Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown. METHODS: In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). RESULTS: A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting. CONCLUSIONS: Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.).

[Histological regression of liver fibrosis with immunosuppressive therapy in autoimmune hepatitis]. / Regresión histológica de la fibrosis hepática con tratamiento inmunosupresor en hepatitis autoinmune.

UNLABELLED: Reversibility of liver fibrosis with immunosuppressive therapy (IT) has been described in autoimmune hepatitis (AIH). OBJECTIVE: To compare initial fibrosis and fibrosis after IT in patients with AIH. METHODS: A total of 54 patients were admitted with positive ANA or AML antibodies, or both, elevated IgG immunoglobulins and who met international criteria for a diagnosis of AIH. The mean age was 39 years (range 13-65) and there were 47 women (87%). Two liver biopsies were taken: one at diagnosis and another at a mean of 28±8 months after initiation of IT with prednisone and azathioprine. The degree of inflammation (0-18) and fibrosis (0-6) according to Ishak score was compared between the initial and the follow-up biopsy. RESULTS: Fibrosis decreased from 2.9±0.3 to 2.2±0.3 (p=0.005) and histological activity index from 6.8±0.45 to 2.6±0.2 (P<.001). In subgroups, fibrosis decreased from 3.6±0.4 to 1.4±0.3 (P<.001) in 22 patients (41%), was unchanged in 27 (50%) and increased in five (9%). There were seven patients with histological cirrhosis at IT initiation. After IT, four showed a reduction in Ishak score (achieving scores of 0-3). Transaminase values were not associated with histological improvement. CONCLUSION: Fibrosis in patients with AIH significantly improved with IT, emphasizing the importance of studying the prognostic factors associated with this favorable response.

Regresión histológica de la fibrosis hepática con tratamiento inmunosupresor en hepatitis autoinmune / Histological regression of liver fibrosis with immunosuppressive therapy in autoimmune hepatitis

Resumen La reversibilidad de la fibrosis hepática se describe en hepatitis autoinmune(HAI) con tratamiento inmunosupresor (TI). Objetivo Comparar fibrosis inicial y con TI en HAI.MétodosIngresaron 54 pacientes con anticuerpos antinucleares y/o antimúsculo liso (+), IgG elevada y biopsia compatible, edad promedio 39 años (rango 13-65), 47 mujeres (87%), en tratamiento con prednisona y azatioprina. Se comparó grado de inflamación (0-18) y fibrosis (0-6) según score de Ishak entre biopsia inicial y control (prom 28±8 meses). Resultados La fibrosis disminuyó de 2,9±0,3 a 2,2±0,3 (p=0,005) y el índice de actividad histológica de 6,8±0,45 a 2,6±0,2 (p<0,001). En subgrupos esta disminuyó de 3,6±0,4 a 1,4±0,3 (p<0,001) en 22 pacientes (41%), no varió en 27 (50%) y aumentó en 5 (9%); 4/7 con cirrosis histológica inicial mejoraron a score 0-3 en control. La evolución de transaminasas no permitió predecir la mejoría histológica. Conclusión En pacientes con HAI el TI mejora significativamente la fibrosis, acentuando la importancia de estudiar factores pronósticos asociados a esta favorable respuesta (AU)

Abstract Reversibility of liver fibrosis with immunosuppressive therapy (IT) has been described in autoimmune hepatitis (AIH) Objective To compare initial fibrosis and fibrosis after IT in patients with AIH. Methods A total of 54 patients were admitted with positive ANA or AML antibodies, or both, elevated IgG immunoglobulins and who met international criteria for a diagnosis of AIH. The mean age was 39 years (range 13-65) and there were 47 women (87%). Two liver biopsies were taken: one at diagnosis and another at a mean of 28±8 months after initiation of IT with prednisone and azathioprine. The degree of inflammation (0-18) and fibrosis (0-6) according to Ishak score was compared between the initial and the follow-up biopsy. Results Fibrosis decreased from 2.9±0.3 to 2.2±0.3 (p=0.005) and histological activity index from 6.8±0.45 to 2.6±0.2 (P<.001). In subgroups, fibrosis decreased from 3.6±0.4 to 1.4±0.3 (P<.001) in 22 patients (41%), was unchanged in 27 (50%) and increased in five (9%). There were seven patients with histological cirrhosis at IT initiation. After IT, four showed a reduction in Ishak score (achieving scores of 0-3). Transaminase values were not associated with histological improvement. Conclusion Fibrosis in patients with AIH significantly improved with IT, emphasizing the importance of studying the prognostic factors associated with this favorable response (AU)

[Study of celiac disease in patients with non-alcoholic fatty liver and autoimmune hepatic diseases]. / Estudio de enfermedad celíaca en pacientes con enfermedad por hígado graso no alcohólico y con hepatopatías autoinmunes.

UNLABELLED: Celiac disease (CD) has been associated with non-alcoholic fatty liver disease (NAFLD) and other chronic liver diseases (CLD), such as primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). AIM: To study the frequency of serological markers of CD in patients with NAFLD and CLD and their correlation with duodenal biopsy. PATIENTS AND METHODS: In patients with NAFLD, PBC, AIH and PSC, we studied anti-endomysium (AE) IgA by indirect immunofluorescence and anti-gliadin IgA-IgG (AG) and human anti-tissue transglutaminase (tTG) IgA antibodies by an ELISA technique. Patients with positive serology for at least one marker underwent endoscopy with duodenal biopsies. RESULTS: Positive CD markers were found in 9 of 101 patients (8.9%): 7 patients were positive for tTG alone, 1 for AE and AG, and 1 patient for 3 antibodies. Positivity was as follows: 3/38 (7.9%) in NAFLD, 3/44 (6.8%) in PBC, 2/16 (12.5%) in AIH and 1/3 in PSC. Endoscopy was performed in 8 patients, with normal duodenal biopsy in 7 and 1 patient with Marsh stage 1 CD with NAFLD, positive AE and AG. The only patient with 3 positive markers died during the study without undergoing endoscopy. None of the patients had symptoms suggestive of CD. CONCLUSION: A high prevalence of positive tTG was found in patients with CLD and NAFLD. However, duodenal biopsy should be performed in these patients, given that the results of this procedure were normal in most patients in this study.

Estudio de enfermedad celíaca en pacientes con enfermedad por hígado graso no alcohólico y con hepatopatías autoinmunes / Study of celiac disease in patients with non-alcoholic fatty liver and autoimmune hepatic diseases

La enfermedad celíaca (EC) se ha asociado con hígado graso no alcohólico (HGNA) y hepatopatías crónicas, como cirrosis biliar primaria (CBP), hepatitis autoinmune (HAI) y colangitis esclerosante primaria (CEP). Objetivo: Estudiar la frecuencia de marcadores serólogicos de EC en pacientes con las hepatopatías mencionadas y su correlación con la biopsia duodenal. Pacientes y métodos: En pacientes con HGNA, CBP, HAI y CEP, se estudiaron los anticuerpos IgA antiendomisio (AE) por inmunofluorescencia indirecta, IgA-IgG antigliadina (AG) y anticuerpos antitransglutaminasa tisular humano (h-ATG) mediante ELISA. En los casos positivos para al menos un marcador, se realizó una biopsia duodenal. Resultados: Nueve de 101 pacientes tuvieron marcadores positivos de EC (8,9%): 7 de ellos sólo h-ATG, uno con AE y AG, y uno con los tres marcadores. Los casos positivos fueron 3/38 (7,9%) en HGNA, 3/44 (6,8%) en CBP, 2/16 (12,5%) en HAI y 1/3 en CEP. Cuatro casos con h-ATG positivos tuvieron títulos bajos (20-30 U; valores normales 30 U). Se realizó una endoscopia con biopsia duodenal en 8 de ellos, que fue normal en 7 y compatible con EC en etapa I de Marsh en un paciente con HGNA, AG y AE positivos. El caso del único paciente con los tres marcadores positivos no se estudió por fallecer contemporáneamente. Ninguno de ellos tenía clínica sugerente de EC. Conclusiones: La frecuencia del marcador serológico h-ATG de EC es significativa en las hepatopatías descritas. Sin embargo, debe confirmarse con biopsia duodenal, dada las elevadas tasas de histología normal en nuestro estudio

Celiac disease (CD) has been associated with non-alcoholic fatty liver disease (NAFLD) and other chronic liver diseases (CLD), such as primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). Aim: To study the frequency of serological markers of CD in patients with NAFLD and CLD and their correlation with duodenal biopsy. Patients and methods: In patients with NAFLD, PBC, AIH and PSC, we studied anti-endomysium (AE) IgA by indirect immunofluorescence and anti-gliadin IgA-IgG (AG) and human anti-tissue transglutaminase (tTG) IgA antibodies by an ELISA technique. Patients with positive serology for at least one marker underwent endoscopy with duodenal biopsies. Results: Positive CD markers were found in 9 of 101 patients (8.9%): 7 patients were positive for tTG alone, 1 for AE and AG, and 1 patient for 3 antibodies. Positivity was as follows: 3/38 (7.9%) in NAFLD, 3/44 (6.8%) in PBC, 2/16 (12.5%) in AIH and 1/3 in PSC. Endoscopy was performed in 8 patients, with normal duodenal biopsy in 7 and 1 patient with Marsh stage 1 CD with NAFLD, positive AE and AG. The only patient with 3 positive markers died during the study without undergoing endoscopy. None of the patients had symptoms suggestive of CD. Conclusion: A high prevalence of positive tTG was found in patients with CLD and NAFLD. However, duodenal biopsy should be performed in these patients, given that the results of this procedure were normal in most patients in this study

[Fulminant liver failure associated with T-cell non-Hodgkin's lymphoma and hepatitis C virus: a case report]. / Fallo hepático fulminante por un linfoma no hodgkiniano de estirpe T asociado al virus de la hepatitis C. Caso clínico.

Hematological malignancies can affect the liver, without producing severe hepatic involvement. We report the case of a 57-year-old man with hepatitis C virus infection and mild chronic hepatitis without antiviral treatment, who developed an aggressive T-cell non-Hodgkin's lymphoma confirmed by histological studies including liver, lymph nodes and bone marrow. The patient developed massive hepatic infiltration and acute liver failure. Rescue chemotherapy was administered but the patient died soon after with severe lactic acidosis. The immunopathological features of this association and the few reports of cases presenting with acute liver failure are reviewed.

Fallo hepático fulminante por un linfoma no hodgkiniano de estirpe T asociado al virus de la hepatitis C. Caso clínico / Fulminant liver failure associated with non-Hodgkin’s lymphoma and hepatitis C virus: a case report

Las neoplasias hematológicas afectan al hígado sin producir una disfunción hepática grave. Presentamos el caso de un paciente de sexo masculino, de 57 años de edad, y portador del virus de la hepatitis C (VHC), con daño hepático leve y sin tratamiento antiviral, que desarrolla un linfoma no hodgkiniano de estirpe T, agresivo, con infiltración hepática masiva y fallo hepático agudo. El estudio histológico del hígado, los ganglios y la médula ósea fue compatible con el diagnóstico de linfoma. Se intenta aplicar quimioterapia de rescate sin respuesta. El paciente falleció a los pocos días con una grave acidosis láctica. Revisamos los mecanismos inmunopatogénicos entre ambas enfermedades y las escasas comunicaciones que se presentan con insuficiencia hepática fulminante en la literatura médica

Hematological malignancies can affect the liver, without producing severe hepatic involvement. We report the case of a 57-year-old man with hepatitis C virus infection and mild chronic hepatitis without antiviral treatment, who developed an aggressive T-cell non-Hodgkin's lymphoma confirmed by histological studies including liver, lymph nodes and bone marrow. The patient developed massive hepatic infiltration and acute liver failure. Rescue chemotherapy was administered but the patient died soon after with severe lactic acidosis. The immunopathological features of this association and the few reports of cases presenting with acute liver failure are reviewed

[Primary sclerosing cholangitis: a twelve-year experience]. / Colangitis esclerosante primaria: revisión de 12 años en dos centros de referencia.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder characterized by progressive inflammation and fibrosis of the biliary tract, evolving to cirrhosis. It is commonly associated with inflammatory bowel disease (IBD). AIM: To communicate the clinical characteristics of patient with PSC seen in two reference centers. PATIENTS AND METHODS: Review of medical records of patients with PSC confirmed by liver biopsies. The clinical picture, laboratory abnormalities, imaging studies and treatment were recorded. RESULTS: Thirty three patients (aged 16 to 73 years, 64% female) were identified. They corresponded to 1.7% of liver biopsies done between 1991-2003. Clinical presentation was a cholestatic picture in 40%, right upper abdominal pain in 36%, a dysenteric syndrome in 9% and varied symptoms in 15%. Laboratory tests showed cholestasis in 94% and positive anti ANCA, SMA, ANA and AMA antibodies in 28, 18, 15 and 9% of cases, respectively. Endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiography were diagnostic in 43 and 58% of patients, respectively. There was an association with ulcerative colitis in 12% of cases. Liver biopsies showed grade I PSC in 76% and grade II-III in 6% of patients. It also showed a concomitant chronic hepatitis and primary biliary cirrhosis in 12 and 6% of cases, respectively. Treatment consisted on ursodeoxycholic acid (UDCA) in 45%, UDCA plus 5-aminosalicylic acid derivatives in 12% and UDCA plus immunosuppresors in 12% of patients. Two patients had to be transplanted. CONCLUSIONS: PSC is an uncommon cause of chronic liver disease. It is suspected in cholestatic patients and confirmed with a liver biopsy. It can be associated with other autoimmune hepatic and extrahepatic diseases.

[Albumin dialysis MARS (Molecular Adsorbent Recirculating System) as a bridge for liver transplantation in acute liver failure. Report of three cases]. / Diálisis con albúmina MARS (Molecular Adsorbent Recirculating System) como puente para el trasplante hepático en insuficiencia hepática fulminante: presentación de 3 casos.

The most successful therapy for acute liver failure is liver transplantation. However, due to the low number of donors, organ support therapies need to be used as a bridge to liver transplantation. Molecular Adsorbents Recirculating System (MARS) is a dialysis treatment that uses a recirculating dialysate containing albumin. This allows the removal of both hydrosoluble and albumin-related substances. This system improves hepatic encephalopathy, renal dysfunction and some clinical parameters in acute liver failure, but there is no clear decrease in mortality. We report three women aged 23, 21 and 61 years, that were subjected to liver transplantation, in whom this therapy was successfully used.

[Current management of achalasia of the esophagus: critical review and clinical experience]. / Manejo actual de la acalasia del esófago: revisión crítica y experiencia clínica.

The therapeutic options for treatment of Achalasia of the esophagus include medical treatment, endoscopic and surgical procedures. The latter can be either conservative, such as cardiomyotomy or more aggressive, such as cardioplasty or esophageal resection. In this article, we discuss the early and long term results after the different therapeutic options. We also present the results of our recent surgical experience. The definitive results seem to be better after surgical treatment compared to medical management or endoscopic procedures.