Higher frequency of gastric neoplasia in advanced chronic liver disease patients: Impact of screening endoscopy in an intermediate-high risk country.

BACKGROUND: The Baveno VII guidelines were proposed to identify which patients could safely avoid screening esophagogastroduodenoscopy (EGD) for gastroesophageal varices. We aimed to evaluate the frequency of gastric neoplasia in compensated advanced chronic liver disease (cACLD) patients who underwent EGD for screening of gastroesophageal varices (GOEV) compared to a healthy population. METHODS: Retrospective study that enrolled all cACLD patients who underwent EGD for GOEV screening (January 2008-June 2018) in a tertiary reference center. cACLD patients were compared with asymptomatic healthy individuals who underwent EGD in a private hospital setting (April 2017-March 2018). RESULTS: We evaluated 1845 patients (481 cACLD patients, 1364 healthy individuals). A significantly higher frequency of gastric neoplasia was observed in patients with cACLD compared to healthy individuals (4.0% vs. 1.0 %; p < 0.001). Rare histopathological subtypes (WHO Classification) accounted for 28.7 % of gastric carcinoma cases in the cACLD cohort. Seven cases of gastric neoplasia (36.8 % of gastric neoplasia cases in the cACLD patients) were diagnosed in patients who, according to the Baveno VII criteria, would have not been submitted to EGD. CONCLUSION: We found an increased frequency of gastric neoplasia in patients with cACLD in comparison with healthy individuals. In countries with intermediate-high risk for GC, continuing to perform EGD could be beneficial.

Association of metabolic syndrome components and NAFLD with quality of life: Insights from a cross-sectional study.

AIM: Metabolic syndrome (MetS) is associated with higher cardiovascular and metabolic risks, as well as with psychosocial disorders. Data regarding quality of life (QoL) in patients with MetS, point towards a significative association between MetS and a worse QoL. It remains unclear whether MetS components and non-alcoholic fatty liver disease (NAFLD) are associated with QoL in these individuals. We aimed to evaluate the association between QoL of patients with MetS and prespecified metabolic parameters (anthropometric, lipidic and glucose profiles), the risk of hepatic steatosis and fibrosis, and hepatic elastography parameters. METHODS: Cross-sectional study including patients from microDHNA cohort. This cohort includes patients diagnosed with MetS, 18 to 75 years old, followed in our tertiary center. The evaluation included anamnesis, physical examination, a QoL questionnaire (Short-Form Health Survey, SF-36), blood sampling and hepatic elastography. We used ordered logistic regression models adjusted to sex, age and body mass index to evaluate the associations between the QoL domains evaluated by SF-36 and the prespecified parameters. RESULTS: We included a total of 65 participants with MetS, with 54% being female and the mean age 61.9 ± 9.6 years old. A worse metabolic profile, specifically higher waist circumference, lower HDL, higher triglycerides, and more severe hepatic steatosis, were associated with worse QoL scores in several domains. We found no significant association of hepatic fibrosis with QoL. CONCLUSION: Our data suggests that there is a link between a worse metabolic profile (specifically poorer lipidic profile and presence of hepatic steatosis) and a worse QoL in patients with MetS.

Lack of complete biochemical response in autoimmune hepatitis leads to adverse outcome: First report of the IAIHG retrospective registry.

BACKGROUND AND AIMS: The International Autoimmune Hepatitis Group retrospective registry (IAIHG-RR) is a web-based platform with subjects enrolled with a clinical diagnosis of autoimmune hepatitis (AIH). As prognostic factor studies with enough power are scarce, this study aimed to ascertain data quality and identify prognostic factors in the IAIHG-RR cohort. METHODS: This retrospective, observational, multicenter study included all patients with a clinical diagnosis of AIH from the IAIHG-RR. The quality assessment consisted of external validation of completeness and consistency for 29 predefined variables. Cox regression was used to identify risk factors for liver-related death and liver transplantation (LT). RESULTS: This analysis included 2559 patients across 7 countries. In 1700 patients, follow-up was available, with a completeness of individual data of 90% (range: 30-100). During a median follow-up period of 10 (range: 0-49) years, there were 229 deaths, of which 116 were liver-related, and 143 patients underwent LT. Non-White ethnicity (HR 4.1 95% CI: 2.3-7.1), cirrhosis (HR 3.5 95% CI: 2.3-5.5), variant syndrome with primary sclerosing cholangitis (PSC) (HR 3.1 95% CI: 1.6-6.2), and lack of complete biochemical response within 6 months (HR 5.7 95% CI: 3.4-9.6) were independent prognostic factors. CONCLUSIONS: The IAIHG-RR represents the world's largest AIH cohort with moderate-to-good data quality and a relevant number of liver-related events. The registry is a suitable platform for patient selection in future studies. Lack of complete biochemical response to treatment, non-White ethnicity, cirrhosis, and PSC-AIH were associated with liver-related death and LT.

Incidence and predictors of hepatocellular carcinoma in patients with autoimmune hepatitis.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a rare chronic liver disease of unknown aetiology; the risk of hepatocellular carcinoma (HCC) remains unclear and risk factors are not well-defined. We aimed to investigate the risk of HCC across a multicentre AIH cohort and to identify predictive factors. METHODS: We performed a retrospective, observational, multicentric study of patients included in the International Autoimmune Hepatitis Group Retrospective Registry. The assessed clinical outcomes were HCC development, liver transplantation, and death. Fine and Gray regression analysis stratified by centre was applied to determine the effects of individual covariates; the cumulative incidence of HCC was estimated using the competing risk method with death as a competing risk. RESULTS: A total of 1,428 patients diagnosed with AIH from 1980 to 2020 from 22 eligible centres across Europe and Canada were included, with a median follow-up of 11.1 years (interquartile range 5.2-15.9). Two hundred and ninety-three (20.5%) patients had cirrhosis at diagnosis. During follow-up, 24 patients developed HCC (1.7%), an incidence rate of 1.44 cases/1,000 patient-years; the cumulative incidence of HCC increased over time (0.6% at 5 years, 0.9% at 10 years, 2.7% at 20 years, and 6.6% at 30 years of follow-up). Patients who developed cirrhosis during follow-up had a significantly higher incidence of HCC. The cumulative incidence of HCC was 2.6%, 4.6%, 5.6% and 6.6% at 5, 10, 15, and 20 years after the development of cirrhosis, respectively. Obesity (hazard ratio [HR] 2.94, p = 0.04), cirrhosis (HR 3.17, p = 0.01), and AIH/PSC variant syndrome (HR 5.18, p = 0.007) at baseline were independent risk factors for HCC development. CONCLUSIONS: HCC incidence in AIH is low even after cirrhosis development and is associated with risk factors including obesity, cirrhosis, and AIH/PSC variant syndrome. IMPACT AND IMPLICATIONS: The risk of developing hepatocellular carcinoma (HCC) in individuals with autoimmune hepatitis (AIH) seems to be lower than for other aetiologies of chronic liver disease. Yet, solid data for this specific patient group remain elusive, given that most of the existing evidence comes from small, single-centre studies. In our study, we found that HCC incidence in patients with AIH is low even after the onset of cirrhosis. Additionally, factors such as advanced age, obesity, cirrhosis, alcohol consumption, and the presence of the AIH/PSC variant syndrome at the time of AIH diagnosis are linked to a higher risk of HCC. Based on these findings, there seems to be merit in adopting a specialized HCC monitoring programme for patients with AIH based on their individual risk factors.

Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report.

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition.

Development of a Model to Predict Liver Decompensation prior to Transarterial Chemoembolization Refractoriness in Patients with Intermediate-Stage Hepatocellular Carcinoma.

Introduction: Transarterial chemoembolization (TACE) is the first-line treatment for patients with intermediate-stage hepatocellular carcinoma (HCC). For patients without an adequate response, current finding suggests that treatment with molecular target agents, approved for advanced stage, might present benefits. However, this requires a preserved liver function. This study aims to evaluate possible predictors of early deterioration of hepatic reserve, prior to TACE refractoriness, in a cohort of patients treated with TACE. Methods: Retrospective analysis of 99 patients with Child-Pugh class A and intermediate-stage HCC who underwent TACE as the first-line treatment. All patients were submitted to a biochemical and medical evaluation prior to initial TACE and every month afterward. Response to initial TACE was evaluated at 1 month. The time to Child-Pugh class deterioration before TACE refractoriness was assessed. Results: Ninety-nine patients were included. Objective response rate (ORR) to initial TACE was assessed as present in 59 (63.4%) and as absent in 34 (36.6%) patients. Liver decompensated before TACE refractoriness in 51 (51.5%) patients, and the median time to liver decompensation was 14 (IQR 8-20) months after first TACE. In multivariate analysis, beyond up-to-7 criteria (HR 2.4, p = 0.031), albumin <35 mg/dL (HR 3.5, p < 0.001) and absence of ORR (HR 2.4, p = 0.020) were associated with decreased overall survival free of liver decompensation. Moreover, beyond up-to-7 criteria, albumin <35 mg/dL and absence of ORR associated negatively with 6-month survival free of liver decompensation. Our model created using those variables was able to predict liver decompensation at 6 months with an AUROC of 0.701 (p = 0.02). Conclusions: The absence of ORR after initial TACE, beyond up-to-7 criteria and albumin <35 mg/dL, was a predictive factor for early liver decompensation before TACE refractoriness in our population. Such patients might benefit from treatment escalation to systemic therapy, in monotherapy or in combination with TACE.

Introdução: A quimioembolização transarterial (TACE) é o tratamento de primeira linha para doentes com carcinoma hepatocelular (HCC) em estadio intermédio. Em doentes sem resposta adequada, a evidência atual sugere que o tratamento com agentes de alvo molecular, aprovado para estágio avançado, pode apresentar benefícios. Porém, isso requer função hepática preservada. O objetivo deste estudo é avaliar possíveis preditores de deterioração precoce da reserva hepática, antes da refratariedade ao TACE, em uma coorte de doentes tratados com TACE. Métodos: Análise retrospectiva de noventa e nove doentes com Child-Pugh classe A e HCC em estadio intermédio que foram submetidos a TACE como tratamento de primeira linha. Todos os doentes foram submetidos a uma avaliação bioquímica e médica antes do TACE inicial e a cada mês após. A resposta ao TACE inicial foi avaliada em 1 mês. O tempo para a deterioração da classe Child-Pugh antes da refratariedade a TACE foi avaliado. Resultados: Noventa e nove doentes foram incluídos. A resposta radiológica objetiva (ORR) ao TACE inicial foi avaliada como presente em 59 (63.4%) e ausente em 34 (36.6%) doentes. Descompensação hepática ocorreu, antes da refratariedade a TACE, em 51 (51.5%) doentes e o tempo médio para a descompensação hepática foi de 14 (IQR 8­20) meses, após o primeiro TACE. Na análise multivariada, além dos critérios up-to-7 (HR 2,4, p = 0.031), albumina <35 mg/dL (HR 3,5, p < 0.001) e ausência de ORR (HR 2,4, p = 0.020) foram associados a diminuição da sobrevida livre de descompensação hepática. Além disso, a sobrevida de 6 meses livre de descompensação hepática apresentou associação, além dos critérios up-to-7 , albumina <35 mg/dL e ausência de ORR. Foi criado um modelo com essas variáveis, capaz de prever a descompensação hepática com AUROC de 0,701 (p = 0.02). Conclusões: A ausência de ORR após TACE inicial, além dos critérios up-to-7 e albumina <35 mg/dL foram fatores preditivos para descompensação hepática antes da refratariedade a TACE na nossa população. Esses doentes podem beneficiar do escalonamento do tratamento para a terapia sistêmica, em monoterapia ou em combinação com TACE.

Splenic-hepatic elastography index is useful in differentiating between porto-sinusoidal vascular disease and cirrhosis in patients with portal hypertension.

INTRODUCTION: In patients with portal hypertension (PH), the differential diagnosis between porto-sinusoidal vascular disease (PSVD) and cirrhosis is challenging. This study aims to evaluate the diagnostic accuracy of the SSM/LSM index in the diagnosis of PSVD. METHODS: Prospective study of patients with PH and PSVD or cirrhosis. Transient liver and spleen elastography were performed and the ratio between spleen stiffness measurement (SSM) and liver stiffness measurement (LSM) was calculated. The relation of SSM/LSM with the diagnosis of PSVD was evaluated. RESULTS: Forty-four patients with PSVD and 44 patients with cirrhosis were evaluated. Median age was 57.5 (IQR 49.0-64.5) years, 66.3% were males. In patients with PSVD, median SSM was 59.4 (33.5-77.7) kPa, median LSM was 6.2 (5.2-10.2) kPa and median SSM/LSM was 5.62 (3.15-9.68). In patients with cirrhosis, median SSM was 47.3 (24.3-60.3) kPa, median LSM was 27.8 (17.7-53.9) kPa and median SSM/LSM was 1.55 (1.06-3.24). The SSM/LSM AUROC was 0.940 (p<0.001). Using 2 as a cut-off, we obtained good sensitivity (86.5%), specificity (92.7%), and accuracy (89.7%) for the diagnosis of PSVD. CONCLUSION: The SSM/LSM index is useful in the differential diagnosis between liver cirrhosis and PSVD. Using the cut-off of 2 we achieved a good sensitivity and specificity for diagnosing PSVD.

Hepatic amyloidosis: a prevalence study and clinical characterization of a rare and severe disease.

BACKGROUND AND AIM: Amyloidosis is a systemic disease characterized by extracellular deposition of amyloid protein, most commonly in the heart and kidney. Hepatic amyloidosis is a rare form of presentation that ranges from mild hepatomegaly and altered liver biochemical tests to acute liver failure. The aims of this study were to evaluate the prevalence of amyloidosis in patients undergoing liver biopsy and describe its main clinical characteristics and prognostic impact. METHODS: A retrospective analysis of all patients with a histological diagnosis of hepatic amyloidosis between January 2010 and December 2019 was performed. MAJOR RESULTS: A total of 7 patients were identified from a total of 1773 liver biopsy procedures (0.4%), with a female predominance (6/7) and median age of diagnosis of 62 years. The most common clinical manifestations included hepatomegaly (4/7), jaundice (2/7) and peripheral edema (2/7), whereas 3/7 patients were asymptomatic. Every patient presented abnormalities in liver biochemical tests, more commonly cholestasis (6/7), but also cytolysis (4/7) or hyperbilirubinemia (2/7). Abnormal imaging findings included hepatomegaly, steatosis or parenchymal heterogeneity. In most patients (5/7), other organs were involved, most commonly with nephrotic syndrome (3/7) and infiltrative cardiomyopathy (3/7). The most common type was AA amyloidosis (3/7) followed by AL amyloidosis (2/7). The 1-year mortality rate was 43% and the median survival was 24 months. CONCLUSIONS: We report a low prevalence (0.4%) of amyloidosis among patients undergoing liver biopsy. Although rare, hepatic amyloidosis is associated with a dismal prognosis and a high index of suspicion is crucial to achieve an early diagnosis. .

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

BACKROUND: In 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. AIMS: To determine early predictors of non-response to corticosteroids and to assess the usefulness of severity scores, namely the recently developed SURFASA. METHODS: Retrospective 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]. RESULTS: We 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. CONCLUSIONS: SURFASA and MELD-Na+ at D3 scores are useful in early identification of non-responders to corticosteroids.

"Long-term follow-up and prognosis of celiac hepatitis".

INTRODUCTION: Celiac disease has been associated with abnormal liver function tests at diagnosis that usually resolve with a gluten-free diet (GFD). The aim of this study was to assess the evolution of liver involvement and possible long-term complications in patients on a GFD. METHODS: Retrospective and single-center study, which included all individuals with Celiac disease followed in specialized consultation in a tertiary referral hospital. RESULTS: A total of 162 patients were included, most of them female (77.8%) with a median age of 24 years (IQR, 7-39). Seventy-four (45.7%) patients had abnormal liver function tests at diagnosis. These individuals had higher anti-tissue transglutaminase IgA (tTG-IgA) antibody titers (126 vs. 29 IU/L; P = 0.003). There were no significant differences in the Marsh classification ( P = 0.599). During follow-up, most celiac hepatitis patients had normalization of liver function tests and tTG-IgA antibodies. At the last follow-up, all the patients had fibrosis-4 index <2.4 and an aspartate aminotransferase-to-platelet ratio index score <0.6. Vibration-controlled transient elastography showed values <6.4 kPa in all cases. On the other hand, it was found that 42.9% of the individuals had a controlled attenuation parameter >206.5 db/m. CONCLUSIONS: In our cohort, liver function tests normalized in the vast majority of celiac hepatitis patients on a GFD, with no progression to chronic liver disease. It should be noted the high number of individuals who present hepatic steatosis during follow-up, which may be related to a diet that tends to be hyperlipidemic and hypercaloric.

Primary Myelofibrosis in the Prefibrotic Stage Presenting as Portal, Splenic, and Superior Mesenteric Vein Thrombosis: A Case Report and Review of the Literature.

Introduction: Myeloproliferative neoplasms are the most common cause of splanchnic vein thrombosis in the absence of cirrhosis or nearby malignancy. Case Presentation: A 31-year-old male presented to the emergency department with epigastric pain associated with mild thrombocytosis and elevated levels of aminotransferases, lactate dehydrogenase, and C-reactive protein. Contrast-enhanced abdominal computed tomography revealed splanchnic venous thrombosis that involved the portal, splenic, and superior mesenteric veins, without signs of chronic liver disease. Anticoagulation with warfarin was immediately started. Diagnostic work-up was remarkable for the presence of the JAK2 V617T mutation and hypercellular bone marrow, with increased myeloid cells and atypical megakaryocytes, consistent with primary myelofibrosis in a prefibrotic stage. No other hypercoagulable conditions were identified. Discussion: We present a rare case of primary myelofibrosis in the prefibrotic stage presenting as portal-splenic-superior mesenteric vein thrombosis. This demonstrates that extensive splanchnic vein thrombosis may be the onset manifestation of myeloproliferative neoplasms, even in early stages and in the absence of concomitant hypercoagulable conditions. The presence of the JAK2 mutation is an important prothrombotic risk factor that can, per se, contribute to large venous thrombosis.

Introdução: As neoplasias mieloproliferativas constituem a causa mais comum de trombose venosa esplâncnica na ausência de cirrose hepatica ou neoplasia regional. Descrição do caso: Um homem de 31 anos apresentou-se no Serviço de Urgência com dor epigástrica associada a trombocitose ligeira e elevação das transamínases, desidrogenase láctica e proteína C-reactiva. Em tomografia computorizada abdominal com contraste, foi identificada trombose venosa esplâncnica envolvendo a veia porta, esplénica e mesentérica superior, sem sinais de doença hepática crónica. Foi de imediato iniciada anticoagulação com varfarina. Da investigação etiológica, destaca-se a presença da mutação JAK2 V617F e medula óssea hiper-celular com aumento das contagens de células mielóides e megacariócitos atípicos, consistente com mielofibrose primária em estadio pré-fibrótico. Não se identificaram distúrbios pro-trombóticos concomitantes. Discussão: Apresenta-se um raro caso de trombose da veia porta, esplénica e mesentérica superior, demonstrando que as neoplasias mieloproliferativas podem apresentar-se sob a forma de trombose venosa esplâncnica extensa, mesmo em estadios precoces e na ausência de distúrbios protrombóticos concomitantes. A presença da mutação JAK2 é um importante factor de risco pro-trombótico que pode por si só contribuir para a formação de tromboses venosas extensas.

Liver injury after SARS-CoV-2 vaccination: Features of immune-mediated hepatitis, role of corticosteroid therapy and outcome.

BACKGROUND AND AIMS: A few case reports of autoimmune hepatitis-like liver injury have been reported after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. We evaluated clinical features, treatment response and outcomes of liver injury following SARS-CoV-2 vaccination in a large case series. APPROACH AND RESULTS: We collected data from cases in 18 countries. The type of liver injury was assessed with the R-value. The study population was categorized according to features of immune-mediated hepatitis (positive autoantibodies and elevated immunoglobulin G levels) and corticosteroid therapy for the liver injury. We identified 87 patients (63%, female), median age 48 (range: 18-79) years at presentation. Liver injury was diagnosed a median 15 (range: 3-65) days after vaccination. Fifty-one cases (59%) were attributed to the Pfizer-BioNTech (BNT162b2) vaccine, 20 (23%) cases to the Oxford-AstraZeneca (ChAdOX1 nCoV-19) vaccine and 16 (18%) cases to the Moderna (mRNA-1273) vaccine. The liver injury was predominantly hepatocellular (84%) and 57% of patients showed features of immune-mediated hepatitis. Corticosteroids were given to 46 (53%) patients, more often for grade 3-4 liver injury than for grade 1-2 liver injury (88.9% vs. 43.5%, p = 0.001) and more often for patients with than without immune-mediated hepatitis (71.1% vs. 38.2%, p = 0.003). All patients showed resolution of liver injury except for one man (1.1%) who developed liver failure and underwent liver transplantation. Steroid therapy was withdrawn during the observation period in 12 (26%) patients after complete biochemical resolution. None had a relapse during follow-up. CONCLUSIONS: SARS-CoV-2 vaccination can be associated with liver injury. Corticosteroid therapy may be beneficial in those with immune-mediated features or severe hepatitis. Outcome was generally favorable, but vaccine-associated liver injury led to fulminant liver failure in one patient.

Wilson disease in Northern Portugal: a long-term follow-up study.

INTRODUCTION: Wilson disease is an autosomal recessive disease of liver copper metabolism with predominant hepatic and neurological manifestations. Long-term data on the clinical follow-up and treatment efficacy are limited due to the low frequency of the disease. We evaluated a large cohort of Wilson disease patients from Northern Portugal during a 20-year follow-up period. METHODS: Twenty-four patients, diagnosed from 1975 to 2020 in a tertiary care center in Portugal, were retrospectively evaluated according to their clinical presentation, therapies and outcomes. RESULTS: Most of the patients were males (54%), with a median age at diagnosis of 19 years old (interquartile range 15-25). The main manifestations of Wilson disease were hepatic (71%) and neurological (25%). Family history was positive in 5 (21%) patients. Four patients (17%) presented with acute liver failure and fifteen (63%) individuals had cirrhosis at diagnosis. Penicillamine therapy was used by 11 (46%) patients, while trientine and zinc were given to 8 (33%) and 1 (4%) patient, respectively. Ten (42%) individuals underwent liver transplantation. The majority of patients (83%) had stable disease or improved outcomes during follow-up. CONCLUSION: This is the largest cohort of adult patients with Wilson disease reported in Northern Portugal. We show that Wilson disease has favorable outcomes with long overall survival, assuming adherence to therapy and lack of other insults to their liver.

Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis.

BACKGROUND AND AIMS: The "gut homing" hypothesis suggests the pathogenesis of primary sclerosing cholangitis (PSC) is driven by aberrant hepatic expression of gut adhesion molecules and subsequent recruitment of gut-derived T cells to the liver. However, inconsistencies lie within this theory including an absence of investigations and comparisons with other chronic liver diseases (CLD). Here, we examine "the gut homing theory" in patients with PSC with associated inflammatory bowel disease (PSC-IBD) and across multiple inflammatory liver diseases. APPROACH AND RESULTS: Expression of MAdCAM-1, CCL25, and E-Cadherin were assessed histologically and using RT-PCR on explanted liver tissue from patients with CLD undergoing OLT and in normal liver. Liver mononuclear cells were isolated from explanted tissue samples and the expression of gut homing integrins and cytokines on hepatic infiltrating gut-derived T cells was assessed using flow cytometry. Hepatic expression of MAdCAM-1, CCL25 and E-Cadherin was up-regulated in all CLDs compared with normal liver. There were no differences between disease groups. Frequencies of α4ß7, αEß7, CCR9, and GPR15 expressing hepatic T cells was increased in PSC-IBD, but also in CLD controls, compared with normal liver. ß7 expressing hepatic T cells displayed an increased inflammatory phenotype compared with ß7 negative cells, although this inflammatory cytokine profile was present in both the inflamed and normal liver. CONCLUSIONS: These findings refute the widely accepted "gut homing" hypothesis as the primary driver of PSC and indicate that aberrant hepatic recruitment of gut-derived T cells is not unique to PSC, but is a panetiological feature of CLD.

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. DESIGN: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. RESULTS: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. CONCLUSION: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

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.

Discontinuation of antiviral therapy in chronic hepatitis B patients.

Nucleos(t)ide analogs (NUC) are the first-line therapy for patients with chronic hepatitis B (CHB) recommended by most current guidelines. NUC therapy decreases progression of liver disease, reduces the risk of liver-related complications, and improves the quality of life of patients with CHB. Although indefinite or long-term NUC therapy is usually recommended, this strategy raises several concerns, such as side-effects, adherence, costs, and patient willingness to stop therapy. Recent data showed the feasibility, efficacy, and safety of stopping antiviral therapy in carefully selected CHB patients, leading to its incorporation in international guidelines. Patients who discontinue NUC have a higher likelihood of hepatitis B surface antigen (HBsAg) loss compared to patients who continue on therapy. Recommendations pertaining endpoints allowing safety discontinuation of NUC therapy differ among international guidelines. For hepatitis B e antigen (HBeAg)-positive patients, durable HBeAg seroconversion is considered an acceptable treatment endpoint. For HBeAg-negative patients, some guidelines propose undetectability hepatitis B virus DNA for at least 2 or 3 years, while others consider HBsAg loss as the only acceptable endpoint. CHB patients who stop therapy should remain under strict clinical and laboratorial follow-up protocols to detect and manage relapses in a timely manner. No reliable predictor of relapse has been consistently identified to date, although quantitative HBsAg has been increasingly studied as a reliable biomarker to predict safe NUC discontinuation.

Transient splenic elastography predicts high-risk esophageal varices in patients with non-cirrhotic portal hypertension.

BACKGROUND AND AIMS: Non-cirrhotic portal hypertension (NCPH) comprise a group of diseases that cause portal hypertension without cirrhosis, leading to a high risk of hemorrhage from esophageal varices. There are no non-invasive predictors of high-risk varices (HRV) described in the literature for NCPH. This study aimed to evaluate whether transient splenic elastography (TSE) can predict HRV in patients with NCPH. METHODS: Prospective study of patients with NCPH who underwent a single timepoint evaluation with transient liver and spleen elastography, ultrasonography, upper endoscopy, and laboratory tests. The study was performed from January to September 2020. Patients were divided into two groups based on the presence of HRV. The relation between TSE, transient liver elastography (TLE), spleen size, and platelet count to the presence of HRV was evaluated. RESULTS: Of 42 patients with NCPH, 50% (21/42) presented HRV. In univariate analysis, TSE (median, 58.4 vs. 28.3, p = 0.009) and spleen size (median, 17.5 vs. 14.5 cm, p = 0.013) were associated with HRV. No statistically significant relationship was found between the presence of HRV and platelet count or TLE. In multivariate analysis, TSE was the only variable related to HRV (OR 1.21, 95% CI 1.02-1.38). TSE had a good performance in predicting HRV in our population (AUROC 0.878; 95% CI 0.751-1000). TSE > 35.4 kPa presents 93.3% sensitivity, 60.0% specificity, and 90.9% negative predictive value. CONCLUSION: In our population of patients with NCPH, TSE is useful in predicting HRV. TLE, spleen size, and platelet count were not related to HRV.