Acute Severe Autoimmune Hepatitis Research Articles

Outcomes of patients with acute severe autoimmune hepatitis: Predictors of non-response to corticosteroids and need for liver transplantation.

Acute severe autoimmune hepatitis (AS-AIH) is an evolving concept and the outcomes and optimal treatment have been less studied. In this study, we aimed to investigate the outcomes of patients with AS-AIH and predictors of non-response to corticosteroid therapy and need for liver transplantation. In a retrospective cohort, we included patients with AS-AIH admitted to our liver center. We defined AS-AIH based on the international autoimmune hepatitis group score as acute presentation of AIH with an international normalized ratio (INR)≥1.5 and without liver cirrhosis and hepatic encephalopathy. All patients received high dose corticosteroid therapy. Treatment response was defined as liver transplant free survival at 4months after presentation. Factors associated with response to corticosteroids and survival of patients were studied. In total, 61 patients with AS-AIH were included. Forty-seven patients responded to corticosteroid therapy. In the multivariate regression model, baseline INR (odds ratio [OR]: 0.184; 95% confidence interval [CI]: 0.048-0.699; p=0.013) and delayed versus early initiation of corticosteroid (after vs. before 5days of presentation) (OR: 0.189; 95% CI: 0.039-0.919; p=0.039) were independent predictors of clinical non-response to corticosteroid therapy. In the multivariable Cox regression model, baseline INR level (OR: 2.542; 95% CI: 1.188-5.440; p=0.016) and delayed initiation of corticosteroids (OR: 3.578; 95% CI: 1.084-11.812; p=0.036) were independent predictors of liver transplant free survival at 6months after diagnosis. Delayed initiation of corticosteroid therapy might be predictive of clinical non-response to medical therapy and need for liver transplantation in patients with AS-AIH.

Severe acute autoimmune hepatitis: How to early predict who will not respond to corticosteroids and needs urgent liver transplantation?

BackroundIn acute severe autoimmune hepatitis (AS-AIH), the early identification of predictors of non-response to corticosteroids and the optimal timing for liver transplantation (LT) remains controversial. AimsTo determine early predictors of non-response to corticosteroids and to assess the usefulness of severity scores, namely the recently developed SURFASA. MethodsRetrospective multicentre cohort study including consecutive patients admitted for AS-AIH between 2016 and 2020. Definitions- response to corticosteroids: LT-free survival at 90 days (D90); SURFASA score: -6.8 + 1.92x(D0-INR)+1.94xINR[(D3-D0)/D0]+1.64xbilirubin[(D3-D0)/D0]. ResultsWe included 26 patients [median age 56 (45–69) years; 22 (84.6%) women]. All patients underwent corticosteroid therapy. Overall survival reached 73%. amongst the non-responders, 2 (7.8%) underwent LT and 5 (19.2%) died. The interval between admission and initiation of corticosteroids was not different between responders and non- responders [13 (7–23) vs. 8 (3–10), P:0.06], respectively. SURFASA and MELD-Na+ (D3) scores showed an AUROC of 0.96 (0.87–1) and 0.92 (0.82–0.99), respectively, for prediction of non-response. SURFASA >-2.5 had a sensitivity of 85.7% and a specificity of 100% and MELD-Na+ (D3) >26 had sensitivity of 85.7% and a specificity of 78% for the prediction of non-response. ConclusionsSURFASA and MELD-Na+ at D3 scores are useful in early identification of non-responders to corticosteroids.

Early predictors of corticosteroid response in acute severe autoimmune hepatitis: a nationwide multicenter study.

SummaryBackground and AimsTo assess whether corticosteroids improve prognosis in patients with AS‐AIH, and to identify factors at therapy initiation and during therapy predictive of the response to corticosteroids.MethodsThis was a retrospective cohort study including all patients with AS‐AIH admitted to 13 tertiary centres from January 2002 to January 2019. The composite primary outcome was death or liver transplantation within 90 days of admission. Kaplan–Meier and Cox regression methods were used for data analysis.ResultsOf 242 consecutive patients enrolled (mean age [SD] 49.7 [16.8] years), 203 received corticosteroids. Overall 90‐day transplant‐free survival was 61.6% (95% confidence interval [CI] 55.4–67.7). Corticosteroids reduced the risk of a poor outcome (adjusted hazard ratio [HR] 0.25; 95% CI 0.2–0.4), but this treatment failed in 30.5%. An internally validated nomogram composed of older age, MELD, encephalopathy and ascites at the initiation of corticosteroids accurately predicted the response (C‐index 0.82; [95% CI 0.8–0.9]). In responders, MELD significantly improved from days 3 to 14 but remained unchanged in non‐responders. MELD on day 7 with a cut‐off of 25 (sensitivity 62.5%[95% CI: 47.0–75.8]; specificity 95.2% [95% CI: 89.9–97.8]) was the best univariate predictor of the response. Prolonging corticosteroids did not increase the overall infection risk (adjusted HR 0.75; 95% CI 0.3–2.1).ConclusionOlder patients with high MELD, encephalopathy or ascites at steroid therapy initiation and during treatment are unlikely to show a favourable response and so prolonged therapy in these patients, especially if they are transplantation candidates, should be avoided.

Analysis of clinical features and prognosis of acute severe autoimmune hepatitis

Objective: To analyze the clinical features and prognosis of acute severe autoimmune hepatitis (AIH). Methods: A retrospective analysis of the clinical data of patients with acute severe AIH admitted to our hospital from 2008 to 2019 was divided into acute AIH (A-AIH) and chronic acute AIH (AC-AIH) according to the presence or absence of liver diseases. Patients' general condition, liver biochemistry, immunology, histological features of liver, hormonal therapies prognosis and related factors were analyzed. Results: A total of 41 cases [39 females, age (54.24 ± 10.55) years] were collected. Alanine aminotransferase (ALT) and total bilirubin (TBil) were significantly increased, and the international normalized ratio (INR) was > 1.5. Acute lobular inflammation was the feature of acute and severe AIH in the histology of liver. The serum IgG level was (28.36 ± 8.35) g / L. The positive rate of antinuclear antibody (ANA) and anti-smooth muscle antibody (ASMA) was 82.9%, and 17.1%, respectively. Over 70% of acute severe AIHs were AC-AIH. The duration of onset of AC-AIH was > 8 weeks, while most A-AIHs < 8 weeks, and the differences between the two groups were statistically significant (P = 0.001). The mortality rate within 30 days after hormonal treatment was 19.5%. There were statistically significant differences in TBil, Model for End-Stage Liver Disease (MELD) score and leukocyte count between the death and survival group. Conclusion: The mortality rate in acute severe AIH is high, and most of them have the basis of chronic liver disease. Serum IgG level, autoantibodies and acute lobular inflammation are important factors for diagnosis. The prognosis of hormonal therapy is related to the patients' condition and course of disease.

Autoimmune hepatitis after COVID-19 vaccine – more than a coincidence

The COVID-19 pandemic is still raging across the world and vaccination is expected to lead us out of this pandemic. Although the efficacy of the vaccines is beyond doubt, safety still remains a concern.We report a case of a 65-year-old woman who experienced acute severe autoimmune hepatitis two weeks after receiving the first dose of Moderna-COVID-19 vaccine. Serum immunoglobulin G was elevated and antinuclear antibody was positive (1:100, speckled pattern). Liver histology showed a marked expansion of the portal tracts, severe interface hepatitis and multiple confluent foci of lobular necrosis. She started treatment with prednisolone, with a favorable clinical and analytical evolution.Some recent reports have been suggested that COVID-19 vaccination can lead to the development of autoimmune diseases. It is speculated that the vaccine can disturb self-tolerance and trigger autoimmune responses through cross-reactivity with host cells. Therefore, healthcare providers must remain vigilant during mass COVID-19 vaccination.

Crossroad of infection and autoimmunity in acute liver failure: a case report

BackgroundAcute liver failure (ALF) is a syndromic diagnosis, consisting of jaundice, coagulopathy, and any degree of encephalopathy in a patient without pre-existing liver disease within 26 weeks of the onset of symptoms. Autoimmune hepatitis has a wide range of presentations and can rarely present as ALF, which frequently tends to be autoantibody negative. Tropical infections like dengue, malaria, and leptospirosis, which present as mimickers of ALF, always remain a differential diagnosis of ALF and mandate an etiology specific management. In rare cases, such infections themselves act as a trigger for autoimmunity. We report a case of diagnostic crossroads of infection and autoimmunity, presenting as acute liver failure and describe the challenges in management.Case presentationA 25-year-old female presented with a syndromic diagnosis of acute liver failure with possibility of tropical illness-related ALF mimic on account of positive Leptospira serology. After initial improvement, there was a rebound worsening of liver functions which prompted a liver biopsy. Biopsy narrowed the differential to Leptospira-associated hepatitis and severe auto-immune hepatitis. Trial of low dose steroid was given which led to dramatic improvement.ConclusionTropical infections can present as ALF mimics and can themselves act as triggers for autoimmunity. Distinguishing such cases from de-novo acute severe autoimmune hepatitis is difficult and requires therapeutic brinksmanship. An early trial of steroid is mandated but comes with its own challenges.

Clinical characteristics and treatment outcomes of acute severe autoimmune hepatitis

Background and aimAcute severe autoimmune hepatitis (AS-AIH) is a rare cause of acute liver failure (ALF), which is often neglected and delayed in treatment. The purpose of this study was to analyze the clinical characteristics and therapeutic effects of AS-AIH.MethodsRetrospective analysis was performed. AIH was diagnosed according to the International Autoimmune Hepatitis Group (IAIHG) criteria revised in 1999. AS-AIH was defined as an acute presentation (onset of symptoms to presentation of ≤ 26 weeks) and INR of ≥ 1.5, and no histologic evidence of cirrhosis.ResultsTwelve patients were diagnosed as AS-AIH. At baseline, median immunoglobulin G was 28.35 g/L (range, 11.4–49.2). Ten (83.3%) patients were antinuclear antibodies and/or anti-smooth muscle antibodies positive. The prominent histologic characteristics were lobular necrosis/inflammation (91.7%) and plasma cell infiltration (100%). All patients received corticosteroid therapy. Death occurred in 2 (16.7%) patients within 30 days resulted from ALF. The average interval between the onset of symptoms and initiation of corticosteroid therapy in deceased patients was 65 days, compared with 19 days for survivors.ConclusionsAS-AIH is an uncommon disease with poor outcomes. Patients with acute severe hepatitis of unknown cause should be minded the possibility of AS-AIH and corticosteroids should be considered as soon as possible.

Early liver transplantation for corticosteroid non-responders with acute severe autoimmune hepatitis: The SURFASA score

In acute severe autoimmune hepatitis (AS-AIH), the optimal timing for liver transplantation (LT) remains controversial. The objectives of this study were to determine early predictive factors for a non-response to corticosteroids and to propose a score to identify patients in whom LT is urgently indicated. This was a retrospective, multicenter study (2009-2016). A diagnosis of AS-AIH was based on: i) Definite or probable AIH based on the simplified IAIHG score; ii) international normalized ratio (INR) ≥1.5 and/or bilirubin >200μmol/L; iii) No previous history of AIH; iv) Histologically proven AIH. A treatment response was defined as LT-free survival at 90 days. The evolution of variables from corticosteroid initiation (day-D0) to D3 was estimated from: Δ%3= (D3-D0)/D0. A total of 128 patients were included, with a median age of 52 (39-62) years; 72% were female. Overall survival reached 88%. One hundred and fifteen (90%) patients received corticosteroids, with a LT-free survival rate of 66% at 90 days. Under multivariate analysis, D0-INR (odds ratio [OR] 6.85; 95% CI 2.23-21.06; p <0.001), Δ%3-INR ≥0.1% (OR 6.97; 95% CI 1.59-30.46; p <0.01) and Δ%3-bilirubin ≥-8% (OR 5.14; 95% CI 1.09-24.28; p <0.04) were predictive of a non-response. The SURFASA score: -6.80+1.92∗(D0-INR)+1.94∗(Δ%3-INR)+1.64∗(Δ%3-bilirubin), created by combining these variables, was highly predictive of LT or death (AUC= 0.93) (88% specificity; 84% sensitivity) with a cut-off point of <-0.9. Below this cut-off, the chance of responding was 75%. With a score higher than 1.75, the risk of dying or being transplanted was between 85% and 100%. In patients with AS-AIH, INR at the introduction of corticosteroids and the evolution of INR and bilirubin are predictive of LT or death. Within 3 days of initiating corticosteroids, the SURFASA score can identify non-responders who require a referral for LT. This score needs to be validated in a prospective cohort. The management of patients with acute severe autoimmune hepatitis is highly challenging, particularly regarding their early referral for liver transplantation. We found that international normalized ratio at the initiation of corticosteroid therapy and the evolution of international normalized ratio and bilirubin values after 3 days of therapy were highly predictive of liver transplantation or death. We are thus proposing a score that combines these variables and identifies patients in whom liver transplantation is urgently required.

Acute severe autoimmune hepatitis with anti-rods and rings autoantibodies; literature first evidence.

Autoimmune hepatitis (AIH) was defined as a progressive, chronic inflammatory autoimmune liver disease (ALD). The diagnosis of AIH requires the presence of characteristic clinical and laboratory features, and the exclusion of other clinical conditions that cause chronic hepatitis and cirrhosis. AIH can have an acute onset that mimics an acute viral or toxic hepatitis or an acute severe (fulminant, ASF) presentation that satisfies criteria for acute liver. Guidelines from the European Association for the Study of Liver Diseases define ALF with absence of pre-existing liver disease, acute onset of ≤ 26 weeks, coagulopathy (international normalised ratio (INR) ≥ 1.5), and presence of hepatic encephalopathy (HE). In recent years, autoantibodies (Aab) targeting subcellular structures described as the rods and rings (R&R) pattern in HEp-2 ANA have been presented as a unique and particular case of Aab generation. These R&R structures are composed of inosine monophosphate dehydrogenase type 2 (IMPDH2), and their formation can be induced in vitro by several small-molecule inhibitors. Aab targeting these relatively unknown structures has been observed in Hepatitis C virus (HCV) patients who have undergone treatment with pegylated interferona/ ribavirin (IFN/RBV) therapy. We presented and characterized a case patient with R&R and SMA Aab in AIH (ASF, fatal, without liver transplantation). To the best of our knowledge, this is the first evidence described in the Literature. Our early experience showed the R&R circulating Aab in one patient with Primary Biliary Cholangitis. This work now demonstrates that R&R Aab can also be present in AIH case.

Early Predictors of Short-Term Prognosis in Acute and Acute Severe Autoimmune Hepatitis.

Presentation of autoimmune hepatitis (AIH) can differ from nonacute to acute autoimmune hepatitis (A‐AIH) with jaundice and acute severe autoimmune hepatitis (AS‐AIH) with jaundice and coagulopathy. The aim of the study was to evaluate the short‐term prognosis of different presentations of AIH and the influence of liver function improvement on short‐term prognosis. In this single‐center retrospective cohort study, AIH patients with repeatedly tested liver function at diagnosis and during at least 1 year of follow‐up were included. A‐AIH was defined as bilirubin >45 µmol and international normalized ratio (INR) <1.5. AS‐AIH was defined as bilirubin level >45 µmol/L and INR ≥1.5. Of the 81 included patients, 17 (21%) presented with A‐AIH, and 14 (17%) presented with AS‐AIH. After the start of immunosuppressive therapy, bilirubin, albumin, and INR normalized in 70%, 77%, and 69%, respectively, in a median of 2.6 months, 3 months, and 4 weeks, respectively, in patients with A‐AIH and AS‐AIH. Liver transplantation (LT)–free survival rate was 100% in nonacute AIH, 94% in A‐AIH, and 57% in AS‐AIH at 12 months after diagnosis. An increase of INR or bilirubin at 2 weeks was the best predictive factor for the need of LT within 12 months with a Youden’s index of 0.85. A‐AIH was present in 21%, and AS‐AIH was present in 17% of AIH patients. In the majority of patients, bilirubin, albumin, and INR normalized in the first months of treatment. Deterioration of liver function after 2 weeks of treatment should lead to rapid evaluation for LT and consideration of second‐line medication.

Approach to the patient with acute severe autoimmune hepatitis.

SummaryAutoimmune hepatitis is associated with varied clinical presentations and natural history, as well as somewhat unpredictable treatment responses. Understanding how to stratify patients who require further escalation of therapy will help clinicians manage these patients. The presentation of acute severe autoimmune hepatitis (AS-AIH) is relatively uncommon, although its prevalence is potentially greater than currently perceived. Previous studies consist of small retrospective single-centre series and are not directly comparable due to the diversity of presentations, disease definitions and non-standardised treatment regimens. We define AS-AIH as those who present acutely with AIH and are icteric with an international normalised ratio ≥1.5 and no evidence of hepatic encephalopathy. Those with hepatic encephalopathy should be defined as having AS-AIH with acute liver failure. In this review, we provide a structured practical approach for diagnosing and managing this unique group of patients.

Prompt initiation of high-dose i.v. corticosteroids seems to prevent progression to liver failure in patients with original acute severe autoimmune hepatitis.

AimsThe 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.MethodsProspectively collected data from 184 AIH patients were analyzed retrospectively. Original AS‐AIH defined as an acute symptomatic presentation of newly diagnosed AIH (transaminases &gt;10× upper limit of normal, bilirubin &gt;4 mg/dL, and international normalized ratio [INR] ≥1.5) without histological lesions of chronic disease.ResultsThirty‐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 &gt;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.ConclusionsPrompt 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.

PS-001 - Treatment and prognosis of acute severe autoimmune hepatitis

PS-001 - Treatment and prognosis of acute severe autoimmune hepatitis

SAT-382 - An Early Definition of Response to Corticosteroids in Acute Severe Autoimmune Hepatitis

SAT-382 - An Early Definition of Response to Corticosteroids in Acute Severe Autoimmune Hepatitis

Liver Biopsy in the Management of Autoimmune Hepatitis Acute Severe Onset

I read with interest the excellent review by Czaja on acute severe autoimmune hepatitis (AIH) [1], which greatly increased my awareness of the clinical and therapeutic characteristics of this extremely serious disease. The precise and extensive description of this medical problem provided by Czaja can be of upmost importance for the management of this specific subgroup of patients by clinicians. AIH is a chronic hepatitis of unknown etiology, and its clinical manifestations are highly variable, sometimes following a fluctuating course [2, 3]. An acute, severe, abrupt presentation is also possible and is secondary to variable causes [1]. The diagnosis of AIH is based on a clinical, biochemical, serological and histological patterns, and sometimes has to be confirmed by the response of the disease to immunosuppressive treatment [1–4]. Compared to patients presenting with a more chronic course, those presenting with acute onset more frequently have interface and centrilobular hepatitis, lobular disarray and central necrosis, but perhaps less fibrosis and cirrhosis [1, 2, 5]. Liver biopsy features in the acute presentation of AIH may be difficult to distinguish from those seen in acute hepatitis due to the effects of the virus or drugs [1, 5]. It is not yet clear whether the clinical presentation of AIH in the setting of drugs used for other diseases unmask and/or induce a typical AIH or simply result in a drug-induced hepatitis with features that mimic AIH [6]. Therefore, the histological assessment of acute and chronic liver is based on an accurate description of the pattern of injury within the tissue specimen. Interpretation of the injury pattern requires review of the characteristic clinical and laboratory features, and the morphological findings only achieve relevance if they satisfactorily explain the clinical syndrome [7]. Thus, the importance of the results of the histological analysis of liver samples with respect to the diagnosis and clinical management of severe acute AIH may be unclear and, occasionally, biopsy results may actually delay therapeutic decisions; in other words, biopsy results may be unnecessary for the rapid initiation of treatment given that early steroid therapy may save lives [8–11]. It has recently been reported that patients with typical laboratory features of AIH rarely need liver biopsy for diagnosis. Most patients presenting with features of AIH based on laboratory tests are likely to have a compatible liver histology, and few patients have atypical histology. Consequently, tissue findings may have little impact on patient management. Thus, biopsy samples might not need to be collected from patients who meet other typical criteria for AIH [9]. When the scoring system based upon titers of autoantibodies, immunoglobulin G (IgG) levels and the exclusion of viral hepatitis is used as a diagnostic tool, a score of six points can be used as a simplified criterium of a probable diagnosis of AIH [5]. At admission, the recommended analyses include general biochemistry, conventional autoantibodies, quantification of immunoglobulins and IgG serum levels. It is important to exclude other virus infections, such as hepatitis A and E viruses, hepatitis C virus (serum HCV-RNA R. Moreno-Otero (&) Liver Unit, and Instituto de Investigacion Sanitaria (IIS-IP), Digestive Diseases Service (Planta 3), Hospital Universitario La Princesa, Universidad Autonoma de Madrid, Diego de Leon, 62, 28028 Madrid, Spain e-mail: rmoreno.hlpr@salud.madrid.org; rmorenoo@salud.madrid.org