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Conflict of interest: No Introduction and Objectives: Wilson's disease (WD) is a rare autosomal recessive disease leading to impairment in copper excretion and subsequent accumulation primarily in the liver and brain. Long-term survival appears to be similar to that of the general population, depending on early diagnosis and treatment. However, studies evaluating WD survival are scarce. We aimed to evaluate the long-term survival of a cohort of WD patients followed at a single Hepatology Center in Brazil. Patients / Materials and Methods: Demographic characteristics, age at diagnosis, type of manifestation (isolated hepatic, isolated neuropsychiatric or associated hepatic and neuropsychiatric) of WD patients, followed between 1999 and 2023, were evaluated. The average survival and its relationship with the predominant disease phenotype were determined. Results and Discussion: 34 patients were evaluated, 53% female, mean age at diagnosis 21 ± 9 years (6 to 42), disease duration of 11 ± 7 years (1 to 25) until outcome. The majority (47%) had the isolated hepatic manifestation, 38% hepatic neuropsychiatric manifestations and 15% isolated neuropsychiatric disorder. The overall population mortality rate was 36%. The mean age at the time of death was 33 ± 12 years (11 to 55). The estimated average survival at 5 years was 85%, at 10 years 70% and at 20 years 40%, from diagnosis. There was a tendency towards lower survival in patients who presented neuropsychiatric manifestations, either alone or in association with liver disease, compared to patients with isolated liver manifestations (50% vs. 80%; p= 0.07). There was no difference in survival curves according to gender (p=0.82) or considering the age at onset of the disease above or below 20 years (p=0.54). Conclusions: Despite being potentially treatable, WD still presents high mortality, affecting young patients, whose survival rate is greatly reduced. WD patients with neuropsychiatric symptoms had worse survival. These data highlight the need for earlier diagnosis and easier access to treatment.

Conflict of interest: No Introduction and Objectives: Wilson's disease (WD) is a rare genetic disease presenting more than 900 mutations in the ATP7B gene. The knowledge of the regional distribution of these mutations can improve the diagnosis of WD. We aimed to evaluate the frequency of ATP7B mutations in a WD Brazilian cohort and the association with disease phenotypes. Patients / Materials and Methods: We performed molecular analysis by NGS of the 21 exons of ATP7B (Mendelics Genomic Analysis Laboratory) in patients with diagnosis of WD and in first-degree relatives undergoing WD investigation, followed in a single hepatology center. Demographic data and predominant type of WD presentation were assessed. Results and Discussion: 28 patients were included (60% female; mean age 25 ± 13 years): 25 had an established diagnosis of WD and 3 were heterozygous relatives without disease. The phenotypes of WD were as follows: 15/25 (60%) with exclusively hepatic manifestation, 8/25 (32%) combination of hepatic and neurological, 1/25 (4.0%) isolated neurological manifestations and 1/25 (4.0%) were pre-symptomatic. We identified 17 ATP7B gene distinct mutations. The pathogenic variants c.3402delC, c.2123T>C and c.3818C>T presented the highest allele frequency, respectively, 25.5%, 15.7% and 15.7%. The majority (80.0%) presented the mutation in compound heterozygosity, 12.0% ​​in homozygosity and 8.0% in simple heterozygosity. The c.2145C>T, c.1552T>C and c.3188C>T variants were considered of undetermined significance; c.2072G>T and c.3071_3072delTG variants were considered probably pathogenic. Regarding the disease phenotype, patients with mutations c.3402delC CG>C and c.2123T>C presented equal distribution of isolated hepatic or hepatic plus neurological phenotype, while c.3818C>T mutation was associated with predominantly hepatic phenotype. Presence of exon 2 deletion was associated with severe neurological manifestations. Conclusions: The mutations c.3402delC, c.2123T>C and c.3818C>T were the most prevalent. The c.2145C>T and c.3188C>T variants, considered of undetermined significance, were found in confirmed cases of WD. An important heterogeneity of the ATP7B genotype associated with variation in phenotypic presentation was observed.

Conflict of interest: No Introduction and Objectives: Liver stiffness (LS) is increased in fibrosis related to chronic liver diseases. Nevertheless, other factors such as liver inflammation, congestion and intrahepatic deposits may also affect hepatic elasticity. We hypothesized that Wilson's disease (WD) intrahepatic copper accumulation can lead to an increase in LS. The aim of this study is to assess the changes in LS during treatment of patients with different presentations of WD. Patients / Materials and Methods: We included patients with confirmed diagnosis of WD (Leipzig score ≥4) under regular use of chelating agents or zinc salts, between 2014 and 2024. Patients who have undergone at least two transient hepatic elastography (THE; Fibroscan, ECHOSENS) during clinical follow-up, were included. The minimum interval between each elastography was one year. Patients submitted to liver transplantation were excluded. Variations in liver stiffness between the last and first THE, the anticopper therapy used, and the main WD manifestations, were evaluated. Results and Discussion: Thirteen patients were included: mean age of 28.8 ± 9.9 years; 54% female. Seven (54%) patients presented predominantly neurologic manifestation and six (46%) hepatic manifestations; 92% used chelating agents. The mean initial LS was 12.2 ± 14.8 kPa (median 7.5 kPa; ranging from 3.8 to 59.3), decreasing during treatment to 7.7 ± 4.6 kPa (median 6.3 kPa; ranging from 3.9 to 18.9) at a mean follow-up interval of 4.9 ± 2.8 years (ranging from 1 to 10) (p < 0.0001). Eight (61%) patients observed a median reduction of 2.3 kPa and five presented a median elevation of 0.3 kPa. There was no difference in LS variations according to clinical presentation of WD (p=0.387). Conclusions: In patients with WD, LS decreased in most patients during chelating therapy. Intrahepatic copper deposit might influence higher values of LS before anticopper therapy, suggesting the possibility of using THE to evaluate hepatic copper accumulation and to monitor WD treatment.

Conflict of interest: Yes, This work was supported by Brazilian Society of Hepatology and Instituto Brasileiro do Fígado - IBRAFIG. Introduction and Objectives: Previous studies have identified risk factors associated with recurrent primary sclerosing cholangitis (rPSC) after liver transplantation (LT) in Caucasians. There is paucity of data regarding rPSC in multiethnic Latin patients. Objectives: To investigate rPSC frequency and its associated risk factors in a highly admixed population from Brazil. Patients / Materials and Methods: The Brazilian Cholestasis Study Group database was retrospectively reviewed for including primary sclerosing cholangitis (PSC) patients who underwent LT. Primary outcome was rPSC. Results and Discussion: A total of 96 patients were included, 60% males, mean age 32 ± 13 years. After a follow-up of 90 months (interquartile range 39-154), rPSC occurred in 29 (30%) of the participants. There were no statistically significant associations between rPSC and age, gender, concurrent or de novo inflammatory bowel disease, MELD score at the time of LT or allograft rejection. The only factor associated with an increased risk of disease recurrence was time after LT. Conclusions: In Brazilian PSC patients who underwent LT, one-third had rPSC. Longer time after LT was associated with rPSC diagnosis.

Conflict of interest: No Introduction and Objectives: Primary biliary cholangitis is a chronic and progressive autoimmune liver disease, whose prognosis can be improved by normalizing alkaline phosphatase and bilirubin. While ursodeoxycholic acid (UDCA) is first line standard of care, approximately 40% of patients exhibit incomplete response. We aimed to identify prognostic markers for deep response to UDCA therapy at presentation. Patients / Materials and Methods: Data from the Brazilian Cholestasis Study Group cohort were analyzed retrospectively. Patients were assessed for deep response (defined as normalization of alkaline phosphatase and bilirubin) after 1 year of UDCA treatment. With the purpose of selecting the set of relevant variables related to the deep response for a parsimonious multivariate model, we applied the Varrank algorithm. Additionally, the performance of the UDCA response score in predicting deep response was evaluated. Results and Discussion: A total of 297 patients were analyzed, with 57.2% achieving an adequate response according to the Toronto criteria, while 22.9% reached deep response. Cirrhosis (OR 0.460; 95% CI 0.225-0.942; p=0.034) and elevated baseline alkaline phosphatase levels (OR 0.629; 95% CI 0.513-0.770; p

Conflict of interest: No Introduction and Objectives: Liver biopsy is considered the gold standard to define fibrosis stage and inflammation degree in Autoimmune Hepatitis (AIH). Noninvasive methods have been utilized for these purposes, However, the respective accuracies in different populations have not been clarified. AIMS: Investigate the performance of TE and APRI and of serum IgG and γ-glob levels in defining liver fibrosis and inflammation degree, respectively, in a group of patients with AIH. Patients / Materials and Methods: Prospective study involving patients with AIH who underwent liver biopsy (classified by Metavir and Ishak) and TE (FibroScan, Echosens 502), with a maximum interval of 6 months between the two procedures. Laboratory parameters for APRI, IgG and γ-glob were obtained within a maximum interval of 3 months from the biopsy. The performances were compared with liver biopsies using ROC curves. Results and Discussion: 63 patients with AIH were included (88% female; mean age 43 ± 18 years), platelets levels: 214.524 ±72.121/µL. Medians: IgG:1530, APRI: 0.4 and TE: 8.8 kPA. Liver fragments had ≥ 8 complete portal spaces. Thirty-four patients (54%) had advanced fibrosis (F≥3 METAVIR) and 67% had inflammation A≤1 by METAVIR and A

Introduction and objectives: Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) and PBC overlap syndrome (AIH/PBC) have been associated with a higher risk of hepatocellular carcinoma (HCC) and extra-hepatic malignancy (EHM). This study aims to assess potential risk factors associated with cancer development in PBC and AIH/PBC. Materials and methods: The Brazilian Cholestasis Study Group database was reviewed to compare clinical and laboratory features of PBC patients with HCC and EHM with those without cancer. Results: Among the 752 PBC patients enrolled, 64 of them with AIH/PBC, 87 cancers were identified in 72 patients, including 20 cases of HCC and 67 of EHM. Patients with HCC had a higher prevalence of cirrhosis (95% vs. 32.5% of those subjects without cancer, p≤0.001), smoking (55% vs. 12.3%, p≤0.001), CREST syndrome (30% vs 7.6%, p=0.003) and prior azathioprine (30% vs 8%, p= 0.005) and prednisone (35% vs 14%, p= 0.018) use, whereas patients with EHM had a higher prevalence of smoking (42.3% vs 12.4% of those subjects without cancer, p=

Introduction and Objectives: Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) and PBC overlap syndrome (AIH/PBC) have been associated with a higher risk of hepatocellular carcinoma (HCC) and extra-hepatic malignancy (EHM). This study aimed to assess potential risk factors associated with cancer development in PBC and AIH/PBC patients. Materials and Methods: The Brazilian Cholestasis Study Group database was reviewed and analyzed. Results: Among the 752 PBC patients enrolled, 64 of them with AIH/PBC, and 87 cancers were identified in 79 patients, including 20 cases of HCC and 67 of EHM. Patients with HCC had a higher prevalence of cirrhosis (95% vs. 32.5%, p=

Aim: Up to 40% of patients with primary biliary cholangitis (PBC) will have a suboptimal biochemical response to ursodeoxycholic acid (UDCA), which can be improved by the addition of fibrates. This exploratory study aims to evaluate the long-term real-life biochemical response of different fibrates, including ciprofibrate, in subjects with UDCA-unresponsive PBC.Methods: The Brazilian Cholestasis Study Group multicenter database was reviewed to assess the response rates to UDCA plus fibrates in patients with UDCA-unresponsive PBC 1 and 2 years after treatment initiation by different validated criteria.Results: In total, 27 patients (100% women, mean age 48.9 ± 9.2 years) with PBC were included. Overall response rates to fibrates by each validated criterion varied from 39 to 60% and 39–76% at 12 and 24 months after treatment combination, respectively. Combination therapy resulted in a significant decrease in ALT and ALP only after 2 years, while GGT significantly improved in the first year of treatment. Treatment response rates at 1 and 2 years appear to be comparable between ciprofibrate and bezafibrate using all available criteria.Conclusion: Our findings endorse the efficacy of fibrate add-on treatment in PBC patients with suboptimal response to UDCA. Ciprofibrate appears to be at least as effective as bezafibrate and should be assessed in large clinical trials as a possibly new, cheaper, and promising option for treatment of UDCA-unresponsive PBC patients.

Introduction and objectives: Little is known about primary biliary cholangitis (PBC) in non-whites. The purpose of this study was to evaluate clinical features and outcomes of PBC in a highly admixed population. Material and methods: The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian patients with PBC. Results: 562 patients (95% females, mean age 51 ± 11 years) with PBC were included. Concurrent autoimmune diseases and overlap with autoimmune hepatitis (AIH) occurred, respectively, in 18.9% and 14%. After a mean follow-up was 6.2 ± 5.3 years, 32% had cirrhosis, 7% underwent liver transplantation and 3% died of liver-related causes. 96% were treated with ursodeoxycholic acid (UDCA) and 12% required add-on therapy with fibrates, either bezafibrate, fenofibrate or ciprofibrate. Response to UDCA and to UDCA/fibrates therapy varied from 39%-67% and 42-61%, respectively, according to different validated criteria. Advanced histological stages and non-adherence to treatment were associated with primary non-response to UDCA, while lower baseline alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels correlated with better responses to both UDCA and UDCA/fibrates.Conclusions: Clinical features of PBC in highly admixed Brazilians were similar to those reported in Caucasians and Asians, but with inferior rates of overlap syndrome with AIH. Response to UDCA was lower than expected and inversely associated with histological stage and baseline AST and ALP levels. Most of patients benefited from add-on fibrates, including ciprofibrate. A huge heterogeneity in response to UDCA therapy according to available international criteria was observed and reinforces the need of global standardization.

Introduction: Little is known about primary biliary cholangitis (PBC) in Latin America, where this disease is thought to be rare. Objectives: To analyze clinical and biochemical features of Brazilian PBC patients. Methods: The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical and laboratory features from PBC patients. Results: 562 patients with PBC were included; 80 (14.2%) had overlapping syndrome with autoimmune hepatitis and were excluded. Most subjects were middle-aged women (95%; mean age 51 ± 11 years) with classical symptoms of pruritus and/or fatigue (65%) and jaundice (22%). Mean time to diagnosis was 2.5 years. Prevalence of antimitochondrial (AMA) and antinuclear antibodies was 82.8% and 72.1%, respectively. Concurrent autoimmune diseases occurred in 18.9%, mainly Hashimoto's thyroiditis and Sjogren syndrome. Celiac disease was diagnosed in 1:80 (1.2%). Osteopenia and osteoporosis were demonstrated in 42% and 26%, respectively. Liver pathology at diagnosis was available for 326 patients (67.6%). One third of them had advanced PBC. After a mean follow-up of 6.2 ± 5.3 years, 32% of the subjects had clinical, laboratory or imaging evidence of cirrhosis. Requirement for liver transplantation and liver-related deaths were reported in 6.6% and 3.2% of the patients, respectively. Hepatocarcinoma was diagnosed in 1.9% of the subjects. Conclusion: A higher predominance of PBC among females, compared to other populations, was observed, while AMA positivity was lower. Concurrent autoimmune, celiac and bone diseases are common and should be adequately screened. Prolonged time to diagnosis and high prevalence of advanced liver disease might reflect difficulties in health care access in Brazil.

Introduction: 15% of patients with autoimmune hepatitis (AIH) are refractory to usual treatment. The management of these cases is still challeging. Aims: To evaluate the efficacy and safety of cyclosporine (CYA), mycophenolate (MMF) and tacrolimus (FK). Methods: This is a retrospective study with alternative therapies (AT) for non-response or intolerance to azathioprine (AZA) and prednisone (PD). Biochemical remission (BR) was defined as the normalization of AST and ALT; and histological remission (HR) as periportal activity 0/1 or histological activity index

Introduction: Primary biliary cholangitis (PBC) diagnosis is based on international criteria, which requires two of the following: (i) elevated alkaline phosphatase (AP), (ii) anti-mitochondrial antibody (AMA) and (iii) liver biopsy (BX) suggestive of PBC. It is still unclear if patients diagnosed by different criteria combinations present peculiarities, especially in highly-admixed populations. Objectives: To investigate if patients diagnosed with PBC by different combinations of validated criteria present clinical or laboratory particularities. Methods: The Brazilian Cholestasis Study Group database was reviewed to compare clinical, biochemical and histological characteristics of PBC between four groups diagnosed by: (1) AP ≥2x upper limit of normality (ULN) + presence of AMA, (2) AP ≥2x ULN + BX suggestive of PBC, (3) presence of AMA + BX suggestive of PBC and (4) all criteria. Results: 482 patients with PBC were included (Table 1). Group-1 presented with higher levels of IgG, lower frequency of arterial hypertension (AH) and lower response to ursodeoxycholic acid (UDCA), while Group-2 had lower: age at diagnosis and HDL-C levels. Group-3 had higher: age at diagnosis, frequency of neoplasms, AH and response to UDCA; and lower: frequency of pruritus and jaundice, levels of aminotransferases, GGT and bilirubin, advanced liver disease and esophageal varices. Group-4 showed higher frequency of symptoms at presentation, especially pruritus. Conclusion: PBC patients diagnosed by different combinations of established criteria may present singular features that can possibly impact in disease presentation and progression.

Background. Primary sclerosing cholangitis (PSC) is associated with a broad phenotypic spectrum in different populations from diverse ethnic and racial backgrounds. This study aimed to describe the clinical characteristics and outcomes of PSC in a multicenter cohort of patients from Brazil. Methods. Data from the Brazilian Cholestasis Study Group were retrospectively reviewed to assess demographic information and clinical characteristics of PSC, as well as the outcomes, such as transplantation-free survival. Results. This cohort included 210 patients. After excluding 33 (15.7%) patients with PSC and overlap syndrome of autoimmune hepatitis, 177 (97 males, median age 33 (21–42) years) with clear-cut PSC were eligible for this study. Most of the patients (n = 139, 78.5%) were symptomatic, and 104 (58.7%) had advanced PSC at the time of diagnosis. Concurrent inflammatory bowel disease was observed in 78 (58.6%) of the investigated patients (n = 133), and most of them had ulcerative colitis (n = 61, 78.2%). The 1- and 5-year survival free of liver transplantation or death were 92.3 ± 2.1% and 66.9 ± 4.2%, respectively, and baseline advanced PSC, pruritus, and elevated bilirubin levels were independent risk factors for the composite adverse outcome. Females were significantly older and had lower bilirubin levels than males at baseline, but survival was not associated with sex. Approximately 12.4% (n = 22) of patients with PSC died, and 32.8% (n = 58) underwent liver transplantation at a median follow-up time of 5.3 and 3.2 years. Conclusion. Multiethnic Brazilian PSC patients exhibited a less pronounced male predominance and a lower frequency of inflammatory bowel disease than Caucasians. Adverse outcomes were more frequent, probably due to advanced disease at baseline.

In Brazil, hepatitis C treatment has been evolving significantly with the licensing of direct-acting antivirals (DAAs). However, viral determinants (amino acid substitutions in hepatitis C virus (HCV) genome and infective genotype) associated with host factors (hepatic condition and prior HCV therapy) might limit the achievement of sustained virologic response (SVR). Here, we described two case reports in which the occurrence of HCV NS5A mutations A30K (subtype 3a) and Y93N (subtype 1a) might have influenced daclatasvir (DCV)/sofosbuvir (SOF) combined therapy non-response. Despite high response rates for DAA combined therapies in Brazil, these case reports stated the importance of an investigation about how to manage a DAA treatment failure since a combination of factors, especially the occurrence of resistance substitutions, could impact a rescue therapy with new available antivirals in clinical routine.

JUSTIFICATIVA E OBJETIVOS: Em 2000, foi publicado o II Consenso Brasileiro de Ventilação Mecânica. Desde então, o conhecimento na área da ventilação mecânica avançou rapidamente, com a publicação de inúmeros estudos clínicos que acrescentaram informações importantes para o manuseio de pacientes críticos em ventilação artificial. Além disso, a expansão do conceito de Medicina Baseada em Evidências determinou a hierarquização das recomendações clínicas, segundo o rigor metodológico dos estudos que as embasaram. Essa abordagem explícita vem ampliando a compreensão e a aplicação das recomendações clínicas. Por esses motivos, a AMIB - Associação de Medicina Intensiva Brasileira - e a SBPT - Sociedade Brasileira de Pneumologia e Tisiologia - julgaram conveniente a atualização das recomendações descritas no Consenso anterior. Dentre os tópicos selecionados a Ventilação Mecânica na Síndrome do Desconforto Respiratório Agudo (SDRA) foi um dos temas propostos. O objetivo foi descrever os pontos mais importantes relacionados à ventilação mecânica na Síndrome do Desconforto Respiratório Agudo e discutir o papel das estratégias protetoras aplicada a esses pacientes. MÉTODO: Objetivou-se chegar a um documento suficientemente sintético, que refletisse a melhor evidência disponível na literatura. A revisão bibliográfica baseou-se na busca de estudos através de palavras-chave e em sua gradação conforme níveis de evidência. As palavras-chave utilizadas para a busca foram: mechanical ventilation e acute respiratory distress syndrome. RESULTADOS: São apresentadas recomendações quanto à utilização das estratégias protetoras (uso de baixos volumes-correntes e limitação da pressão de platô inspiratório), assim como, o estado atual da aplicação da PEEP e o papel das manobras de recrutamento. CONCLUSÕES: A ventilação mecânica na SDRA apresentou muitas mudanças nesses últimos anos e o uso de estratégias ventilatórias que preservem a micro-arquitetura pulmonar é a forma mais indicada no momento.BACKGROUND AND OBJECTIVES: The II Brazilian Consensus Conference on Mechanical Ventilation was published in 2000. Knowledge on the field of mechanical ventilation evolved rapidly since then, with the publication of numerous clinical studies with potential impact on the ventilatory management of critically ill patients. Moreover, the evolving concept of evidence - based medicine determined the grading of clinical recommendations according to the methodological value of the studies on which they are based. This explicit approach has broadened the understanding and adoption of clinical recommendations. For these reasons, AMIB - Associação de Medicina Intensiva Brasileira and SBPT - Sociedade Brasileira de Pneumologia e Tisiologia - decided to update the recommendations of the II Brazilian Consensus. Acute Respiratory Distress Syndrome (ARDS) has been one of the updated topics. This objective was described the most important topics related to mechanical ventilation in patients with acute respiratory distress syndrome. METHODS: Systematic review of the published literature and gradation of the studies in levels of evidence, using the key words mechanical ventilation and acute respiratory distress syndrome. RESULTS: Recommendations on the use of lung protective strategies during mechanical ventilation based on reduced tidal volumes and limitation of plateau pressure. The state of the art of recruitment maneuvers and PEEP titration is also discussed. CONCLUSIONS: The mechanical ventilation of patients with ADRS changed in the last few years. We presented the role of lung protective strategies that could be applied to these patients.