Prevalence and significance of autoantibodies in children with metabolic dysfunction-associated steatotic liver disease: A systematic review and meta-analysis.

Significance of autoantibodies in pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) is unknown. Our aim was to determine the prevalence and significance of autoantibodies in MASLD. PubMed and Scopus were searched and six articles (689 [487 males] MASLD patients) were identified. Antinuclear antibodies (ANA) was positive in 28% (95% confidence interval [CI]: 17%-39%, n = 6 studies), Antismooth muscle antibodies (ASMA) in 28% (95% CI: 8%-50%, n = 5 studies), Actin-positive in 15% (95% CI: 10%-20%, n = 2 studies) and elevated immunoglobulin G in 17% (95% CI: 1%-39%, n = 4 studies). Anti-liver-kidney-microsomal antibody was not present in any patient. There was no significant association of ANA positivity with degree of liver steatosis, liver fibrosis or nonalcoholic fatty liver disease activity score (NAS) but patients with ASMA positivity had advanced fibrosis (pooled risk ratio [RR] 1.77; 95% CI 1.16-2.71) and higher risk of NAS ≥5 (pooled RR 1.21; 95% CI: 1.01-1.44, n = 2 studies, 243 patients). To conclude, non-organ specific autoantibodies are present in over one-fourth of children with MASLD and the presence of ASMA maybe associated with increased disease severity.

PNPLA3 I148 M genetic variant in autoimmune hepatitis characterises advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related mortality.

Background: 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). Aim: Our aim was to investigate the significance of PNPLA3 I148 M variant in AIH. Method: 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). Results: 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. Conclusions: 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.

Comparison of the recommendation of international autoimmune hepatitis pathology group 2022 and the simplified criteria for autoimmune hepatitis 2008: A preliminary study.

Background and Aim: The histological diagnosis of autoimmune hepatitis (AIH) is challenging. A new consensus recommendation was provided by the International AIH Pathology Group to address the problems in the histological diagnosis. The purpose of this study is to compare the 2008 'simplified' criteria for AIH with the 'consensus recommendation' of 2022 in terms of diagnostic sensitivity. Materials and Methods: A retrospective analysis was conducted on pathological specimens of patients diagnosed with Autoimmune Hepatitis (AIH) between 2010 and 2022. Out of 188 patients enlisted, 88 were selected based on exclusion criteria. The specimens were examined by two experienced hepatopathologists and a resident pathologist. All specimens were analyzed using both the "simplified" criteria and the new consensus recommendations. Results: Out of a total of 78 patients, the 2022 consensus recommendations raised the diagnostic category of 16 patients (20.5%) to a higher level. Six patients who were previously diagnosed as "atypical" were now considered "possible AIH", while 10 patients with a "compatible" diagnosis were elevated to "likely AIH" category. No patients were found to fall into a lower diagnostic category according to the new recommendations. A significant difference in diagnostic sensitivity was observed between the 2008 criteria and the 2022 consensus report (p<0.001). Conclusion: The 2022 consensus recommendation may be more sensitive in the diagnosis of AIH in comparison to the 2008 'simplified' histological criteria. More studies are needed both for the validation of the sensitivity of the new consensus recommendation and for the determination of the specificity.

Diagnostic features of autoimmune hepatitis in SARS­CoV­2­vaccinated vs. unvaccinated individuals.

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected millions of lives, leading to significant morbidity and mortality. With >772 million cases and nearly seven million deaths reported worldwide to date, the development of vaccines has been a critical step in mitigating the impact of COVID-19. However, concerns have arisen regarding the potential for SARS-CoV-2 mRNA vaccination to trigger autoimmune diseases, including autoimmune hepatitis (AIH). The present single-center, retrospective study aimed to compare the clinical and pathological features of AIH in patients with or without a history of SARS-CoV-2 mRNA vaccination. A total of 72 patients with AIH were examined. Among them, 10 had received the SARS-CoV-2 mRNA vaccination prior to AIH onset. These patients exhibited more pronounced CD4+ T cell infiltration into the liver tissue compared with those who were unvaccinated. No significant differences in the levels of other liver enzymes, autoimmune antibodies, or CD8+ T cell infiltration were observed between the groups. Moreover, the AIH patients with a history of SARS-CoV-2 mRNA vaccination had more extensive CD4+ T cell infiltration in their liver tissues than the unvaccinated patients. These findings suggested that the immune response to SARS-CoV-2 mRNA vaccination may influence the pathogenesis of AIH, highlighting the need for further research into the relationship between SARS-CoV-2 mRNA vaccination and autoimmune liver diseases. Such studies will also help clarify the distinction between vaccine-induced liver injury and traditional AIH.

Exploring the Pathogenesis of Autoimmune Liver Diseases from the Heterogeneity of Target Cells.

The incidence of autoimmune liver diseases (ALDs) and research on their pathogenesis are increasing annually. However, except for autoimmune hepatitis, which responds well to immunosuppression, primary biliary cholangitis and primary sclerosing cholangitis are insensitive to immunosuppressive therapy. Besides the known effects of the environment, genetics, and immunity on ALDs, the heterogeneity of target cells provides new insights into their pathogenesis. This review started by exploring the heterogeneity in the development, structures, and functions of hepatocytes and epithelial cells of the small and large bile ducts. For example, cytokeratin (CK) 8 and CK18 are primarily expressed in hepatocytes, while CK7 and CK19 are primarily expressed in intrahepatic cholangiocytes. Additionally, emerging technologies of single-cell RNA sequencing and spatial transcriptomic are being applied to study ALDs. This review offered a new perspective on understanding the pathogenic mechanisms and potential treatment strategies for ALDs.

Role of Sirolimus and Rituximab in the Treatment of Autoimmune Hepatitis.

Autoimmune hepatitis (AIH) is a rare chronic liver disease affecting annually 100,000-200,000 individuals in the United States. The first-line therapy in AIH is azathioprine and corticosteroids. However, adverse events may occur, which can preclude disease remission. In these cases, mycophenolate, mercaptopurine, and tacrolimus can be used. Rituximab is offered in difficult to treat cases. Sirolimus is an alternative regimen. However, little is known about its use in AIH. This is a challenging case of "difficult to treat" AIH managed with sirolimus and rituximab, after multiple unsuccessful trials with other medications.

Knockout of C6orf120 in Rats Alleviates Concanavalin A-induced Autoimmune Hepatitis by Regulating Macrophage Polarization.

Objective: The effect of the functionally unknown gene C6orf120 on autoimmune hepatitis was investigated on C6orf120 knockout rats ( C6orf120 -/- ) and THP-1 cells. Method: Six-eight-week-old C6orf120 -/- and wild-type (WT) SD rats were injected with Con A (16 mg/kg), and euthanized after 24 h. The sera, livers, and spleens were collected. THP-1 cells and the recombinant protein (rC6ORF120) were used to explore the mechanism in vitro. The frequency of M1 and M2 macrophages was analyzed using flow cytometry. Western blotting and PCR were used to detect macrophage polarization-associated factors. Results: C6orf120 knockout attenuated Con A-induced autoimmune hepatitis. Flow cytometry indicated that the proportion of CD68 +CD86 +M1 macrophages from the liver and spleen in the C6orf120 -/- rats decreased. C6orf120 knockout induced downregulation of CD86 protein and the mRNA levels of related inflammatory factors TNF-α, IL-1ß, and IL-6 in the liver. C6orf120 knockout did not affect the polarization of THP-1 cells. However, rC6ORF120 promoted the THP-1 cells toward CD68 +CD80 +M1 macrophages and inhibited the CD68 +CD206 +M2 phenotype. Conclusion: C6orf120 knockout alleviates Con A-induced autoimmune hepatitis by inhibiting macrophage polarization toward M1 macrophages and reducing the expression of related inflammatory factors in C6orf120 -/- rats.

Diagnostic criteria and long-term outcomes in AIH-PBC variant syndrome under combination therapy.

Background & Aims: Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) can co-exist in AIH-PBC, requiring combined treatment with immunosuppression and ursodeoxycholic acid (UDCA). The Paris criteria are commonly used to identify these patients; however, the optimal diagnostic criteria are unknown. We aimed to evaluate the use and clinical relevance of both Paris and Zhang criteria. Methods: Eighty-three patients with a clinical suspicion of AIH-PBC who were treated with combination therapy were included. Histology was re-evaluated. Characteristics and long-term outcomes were retrospectively compared to patients with AIH and PBC. Results: Seventeen (24%) patients treated with combination therapy fulfilled the Paris criteria. Fifty-two patients (70%) fulfilled the Zhang criteria. Patients who met Paris and Zhang criteria more often had inflammation and fibrosis on histology compared to patients only meeting the Zhang criteria. Ten-year liver transplant (LT)-free survival was 87.3% (95% CI 78.9-95.7%) in patients with AIH-PBC. This did not differ in patients in or outside the Paris or Zhang criteria (p = 0.46 and p = 0.40, respectively) or from AIH (p = 0.086). LT-free survival was significantly lower in patients with PBC and severe hepatic inflammation - not receiving immunosuppression - compared to those with AIH-PBC (65%; 95% CI 52.2-77.8% vs. 87%; 95% CI 83.2-90.8%; hazard ratio 0.52; p = 0.043). Conclusions: In this study, patients with AIH-PBC outside Paris or Zhang criteria were frequently labeled as having AIH-PBC and were successfully treated with combination therapy with similar outcomes. LT-free survival was worse in patients with PBC and hepatic inflammation than in those treated as having AIH-PBC. More patients may benefit from combination therapy. Impact and implications: This study demonstrated that patients with AIH-PBC variant syndrome treated with combined therapy consisting of immunosuppressants and ursodeoxycholic acid often do not fulfill the Paris criteria. They do however have comparable response to therapy and long-term outcomes as patients who do fulfill the diagnostic criteria. Additionally, patients with PBC and additional signs of hepatic inflammation have poorer long-term outcomes compared to patients treated as having AIH-PBC. These results implicate that a larger group of patients with features of both AIH and PBC may benefit from combined treatment. With our results, we call for improved consensus among experts in the field on the diagnosis and management of AIH-PBC variant syndrome.

Liver Transplantation Profile Among Teenagers in the United States.

PURPOSE: Indications for liver transplantation (LT) vary across age groups. We identified predictors of outcomes for teenage LT waitlisted candidates and recipients in the United States from 2008 to 2022. METHODS: The Scientific Registry of Transplant Recipients 2008-2022 provided data (clinical, sociodemographic, indications for LT, outcomes) for all teenagers (13-19 years) waitlisted for LT in the United States. Sociodemographic and clinical characteristics, including primary listing diagnoses, were evaluated and compared by age group (13-16 vs. 17-19 years) among waitlisted teenage candidates. RESULTS: There were 2,813 teenage LT candidates listed between 2008 and 2022. The most common LT indication was acute liver disease (23.5%), followed by biliary atresia or hypoplasia (11.9%), autoimmune hepatitis (11.1%), and primary sclerosing cholangitis (9.7%). In contrast, chronic viral hepatitis, metabolic dysfunction-associated steatotic liver disease, and alcohol-related liver disease (the most common indications in adults) did not exceed 1% each; 2.8% had hepatocellular carcinoma. Excluding the two most recent years, 67.2% of candidates received a transplant; mean time to transplant was 217.0 days (standard deviation 371.6). Independent predictors of receiving a transplant were a more recent calendar year, younger age, higher model for end-stage liver disease score, and an acute liver disease diagnosis (all p < .05). Among the LT group, 3-year survival was 90%, with an improving survival trend. Higher post-transplant mortality was associated with earlier years of transplantation, older age, having Medicaid, being retransplanted, and having hepatocellular carcinoma (adjusted hazard ratios >1, all p < .05). DISCUSSION: Indications for LT among US teenagers are different from adults or younger children. There is a trend toward improved post-transplant outcomes.

Immunological crossroads: The intriguing dance between hepatitis C and autoimmune hepatitis.

Delving into the immunological crossroads of liver diseases, this editorial explores the dynamic interplay between hepatitis C virus (HCV) and autoimmune hepatitis (AIH). While HCV primarily manifests as a viral infection impacting the liver, previous studies unveil a captivating connection between HCV and the emergence of AIH. The dance of the immune system in response to HCV appears to set the stage for an intriguing phenomenon-an aberrant autoimmune response leading to the onset of AIH. Evidence suggests a heightened presence of autoimmune markers in individuals with chronic HCV infection, hinting at a potential overlap between viral and autoimmune liver diseases. Navigating the intricate terrain of viral replication, immune response dynamics, and genetic predisposition, this editorial adds a layer of complexity to our understanding of the relationship between HCV and AIH. In this immunological crossroads, we aim to unearth insights into the complex interplay, using a compelling case where AIH and primary sclerosing cholangitis overlapped following HCV treatment with direct-acting antivirals as background.

Etiology-Specific Effects of Impaired Functional Status on Liver Transplant Outcomes.

BACKGROUND AND AIMS: Pre-liver transplant (LT) functional status is an important determinant of prognosis post LT. There is insufficient data on how functional status affects outcomes of transplant recipients based on the specific etiology of liver disease. We stratified LT recipients by etiology of liver disease to evaluate the effects of functional status on post-LT prognosis in each subgroup. METHODS: 2005-2019 United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research (STAR) was used to select patients with liver transplant. A total of 14,290 patients were included in the analysis. These patients were stratified by functional status according to Karnofsky Performance Scale (KPS) score: no assistance, some assistance, or total assistance. They were then further divided into six diagnosis categories: metabolic dysfunction-associated steatotic liver disease (MASLD), hereditary disorders, hepatitis C, hepatitis B, autoimmune disease (AID), and alcoholic liver disease (ALD). Primary endpoints included all-cause mortality and graft failure, while secondary endpoints included organ-specific causes of death. Those under the age of 18 and those with non-whole liver or prior liver transplantation were excluded. RESULTS: Patients with MASLD requiring some assistance (aHR: 1.57, 95% CI 1.03-2.39, p = 0.04) and those requiring total assistance (aHR: 2.32, 95% CI 1.48-3.64, p < 0.001) had higher incidences of graft failure compared to those requiring no assistance. Those with MASLD requiring total assistance had a higher all-cause mortality rate than those needing no assistance (aHR: 1.62, 95% CI 1.38-1.89, p < 0.001). Patients with hereditary causes of liver disease showed a lower incidence of all-cause mortality in recipients needing some assistance compared with those needing no assistance (aHR: 0.52, 95% CI 0.34-0.80, p = 0.003). LT recipients with hepatitis C, AID, and ALD all showed higher incidences of all-cause mortality in the total assistance cohort when compared to the no assistance cohort. For the secondary endpoints of specific cause of death, transplant recipients with MASLD needing total assistance had higher rates of death due to general cardiac causes, graft rejection, general infectious causes, sepsis, general renal causes, and general respiratory causes. CONCLUSION: Patients with MASLD cirrhosis demonstrated the worst overall outcomes, suggesting that this population may be particularly vulnerable. Poor functional status in patients with end-stage liver disease from hepatitis B or hereditary disease was not associated with a significantly increased rate of adverse outcomes, suggesting that the KPS score may not be broadly applicable to all patients awaiting LT.

Autoimmune Hepatitis Induced by Hepatitis Delta Virus: A Conundrum.

Introduction: The association of hepatitis delta virus (HDV) infection with positive autoantibodies and autoimmune features has been known for decades. However, to date, very few cases of clinical autoimmune hepatitis (AIH) have been reported in association with HDV infection, most of them being in the context of treatment with peginterferon. Case Report: This case refers to a 46-year-old woman born in Guinea-Bissau who moved to Portugal in 2018 to investigate complaints of diffuse abdominal discomfort and nausea. Her initial work-up, including laboratory and liver histology, was consistent with type 1 AIH. She had HBe antigen-negative chronic hepatitis B virus infection with negative DNA and also a positive total anti-HDV antibody, with negative IgM and undetectable RNA. Therefore, after initiating prophylactic tenofovir difumarate, she was started on prednisolone followed by azathioprine, which was later stopped due to presumed hepatotoxicity. Repeated histology showed signs of viral superinfection, and she was treated with acyclovir due to a positive herpes simplex IgM, with HDV RNA remaining negative. A third flare in transaminases prompted the introduction of mycophenolate mofetil (MMF) after a thorough exclusion of additional causes of liver disease. About 6 months later, during another bout of hepatitis, HDV RNA was finally positive and classified as genotype 5. MMF was stopped, and, considering a contraindication to interferon, the patient was offered therapy with bulevirtide, which she refused for personal reasons as she is currently living in her home country. Discussion: This is a challenging case of autoimmune or "autoimmune-like" hepatitis, probably induced by chronic HDV infection. High suspicion of HDV was essential because, had the case been interpreted as refractory AIH, with escalation of immunosuppression, a more severe course of the viral infection might have ensued. Recently, HDV suppression with bulevirtide was shown to reverse autoimmune liver disease. We hypothesize that the same could have happened to our patient, had she accepted this treatment.

Introdução: A associação da infeção pelo vírus da hepatite delta (VHD) com a presença de autoanticorpos e outros aspetos de autoimunidade é conhecida desde há várias décadas. Contudo, até à data, muito poucos casos de hepatite autoimune (HAI) clínica foram reportados em relação com a infeção VHD, sendo a maioria destes no contexto de terapêutica com interferão peguilado. Caso clínico: O caso refere-se a uma mulher de 46 anos natural da Guiné-Bissau, que se mudou para Portugal em 2018 para investigação de queixas de desconforto abdominal difuso e náuseas. A avaliação laboratorial inicial e a histologia hepática foram compatíveis com HAI tipo 1. A doente apresentava também infeção crónica a VHB (vírus da hepatite B) antigénio HBe negativa, com DNA negativo, e anti-VHD (vírus da hepatite delta) total positivo, com IgM negativo e RNA indetetável. Assim, após início de tenofovir difumarato profilático, foi iniciada terapêutica com prednisolona seguida de azatioprina, que posteriormente se interrompeu por presumível hepatotoxicidade. Uma segunda biópsia mostrou aspetos de superinfeção viral e como tal a doente foi tratada com aciclovir, tendo em conta IgM positivo para Herpes Simplex, mantendo-se o RNA VHD negativo. Um terceiro flare de transaminases motivou o início de micofenolato de mofetil, após extensa investigação e exclusão de outras causas de doença hepática. Cerca de 6 meses mais tarde, durante novo episódio de hepatite, o RNA VHD revelou-se finalmente positivo e este foi classificado como genotipo 5. O MMF foi suspenso e, considerando a contra-indicação para interferão, foi proposto à doente tratamento com bulevirtide, que esta recusou, alegando motivos pessoais, visto estar atualmente a residir no seu país de origem. Discussão: Este é um caso desafiante de hepatite autoimune, ou autoimune-like, provavelmente induzida pela infeção crónica pelo VHD. Um elevado índice de suspeição para VHD foi essencial porque, se o caso tivesse sido interpretado como HAI refratária, com incremento de imunossupressão, poderia ter-se verificado um agravamento da hepatite viral. Recentemente, foi reportado que a supressão do VHD pelo bulevirtide pode reverter a doença hepática autoimune. Questionamo-nos se o mesmo poderia ter sucedido com a nossa doente, caso esta tivesse aceite este tratamento.

The Autoimmune Gender Gap: A Rare Case of a Male Patient With Overlapping Autoimmune Hepatitis and Primary Biliary Cholangitis.

Autoimmune hepatitis (AIH) is a condition resulting in chronic, inflammatory changes to the liver. Primary biliary cholangitis (PBC) is an autoimmune condition that destroys intrahepatic bile ducts. Overlap syndrome with concomitant AIH and PBC comprises a rare subgroup of patients with immune-mediated liver disease, with incidence rates of male patients being exceedingly uncommon in a predominantly female patient population. Our case report investigates a rare case of a 41-year-old male patient diagnosed with overlapping AIH and PBC. He initially presented with symptoms of fatigue, pruritus, and episodes of Raynaud's phenomenon, in addition to findings of persistently elevated liver enzymes despite lifestyle modifications. He had no past medical history, no history of alcohol use disorder, and no family medical history of chronic liver disease. Imaging did not reveal evidence of cirrhosis. Further diagnostic workup was significant for elevated immunologic markers for antinuclear antibodies (ANA) with positive centromere and cytoplasmic patterns, antimitochondrial antibodies (AMA) with F-actin antibodies, anti-smooth muscle antibodies (ASMA), and cytoplasmic antinuclear cytoplasmic antibodies (ANCA C). Liver biopsy showed prominent plasma cells and rare granulomas, consistent with the diagnosis of AIH with a component of PBC, respectively. He was started on ursodeoxycholic acid (UDCA), demonstrating a near-complete clinical response with resolution of symptoms and normalization of liver enzymes. Studies investigating the low incidence of male patients with overlap syndrome are limited, as current research is overwhelmingly based on studies with predominantly female subjects. However, most studies generally recommend treatment with both UDCA and corticosteroids to reduce symptoms and biochemical markers. Our case report highlights a rare case of a male patient documenting excellent biochemical and clinical responses to monotherapy with UDCA. A possible theory is that our patient's early treatment (prior to advanced disease progression) is associated with his near-complete biochemical response and symptomatic resolution on UDCA alone. Further research is needed to fully understand the clinical course and long-term prognosis of male patients with overlap syndrome. Our patient remains in life-long follow-up to monitor if or when he requires treatment with corticosteroids in addition to current monotherapy with UDCA.​.

Analysis of autoimmune hepatitis with acute presentation in the early stage of illness.

BACKGROUND AND AIM: There is no gold standard for making the diagnosis of autoimmune hepatitis (AIH), and the diagnosis of acute onset AIH (A-AIH) is most challenging. A-AIH sometimes develops into acute liver failure with poor prognosis if the diagnosis is delayed. Therefore, it is most important for the better prognosis to diagnose non-severe A-AIH early and treat appropriately. However, features in the early stage of A-AIH are unclear. We examined initial characteristics of non-severe A-AIH in detail and tried to find novel clinical features for the early diagnosis. METHODS: Clinical, biochemical, immunological, radiological, and histological features of 71 patients (54 women, mean age 57.9 ± 14.3 years) with non-severe A-AIH admitted to community hospitals between 2001 and 2022 were analyzed retrospectively. RESULT: Forty-six had no symptom on onset and liver injuries were discovered by regular medical checkups. The mean duration from onset to consultation was 25.0 ± 29.3 days. Liver histology showed acute hepatitis in 59% and chronic hepatitis in 41%. Patients with symptoms revealed more male sex (P = 0.039), higher alanine aminotransferase (P < 0.001), higher total bilirubin (P < 0.001), and higher rate of histological acute hepatitis (P = 0.0013) than those without symptoms significantly. Male sex, presence of symptoms on onset, occurrence of jaundice in the course, and histological acute hepatitis were correlated. CONCLUSIONS: Sixty-five percent of non-severe A-AIH patients were asymptomatic on onset, suggesting that A-AIH would develop insidiously and present a longer clinical course than that reported. Male patients more often revealed true acute hepatitis clinically, biochemically, and histologically than female ones.

Different Course And Management of Khat-Induced Autoimmune Hepatitis: Report On Three Cases.

Khat is a plant that is commonly used for its stimulating effects and is chewed for its psychoactive properties. It creates feelings of euphoria that are similar to when taking amphetamines. There is an association between khat and liver injury, but the mechanism is not well known. We present three cases of khat-induced liver injury. All cases have elevated IgG and either positive antinuclear antibodies (ANA) or anti-smooth muscle antibody (ASMA); each case has a different course and requires different management. One case improved only by stopping khat, one required a short course of steroids and the last case required treatment such as that for autoimmune hepatitis (AIH). LEARNING POINTS: This is the first report on different courses and management of khat-induced hepatitis.Although khat-induced AIH is rare, early detection and management have a significant effect on disease remission.Further studies are needed to evaluate the mechanism of how khat-induced autoimmune hepatitis as it is not well understood.

Efficacy of Combination Therapies for Autoimmune Hepatitis: A Systematic Review and Meta-Analysis.

Autoimmune hepatitis (AIH) is a hepatocellular disorder thought to be caused by an immune system that cannot tolerate autoantigens specific to hepatocytes. This study aims to evaluate the efficacy of using corticosteroids (prednisolone and azathioprine) as a combination therapy in treating AIH. This study aims to synthesize and analyze existing evidence to inform clinical practices concerning the overall clinical efficacy of this treatment approach in managing AIH. A comprehensive search was conducted across multiple online databases and search engines, including PubMed, Google Scholar, ScienceDirect, Medline, and Embase. RevMan 5.4 software was used for meta-analysis, with forest plots created for each outcome. Thirteen studies were included in this systematic review and meta-analysis. The results indicate that the combination of prednisolone and azathioprine for treating AIH leads to less recurrence and better disease control.

[Seronegative autoimmune hepatitis]. / Hepatitis autoinmune seronegativa.

Autoimmune hepatitis (AIH) is a rare, chronic, inflammatory, and necrotic liver disease characterized by the presence of autoantibodies. Its etiology is unknown. It affects 1 in 200 000 people annually in the US and occurs predominantly in women. Its presentation varies from asymptomatic forms to cirrhosis and acute liver failure and its diagnosis is based on the measurement of autoantibodies, such as antinuclear autoantibodies (ANA), anti-smooth muscle antibodies (ASMA) and anti-liver and kidney microsomal antibodies (anti-LKM). 1). 10% of HAIs do not present antibodies, being called seronegative HAI, requiring a liver biopsy for diagnosis. To date the evidence remains limited and different societies have issued suggestions and recommendations. For this reason, we believe it is relevant to carry out a bibliographic review on the subject, capturing in this document the important information for the understanding and management of this pathology.

La hepatitis autoinmune (HAI) es una enfermedad inflamatoria y necrótica del hígado, crónica e infrecuente caracterizada por la presencia de autoanticuerpos. Su etiología es desconocida. Afecta a 1 de cada 200 000 personas anualmente en los EE. UU. y se presenta predominantemente en mujeres. Su presentación varía desde formas asintomáticas hasta la cirrosis y falla hepática aguda y su diagnóstico se basa en la medición de autoanticuerpos, como los autoanticuerpos antinucleares (ANA), anticuerpos antimúsculo liso (ASMA) y anticuerpos antimicrosomales de hígado y riñón (anti-LKM-1). El 10% de las HAI no presentan anticuerpos, denominándose HAI seronegativa, necesitando biopsia hepática para el diagnóstico. Hasta la fecha la evidencia sigue siendo limitada y diferentes sociedades han emitido sugerencias y recomendaciones. Por tal motivo creemos relevante realizar una revisión bibliográfica sobre el tema plasmando en este documento la información importante para la compresión y el manejo de esta patología.

Systemic lupus erythematosus and autoimmune hepatitis overlap disease in a hospitalized systemic lupus erythematosus cohort.

Liver dysfunction in systemic lupus erythematosus (SLE) is caused by disease activity or secondary conditions like coexistent autoimmune liver diseases. In Taiwan, despite sporadically reported cases of SLE-autoimmune hepatitis (AIH) overlap disease, larger-scale monocentric investigations for such overlapping patients are not available. Retrospective analyses were performed in a hospitalized SLE cohort with 805 patients for identifying co-existent AIH from 2014 to 2023, focusing on distinct therapeutic modalities and differential diagnosis between SLE-AIH overlap and lupus hepatitis (LH). There were 5 cases (a 0.6% occurrence), all females aged 25-58 years (44 ± 13). Ages for the SLE diagnosis were 19-51 years (30 ± 13), while ages for the AIH diagnosis were 22-57 years (36 ± 14). Contradictory to interface hepatitis in SLE-AIH overlap, liver biopsy only demonstrated non-specific abnormalities in LH. Liver cirrhosis was identified in SLE-AIH overlap but not in LH. After corticosteroids/azathioprine therapy, there were normalized liver function in all LH. In 2 SLE-AIH overlap cases refractory to such therapy, one received B-cell depletion therapy (annual rituximab infusion, 375 mg/m2 weekly × 4) and another accepted living-donor liver transplantation from sibling due to advanced liver cirrhosis, leading to improved hepatic dysfunction in both.

Cyclophosphamide in refractory autoimmune hepatitis and autoimmune hepatitis coexisting extrahepatic autoimmune disorders: A review.

INTRODUCTION AND OBJECTIVES: Despite tacrolimus (TAC) or mycophenolate mofetil (MMF) for alternate approaches, a proportion of patients still required further exploration of other therapeutic options due to uncontrolled autoimmune hepatitis(AIH). The role of cyclophosphamide (CYC) for AIH has been explored in isolated case reports and small series. We present a review of CYC therapy in AIH patients. MATERIALS AND METHODS: A search for studies with keywords 'autoimmune hepatitis' and 'cyclophosphamide' was performed. Data recorded included gender, age, laboratory parameters and histological findings at the time of AIH diagnosis and before initiation of CYC therapy. RESULTS: We identified 13 patients across 7 studies who met criteria for study inclusion, of whom around 69.2% (9/13) were primary refractory; 30.8% (4/13) patients used CYC as rescue therapy due to their coexisting autoimmune complications. The main findings of the study were that CYC appears to have an acceptable safety profile in difficult-to-treat AIH patients, with an overall remission rate of 88.9% (8/9). The other four patients with AIH accompanied by extrahepatic autoimmune disorders also achieved remission of transaminase levels and stability of liver function after the addition of CYC. A positive response to CYC treatment was seen in 12(92.3%) patients and none of them relapsed during the follow-up. CONCLUSIONS: We cautiously recommend that CYC could be a conditioning alternative to starting second-line therapy after unsuccessful intensification of first-line treatment. Pharmacogenetic methods may play a role in guiding cyclophosphamide therapy. Given our small sample size, results should be considered preliminary.

A deep-learning-based model for assessment of autoimmune hepatitis from histology: AI(H).

Histological assessment of autoimmune hepatitis (AIH) is challenging. As one of the possible results of these challenges, nonclassical features such as bile-duct injury stays understudied in AIH. We aim to develop a deep learning tool (artificial intelligence for autoimmune hepatitis [AI(H)]) that analyzes the liver biopsies and provides reproducible, quantifiable, and interpretable results directly from routine pathology slides. A total of 123 pre-treatment liver biopsies, whole-slide images with confirmed AIH diagnosis from the archives of the Institute of Pathology at University Hospital Basel, were used to train several convolutional neural network models in the Aiforia artificial intelligence (AI) platform. The performance of AI models was evaluated on independent test set slides against pathologist's manual annotations. The AI models were 99.4%, 88.0%, 83.9%, 81.7%, and 79.2% accurate (ratios of correct predictions) for tissue detection, liver microanatomy, necroinflammation features, bile duct damage detection, and portal inflammation detection, respectively, on hematoxylin and eosin-stained slides. Additionally, the immune cells model could detect and classify different immune cells (lymphocyte, plasma cell, macrophage, eosinophil, and neutrophil) with 72.4% accuracy. On Sirius red-stained slides, the test accuracies were 99.4%, 94.0%, and 87.6% for tissue detection, liver microanatomy, and fibrosis detection, respectively. Additionally, AI(H) showed bile duct injury in 81 AIH cases (68.6%). The AI models were found to be accurate and efficient in predicting various morphological components of AIH biopsies. The computational analysis of biopsy slides provides detailed spatial and density data of immune cells in AIH landscape, which is difficult by manual counting. AI(H) can aid in improving the reproducibility of AIH biopsy assessment and bring new descriptive and quantitative aspects to AIH histology.