Combination of <i>N</i>‐acetylcysteine and metformin improves histological steatosis and fibrosis in patients with non‐alcoholic steatohepatitis

Oliveira, Cláudia Pinto Marques Souza de; Stefano, José Tadeu; Siqueira, Érika Rabelo Forte de; Silva, Leonardo Soares; Mazo, Daniel Ferraz de Campos; Lima, Verônica Castro; Furuya, Carlos K; Mello, Evandro Sobroza de; Souza, Francis Ribeiro de; Rabello, Fabíola; Santos, Telma; Nogueira, Monize Aydar; Caldwell, Stephen H.; Alves, Venâncio Avancini Ferreira; Carrilho, Flair José

doi:10.1111/j.1872-034x.2007.00215.x

Cited by 103 publications

(66 citation statements)

References 42 publications

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“…248 Patients with NAFLD have had better histologi-cal activity scores and less hepatic fibrosis after treatment with N-acetylcysteine and metformin. 110 Similar anti-fibrotic actions have been demonstrated after therapy with other anti-oxidants (SAMe and vitamin E) (Figure 1). 59,89,250 Mortality or the need for liver transplantation has decreased from 29% to 12% in patients with alcoholic cirrhosis who have been treated with SAMe, 242 and this treatment has also increased the frequency of an early virological response in otherwise non-responsive patients with chronic hepatitis C (genotype 1).…”

Section: Inhibitors Of Oxidative Stress As Anti-fibrotic Agents In Ausupporting

confidence: 62%

Review article: the prevention and reversal of hepatic fibrosis in autoimmune hepatitis

Czaja

2014

Aliment Pharmacol Ther

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SummaryBackgroundImmunosuppressive treatment of autoimmune hepatitis can prevent or reverse hepatic fibrosis, but these anti‐fibrotic effects are inconsistent secondary gains.AimTo describe the anti‐fibrotic effects of current therapies for autoimmune hepatitis, discuss the pathogenic mechanisms of hepatic fibrosis that might be targeted by anti‐fibrotic interventions, indicate the non‐invasive diagnostic tests of hepatic fibrosis that must be validated in autoimmune hepatitis and to suggest promising treatment opportunities.MethodsStudies cited in PubMed from 1972 to 2013 for autoimmune hepatitis, hepatic fibrosis, cirrhosis, anti‐fibrotic therapy and non‐invasive tests of hepatic fibrosis were selected.ResultsHepatic fibrosis improves in 53–57% of corticosteroid‐treated patients with autoimmune hepatitis; progressive fibrosis slows or is prevented in 79%; and cirrhosis may be reversed. Progressive hepatic fibrosis is associated with liver inflammation, and the inability to fully suppress inflammatory activity within 12 months is associated with progression to cirrhosis (54%) and death or need for liver transplantation (15%). Liver tissue examination remains the gold standard for assessing hepatic fibrosis, but laboratory and radiological tests may be useful non‐invasive methods to measure the fibrotic response. Severe liver inflammation can confound radiological assessments, and the preferred non‐invasive test in autoimmune hepatitis is uncertain. Individualised treatment adjustments and adjunctive anti‐fibrotic therapies are poised for study in this disease.ConclusionsThe prevention and reversal of hepatic fibrosis are achievable objectives in autoimmune hepatitis. Strategies that evaluate individualised therapies adjusted to the rapidity and completeness of the inflammatory response, and the use of adjunctive anti‐fibrotic interventions, must be evaluated.

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Section: Inhibitors Of Oxidative Stress As Anti-fibrotic Agents In Ausupporting

confidence: 62%

Review article: the prevention and reversal of hepatic fibrosis in autoimmune hepatitis

Czaja

2014

Aliment Pharmacol Ther

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“…Results with metformin (a biguanide) have been heterogeneous, most studies have been small and have flaws in the design, and its effect may be largely related to its ability to induce weight loss. [134][135][136][137][138] Data with thiazolidinediones (pioglitazone, troglitazone, and rosiglitazone) for the treatment of NASH are more robust. [139][140][141][142] However, it is unclear whether a thiazolidinedione-associated increase in adiposity and weight gain would ultimately limit its benefits.…”

Section: Prevention and Management Of Haart Liver Toxicitymentioning

confidence: 99%

Clinical Syndromes and Consequences of Antiretroviral-Related Hepatotoxicity5, 1, 3

Núñez

2010

Hepatology

160

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Highly active antiretroviral therapy (HAART)-related hepatotoxicity complicates the management of patients infected with human immunodeficiency virus (HIV), increases medical costs, alters the prescription patterns, and affects the guideline recommendations. Among the clinical consequences derived from HAART-related liver toxicity, hypersensitivity reactions and lactic acidosis are recognized as acute events with potential to evolve into fatal cases, whereas there seems to be other syndromes not as well characterized but of equal concern as possible long-term liver complications. Belonging to the latter category of syndrome, HAART-related nonalcoholic steatohepatitis, liver fibrosis, portal hypertension, and nodular regenerative hyperplasia are discussed in this review. Updated information on liver toxicity of current antiretroviral drugs, including the most recently licensed, is provided. Management and prevention of liver toxicity among HIV-infected patients treated with HAART are reviewed as well.

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“…Human studies have documented a reduction in aminotransferases with metformin. [6][7][8][9][10][11] However, alanine aminotransferase (ALT) breakthrough was reported, 12 suggesting that there is no sustained effect. Other 1-year trials showed no overall significant reduction in ALT values.…”

Section: Efficacy Outcomes In Nashmentioning

confidence: 99%

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

2010

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Insulin sensitizers are attractive candidate therapies for nonalcoholic steatohepatitis mainly because of the strong association between this disease and insulin resistance. This review provides a critical overview of the mechanisms of action, clinical trial results, and safety issues of metformin and glitazones in nonalcoholic steatohepatitis. It also highlights methodological challenges for trial design and proposes endpoints for future proof of principle, registrational, and postmarketing trials. (HEPATOLOGY 2010;52:2206-2215 N onalcoholic steatohepatitis (NASH) is emerging as the next big therapeutic challenge in hepatology. 1 Currently the top cause of newly identified chronic liver diseases, NASH has potential for fibrosis, cirrhosis decompensation, and hepatocellular carcinoma. Not all individuals with metabolic risk factors will experience these adverse outcomes and identifying those at risk is critical. Prognostic markers for progression have mostly been derived from histological studies. Compared to steatosis alone or to steatosis and minimal inflammation, the coexistence of inflammation, cell injury (ballooning), and steatosis, a pathological aggregate labeled steatohepatitis, is associated with a significant increase in overall mortality and in liver-related mortality. The degree of inflammation is the best predictor of fibrosis progression, 2 a widely accepted surrogate for hard endpoints such as cirrhosis, endstage liver disease, and possibly hepatocellular carcinoma.Insulin resistance (IR) is consistently found in patients with NASH in both cross-sectional and longitudinal studies. Moreover, there is a stepwise increase in the severity of IR and its phenotypic complications (clustered as elements of the metabolic syndrome) between normal liver, isolated steatosis, and steatohepatitis that has prompted speculation that IR might contribute to liver damage. Logically, most therapeutic trials focused on insulin sensitizers (IS) as candidate therapies.The aim of this report is to critically review the results of trials of metformin and glitazones for NASH. We highlight methodological challenges for trial design and propose endpoints for future proof of principle, registrational, and postmarketing trials.

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Combination of N‐acetylcysteine and metformin improves histological steatosis and fibrosis in patients with non‐alcoholic steatohepatitis

Abstract: Based on the biochemical and histological evidence in this pilot study, NAC in combination with MTF appears to ameliorate several aspects of NASH, including fibrosis. Further studies of this form of combination therapy are warranted to assess its potential efficacy.

Cited by 103 publications

References 42 publications

Review article: the prevention and reversal of hepatic fibrosis in autoimmune hepatitis

Review article: the prevention and reversal of hepatic fibrosis in autoimmune hepatitis

Clinical Syndromes and Consequences of Antiretroviral-Related Hepatotoxicity5, 1, 3

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

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