A new and simple score to predict adequate and deep response to ursodeoxycholic acid in patients with primary biliary cholangitis: the ALP-A score.

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.

PNPLA3 GENE POLYMORPHISM AND RED MEAT CONSUMPTION INCREASED FIBROSIS RISK IN NASH BIOPSY-PROVEN PATIENTS UNDER MEDICAL FOLLOW-UP IN A TERTIARY CENTER IN SOUTHWEST BRAZIL.

BACKGROUND: Recent studies show an increase in nonalcoholic fatty liver disease (NAFLD) in populations with higher consumption of red meat, processed and cooked at high temperatures. On the other hand, the single nucleotide polymorphism rs738409 in the Patatin-like phospholipase domain containing 3 (PNPLA3) gene has been implicated in susceptibility to NAFLD and liver fibrosis. However, the synergistic effect between red meat consumption and the PNPLA3 gene polymorphism in NAFLD has not yet been evaluated. OBJECTIVE: To evaluate the association between the presence of the polymorphism in the PNPLA3 gene and the consumption of macronutrients, including meat consumption and its cooking method among NAFLD patients. METHODS: This was a cross-sectional study with 91 patients diagnosed with NAFLD by liver biopsy with genotyping for the polymorphism in the PNPLA3 gene were included. The consumption of calories and macronutrients was verified using the semi-quantitative food frequency questionnaire and the specific questionnaire on meat consumption. PNPLA3 gene polymorphism was analyzed by real-time polymerase chain reaction (RT-PCR) and anthropometric evaluation was realized. RESULTS: The mean BMI was 32.38±4.58 kg/m² and the waist circumference was 107±10 cm. On liver biopsy, 42% of patients had significant fibrosis (F≥2). The odds ratio of F≥2 was 2.12 for the GG group and 1.54 for the CG group, compared to the CC group. The mean caloric intake was 1170±463.20 kcal/d. The odds ratio in the CC group concerning high red meat consumption in comparison to low consumption was 1.33. For white meat, the odds ratio was 0.8 when comparing high and low intake, also in the CC group. CONCLUSION: High red meat intake and PNPLA3 gene polymorphism seem to synergistically affect NAFLD and liver fibrosis, requiring confirmation in a larger number of patients and in different populations.

Autoimmune hepatitis and primary biliary cholangitis overlap syndrome after COVID-19.

COVID-19 is commonly associated with high serum levels of pro-inflammatory cytokines, and the post-infection status can disturb self-tolerance and trigger autoimmune responses. We are reporting a 45-year-old male who was admitted with fatigue, jaundice, elevated liver enzymes (with cholestatic pattern), and acute kidney injury two weeks after recovering from a mild SARS-CoV-2 infection. Serologies for viral hepatitis and anti-mitochondrial antibody were negative, while anti-nuclear and anti-smooth muscle antibodies were positive. There were no signs of chronic liver disease, and a magnetic resonance cholangiography showed no dilatation of biliary ducts. Histologic evaluation of the liver evidenced numerous foci of lobular necrosis without ductopenia or portal biliary reaction. Considering the autoantibody profile and histologic changes, the medical team started oral prednisone, but there was a suboptimal biochemical response in the outpatient follow-up. Two months later, a second liver biopsy was performed and revealed non-suppurative destructive chronic cholangitis, extensive areas of confluent necrosis with hepatocytes regenerating into pseudorosettes, and numerous plasma cells. According to the Paris Criteria, the patient was then diagnosed with an autoimmune hepatitis-primary biliary cholangitis overlap syndrome (AIH-PBC-OS). After adding azathioprine and ursodeoxycholic acid to the treatment, there was a satisfactory response. This is the second worldwide report of an AIH-PBC-OS triggered by COVID-19, but the first case with a negative anti-mitochondrial antibody. In this setting, histologic evaluation of the liver by an experienced pathologist is a hallmark of achieving the diagnosis and correctly treat the patient.

Polimorfismo no gene PNPLA3 e o consumo de carne vermelha aumentam o risco de fibrose em pacientes com DHGNA comprovado por biópsia em acompanhamento médico em um centro terciário no Sudoeste do Brasil / Pnpla3 gene polymorphism and red meat consumption increased fibrosis risk in nash biopsy-proven patients under medical follow-up in a tertiary center in southwest brazil

ABSTRACT Background: Recent studies show an increase in nonalcoholic fatty liver disease (NAFLD) in populations with higher consumption of red meat, processed and cooked at high temperatures. On the other hand, the single nucleotide polymorphism rs738409 in the Patatin-like phospholipase domain containing 3 (PNPLA3) gene has been implicated in susceptibility to NAFLD and liver fibrosis. However, the synergistic effect between red meat consumption and the PNPLA3 gene polymorphism in NAFLD has not yet been evaluated. Objective: To evaluate the association between the presence of the polymorphism in the PNPLA3 gene and the consumption of macronutrients, including meat consumption and its cooking method among NAFLD patients. Methods: This was a cross-sectional study with 91 patients diagnosed with NAFLD by liver biopsy with genotyping for the polymorphism in the PNPLA3 gene were included. The consumption of calories and macronutrients was verified using the semi-quantitative food frequency questionnaire and the specific questionnaire on meat consumption. PNPLA3 gene polymorphism was analyzed by real-time polymerase chain reaction (RT-PCR) and anthropometric evaluation was realized. Results: The mean BMI was 32.38±4.58 kg/m² and the waist circumference was 107±10 cm. On liver biopsy, 42% of patients had significant fibrosis (F≥2). The odds ratio of F≥2 was 2.12 for the GG group and 1.54 for the CG group, compared to the CC group. The mean caloric intake was 1170±463.20 kcal/d. The odds ratio in the CC group concerning high red meat consumption in comparison to low consumption was 1.33. For white meat, the odds ratio was 0.8 when comparing high and low intake, also in the CC group. Conclusion: High red meat intake and PNPLA3 gene polymorphism seem to synergistically affect NAFLD and liver fibrosis, requiring confirmation in a larger number of patients and in different populations.

RESUMO Contexto: Estudos recentes mostram um aumento da doença hepática gordurosa não alcoólica (DHGNA) em populações com maior consumo de carne vermelha, processada e cozida em altas temperaturas. Por outro lado, o polimorfismo rs738409 no gene Patatin-like fosfolipase contendo 3 (PNPLA3) tem sido implicado na suscetibilidade à DHGNA e fibrose hepática. No entanto, o efeito sinérgico entre o consumo de carne vermelha e o polimorfismo no gene PNPLA3 na DHGNA ainda não foi avaliado. Objetivo: Avaliar a associação entre a presença do polimorfismo no gene PNPLA3 e o consumo de macronutrientes, incluindo o consumo de carne e seu modo de cozimento em pacientes com DHGNA. Métodos: Realizamos um estudo transversal com 91 pacientes diagnosticados com DHGNA por biópsia hepática e genotipados para o polimorfismo no gene PNPLA3. O consumo de calorias e macronutrientes foi verificado por meio do questionário de frequência alimentar semi-quantitativo (QFA) e do questionário específico sobre consumo de carnes. O polimorfismo no gene PNPLA3 foi analisado por reação em cadeia da polimerase em tempo real (RT-PCR) e a avaliação antropométrica foi realizada. Resultados: O índice de massa corporal médio foi de 32,38±4,58 kg/m² e a circunferência da cintura foi de 107±10 cm. Na biópsia hepática, 42% dos pacientes apresentavam fibrose significativa (F≥2). O odds ratio de F≥2 foi de 2,12 para o grupo GG e 1,54 para o grupo GC, comparado ao grupo CC. A ingestão calórica média foi de 1.170±463,20 kcal/d. O odds ratio para alto consumo de carne vermelha no grupo CC em comparação ao baixo consumo foi de 1,33. Para a carne branca, este valor foi de 0,8 ao comparar o alto e o baixo consumo, também no grupo CC. Conclusão: A alta ingestão de carne vermelha e o polimorfismo no gene PNPLA3 parecem afetar sinergicamente a DHGNA e a fibrose hepática, necessitando de confirmação em maior número de pacientes e em diferentes populações.

Autoimmune hepatitis and primary biliary cholangitis overlap syndrome after COVID-19

ABSTRACT COVID-19 is commonly associated with high serum levels of pro-inflammatory cytokines, and the post-infection status can disturb self-tolerance and trigger autoimmune responses. We are reporting a 45-year-old male who was admitted with fatigue, jaundice, elevated liver enzymes (with cholestatic pattern), and acute kidney injury two weeks after recovering from a mild SARS-CoV-2 infection. Serologies for viral hepatitis and anti-mitochondrial antibody were negative, while anti-nuclear and anti-smooth muscle antibodies were positive. There were no signs of chronic liver disease, and a magnetic resonance cholangiography showed no dilatation of biliary ducts. Histologic evaluation of the liver evidenced numerous foci of lobular necrosis without ductopenia or portal biliary reaction. Considering the autoantibody profile and histologic changes, the medical team started oral prednisone, but there was a suboptimal biochemical response in the outpatient follow-up. Two months later, a second liver biopsy was performed and revealed non-suppurative destructive chronic cholangitis, extensive areas of confluent necrosis with hepatocytes regenerating into pseudorosettes, and numerous plasma cells. According to the Paris Criteria, the patient was then diagnosed with an autoimmune hepatitis-primary biliary cholangitis overlap syndrome (AIH-PBC-OS). After adding azathioprine and ursodeoxycholic acid to the treatment, there was a satisfactory response. This is the second worldwide report of an AIH-PBC-OS triggered by COVID-19, but the first case with a negative anti-mitochondrial antibody. In this setting, histologic evaluation of the liver by an experienced pathologist is a hallmark of achieving the diagnosis and correctly treat the patient.

15-Year progression to liver cancer in the lack of treatment for lysosomal acid lipase deficiency: A case report.

RATIONALE: Lysosomal acid lipase deficiency (LAL-D) is a poorly diagnosed genetic disorder characterized by the accumulation of cholesteryl esters and triglycerides in many tissues, leading to dyslipidemia and cardiovascular complications. In the liver, deposits are found within hepatocytes and Kupffer cells, generating microvesicular steatosis, progressive fibrosis, and cirrhosis. Sebelipase alfa is the target therapy which can improve laboratory changes and reduce the progression of liver damage, but this is not yet widely available. PATIENT CONCERNS: We are reporting a 15-year follow-up of a Brazilian man who was diagnosed with cirrhosis at age 43 and with LAL-D at age 53, but he has never been treated with sebelipase alfa for economic reasons. During the coronavirus disease 2019 (COVID-19) pandemic, he lost follow-up and missed three 6-month ultrasound exams for liver cancer screening. DIAGNOSIS: At age 58, a remarkable deterioration in liver function was observed and he was diagnosed with hepatocellular carcinoma (HCC) outside the Milan Criteria (two nodules measuring 48mm and 25mm). Three other individuals with LAL-D and progression to liver cancer have been reported so far and none of them underwent enzyme replacement therapy: an 11-year-old girl with HCC, a 51-year-old male with cholangiocarcinoma, and a 21-year-old male with hepatocellular-cholangiocarcinoma. The latter had the same mutation in the gene LIPA as our patient, but a relationship between this variant and malignancies has not yet been established. LESSONS: We emphasize how important is to treat LAL-D patients after diagnosis in order to avoid worsening liver function and progression to neoplasms. Untreated individuals should be considered at a higher risk but the most appropriate liver cancer screening program for this subgroup is still unknown.

National Brazilian survey on the outcomes of hepatitis c retreatment in patients non-responders to direct antiviral agents.

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.

COST EFFECTIVENESS OF USING TERLIPRESSIN TO TREAT HEPATORENAL SYNDROME.

BACKGROUND: Hepatorenal syndrome (HRS) is the most severe form of acute kidney injury in patients with advanced cirrhosis, and it is associated with high mortality. It is usually diagnosed according to criteria defined by the International Ascites Club. Currently, the most frequently indicated pharmacological therapy for the treatment of HRS is a combination of splanchnic vasoconstrictors (terlipressin or norepinephrine) in combination with albumin. With the progressive increase in healthcare spending, it is important to conduct a cost-effectiveness analysis of pharmacological treatment in patients who are diagnosed with HRS. OBJECTIVE: To perform a cost-effectiveness assessment for the use of terlipressin in combination with albumin to treat HRS in patients with cirrhosis. METHODS: Economic evaluation of cost-effectiveness based on secondary data from studies showed the efficacy of terlipressin therapy compared with norepinephrine combined with albumin or albumin alone. The cost-effectiveness analysis was calculated using an incremental cost-effectiveness ratio (ICER), and a sensitivity analysis was developed by varying the values of therapies and probabilities. The Brazilian real was the currency used in the analysis, and the results were converted to US dollars. RESULTS: After selection, eligibility, and evaluation of the quality of publications, the results demonstrated that administration of terlipressin or norepinephrine in combination with albumin in patients diagnosed with HRS type 1 was efficacious. The cost of treatment with terlipressin in combination with albumin was USD $1,644.06, administration of albumin alone was USD $912.02, and norepinephrine plus albumin was USD $2,310.78. Considering that the combination therapies demonstrated effectiveness, the incremental cost of terlipressin and norepinephrine in combination with albumin was USD $666.73, and an effectiveness of 0.570 was found for terlipressin in combination with albumin and 0.200 for norepinephrine in combination with albumin. The incremental effectiveness was 0.370, and the ICER was USD $1,801.97. Thus, the parameters of increasing cost per therapy and ICER indicated that the combined therapy of terlipressin plus albumin was cost effective compared to albumin alone or norepinephrine plus albumin in a public single-payer healthcare system. CONCLUSION: A cost-effectiveness analysis showed that terlipressin in combination with albumin when administered concomitantly to patients who were diagnosed with type 1 HRS is cost-effective compared to norepinephrine in combination with albumin administered in a controlled environment.

Acute Hepatitis with Positive Autoantibodies: A Case of Natalizumab-Induced Early-Onset Liver Injury.

BACKGROUND Natalizumab is an anti-integrin monoclonal antibody used as an alternative treatment regimen for patients with autoimmune disorders, especially multiple sclerosis and Crohn's disease. Natalizumab-induced liver injury has been rarely reported and may follow the first dose (with increases in liver enzymes usually after 6 or more days), or after multiple doses. In general, it is non-severe acute hepatitis (with a hepatocellular pattern) and autoantibodies can be positive, mainly anti-nuclear and anti-smooth muscle antibodies. CASE REPORT We are reporting the case of a 60-year-old woman diagnosed with multiple sclerosis previously treated with interferon-beta, dimethyl fumarate, and fingolimod, who presented jaundice 1 day after the first infusion of natalizumab. She had an early-onset acute hepatitis with aminotransferases levels higher than 1000 IU/L and total bilirubin almost 41 mg/dL. Anti-nuclear and anti-smooth muscle antibodies were positive and the histopathological analysis of the liver showed intrahepatic cholestasis associated with moderate necroinflammatory activity (subacute cholestatic hepatitis) and mild diffuse perisinusoidal fibrosis, which could be compatible with the hypothesis of drug-induced liver injury. The scenario of an autoimmune-like hepatitis led the medical team to start oral prednisone and she progressively improved in clinical and laboratory features. Serum levels of liver enzymes and bilirubin were normal within 3 months and there was no further increase after discontinuation of corticosteroid therapy. CONCLUSIONS Physicians should be aware of the risk of early-onset acute hepatitis in patients starting natalizumab, especially women with multiple sclerosis. Treatment with corticosteroid for a few months may be beneficial.

Custo efetividade do uso da terlipressina no tratamento da síndrome hepatorrenal / Cost effectiveness of using terlipressin to treat hepatorenal syndrome

ABSTRACT Background Hepatorenal syndrome (HRS) is the most severe form of acute kidney injury in patients with advanced cirrhosis, and it is associated with high mortality. It is usually diagnosed according to criteria defined by the International Ascites Club. Currently, the most frequently indicated pharmacological therapy for the treatment of HRS is a combination of splanchnic vasoconstrictors (terlipressin or norepinephrine) in combination with albumin. With the progressive increase in healthcare spending, it is important to conduct a cost-effectiveness analysis of pharmacological treatment in patients who are diagnosed with HRS. Objective: To perform a cost-effectiveness assessment for the use of terlipressin in combination with albumin to treat HRS in patients with cirrhosis. Methods: Economic evaluation of cost-effectiveness based on secondary data from studies showed the efficacy of terlipressin therapy compared with norepinephrine combined with albumin or albumin alone. The cost-effectiveness analysis was calculated using an incremental cost-effectiveness ratio (ICER), and a sensitivity analysis was developed by varying the values of therapies and probabilities. The Brazilian real was the currency used in the analysis, and the results were converted to US dollars. Results: After selection, eligibility, and evaluation of the quality of publications, the results demonstrated that administration of terlipressin or norepinephrine in combination with albumin in patients diagnosed with HRS type 1 was efficacious. The cost of treatment with terlipressin in combination with albumin was USD $1,644.06, administration of albumin alone was USD $912.02, and norepinephrine plus albumin was USD $2,310.78. Considering that the combination therapies demonstrated effectiveness, the incremental cost of terlipressin and norepinephrine in combination with albumin was USD $666.73, and an effectiveness of 0.570 was found for terlipressin in combination with albumin and 0.200 for norepinephrine in combination with albumin. The incremental effectiveness was 0.370, and the ICER was USD $1,801.97. Thus, the parameters of increasing cost per therapy and ICER indicated that the combined therapy of terlipressin plus albumin was cost effective compared to albumin alone or norepinephrine plus albumin in a public single-payer healthcare system. Conclusion: A cost-effectiveness analysis showed that terlipressin in combination with albumin when administered concomitantly to patients who were diagnosed with type 1 HRS is cost-effective compared to norepinephrine in combination with albumin administered in a controlled environment.

RESUMO Contexto: A Síndrome Hepatorrenal (SHR) é a forma mais grave de lesão renal aguda em pacientes com cirrose avançada, estando diretamente associada a alta taxa de mortalidade. Normalmente é diagnosticada seguindo critérios definidos pela International Ascites Club (IAC). Atualmente, as terapias farmacológicas mais indicadas no tratamento da SHR são a combinação de vasoconstritores esplâncnicos (terlipressina ou norepinefrina) associados à albumina. Com o aumento progressivo dos gastos em saúde, torna-se relevante realizar uma análise de custo-efetividade do tratamento farmacológico em pacientes com diagnóstico de SHR. Objetivo: Realizar avaliação de custo-efetividade do uso da terlipressina associada à albumina no tratamento da SHR em pacientes com cirrose. Métodos: Avaliação econômica de custo-efetividade, com base em dados secundários de estudos publicados com resultado da eficácia da terapia com terlipressina, em comparação com norepinefrina combinada com albumina ou apenas albumina. A análise de custo-efetividade foi calculada usando a razão de custo-efetividade incremental (RCEI) e uma análise de sensibilidade foi desenvolvida variando os valores das terapias e probabilidades. O real foi a moeda utilizada na análise. Resultados: Após a seleção, elegibilidade e avaliação da qualidade das publicações, os resultados demonstraram que a administração da associação de terlipressina ou norepinefrina com albumina em pacientes diagnosticados com SHR tipo 1 possui eficácia comprovada. Os custos do tratamento com a terapia combinada de terlipressina com albumina foram de USD $1,644.06, administração de somente albumina USD $912.02 e norepinefrina mais albumina USD $2,310.78. Considerando as terapias combinadas com efetividade terapêutica comprovada, isto é, terlipressina e norepinefrina associada a albumina, o custo incremental foi de USD $666.73 e efetividade de 0,570 para o grupo da terlipressina associada a albumina e de 0,200 para o grupo da norepinefrina associada a albumina. A efetividade incremental foi de 0,370 e o valor da RCEI foi de USD $1,801.97. Assim, os fatores de incremento do custo por terapia e razão de custo-efetividade incremental definem que a terapia combinada de terlipressina mais albumina é custo efetiva quando comparada a administração de somente albumina ou norepinefrina no cenário do sistema único de saúde. Conclusão: O estudo demonstrou por meio de uma análise de custo-efetividade que a terlipressina associada à albumina quando administrada concomitantemente a pacientes com diagnóstico de SHR tipo 1 é custo-efetiva quando comparada à albumina sozinha e com norepinefrina associada à albumina administrada em um ambiente controlado.

Clinical features and treatment outcomes of primary biliary cholangitis in a highly admixed population.

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.

National Brazilian survey on the outcomes of hepatitis c retreatment in patients non-responders to direct antiviral agents

ABSTRACT 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.

Fibrates for the Treatment of Primary Biliary Cholangitis Unresponsive to Ursodeoxycholic Acid: An Exploratory Study.

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.

Massive iron overload and acute-on-chronic liver failure in a patient with Diamond-Blackfan anaemia: a case report.

BACKGROUND: Genetic anaemias lead us to reflect on the classic 'trolley dilemma', when there are two choices but neither one is satisfactory. Either we do not treat anaemia and the patient suffers from chronic tiredness and fatigue, or we do treat it through blood transfusions, leading to iron overload, which is a quite harmful consequence. CASE PRESENTATION: We present the case of a 34-year-old woman with Diamond-Blackfan anaemia (DBA). Bone marrow stem cell transplantation had not been accessible during her childhood, so she had been submitted to monthly blood transfusions throughout her life, leading to a hepatitis C virus infection (which was treated, achieving a sustained virological response when she was 18 years old), and secondary haemochromatosis. Despite chelation therapy, diffuse iron deposition was occurring in multiple organs, markedly in the heart and liver. Her serum ferritin was higher than 21,000 ng/mL and transferrin saturation reached 102%. When she faced heart decompensation, this congestive condition led to an acute liver injury overlapping pre-existing hepatic fibrosis. She progressed to haemodynamic and hepatic failure, with clinical features of acute-on-chronic liver failure (ACLF). Despite therapeutic optimisation, she died of respiratory insufficiency. An autopsy was performed and revealed the macroscopic and microscopic findings of a massive iron deposition in the liver, heart, lungs, spleen, bone marrow, thyroid and adrenal glands. We found marked advance of liver fibrosis (chronic damage), as well as necrosis of hepatocytes in zone 3 of the Rappaport acinus (acute damage), supporting the hypothesis of ACLF. The main feature responsible for acute liver decompensation seemed to be heart insufficiency. CONCLUSION: This is the first case reporting the sequence: DBA, multiple blood transfusions, secondary haemochromatosis, advanced liver fibrosis, heart failure, ACLF and death. A multidisciplinary team is essential to care for DBA patients, since there is a significant emotional burden related to the disease, which might impair an effective chelation therapy and lead to severe consequences due to iron deposition.

Diarrhea: a missed D in the 4D glucagonoma syndrome.

Glucagonoma is a rare and slow-growing pancreatic tumor that usually manifests as glucagonoma syndrome. It is mainly characterized by a typical Dermatosis named necrolytic migratory erythema (NME), Diabetes and glucagon oversecretion. Deep vein thrombosis and Depression complete this set. We report the case of an advanced glucagonoma with liver spread, where all these 4D symptoms occurred but a chronic secretory Diarrhea was the most relevant feature. A 65-year-old man was referred to our center to investigate multiple hepatic nodules evidenced by abdominal tomography. He had a recent diagnosis of diabetes and complained of significant weight loss (25 kg), crusted skin lesions and episodes of a large amount of liquid diarrhea during the past 6 months. On admission, there were erythematous plaques and crusted erosions on his face, back and limbs, plus angular cheilitis and atrophic glossitis. The typical skin manifestation promptly led dermatologists to suspect glucagonoma as the source of our patient's symptoms. A contrast-enhanced abdominal computed tomography showed a hypervascularized pancreatic lesion and multiple hepatic nodules also hypervascularized in the arterial phase. Despite initial improvement of diarrhea after subcutaneous octreotide, the patient's impaired nutritional status limited other therapeutic approaches and he died of respiratory failure due to sepsis. His high levels of serum glucagon were not yet available so we performed an autopsy, confirming the diagnosis of metastatic glucagonoma with NME on histology. Chronic diarrhea is not a common feature in glucagonoma syndrome; however, its severity can lead to serious nutritional impairment and set a poor outcome.

Multiple hepatic metastases of cardiac angiosarcoma

The differential diagnosis of hepatic focal lesions is challenging because the etiology can be inflammatory, infectious, and even neoplastic. A rare cause of metastatic liver nodules is cardiac angiosarcoma. We report a case of this tumor, which was diagnosed only after autopsy. A 26-year-old Caucasian man was admitted for progressive dyspnea and cough over the past 3 weeks. Physical examination showed only hypophonetic heart sounds. Laboratory analysis demonstrated anemia and elevated inflammatory markers, despite normal biochemical parameters and liver function. Transthoracic echocardiography revealed massive pericardial effusion. Abdomen computed tomography (CT) showed multiple hepatic nodules, the largest of which measured 3 cm, but the percutaneous biopsy revealed only lobular necrosis and perisinusoidal fibrosis without granulomas or neoplastic cells. During hospitalization, the patient had fever and night sweats with weight loss, and empiric treatment for extrapulmonary tuberculosis associated with corticosteroids was initiated. The outpatient follow-up revealed complete improvement of the pericardial effusion, but maintenance of the liver lesions. After 2 months of hospital discharge, the patient was readmitted with hemorrhagic shock due to bleeding liver lesions, which were evidenced by CT. Embolization of the right hepatic artery was performed, but the patient soon died. The autopsy revealed a primary cardiac angiosarcoma with multiple hepatic metastases, rupture of the Glisson's capsule and laceration of the liver. The case shows how important and difficult the diagnosis of focal liver lesions is, since it may result in an unexpected fatal outcome.

Association between the CYBA and NOX4 genes of NADPH oxidase and its relationship with metabolic syndrome in non-alcoholic fatty liver disease in Brazilian population.

BACKGROUND: Oxidative stress has been implicated in the progression of severe forms of non-alcoholic fatty liver disease (NAFLD). NADPH oxidase produces reactive oxygen species. In the present study, we investigated for the first time two single nucleotide polymorphisms (SNPs) in the regulatory region of genes encoding NADPH oxidase 4 (NOX4) and p22phox (CYBA) in NAFLD. METHODS: A total of 207 biopsy-proven NAFLD patients [simple steatosis (n = 27); nonalcoholic steatohepatitis (NASH) (n = 180)] were evaluated. Genomic DNA was extracted from peripheral blood cells, and polymorphisms in CYBA (unregistered) and NOX4 (rs3017887) were determined by direct sequencing of PCR. RESULTS: Associations of CYBA-675 T/A with high-density lipoprotein (HDL) (TT vs TA vs AA; P < 0.01) and triglycerides (TGL) (TT vs XA; P < 0.01) were observed only in NASH patients. For polymorphisms in the NOX4 gene, NOX4 (rs3017887) CA + AA genotypes was significant associated with alanine aminotransferase (ALT) (CA + AA vs CC; P = 0.02). However, there was no association of SNPs in the CYBA and NOX4 genes encoding the NADPH oxidase system proteins and the presence of NASH. Regarding the clinical results, it was observed that the most advanced degrees of fibrosis occurred in patients diagnosed with type 2 diabetes mellitus (66.9% vs 37.5%, P < 0.01) and those who were more obese (32.2 vs 29.0 kg/m2, P < 0.01). In addition, serum glucose and insulin levels increased significantly in the presence of NASH. CONCLUSIONS: There were associations between the presence of the allele A in the NOX4 SNP and a higher concentration of ALT in the NAFLD population; between the presence of the AA genotype in the polymorphism of the CYBA-675 T/A CYBA gene and a higher level of TGL and lower HDL in NASH patients. The presence of metabolic syndrome was associated with advanced degrees of fibrosis in NAFLD patients.

Multiple hepatic metastases of cardiac angiosarcoma.

The differential diagnosis of hepatic focal lesions is challenging because the etiology can be inflammatory, infectious, and even neoplastic. A rare cause of metastatic liver nodules is cardiac angiosarcoma. We report a case of this tumor, which was diagnosed only after autopsy. A 26-year-old Caucasian man was admitted for progressive dyspnea and cough over the past 3 weeks. Physical examination showed only hypophonetic heart sounds. Laboratory analysis demonstrated anemia and elevated inflammatory markers, despite normal biochemical parameters and liver function. Transthoracic echocardiography revealed massive pericardial effusion. Abdomen computed tomography (CT) showed multiple hepatic nodules, the largest of which measured 3 cm, but the percutaneous biopsy revealed only lobular necrosis and perisinusoidal fibrosis without granulomas or neoplastic cells. During hospitalization, the patient had fever and night sweats with weight loss, and empiric treatment for extrapulmonary tuberculosis associated with corticosteroids was initiated. The outpatient follow-up revealed complete improvement of the pericardial effusion, but maintenance of the liver lesions. After 2 months of hospital discharge, the patient was readmitted with hemorrhagic shock due to bleeding liver lesions, which were evidenced by CT. Embolization of the right hepatic artery was performed, but the patient soon died. The autopsy revealed a primary cardiac angiosarcoma with multiple hepatic metastases, rupture of the Glisson's capsule and laceration of the liver. The case shows how important and difficult the diagnosis of focal liver lesions is, since it may result in an unexpected fatal outcome.

Hepatitis C virus eradication improves immediate and delayed episodic memory in patients treated with interferon and ribavirin.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is associated with impairment of cognitive function and mood disorders. Our aim was to evaluate the impact of sustained virological response (SVR) on cognitive function and mood disorders. METHOD: A prospective exploratory one arm study was conducted. Adult clinically compensated HVC patients were consecutively recruited before treatment with interferon and ribavirin for 24 to 48 weeks, according to HCV genotype. Clinical, neurocognitive and mood assessments using the PRIME-MD and BDI instruments were performed at baseline, right after half of the expected treatment has been reached and 6 months after the end of antiviral treatment. Exclusion criteria were the use of illicit psychotropic substances, mental confusion, hepatic encephalopathy, hepatocellular carcinoma, severe anemia, untreated hypothyroidism, Addison syndrome and major depression before treatment. RESULTS: Thirty six patients were enrolled and 21 completed HCV treatment (n = 16 with SVR and n = 5 without). Regardless of the viral clearance at the end of treatment, there was a significant improvement in the immediate verbal episodic memory (p = 0.010), delayed verbal episodic memory (p = 0.007), selective attention (p < 0.001) and phonemic fluency (p = 0.043). Patients with SVR displayed significant improvement in immediate (p = 0.045) and delayed verbal episodic memory (p = 0.040) compared to baseline. The baseline frequency of depression was 9.5%, which rose to 52.4% during treatment, and returned to 9.5% 6 months after the end of treatment, without significant difference between patients with and without SVR. Depressive symptoms were observed in 19.1% before treatment, 62% during (p = 0.016) and 28.6% 6 months after the end of treatment (p = 0.719). CONCLUSIONS: Eradication of HCV infection improved cognitive performance but did not affect the frequency of depressive symptoms at least in the short range.

Peginterferon still has a place in the treatment of hepatitis C caused by genotype 3 virus.

Despite recent advances in therapy for chronic hepatitis C (CHC), the disease caused by genotype 3 virus (GEN3) is still considered a treatment challenge in certain patient subgroups. The aim of this retrospective study was to evaluate the effectiveness and safety of the peginterferon (Peg-IFN) and ribavirin (RBV) combination treatment for GEN3/CHC patients, and to evaluate sustained virological response (SVR) indicators and early treatment interruption due to serious adverse events (SAE). This was a retrospective observational study of GEN3/CHC patients, co-infected or not by HIV and treated with Peg-IFN/RBV in nine Brazilian healthcare centers. The study sample included 184 GEN3/CHC patients; 70 (38%) were co-infected with HIV. The overall SVR rate was 57.1% (95% CI 50-64). Among co-infected and mono-infected patients, the SVR rate was 51.4% (36/70) and 60.5% (69/114), respectively (p=0.241). Thirty-four (18.5%) patients experienced SAE and interrupted treatment. SVR was negatively associated with the use of Peg-IFN alpha 2b (PR 0.75; 95% CI 0.58-0.99; p=0.045) and to early treatment interruption due to SAE (PR 0.36; 95% CI 0.20-0.68; p=0.001). Early treatment interruption due to SAE was associated with age (PR 1.06; 95% CI 1.02-1.10; p<0.001) and occurrence of liver cirrhosis (PR 2.06; 95% CI 1.11-3.83; p=0.022). In conclusion, Peg-IFN/RBV might represent an adequate treatment option, mainly in young patients without advanced liver disease or when the use of direct-action drugs is limited to specific patient groups.