Focus
Authors: Daniel Shouval
Journal: Journal of Hepatology (2010)

Low-dose methotrexate (MTx, 2.5–25 mg/week) has been used successfully for several decades in the treatment of non-malignant diseases such as psoriasis (Ps), rheumatoid arthritis (RA) [1Curtis J.R. Beukelman T. Onofrei A. Cassell S. Greenberg J.D. Kavanaugh A. et al.Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide.Ann Rheum Dis. 2010; 69: 43-47Crossref PubMed Scopus (177) Google Scholar, 2Roenigk Jr., H.H. Auerbach R. Maibach H. Weinstein G. Lebwohl M. Methotrexate in psoriasis: consensus conference.J Am Acad Dermatol. 1998; 38: 478-485Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar, 3Erickson A.R. Reddy V. Vogelgesang S.A. West S.G. Usefulness of the American College of Rheumatology recommendations for liver biopsy in methotrexate-treated rheumatoid arthritis patients.Arthritis Rheum. 1995; 38: 1115-1119Crossref PubMed Scopus (93) Google Scholar, 4Kalb R.E. Strober B. Weinstein G. Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference.J Am Acad Dermatol. 2009; 60: 824-837Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar], as well as Crohn’s disease (CrD). High-dose administration of MTx (at 100–1000 mg/mm2) for various malignancies may lead to stomatitis, gastrointestinal, hepatic, and pulmonary toxicity as well as bone-marrow suppression. In contrast, low-dose MTx is less toxic and the main undesired effect is hepatotoxicity. Soon after the introduction of MTx for long-term, low-dose treatment regimens, it became clear that aminotransferase and alkaline phosphatase elevations are relatively frequent and often reversible. Conflicting data have been reported regarding the incidence of MTx-associated hepatotoxicity. In one report, 22% of MTx recipients with RA and twice as much with Ps arthritis had evidence for abnormal liver functions [[1]Curtis J.R. Beukelman T. Onofrei A. Cassell S. Greenberg J.D. Kavanaugh A. et al.Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide.Ann Rheum Dis. 2010; 69: 43-47Crossref PubMed Scopus (177) Google Scholar]. Cirrhosis was reported in 25% of patients with Ps arthritis receiving long-term low-dose MTX [[2]Roenigk Jr., H.H. Auerbach R. Maibach H. Weinstein G. Lebwohl M. Methotrexate in psoriasis: consensus conference.J Am Acad Dermatol. 1998; 38: 478-485Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar] and in <2% of patients with RA [[3]Erickson A.R. Reddy V. Vogelgesang S.A. West S.G. Usefulness of the American College of Rheumatology recommendations for liver biopsy in methotrexate-treated rheumatoid arthritis patients.Arthritis Rheum. 1995; 38: 1115-1119Crossref PubMed Scopus (93) Google Scholar] This difference in the hepatoxic potential of MTx between patients with Ps and RA was not confirmed in a recent study [[5]Amital H. Arnson Y. Chodick G. Shalev V. Hepatotoxicity rates do not differ in patients with rheumatoid arthritis and psoriasis treated with methotrexate.Rheumatology (Oxford). 2009; 48: 1107-1110Crossref PubMed Scopus (43) Google Scholar]. MTx may lead to a spectrum of hepatic histologic abnormalities including steatosis, hypertrophy of stellate cells, variations in hepatocyte nuclei size, as well as fibrosis which are not always associated with elevated AST or ALT. Until recently, it was believed that MTx-induced hepatotoxicity was dose dependent and guidelines recommended performing a liver biopsy after every 1.0–1.5 g of cumulative MTx intake. Nowadays, it seems that hepatotoxicity is not necessarily MTx dose dependent and may be associated with a number of risk factors including a history of more than moderate alcohol intake, diabetes mellitus, obesity, hyperlipidemia, presence of underlying liver disease, female gender, and inadequate supplementation with folate. Consequently, recent guidelines have limited the use of liver biopsies in the monitoring of Ps patients without such risk factors [[4]Kalb R.E. Strober B. Weinstein G. Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference.J Am Acad Dermatol. 2009; 60: 824-837Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar]. Hepatologists are frequently confronted with questions regarding the safety of continuous administration of MTx in patients with Ps, RA, or CrD disease. The introduction of new non-invasive tests such as FibroTest and FibroScan for the assessment of hepatic inflammatory activity and fibrosis is now being explored in a variety of liver diseases as a means for replacing liver biopsies in the diagnosis and monitoring of occult and overt liver injury. Pilot studies performed in a small number of patients with Ps and CrD have already provided some preliminary evidence that FibroTest predicts the presence of fibrosis, whereas FibroScan, the absence of fibrosis in MTx-treated patients [6Berends M.A. Snoek J. de Jong E.M. Van Krieken J.H. de Knegt R.J. van Oijen M.G. et al.Biochemical and biophysical assessment of MTX-induced liver fibrosis in psoriasis patients: Fibrotest predicts the presence and Fibroscan predicts the absence of significant liver fibrosis.Liver Int. 2007; 27: 639-645Crossref PubMed Scopus (65) Google Scholar, 7Laharie D. Zerbib F. Adhoute X. Boue-Lahorgue X. Foucher J. Castera L. et al.Diagnosis of liver fibrosis by transient elastography (FibroScan) and non-invasive methods in Crohn’s disease patients treated with methotrexate.Aliment Pharmacol Ther. 2006; 23: 1621-1628Crossref PubMed Scopus (76) Google Scholar]. In this issue of the Journal, Laharie and co-workers [[8]Laharie D. Seneschal J. Schaeverbeke T. Doutre M.-S. Longy-Boursier M. Pellegrin J.-L. et al.Does methotrexate induce liver fibrosis? A prospective study with non-invasive methods.J Hepatol. 2010; 53: 1035-1040Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar] have expanded their initial observation using FibroTest and FibroScan in 384 MTx-treated patients and 128 case controls (124, 149, and 111 patients with CrD, RA, and PS, respectively). An additional group of 134 patients, with other inflammatory diseases treated by MTx, were also evaluated by the same methodology. The main findings of this large prospective study revealed that only an overall 8.5% of MTx recipients had indirect evidence by FibroTest (0.58 cut off) and/or FibroScan (7.9 kPa cut off) for severe fibrosis. Interestingly, and confirming earlier small-scale observations, multivariate analysis revealed that neither cumulative dose nor treatment duration of MTx was associated with significant fibrosis. On the other hand, risk factors such as an increased intake of alcohol and body mass index >28 kg/m2 were associated with a higher rate of fibrosis as determined by these non-invasive procedures. Furthermore, of the 43 patients with evidence for severe liver fibrosis based on either of these tests, advanced fibrosis was detected by both non-invasive tests in only 7/43 patients, while 24/43 were positive by FibroScan alone and 12 by FibroTest alone. The discrepancy between the results obtained by the different non-invasive methods does not enable to distinguish which of the two tests is superior for monitoring MTx recipients. Further exploration is required to form an opinion whether both FibroTest and FibroScan or only one of these tests will be enough for follow-ups. Nevertheless, these data provide an important contribution in addressing the controversy surrounding the relevance and timing for the indication of a liver biopsy and support the introduction of such technique(s) in the follow-up of low-dose MTx recipients (especially in Ps). One should, however, keep in mind that the study had some limitations including the relatively short follow-up time of MTx recipients, the relatively low cumulative median dose of MTx administered, the small number of patients with fibrosis who underwent a liver biopsy, and the disparities between the results of FibroScan and FibroTest. Based on the results of this study, it seems at present premature to recommend an overall transition from cumulative MTx-driven liver biopsies to the non-invasive follow-up of patients with FibroScan and or FibroTest. Yet, the future looks promising regarding the role of such tests in the follow-up of patients at risk. Decisions regarding the performance of a liver biopsy during the follow-up of MTx recipients should be individualized based on the clinical evidence of advanced fibrosis by non-invasive techniques, and/or suspicion for an underlying liver disease or risk factor not related to MTX intake. A longer follow-up of the patients included in this study is required. The good news is that the rates of advanced fibrosis and cirrhosis in this large cohort of MTx recipients seem to be lower than those previously reported. Severe acute alcoholic hepatitis is associated with a 40–50% mortality within ∼8 weeks in hospitalized patients with a discriminant function (DF) ⩾32 and/or hepatic encephalopathy. Several therapeutic interventions have been evaluated so far in an attempt to control the devastating alcohol-induced hepatic injury and its consequences. These include administration of corticosteroids, pentoxifylline, anti-TNF agents, oxandrolone, silymarine, nutritional and general support measures, and anti-oxidants [9Lucey M.R. Management of alcoholic liver disease.Clin Liver Dis. 2009; 13: 267-275Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 10Lucey M.R. Mathurin P. Morgan T.R. Alcoholic hepatitis.N Engl J Med. 2009; 360: 2758-2769Crossref PubMed Scopus (725) Google Scholar]. Treatment with corticosteroids in a subgroup of non-bleeding, non-septic patients remains so far the most effective therapeutic intervention to improve the short-term (one month) survival in such patients [[11]Mathurin P. Mendenhall C.L. Carithers Jr., R.L. Ramond M.J. Maddrey W.C. Garstide P. et al.Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH.J Hepatol. 2002; 36: 480-487Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar]. In one study, the administration of pentoxifylline was shown to improve the 28 day mortality rate by almost 50% in a small placebo controlled trial and reduced the development of hepatorenal syndrome [[12]Akriviadis E. Botla R. Briggs W. Han S. Reynolds T. Shakil O. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial.Gastroenterology. 2000; 119: 1637-1648Abstract Full Text Full Text PDF PubMed Scopus (669) Google Scholar]. Except for these two modalities, none of the other above-mentioned measures has been shown to provide significant survival benefits in such patients. Yet, treatment with anti-oxidants for alcoholic hepatitis continues to attract the attention of investigators in the field despite repeated failures recorded in clinical trials using, among others, vitamins E, biotin, desferrioxamine, selenium, zinc, manganese, copper, and magnesium [13Mezey E. Potter J.J. Rennie-Tankersley L. Caballeria J. Pares A. A randomized placebo controlled trial of vitamin E for alcoholic hepatitis.J Hepatol. 2004; 40: 40-46Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 14Stewart S. Prince M. Bassendine M. Hudson M. James O. Jones D. et al.A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis.J Hepatol. 2007; 47: 277-283Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar]. The continued interest in the potential value of anti-oxidants in the treatment of alcoholic hepatitis is driven by ample evidence obtained in experimental models as well as in humans, implicating oxidative stress as an important mechanism involved in hepatic injury. Hence, blocking pro-oxidant reactive oxygen species (ROS) and, as a consequence, slowing down lipid peroxidation and mitochondrial injury remain an important goal. N-Acetylcystein (NAC) is a potent anti-oxidant with an established record as an antidote in paracetamol over-dose. NAC, a glutathione precursor, replenishes hepatic glutathione and suppresses ROS. The evidence regarding the efficacy of NAC in fulminant hepatitis, not related to paracetamol over-dose, is rather limited. However, NAC is by now frequently used as part of intensive care in patients with acute liver failure (ALF), irrespective of the etiology. Support for the use of NAC in ALF was recently obtained by the US Acute Liver Failure Study Group who conducted a double blind, randomized controlled trial using intravenous (IV) NAC or placebo for 72 h in 173 ALF patients (non-acetaminophen ALF of whom 45 were related to drug injury) [[15]Lee W.M. Hynan L.S. Rossaro L. Fontana R.J. Stravitz R.T. Larson A.M. et al.Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.Gastroenterology. 2009; 864: 856-864Abstract Full Text Full Text PDF Scopus (466) Google Scholar]. IV NAC did not improve the short-term 3 week survival but significantly improved the transplant-free survival in 40% vs 27% of NAC and placebo recipients, respectively (p= 0.043). It was, therefore, expected that NAC treatment would also be evaluated in alcoholic hepatitis. An early study performed in 70 patients with alcoholic hepatitis, all of whom were treated by corticosteroids, compared 1 week of NAC treatment followed by the intake of a cocktail of anti-oxidants with placebo for 6 months [[14]Stewart S. Prince M. Bassendine M. Hudson M. James O. Jones D. et al.A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis.J Hepatol. 2007; 47: 277-283Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar]. In this study, anti-oxidant treatment with or without corticosteroids did not provide a survival benefit by 6 months. In the present issue of the Journal, Moreno and co-workers evaluated, in a single blinded study, the 1 and 6 months survival rates in 52 patients receiving entral nutrition with or without IV NAC at 300 mg/kg for 14 days [[16]Moreno C. Langlet P. Hittelet A. Lasser A. Degré D. Evrard S. et al.Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute alcoholic hepatitis: a randomized multicenter controlled trial.J Hepatol. 2010; 53: 1117-1122Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar]. The study design differed from the study of Stewart et al. [[14]Stewart S. Prince M. Bassendine M. Hudson M. James O. Jones D. et al.A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis.J Hepatol. 2007; 47: 277-283Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar] and included a longer intake of NAC and the absence of corticosteroid treatment. No statistically significant difference at 1 and 6 months could be demonstrated between the study groups after recruiting the first 52 patients. An interim analysis performed at that stage concluded that in order to reach the study goals and a definite conclusion at a power of 80%, the study population should be expanded to 1022 patients. As a result, the study was discontinued and the value of NAC in the treatment of alcoholic hepatitis remains questionable at best. Based on the information obtained in the study of Stewart et al. and the present and incomplete study by Moreno et al., there still is no proof for a beneficial effect on survival of anti-oxidant therapies in general and of NAC in particular. This impression is also reflected in the recent guidelines on alcoholic liver disease of the American Association for the Study of the Liver which do not support the inclusion of NAC in the treatment of severe alcoholic hepatitis [[17]O’Shea R.S. Dasarathy S. McCullough A.J. Alcoholic liver disease.Hepatology. 2009; 51: 307-328Crossref Scopus (969) Google Scholar]. It remains to be seen if this new report will be the last nail in the coffin of anti-oxidant therapy in alcoholic hepatitis. The author who has taken part in this study declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.