Psoriasis patients with diabetes type 2 are at high risk of developing liver fibrosis during methotrexate treatment☆
Introduction
Methotrexate (MTX) has over the last three decades been used as a well-established and effective drug for treatment of severe psoriasis. Several studies performed in the 1960s and 1970s indicated a high incidence of liver cirrhosis, up to 26%, in patients treated long-term with low-dose MTX [1]. To meet the need for preventing severe hepatotoxicity among MTX treated psoriasis patients, guidelines for surveillance were formulated by Roenigk et al. in 1972 [2], latest revision 1998 [3]. A central part of these guidelines are repeatedly performed liver biopsies, since blood chemistry liver function tests alone are not reliable in predicting liver fibrosis in MTX treated psoriasis patients [4], [5], [6]. The risks of severe complications to percutaneous liver are well documented. Large studies have shown fatality rates between 0.03% and 0.32% [7] and a total risk for complications that require hospitalization at 1–3% [8]. The procedure also often evokes anxiety and discomfort in patients.
In more recent years, new studies have clearly indicated that the risk for patients on low-dose treatment with MTX to develop liver fibrosis probably is less than what was seen in earlier studies [5], [9], [10]. The need for surveillance with liver biopsies has therefore been questioned since the potential risk associated with the procedure has been regarded as not outweighing the potential benefit [5], [10]. Moreover, the development of alternative screening methods [11] for liver fibrosis, such as transient elastography (Fibroscan®) [12], [13] or measurement of serum markers [14], has given support to the opinion that the use of liver biopsy to monitor MTX treated patients can be substantially reduced.
MTX is a folic acid antagonist, which inhibits the dihydrofolate reductase necessary for a normal synthesis of nucleic acids. Proliferating cells die in the S phase, while there is little effect on resting cells [15]. In psoriasis, MTX blocks the rapid epidermal cell turnover and prevents inflammation through reducing neutrophil and monocyte chemotaxis and decreasing leukotriene-induced intra-epidermal penetration of granulocytes [3]. The mechanisms of methotrexate induced hepatotoxicity are not fully understood. From the results of in vitro experiments it has been suggested that increased oxidative stress contributes to methotrexate hepatotoxicity [16], [17], both through increased reactive oxygen species activity and impaired anti-oxidative defence via depleted intrahepatic glutathione depots [18]. Typical histopathological findings in MTX induced liver disease include nuclear atypia, vacuolization, and mild fatty metamorphosis [19].
Several risk factors for steato-hepatitis such as alcohol over-consumption [9], obesity [20], diabetes mellitus type 2 and insulin resistance [21], [22] are shared with MTX induced liver disease. This and the similarities in histological appearance have led to the hypothesis that non-alcohol steato-hepatitis (NASH) predisposes or contributes to MTX induced liver injury [23], [24]. Concomitant medication with hepatotoxic potential (e.g. leflunomide, azatioprine, sulfasalazine and retinoids), viral hepatitis, and older age at start of MTX treatment [6], [25] have also been shown to increase the risk of developing liver fibrosis during MTX therapy. Both NASH [26] and chronic viral hepatitis [27], [28] are common diseases worldwide and in most cases without any symptoms until complications occur.
In recent years increasing evidence has implicated that oxidative damage is a strong contributor in the pathogenesis of steato-hepatitis including alcohol, non-alcohol and viral hepatitis.
Our primary aim of this study was therefore to investigate the impact of risk factors associated with steato-hepatitis; diabetes mellitus type 2, overweight, alcohol over-consumption and chronic viral hepatitis on development of liver fibrosis in psoriasis patients treated with long-term, low-dose, MTX.
Second, we wanted to evaluate steato-hepatitis in these patients. The biopsies were therefore scored according to the proposed NAFLD activity score. We also investigated the predictive value of increased levels of biochemical markers before and during MTX treatment. The serum markers analyzed were Alanine Amino Transferase (ALT), Gamma-Glutamyl-Transferase (γGT), and Aspartate Amino Transferase AST/ALT ratio.
Third and finally, the correlation between liver steatosis and fibrosis development was studied.
Section snippets
Patients
The study was performed after a priori approval by the Regional Ethical Review Board in Stockholm.
Seventy-one patients (35 females and 36 males), that had undergone one or several liver protocol biopsies as part of the monitoring process of methotrexate treatment between 1975 and 2003, were studied. Twenty-six of these patients (11 females and 15 males) had one or more recognized risk factors for liver injury, distributed as shown in Table 2.
Median age at first biopsy was 52 (range 35–72) years
Liver fibrosis
Twenty-five (96%) of the patients with an identified risk factor (mean cumulative dose MTX 1500 mg) developed liver fibrosis, while in the group of 45 patients without any risk factors, 26 (58%) (p = 0.012) developed fibrosis (median cumulative dose methotrexate 2100 mg). In total, 51 (71%) of the patients in the study developed liver fibrosis of any degree (Fig. 1).
Analysis of patients with severe fibrosis revealed a more prominent difference between the groups. Ten (38%) of the patients with risk
Discussion
In this study, we have evaluated the impact of risk factors for steato-hepatitis on fibrosis development in MTX treated psoriasis patients. All patients treated at the participating clinics have been monitored according to guidelines issued by the American Academy of Dermatology (AAD) and we therefore consider the impact of selection bias to be of minor significance.
Chronic viral hepatitis was included as a risk factor since both chronic hepatitis B and C are commonly associated with hepatic
Acknowledgements
This study was supported by grants from the Swedish research council (No. 9127), the Bengt Ihre foundation and Karolinska Institutet. We wish to thank Jan Kowalski for the statistical analysis.
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The authors who have taken part in this study declared that they have no relationship with the manufacturers of the drugs involved either in the past or present and did not receive funding from the manufacturers to carry out their research. They received funding from the Swedish Research Council, The Bengt Ihre Foundation (Sweden) and Karolinska Institutet. Dr. N. Kinnman is employed by Merck Sirono Int.