Autoimmune hepatitis(AIH) is an unresolving progressive liver disease of unknown etiology characterized byhypergammaglobulinemia,autoantibodies detection and interface hepatitis.Due to the absence of ...specific diagnostic markers and the large heterogeneity of its clinical,laboratory and histological features,AIH diagnosis may be potentially difficult.Therefore,in this in-depth review we summarize the substantial progress on etiopathogenesis,clinical,serological and histological phenotypes of AIH.AIH has a global distribution affecting any age,both sexes and all ethnic groups.Clinical manifestations vary from asymptomatic to severe or rarely fulminant hepatitis.Hypergammaglobulinemia with selective elevation of IgG is found in most cases.Autoimmune attack is perpetuated,possibly via molecular mimicry,and favored by the impaired control of T-regulatory cells.Histology(interface hepatitis,emperipolesis and hepatic rosette formation) and autoantibodies detection although not pathognomonic,are still the hallmark for a timely diagnosis.AIH remains a major diagnostic challenge.AIH should be considered in every case in the absence of viral,metabolic,genetic and toxic etiology of chronic or acute hepatitis.Laboratory personnel,hepato-pathologists and clinicians need to become more familiar with disease expressions and the interpretation of liver histology and autoimmune serology to derive maximum benefit for the patient.
Background & Aims Standard therapy for autoimmune hepatitis (AIH) is corticosteroids with or without azathioprine. However, 20% of patients do not respond or are intolerant to conventional treatment. ...Therefore, we evaluated prospectively the efficacy and safety of mycophenolate mofetil (MMF) in inducing and/or maintaining remission in treatment-naïve AIH patients. Methods Fifty-nine treatment-naïve patients with well defined AIH were treated with prednisolone plus 1.5–2 g/d of MMF. Patients were candidates for MMF withdrawal after at least 4 years. Treatment outcomes were defined according to the International Autoimmune Hepatitis Group report. Results Treatment duration with MMF was 26 months (range 3–92). Eighty-eight percent (52/59) of patients responded initially clinically and biochemically (normalization of transaminases and γ-globulins) most of them within 3 months. The remaining 7 patients (12%) had partial response. In total, 59.3% (35/59) of patients had complete response (CR) with 37% (22/59) of them having achieved CR off prednisolone, while 28.8% (17/59) had initial CR with relapses. No patient was non-responder. Prednisolone withdrew in 57.6% (34/59) of patients in 8 months. The only independent predictor of treatment outcome, was γ-GT (baseline γ-GT, p = 0.008 and γ-GT on month 24, p <0.05). Severe side effects leading to MMF discontinuation occurred in only 3.4% (2/59) of patients. Six patients (2 according to protocol and 4 for personal reasons), stopped treatment with MMF, but 3 relapsed. Conclusions MMF seems safe and effective as first-line therapy in inducing and maintaining remission in treatment-naive patients with AIH, having a significant and rapid steroid sparing effect as attested by the fact that so far, 37% (22/59) of AIH patients achieved CR off prednisolone.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Aims
The definition of original acute severe autoimmune hepatitis (AS‐AIH) is unclear. However, its rapid recognition and early treatment is potentially life‐saving. Therefore, we present herein an ...open, real‐world observational study for the assessment of the efficacy and safety of early high‐dose i.v. corticosteroids in original AS‐AIH patients.
Methods
Prospectively collected data from 184 AIH patients were analyzed retrospectively. Original AS‐AIH defined as an acute symptomatic presentation of newly diagnosed AIH (transaminases >10× upper limit of normal, bilirubin >4 mg/dL, and international normalized ratio INR ≥1.5) without histological lesions of chronic disease.
Results
Thirty‐four of 184 (18.5%) patients had original AS‐AIH. These patients were promptly treated with i.v. corticosteroids (either 1 g methylprednisolone for 3 consecutive days followed by i.v. 1 mg/kg/day prednisolone or i.v. 1.5 mg/kg/day prednisolone from the beginning). Only 1/34 (2.9%) died due to sepsis; none required liver transplantation during follow‐up (65 1–175 months). No significant differences were detected in baseline characteristics between original AS‐AIH patients and those with insidious presentation (not‐AS‐AIH; n = 117) apart from antinuclear antibodies negativity (P = 0.038), and higher immunoglobulin G, transaminases, INR, and bilirubin in original AS‐AIH patients (P = 0.001 for all). Complete response and corticosteroids withdrawal (for patients treated >12 months) were significantly more frequent in original AS‐AIH (n = 28) than in not‐AS‐AIH (n = 79; P = 0.026 and P = 0.016, respectively). Presence of original AS‐AIH was the only independent predictor for achieving complete response.
Conclusions
Prompt initiation of high‐dose i.v. corticosteroids in original AS‐AIH seems safe and efficient as it prevents disease deterioration and the need for liver transplantation. The long‐term overall survival of these patients was high (97% for 5.3 years), and the long‐term treatment response and corticosteroids withdrawal rates were higher compared to not‐AS‐AIH patients.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
As previous real-world studies and meta-analyses have shown that mycophenolate mofetil (MMF) might have better efficacy than azathioprine (AZA) in autoimmune hepatitis (AIH), we conducted a ...propensity matching study to assess the efficacy and safety of MMF vs. AZA.
All 126 consecutive treatment-naive adult AIH patients, diagnosed and followed in our department since 2016, were included. Patients received prednisolone 0.5-1 mg/kg/day plus either AZA 1-2 mg/kg/day or 1.5-2 g/day MMF. The tapering of prednisolone was identical between groups.
After propensity matching score and adjustment for known factors affecting response to treatment and outcome, 64 patients were included in the study (MMF = 32 and AZA = 32). Rates of non-response, complete biochemical response (CBR) at 6 and 12 months, and prednisolone withdrawal (6 months, 12 months, and end of follow-up) were identical between groups. However, MMF treatment was significantly associated with CBR at the end of follow-up odds ratio (OR) 11.259; 95% CI: 1.3-97.4, p = 0.028. AZA patients were more prone to stop treatment due to AZA intolerance/insufficient response (p = 0.0001). At the end of follow-up, the overall efficacy of each schedule was also significantly higher in the MMF group compared to the AZA group (p = 0.0001).
We showed for the first time in a propensity matching study that MMF can be used as first-line therapy in AIH as attested by the significantly higher CBR at end of follow-up compared to AZA. Whether this better efficacy is also associated with higher histological remission rates and sustained CBR off immunosuppression needs further evaluation.
Autoimmune hepatitis (AIH) is a relatively rare autoimmune disease with a strong genetic background. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148 M (rs738409 C/G) variant ...has been associated with hepatic inflammation and fibrosis in chronic hepatic diseases beyond metabolic dysfunction-associated steatotic liver disease (MASLD).
Our aim was to investigate the significance of PNPLA3 I148 M variant in AIH.
Two hundred AIH patients, followed in our centre, were evaluated while 100 healthy subjects served as controls. Genotyping was performed with allelic discrimination end-point polymerase chain reaction (PCR).
The I148 M variant was present in 95/200 (47.5 %) AIH patients compared to 47/100 (47 %) healthy controls (p = 1.000). Patients with GG/CG genotypes were more likely to present with decompensated cirrhosis at diagnosis (GG/CG 6.3 % vs. CC 1 %, p = 0.039). Comorbidity with cardiometabolic risk factors and concurrence of MASLD was similar across genotypes. Simple steatosis was present in 37/186 (19.9 %) and steatohepatitis in 14/186 (7.5 %) patients with available liver biopsy without correlation with PNPLA3 genotype. Fibrosis stage and grade of inflammation were not correlated with any genotype. Response to treatment was also independent of the presence of the I148 M variant, even though a longer time was needed to achieve complete biochemical response in those carrying the GG/CG genotypes (p = 0.07). On Kaplan Meier analysis homozygosity for the G allele corelated with reduced survival free of decompensation (p = 0.006), cirrhotic events (decompensation, liver transplantation, hepatocellular carcinoma; p = 0.001) and liver-related death or liver transplantation (p = 0.011) in treated patients.
The PNPLA3 I148 M variant in AIH patients is associated with increased risk of advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related death or liver transplantation, regardless of the presence of MASLD. This signifies a potential role for the PNPLA3 I148 M variant as a new AIH biomarker allowing to identify patients at increased risk of disease progression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The cartilage oligomeric matrix protein (COMP) and Golgi-protein-73 (GP73) have been proposed as markers of liver fibrosis and hepatocellular carcinoma (HCC). Our aim was to assess the performance of ...the combination of these markers in diagnosing cirrhosis and predicting HCC development. Sera from 288 consecutive patients with chronic liver diseases were investigated by using COMP and GP73-ELISAs. Dual positivity for COMP (>15 U/L) and GP73 (>20 units) was observed in 24 (8.3%) patients, while 30 (10.4%) were GP73(+)/COMP(−), 37/288 (12.8%) GP73(−)/COMP(+), and 197 (68.5%) GP73(−)/COMP(−). Positivity for both markers was associated with cirrhosis 23/24 (95.8%) for GP73(+)/COMP(+) vs. 22/30 (73.3%) for GP73(+)/COMP(−) vs. 25/37 (67.6%) for GP73(−)/COMP(+) vs. 46/197 (23.4%) for GP73(−)/COMP(−); P < 0.001. The combination of GP73, COMP, the aspartate aminotransferase/platelets ratio index, and the Fibrosis-4 score had even higher diagnostic accuracy to detect the presence of cirrhosis AUC (95% CI): 0.916 (0.878–0.946) or significant liver fibrosis (METAVIR ≥ F2) AUC (95% CI): 0.832 (0.768–0.883) than each marker alone. Kaplan-Meier analysis showed that positivity for both GP73 and COMP was associated with higher rates of HCC development (P < 0.001) and liver-related deaths (P < 0.001) during follow-up. In conclusion, the combination of GP73 and COMP seems efficient to detect cirrhosis and predict worse outcomes and the development of HCC in patients with chronic liver diseases.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Background & aims Primary biliary cholangitis (PBC) is a disease with rising prevalence and considerable geographical variation. To describe the prevalence, spatial and time distribution, ...baseline characteristics, response to treatment, outcome and the validity of GLOBE score in a large cohort of Greek PBC patients as an independent validation of this score has not been done so far. Methods The last 16 years, 482 PBC patients (86.5% females) were evaluated and analysed retrospectively, using a prospectively collected database. Special attention was paid to the assessment of treatment response according to GLOBE score. Results Age at initial evaluation was 56.3 ± 13.7 years. Among 432 Thessaly residents, prevalence was 582/million (non-homogeneous distribution). Nineteen districts showed a prevalence > 800/million. Symptomatic disease onset could be identified in 91 patients, with a significant peak during spring ( P = 0.03). At diagnosis, 43.6% were asymptomatic and 16.2% cirrhotic. Male sex ( P = 0.02), older age ( P < 0.001), alcohol consumption ( P < 0.01) and concomitant liver disease ( P < 0.001) were negative prognostic factors for cirrhosis. During a median interquartile range, range follow-up of 5.1 (7.8, 15.7) years, 62 patients died or underwent liver transplantation. Patients with GLOBE score > 0.30 had significantly worse prognosis ( P < 0.001) with 5-, 10-, and 15-year survival rates of 84%, 50% and 42%. Conclusions There is increased PBC prevalence in Thessaly with remarkable geographic clustering and seasonal variability. PBC is diagnosed at early stages although males had a more advanced disease. GLOBE score applies perfectly in Greek patients and this will likely help detecting patients that may benefit from new therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We assessed FibroMeter virus (FMvirus) and FibroMeter vibration-controlled transient elastography (FMVCTE) in 134 patients with autoimmune liver diseases ALD, autoimmune hepatitis (AIH) and primary ...biliary cholangitis (PBC), in order to assess new potential non-invasive biomarkers of liver fibrosis in patients with ALD, as similar data are missing.
The following groups were included: group 1: n = 78 AIH; group 2: n = 56 PBC. FMvirus and FMVCTE were determined in all 134 patients who underwent liver biopsy and TE the same day with sera collection. In addition, APRI and FIB-4 scores were calculated.
The AUCs for TE and FMVCTE were significantly better (0.809; p < 0.001 and 0.772; p = 0.001, respectively for AIH and 0.997; p < 0.001 and 1; p < 0.001, for PBC) than the other three markers in predicting ≥ F3 fibrosis irrespective of the biochemical activity. FMVCTE and TE had good diagnostic accuracy (75.6% and 73%, respectively) for predicting severe fibrosis in AIH and performed even better in PBC (94.6% and 96.4%, respectively). The cut-offs of TE and FMVCTE had the best sensitivity and specificity in predicting ≥ F3 fibrosis in both AIH and PBC.
FMVCTE seems to detect severe fibrosis equally to TE in patients with ALD but with better specificity. Biochemical disease activity did not seem to affect their diagnostic accuracy in ALD and therefore, could be helpful for the assessment of fibrosis, especially if they are performed sequentially (first TE with the best sensitivity and then FMVCTE with the best specificity).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Autoimmune hepatitis (AIH) is a chronic non-resolving liver disease characterized by diffuse hypergammaglobulinemia, the presence of autoantibodies and characteristic histological findings. The ...disease can have catastrophic outcome with the development of end-stage liver disease if misdiagnosed/undiagnosed and left untreated. AIH pathogenesis remains obscure and the main hypothesis supports its development in genetically predisposed individuals after being exposed to certain environmental triggers. Genetic predisposition is linked to the presence of certain HLA alleles, mainly HLA-DR3 and HLA-DR4. However, a wide number of non-HLA epitopes have also been associated with the disease although data vary significantly among different ethnic groups. Therefore, it is likely that epigenetic alterations may also play a crucial role in disease's pathogenesis, although not yet extensively studied. The aim of this review was to summarize the genetic and environmental factors that have been associated with AIH, but also to open new insights towards the role of epigenetic modifications in the etiology of the disease.
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•Autoimmune hepatitis (AIH) pathogenesis remains unknown.•AIH genetic predisposition is associated mainly with HLADR3 and HLADR4 alleles but also several non-HLA epitopes.•Environmental factors such as viruses, drugs, xenobiotics have been implicated.•Recently, epigenetic factors have also been found to confer to AIH pathogenesis.•These findings may contribute to the development of novel epigenetic-based therapeutic strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Autoimmune hepatitis (AIH) is a disease of unknown aetiology with a favourable response to immunosuppression. However, in the clinic, it appears that <50% of patients achieve complete response on ...standard treatment. Serum B cell-activating factor (BAFF) levels are elevated in patients with AIH and are likely to contribute to disease pathogenesis. Given that belimumab, a BAFF inhibitor, has been shown to be effective in other autoimmune diseases, we investigated its use as a third-line add-on treatment option in patients with advanced AIH who did not respond to conventional treatment.
Herein, we report for the first time two patients, a 27-year-old female and a 58-year-old male, both with AIH-related compensated cirrhosis at diagnosis, who were refractory to standard immunosuppressive therapies and received add-on third-line therapy with belimumab.
Both patients achieved a complete response and remained in remission while receiving low-dose corticosteroids. No adverse events related to belimumab and/or disease decompensation were observed.
These preliminary findings indicate belimumab as a promising treatment option for patients with AIH and refractory and advanced liver-related fibrosis.
A small proportion of patients with autoimmune hepatitis (AIH) are refractory to standard treatments; these patients bear the highest probability of developing decompensated cirrhosis and hepatocellular carcinoma because third-line treatment options are not well established. In this case study, we showed that third-line add-on therapy with belimumab, a B cell-activating factor inhibitor, could be an alternative and promising treatment option in patients with advanced AIH who did not respond to conventional treatment.
•Belimumab is a B cell-activating factor inhibitor that has been proposed for the treatment of autoimmune hepatitis.•In 2 patients with autoimmune hepatitis, belimumab led to complete response and remission.•No adverse events related to belimumab and/or disease decompensation were observed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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