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BACKGROUND: Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cholangitis (PBC), but a significant proportion of patients do not respond adequately, leading to increased risk of adverse outcomes. This study aims to develop a new and straightforward predictive score to identify PBC patients likely to achieve a complete response to UDCA. METHODS: A logistic regression analysis was conducted using a derivation cohort of PBC patients to identify pre-treatment variables associated with response to UDCA. This analysis led to the development of the ALP-A score, calculated as: Age at diagnosis divided by (alkaline phosphatase at diagnosis/upper limit of normal). ALP-A score accuracy was evaluated using the area under the ROC curve, validated with a large external cohort from Brazil. Additionally, the correlation between the ALP-A score and the previously validated UDCA response score (URS) was assessed. RESULTS: ALP-A score had good predictive power for adequate (AUC 0.794; 95% CI, 0.737-0.852) and deep (0.76; 95% CI, 0.69-0.83) UDCA response at 1 year of treatment. A cutoff score of 17 and 23 points was determined to be the optimal threshold for distinguishing adequate and deep responders, respectively, from non-responders. ALP-A score demonstrated a sensitivity of 73%, specificity of 71%, positive predictive value of 65%, negative predictive value of 78%, and overall accuracy of 72% for biochemical response. The URS displayed similar discriminative ability (AUC 0.798; 95% CI, 0.741-0.855). CONCLUSION: ALP-A score performs comparably to URS but offers the great advantage of simplicity for routine clinical use. It serves as a valuable tool to identify PBC patients less likely to respond to UDCA treatment, facilitating early consideration of alternative therapeutic approaches.
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Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Ácido Ursodesoxicólico/uso terapêutico , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Colagogos e Coleréticos/uso terapêutico , Fosfatase Alcalina , Brasil , Resultado do TratamentoRESUMO
INTRODUCTION AND OBJECTIVES: A high prevalence of steatotic liver disease has been described in psoriasis. However, the influence of genetic polymorphisms has yet to be investigated in this scenario. This study aims to determine the frequency of steatosis, advanced liver fibrosis and PNPLA3/TM6SF2 genotypes in individuals with psoriasis and to evaluate the impact of genetic polymorphisms, metabolic parameters and cumulative methotrexate dose on steatosis and fibrosis. MATERIALS AND METHODS: Cross-sectional study that prospectively included psoriasis outpatients, submitted to clinical and laboratory analysis, transient elastography (FibroScan®, Fr) and PNPLA3/TM6SF2 genotyping. Steatosis was defined by CAP ≥275 dB/m and advanced liver fibrosis as transient elastography ≥10 kPa. Logistic regression analysis evaluated the independent variables related to steatosis and fibrosis; p-value< 0.05 was considered significant. RESULTS: One hundred and ninety-nine patients were enrolled (age 54.6 ± 12.6 years, 57.3% female). Metabolic syndrome (MetS), steatosis and advanced liver fibrosis prevalence were 55.8%, 54.8% and 9%, respectively. PNPLA3 and TM6SF2 genotypes frequencies were CC 42.3%/CG 49.5%/GG 8.2% and CC 88.7%/ CT 11.3%/ TT 0%. MetS (OR3.01 95%CI 1.51-5.98; p = 0.002) and body mass index (OR1.17 95%CI 1.08-1.26; p < 0.01) were independently associated with steatosis. Diabetes Mellitus (T2DM) (OR10.76 95%CI 2.42-47.87; p = 0.002) and harboring at least one PNPLA3 G allele (OR5.66 95%CI 1.08-29.52; p = 0.039) were associated with advanced fibrosis, but not TM6SF2 polymorphism or cumulative MTX dose. CONCLUSIONS: MetS and T2DM confer higher odds for steatosis and advanced fibrosis in individuals with psoriasis. PNPLA3 G allele, but not TM6SF2 polymorphism, impacts a 5-fold odds of advanced liver fibrosis.
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Técnicas de Imagem por Elasticidade , Lipase , Cirrose Hepática , Proteínas de Membrana , Psoríase , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Lipase/genética , Proteínas de Membrana/genética , Estudos Transversais , Cirrose Hepática/genética , Psoríase/genética , Adulto , Idoso , Estudos Prospectivos , Fígado Gorduroso/genética , Prevalência , Predisposição Genética para Doença , Fatores de Risco , Síndrome Metabólica/genética , Síndrome Metabólica/complicações , Polimorfismo Genético , Genótipo , Aciltransferases , Fosfolipases A2 Independentes de CálcioRESUMO
BACKGROUND/AIMS: Longitudinal studies assessing the impact of genetic polymorphisms on outcomes in patients with Type 2 Diabetes Mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) are scarce. This study aimed to evaluate the effect of PNPLA3 and TM6SF2 risk alleles on hepatic and extrahepatic outcomes in T2DM-MASLD individuals. METHODS: Patients' polymorphisms were analysed as follows: PNPLA3 CC, CG and GG; TM6SF2 CC and CT + TT; combined comparing no mutant allele, one allele G or T or ≥2 alleles G or T. Hierarchical models were built to assess associations between polymorphisms and outcomes, independently of confounding factors. Multivariate logistic regression was used for cirrhosis and its complications and extrahepatic cancer, and Cox regression for cardiovascular events (CVEs) and all-cause mortality. RESULTS: In total, 407 T2DM-MASLD patients (62.1 ± 10.5 years, 67.6% women) were followed for 11 (6-13) years. Having at least one G or T allele independently increased the risk of cirrhosis in the separate analysis of PNPLA3 and TM6SF2. Combined polymorphism analysis demonstrated an even higher risk of cirrhosis if two or more risk alleles were present (OR 18.48; 95% CI 6.15-55.58; p < .001). Regarding cirrhosis complications, the risk was higher in PNPLA3 GG and TM6SF2 CT + TT, also with an even higher risk when two or more risk alleles were present in the combined evaluation (OR 27.20; 95% CI 5.26-140.62; p < .001). There were no associations with CVEs or mortality outcomes. CONCLUSION: In T2DM, PNPLA3 and TM6SF2 polymorphisms, individually and additively, impact MASLD severity, with an increased risk of cirrhosis and its complications.
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Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Hepatopatia Gordurosa não Alcoólica , Humanos , Feminino , Masculino , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Cirrose Hepática/genética , Fibrose , Prognóstico , Hepatopatia Gordurosa não Alcoólica/genética , Genótipo , Proteínas de Membrana/genéticaRESUMO
Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as Nonalcoholic fatty liver disease (NAFLD), is one of the most common hepatic diseases in individuals with overweight or obesity. In this context, a panel of experts from three medical societies was organized to develop an evidence-based guideline on the screening, diagnosis, treatment, and follow-up of MASLD. Material and methods: A MEDLINE search was performed to identify randomized clinical trials, meta-analyses, cohort studies, observational studies, and other relevant studies on NAFLD. In the absence of studies on a certain topic or when the quality of the study was not adequate, the opinion of experts was adopted. Classes of Recommendation and Levels of Evidence were determined using prespecified criteria. Results: Based on the literature review, 48 specific recommendations were elaborated, including 11 on screening and diagnosis, 9 on follow-up,14 on nonpharmacologic treatment, and 14 on pharmacologic and surgical treatment. Conclusion: A literature search allowed the development of evidence-based guidelines on the screening, diagnosis, treatment, and follow-up of MASLD in individuals with overweight or obesity.
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Gastroenterologia , Doenças Metabólicas , Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Adulto , Humanos , Brasil , Seguimentos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/terapia , Obesidade/complicações , Obesidade/terapia , Sobrepeso/complicações , Sobrepeso/diagnóstico , Sobrepeso/terapiaRESUMO
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= <0.001), AMA positivity (96.6% vs 80.1%, p≤0.001), azathioprine therapy (21% vs 7.9%, p= 0.01) and concurrent other autoimmune diseases. In multivariate analysis, cirrhosis, obesity and prior azathioprine therapy were independent risk factors for HCC, while Sjogren syndrome and psoriasis were associated with EHM. Fibrates reduced EHM risk. CONCLUSIONS: The prevalence of EHM is higher when compared to HCC in PBC patients. Cirrhosis, obesity, prior azathioprine use, and concurrent autoimmune diseases were significantly associated with cancer in PBC.
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Carcinoma Hepatocelular , Hepatite Autoimune , Cirrose Hepática Biliar , Neoplasias Hepáticas , Humanos , Hepatite Autoimune/complicações , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/epidemiologia , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/epidemiologia , Cirrose Hepática Biliar/complicações , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/complicações , Azatioprina/uso terapêutico , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/complicações , Cirrose Hepática/complicações , Fatores de Risco , Síndrome , Obesidade/complicaçõesRESUMO
BACKGROUND: Response to ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has been traditionally assessed 1 to 2 years after treatment initiation. With the development of new drugs, some patients may benefit from an earlier introduction of second-line therapies. AIMS: This study aims to identify whether well-validated response criteria could correctly identify individuals likely to benefit from add-on second-line therapy at 6 months. METHODS: Analysis of a multicenter retrospective cohort which included only patients with clear-cut PBC. RESULTS: 206 patients with PBC (96.6% women; mean age 54 ± 12 years) were included. Kappa concordance was substantial for Toronto (0.67), Rotterdam (0.65), Paris 1 (0.63) and 2 (0.63) criteria at 6 and 12 months, whereas Barcelona (0.47) and POISE trial (0.59) criteria exhibited moderate agreement. Non-response rates to UDCA was not statistically different when assessed either at 6 or 12 months using Toronto, Rotterdam or Paris 2 criteria. Those differences were even smaller or absent in those subjects with advanced PBC. Mean baseline alkaline phosphatase was 2.73 ± 1.95 times the upper limit of normal (× ULN) among responders versus 5.05 ± 3.08 × ULN in non-responders (p < 0.001). CONCLUSIONS: After 6 months of treatment with UDCA, the absence of response by different criteria could properly identify patients who could benefit from early addition of second-line therapies, especially in patients with advanced disease or high baseline liver enzymes levels.
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Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Masculino , Ácido Ursodesoxicólico/uso terapêutico , Cirrose Hepática Biliar/tratamento farmacológico , Colagogos e Coleréticos/uso terapêutico , Estudos RetrospectivosRESUMO
ABSTRACT Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as Nonalcoholic fatty liver disease (NAFLD), is one of the most common hepatic diseases in individuals with overweight or obesity. In this context, a panel of experts from three medical societies was organized to develop an evidence-based guideline on the screening, diagnosis, treatment, and follow-up of MASLD. Material and methods: A MEDLINE search was performed to identify randomized clinical trials, meta-analyses, cohort studies, observational studies, and other relevant studies on NAFLD. In the absence of studies on a certain topic or when the quality of the study was not adequate, the opinion of experts was adopted. Classes of Recommendation and Levels of Evidence were determined using prespecified criteria. Results: Based on the literature review, 48 specific recommendations were elaborated, including 11 on screening and diagnosis, 9 on follow-up, 14 on nonpharmacologic treatment, and 14 on pharmacologic and surgical treatment. Conclusions: A literature search allowed the development of evidence-based guidelines on the screening, diagnosis, treatment, and follow-up of MASLD in individuals with overweight or obesity.
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BACKGROUND AND AIMS: Treatment of hepatitis C with direct antiviral agents (DAA) is associated with almost 95% of sustained virological response. However, some patients need retreatment. In Brazil, it should be done according to the Ministry of Health guidelines, frequently updated to include newly available drugs. This study aimed to conduct a national survey about the characteristics and outcomes of retreatment of hepatitis C in previously non-responders to DAAs. PATIENTS AND METHODS: Institutions from all over the country were invited to participate in a national registry for retreatment, including information about clinical and epidemiological characteristics of the patients, type and outcomes of retreatment regimens. Only patients previously treated with interferon-free regimens were included. RESULTS: As previous treatments the distribution was: SOF/DCV (56%), SOF/SIM (22%), 3D (11%), SOF/LED (6%) and SOF/RBV (5%). For retreatment the most frequently used drugs were SOF/GP (46%), SOF/DCV (23%) and SOF/VEL (11%). From 159 patients retreated, 132/159 (83%) had complete information in the registry and among them only seven patients were non-responders (SVR of 94.6%). All retreatments were well tolerated, without any serious adverse events or interruptions. CONCLUSION: The retreatment of patients previously non-responders to DAAs was associated with high rate of SVR in this sample of Brazilian patients. This finding allows us to conclude that the retreatment options available in the public health system in Brazil are effective and safe and are an important component of the strategy of elimination of hepatitis C in our country.
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Hepatite C Crônica , Hepatite C , Antivirais , Brasil , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Quimioterapia Combinada , Genótipo , Hepacivirus/genética , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Retratamento , Ribavirina/farmacologia , Sofosbuvir/uso terapêutico , Resultado do Tratamento , ValinaRESUMO
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.
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Cirrose Hepática Biliar/tratamento farmacológico , Vigilância da População , Ácido Ursodesoxicólico/uso terapêutico , Brasil/epidemiologia , Colagogos e Coleréticos/uso terapêutico , Feminino , Seguimentos , Humanos , Incidência , Cirrose Hepática Biliar/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Hepatitis C virus (HCV) is a global public health problem. Second-generation direct-acting antivirals targeting non-structural regions on the viral genome are the cornerstone for treatment of chronic infection. However, resistance-associated variants (RAVs) have been reported to be associated with therapeutic failure. The aim of this study was to assess the frequency of variants, including RAVs, in the NS3, NS5A and NS5B regions at baseline in Brazilian patients with chronic hepatitis C with HCV genotypes 1a, 1b and 3a. METHODS: Serum samples from 13 patients were used to obtain viral RNA. Massively parallel sequencing was performed using genotype-specific amplicons and a panel of Ampliseq technology for all genotypes. RESULTS: Several non-synonymous substitutions were detected at baseline for 11 responders and pre-/post-treatment for two non-responders. HCV genotype 3a was found to have significantly more non-synonymous substitutions than HCV genotype 1 in the NS3 and NS5A regions. Analyses were conducted using quantitative and qualitative inter- and intrapatient comparisons. Variants that confer resistance to the treatment used by the patients were found in both responders and non-responders. CONCLUSIONS: A wide frequency distribution of RAVs was found at baseline, and this did not interfere with the achievement of a sustained response. Evaluation of the presence of RAVs requires additional study in order to determine clinical relevance.