N-acetilcisteína e/ou ácido ursodeoxicólico associados à metformina na esteato-hepatite não alcoólica: um estudo aberto, multicêntrico, randomizado controlado / N-acetylcysteine and/or ursodeoxycholic acid associated with metformin in non-alcoholic steatohepatitis: an open-label multicenter randomized controlled trial

ABSTRACT BACKGROUND: Nowadays, pharmacological treatment of non-alcoholic fatty liver disease (NAFLD) is still limited and it is based on the treatment of conditions associated comorbities. Oxidative stress and insulin resistance are the mechanisms that seem to be mostly involved in its pathogenesis. OBJECTIVE: To evaluate the efficacy of N-acetylcysteine (NAC) in combination with metformin (MTF) and/or ursodeoxycholic acid (UDCA) for treatment of non-alcoholic steatohepatitis (NASH). METHODS: Open-label multicenter randomized trial was conducted for 48 weeks. It included patients with biopsy-proven NASH. The patients were randomized into three groups: NAC (1.2 g) + UDCA (15 mg/kg) + MTF (850-1500 mg/day) (n=26); UDCA (20 mg/kg) + MTF (850-1500 mg/day) (n=13); NAC (1.2g) + MTF (850-1500 mg/day) (n=14) for 48 weeks. Clinical, laboratory and the second liver biopsies were performed after 48 weeks. RESULTS: A total of 53 patients were evaluated; 17 (32.1%) were males; median age ±54 (IQR=15, 21-71) years. In the baseline, no difference was seen between groups according clinical and histological parameters. The groups differed only in cholesterol, LDL and triglycerides. No significant differences in biochemical and histologic parameters were found between these the three groups after 48 weeks of treatment. In the intragroup analysis (intention-to-treat) comparing histological and biochemical features, there were significant improvements in the steatosis degree (P=0.014), ballooning (0.027) and, consequently, in the NAFLD Activity Score (NAS) (P=0.005), and in the ALT levels at the end of the treatment only in the NAC + MTF group. No significant evidence of modification in the liver fibrosis could be observed in any of the groups. CONCLUSION: This multicenter study suggests that the association of NAC + MTF could reduce the liver disease activity in patients with NASH. These data stimulate further controlled studies with this therapy for these patients.

RESUMO CONTEXTO: Atualmente, o tratamento farmacológico da doença hepática gordurosa não alcoólica (DHGNA) ainda é limitado e baseia-se no tratamento de condições associadas às comorbidades. O estresse oxidativo e a resistência à insulina são os mecanismos que parecem estar mais envolvidos em sua patogênese. OBJETIVO: Avaliar a eficácia da N-acetilcisteína (NAC) em associação à metformina (MTF) e/ou ácido ursodesoxicólico (UDCA) no tratamento da EHNA. MÉTODOS: Estudo randomizado, multicêntrico e aberto, conduzido por 48 semanas. Incluiu pacientes com esteato-hepatite não alcoólica (EHNA) comprovada por biópsia. Os pacientes foram distribuídos aleatoriamente em três grupos: NAC (1,2 g) + UDCA (15 mg/kg) + MTF (850-1500 mg/dia) (n=26); UDCA (20 mg/kg) + MTF (850-1500 mg/dia) (n=13); NAC (1,2 g) + MTF (850-1500 mg/dia) (n=14) durante 48 semanas. Os dados clínicos, laboratoriais e as segundas biópsias hepáticas foram realizados após 48 semanas. RESULTADOS - Um total de 53 pacientes foram avaliados; 17 (32,1%) eram do sexo masculino; idade mediana de ±54 (IQR=15, 21-71) anos. No baseline, nenhuma diferença foi observada entre os grupos de acordo com parâmetros clínicos e histológicos. Os grupos diferiram apenas em colesterol, LDL e triglicerídeos. Não foram encontradas diferenças significativas nos parâmetros bioquímicos e histológicos entre os três grupos após 48 semanas de tratamento. Contudo, na análise intragrupos (intenção de tratar) comparando características histológicas e bioquímicas, houve melhora significativa no grau de esteatose (P=0,014), balonização (P=0,027) e, consequentemente, no NAFLD Activity Score (NAS) (P=0,005), e nos níveis de ALT no final do tratamento apenas no grupo NAC+MTF. Nenhuma evidência significativa de modificaçãona fibrose hepática pôde ser observada em nenhum dos grupos. CONCLUSÃO: - Este estudo multicêntrico sugere que a associação de NAC+MTF poderia reduzir a atividade da doença hepática em pacientes com EHNA. Esses dados estimulam estudos adicionais controlados com essa terapia para esses pacientes.

Renoprotective effect of high periprocedural doses of oral N-acetylcysteine in patients scheduled to undergo a same-day angiography

BACKGROUND: Few studies that have assessed the effect of abbreviated oral N-acetylcysteine (NAC) regimens in radiocontrast-induced nephropathy (RCIN) yield mixed results. OBJECTIVE: To evaluate the renoprotective effect of high periprocedural oral doses (HPOD) of NAC in patients with chronic renal impairment undergoing a same-day angiography. METHODS: Sixty one patients with renal impaired function scheduled to undergo a same-day angiography were randomly assigned to NAC 1200 mg orally 3 hours before and 3 after the procedure, or a placebo. All patients received 0.9% saline intravenous. RCIN was defined as an increase in SCC > 0.5 mg/dl 48 hours after the procedure. RESULTS: The mean baseline SCC for all patients was 1.44 +/- 0.42 mg/dl. A significant difference in SCC change at 48 hours after the angiography was found (-0.07 mg/dl NAC, 0.09 mg/dl placebo, P = 0.04). RCIN occurred in 1 (3%) patient of NAC group and in 2 (7.1%) patients of placebo group (P = 0.59). Adverse effects were similar in both groups. CONCLUSIONS: In patients with mild renal impairment patients undergoing angiographic procedures, HPOD of NAC were more effective than placebo in preventing SCC change 48 hours. A non significant benefit in RCIN incidence was found.

Los escasos estudios que han evaluados los efectos de regimenes abreviados de Nacetilcisteína (NAC) oral en la nefropatía por contraste (NC) han encontrado resultados contrapuestos. OBJETIVO: Evaluar el efecto renoprotector de altas dosis orales periprocedimiento (ADOP) de NAC en pacientes con insuficiencia renal con angiografía programada el mismo día. MATERIAL y METODOS: Sesenta y un pacientes con insuficiencia renal y angiografía programada para el mismo día fueron asignados aleatoriamente a 1200 mg de NAC 3 horas previas y 3 horas posteriores al cateterismo o un placebo. Todos los pacientes recibieron hidratación endovenosa con solución salina al 0.9%. La NC se definió como el aumento en la creatinina sérica (CS) > 0.5 mg/dl a las 48 horas del procedimiento. RESULTADOS: La CS media en todos los pacientes fue 1.44: t 0.42 mg/dl. Se encontró una diferencia significativa entre ambos grupos en el cambio de CS a las 48 horas de la angiografía (-0.07 mg/dl NAC, 0.09 mg/dl placebo, P=0.04). La NC se presentó en 1 (3%) paciente del grupo NAC y en 2 (7.1 %) pacientes del grupo placebo (P=0.59). Los efectos adversos fueron similares en ambos grupos. CONCLUSION: En pacientes con insuficiencia renal leve sometidos a angiografía en el mismo día, las ADOP de NAC fueron más efectivas que el placebo en la prevención del cambio de CS a las 48 horas del procedimiento. Se encontró un beneficio no significativo en la incidencia de NC.