH. The clinical symptoms and laboratory findings of SLE improved with ongoing treatment with corticosteroids and azathioprine, accompanied with hydroxychloroquine sulfate. The present case indicates that AIH can be the first manifestation of SLE in children.

Long-term follow-up of patients with difficult to treat type 1 autoimmune hepatitis on Tacrolimus therapy

ABSTRACTIntroduction: Autoimmune hepatitis (AIH) is an immune-mediated liver disease, which requires long-term immunosuppression. Ten to fifteen percent of patients experience insufficient/intolerance response to standard therapy. Although alternate immunosuppression has been applied, there is little long-term data reported on safety, efficacy, steroid-dose reduction and disease evolution in patients with difficult AIH who were on Tacrolimus therapy. Materials and methods: Clinical, biochemical, immunological profiles, treatment response and side effects of 17 AIH patients treated with Tacrolimus between 2003 and 2014 were analyzed from two tertiary referral liver centers. Results: Tacrolimus was started on 16/17 (94%) patients due to insufficient response to standard therapy. The median duration of treatment was 24 months and patients were followed up for median of 60 months. Tacrolimus dosage was 2 mg/day (median). During first year of therapy, there was a significant improvement in immunoglobulin G and Aspartate transaminase level. 9/17 (52%) compliant and definite AIH patients remained on Tacrolimus at end of follow-up and prednisolone dose reduction was achieved from 10 to 5 mg. All patients are alive and one patient underwent liver transplantation. 4/17 (24%) patients developed overlap with primary sclerosing cholangitis over follow-up period. No significant side effects were observed with Tacrolimus therapy. Conclusion: Tacrolimus could be used in compliant patients with difficult to treat AIH in experienced centers. Its use is safe and can improve liver biochemistry, IgG and reduce steroid requirement. However, due to the lack of immunomodulatory effect, unmet need for effective immune-regulatory therapies still remain for AIH patients.

Evaluation of the revised versus the simplified scoring system in patients with autoimmune hepatitis

The aim of this study was to evaluate the simplified and revised scoring systems for the diagnosis of autoimmune hepatitis (AIH). Seventy-seven patients diagnosed with AIH via the revised scoring system were enrolled in this study. Statistical analysis was performed by means of the χ2 test and logistic regression analysis. A total of 39 patients with definite AIH and 38 patients with probable AIH were diagnosed by the revised scoring system, whereas among these 77 patients, the simplified scoring system classified nine cases as definite AIH, 39 as probable AIH and 29 without AIH. In this study, the parameters contributing to the discrepant diagnosis of AIH were compared using the revised and simplified systems. A χ2 test showed that antinuclear antibody (ANA) or smooth muscle antibody (SMA) titers were significantly lower in the patients with discrepant diagnoses (χ2=15.0, P=0.001). Logistic regression with backward selection revealed that for the discrepant diagnosis of patients, the presence of other concurrent autoimmune diseases [odds ratio (OR)=7.25; P=0.018; 95% confidence interval (CI), 1.41–37.29] was the only independent risk factor. In addition, the presence of anti-soluble liver antigen/liver-pancreas antigen (SLA/LP) or perinuclear antineutrophil cytoplasmic antibody (pANCA) (OR=0.12; P=0.022; 95% CI, 0.02–0.74), the level of immunoglobulin G (IgG) with 1–1.1 × Normal (N) (OR=0.02; P=0.044; 95% CI, 0.00–0.89) and ANA or SMA titers ≥1:80 (OR=0.04; P=<0.001; 95% CI, 0.01–0.23) were three independent protective factors. In conclusion, the revised scoring system has a superior performance in the diagnosis of patients with AIH compared with the simplified scoring system. According to the simplified scoring system, other concurrent autoimmune diseases are the risk factor for the AIH diagnosis.

Autoimmune Hepatitis Outcomes in an Urban County Hospital with a Largely Hispanic Population

Purpose: Autoimmune hepatitis (AIH) is an inflammatory condition of the liver that can result in cirrhosis and other poor outcomes. Ten-year rates of transplant-free survival are 85-95% in treated patients. However, this data is largely from tertiary care centers with primarily Caucasian patients, and is consequently lacking in other settings and populations. We aimed to characterize the outcomes of AIH patients from our institution, a public county hospital in Los Angeles, which serves a largely Hispanic population. Methods: We retrospectively identified all 113 patients who were newly diagnosed with AIH at our center and had liver biopsies to help exclude alternate diagnoses between 2001 and 2013. We reviewed their clinical presentation and treatment course in paper and electronic records. We used Kaplan-Meier analysis to evaluate their transplant-free survival without loss to follow-up, and the log-rank test to evaluate for clinical factors that could affect these outcomes. Results: The median follow-up time was 27 months (range 0-148 months). 26% of patients were considered lost to follow-up, as they had no visits in 18 consecutive months. The median age at presentation was 49.2 years (range 19.4-76.6 years). 86% were female and 79% were identified as Hispanic, per clinic notes. By simplified scoring criteria, 49% had definite AIH, 31% had probable, and 20% did not meet clinical criteria, despite biopsy diagnosis of AIH. 40% had cirrhosis on biopsy, and 26% presented with a cirrhotic decompensation. Eighty-three patients were treated (78 received steroids, five received immunomodulators, and 71 received combination therapy). Forty-seven of 53 patients with ALTs two times the upper limit of normal responded biochemically within 12 months of starting treatment. Within the overall cohort, five and 10-year transplant-free survival was 71% (95% CI, 60-82%) and 38% (95% CI, 11-60%), respectively. Meanwhile, among our treated patients, 5- and 10-year transplant-free survival was 87% (95% CI, 77-97%) and 65% (95% CI, 35-95%), respectively. The log-rank test showed that cirrhosis, any decompensation, lack of treatment, and debilitating symptoms were all associated with significantly worse survival. Conclusion: Compared to established literature on the prognosis of AIH patients, our experiences in a public hospital with mostly Hispanic patients show poorer outcomes. Despite our use of guideline-based standard therapy and good ALT responses, survival rates are lower than in other large cohort studies. There may be genetically determined racial differences in AIH disease activity and treatment responsiveness, along with differing socioeconomic factors, which account for the poorer outcomes in our setting.

Autoimmune hepatitis. A descriptive analysis

Objective: Autoimmune hepatitis (AIH) is a chronic disorder characterized by sustained hepatocellular necrosis and inflammation, usually with fibrosis, of unknown cause. The aim of our study is to describe the epidemiological data, clinical features, treatment administered and outcome of patients with AIH in our area. Methods: We conducted a retrospective descriptive study by reviewing medical records of all patients >18years-old diagnosed of definite AIH in POVISA hospital in Vigo from January 2005 to the present.