Journal of Hepatology
Volume 46, Issue 6 , Pages 995-998, June 2007

Dangerous liaisons: Drug, host and the environment

Division of Gastroenterology and Pathology, Queen’s Medical Centre University Hospital, Nottingham, UK

published online 07 April 2007.

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Keywords: Methotrexate, Fibrosis, Steatosis, Endoplasmic reticulum (ER) stress, Drug induced

 

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1. Introduction 

Methotrexate is an effective treatment for moderate to severe psoriasis, especially in the presence of arthritis with significant and sustained benefit in 75% of treated patients [1]. The most feared adverse effect of long-term methotrexate treatment is hepatic steatosis and fibrosis. Reports that up to 26% of psoriatic patients on long-term methotrexate develop cirrhosis [2] fuelled concerns over methotrexate-induced liver injury and lead to the intensive regime of liver biopsies advised in the guidelines [3]. Clinicians and patients have been discouraged from using methotrexate, because of the need for routine liver biopsies to detect hepatic fibrosis [4].

However, there is a wide variation in the reported frequency of significant fibrosis ranging from 2% to 33% and cirrhosis from 0% to 26% (summarised in Table 1). These studies not only vary in sample size, design and the endpoints, but also include patients with a variety of risk factors, different methotrexate dosage regimes and cumulative doses. Interaction between varieties of factors related to the drug, host and the environment determines the likelihood and magnitude of liver injury in patients receiving methotrexate therapy.

Table 1. Studies investigating the frequency of liver injury in patients with psoriasis on long-term methotrexate therapy
StudynRegimeMean cumulative dose (g)Mean duration (months)Advanced fibrosis (%)Cirrhosis (%)
Reese et al. [5]35WSNA (25–50mg/wk)NA63
Zachariae et al. [2]39WD>4>60NA25.6
Robinson et al. [6]43WD1.272725.60
Lanse et al. [7]30WS0.27–6.912–120130
Mitchell et al. [8]51WS2.54 median62 median206
Themido et al. [9]21NA5.78NA33.39.5
Van Dooren Greebe et al. [10]55WD4.810724
Boffa et al. [11]49WS2.763220
Malatjalian et al. [12]104WS/WDNA (20–30mg/wk)44203
Aithal et al. [13]66WS3.2 median65.54.50
Berendis et al. [14]125WS2.1 median57 median42

NA, not available; WS, single weekly dose of methotrexate; WD, divided weekly dose of methotrexate.

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2. Drug 

2.1. Dose effect 

Observations from previous studies indicate that the liver injury in patients on methotrexate therapy is linked closely to its mechanism of action. Both dose and frequency of drug administration influence the risk of liver disease. Frequency of advanced fibrosis increases with the cumulative dose of methotrexate [2], [6], [13], [15]. Low doses given daily or on alternate days result in up to a fourfold increase in the incidence of fibrosis or cirrhosis relative to larger doses given once weekly [16], [17], [18]. Incidence of cirrhosis in patients maintained on a maximum weekly dose of 20mg is lower (0–4%) [6], [10], [11], [13], compared with patients maintained on >20mg weekly doses (3–25.6%) [2], [12], [19]. The use of higher and more frequent dosing in the older studies may well have contributed to the higher rates of histological abnormalities detected.

2.2. Potential mechanism of liver injury 

The pathogenesis of chronic methotrexate hepatotoxicity is not well understood. Methotrexate is a folate analogue and is taken up by specific transporters into the cells where it inhibits synthesis of purines and pyrimidines as well as conversion of homocysteine to methionine. Once inside the cell, methotrexate is metabolised into a polyglutamate, which in itself inhibits de novo purine synthesis and is stored in the cell long-term [20]. Both methotrexate and its active metabolites could cause chronic inhibition of hepatic folate metabolism [21]. Excess homocysteine may lead to liver injury in three different ways. Firstly, it can sensitise the cell to cytotoxic effect of agents or conditions that generate oxidative stress [22]. Second, homocysteine disrupts disulphide bond formation leading to misfolding of proteins. Endoplasmic reticulum (ER) stress is a condition under which unfolded and misfolded proteins accumulate triggering activation of a number of transcription factors including the sterol regulatory element-binding protein [23]. These increase lipid synthesis needed for the generation of more ER membranes, but can lead to fatty liver. Prolonged unfolded protein response results in apoptosis [23]. Third, homocysteine has been shown to activate proinflammatory cytokines. A wide range of these hepatic insults converge on the hepatic stellate cell which responds by becoming activated and altering extracellular matrix metabolism in favour of fibrosis.

Whatever the precise mechanism of hepatotoxicity, the deleterious effects of methotrexate probably act in conjunction with other injurious stimuli e.g. alcohol and other risk factors for liver disease leading to fibrosis and ultimately to cirrhosis.

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3. Host 

Genetic factors may account for some of the variation in the frequency of liver injury in different cohorts and the degree of histological changes between individuals. Genetic factors may influence the bioavailability, metabolism and elimination of the drug as well as the consequences of liver injury. Mild hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) 677C to T polymorphism has been associated with steatosis and fibrosis in chronic hepatitis C patients [24]. But, a study including 150 patients with rheumatoid arthritis on methotrexate did not show any association of MTHFR polymorphism with hepatotoxicity [25]. As liver enzymes were used as markers of liver injury in this study, no firm conclusions can be drawn from these observations. Considering the low frequency of hepatotoxicity during methotrexate therapy and lack of reliable and validated biomarkers of liver injury, studies on genetic susceptibility to liver injury will need to recruit a large cohort of patients including a significant number with fibrosis on liver biopsy.

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4. Environment 

It could be argued that identification of environmental risk factors and selection of low risk individuals for methotrexate therapy has been the key factor behind the relatively low frequency of serious hepatotoxicity in recent reports [13], [14]. The influence of alcohol in causing or contributing to histological damage in psoriasis patients on methotrexate is well recognised. A meta-analysis by Whiting-O’Keefe et al. demonstrated that the rate of progression to advanced histological changes on methotrexate is increased 2.5- to 5-fold in heavy alcohol users [26]. Rates of fibrosis and cirrhosis are low in studies where significant efforts have been made to limit alcohol intake in the study population [5], [7], [13]. Diabetes mellitus [12], [16] and obesity [15], [16] are also independent risk factors for liver disease that have been shown to correlate with advanced biopsy findings in patients on methotrexate.

Rosenberg et al. [27] have reviewed 169 monitoring liver biopsies from 71 patients with psoriasis on methotrexate therapy to assess the impact of risk factors on the development of fibrosis. Consistent with previous observations, the authors demonstrate that patients with risk factors such as diabetes, alcohol excess, obesity and chronic viral hepatitis are more likely to develop advanced fibrosis at a lower cumulative dose when compared with those without such risk factors. However, as in the case of almost all previous reports of methotrexate-induced liver fibrosis, the current study is also based on retrospective, observational data without a comparable control group (such as psoriasis patients with similar risk factor profile, who are not on methotrexate therapy). The study includes patients with a wide range of risk categories and duration of exposure to methotrexate; hence, it is difficult to accurately quantify the individual contribution of each of these factors to hepatotoxicity. Despite the implied emphasis in the title on type 2 diabetes, only 7 patients with diabetes were included in the study. As shown in previous studies on the natural history of non-alcoholic fatty liver disease (unrelated to methotrexate therapy), simple steatosis does not correlate with advanced histological changes, whereas steatohepatitis readily progresses to fibrosis. Even in patients on methotrexate therapy investigated in this study, it is the risk factors that are associated with steatohepatitis and the drug is judged guilty just based on association.

Emerging data suggest that ER stress may be a key mechanistic link between obesity, insulin resistance and type 2 diabetes [28]. ER stress may underlie alcohol-induced liver injury and may also explain the interaction between alcohol and chronic viral hepatitis [29]. Therefore, it is tempting to speculate that the drug, methotrexate, generates ER stress, which is perpetuated by the environmental factors such as alcohol, diabetes, obesity and chronic viral hepatitis that augment this process eventually determining the extent of the liver injury in a given individual.

Clinical experience and observational studies over the past three decades have highlighted the importance of recognising the risk factors in the primary prevention of hepatotoxicity and reducing its risk in psoriasis patients on methotrexate therapy [30]. Evolving epidemic of metabolic syndrome will certainly increase the proportion of patients with one or more of these risk factors. This will be compounded further by the potential interaction between metabolic syndrome and psoriasis [31]. Understanding of mechanisms mediating the liver injury and the host factors that contribute to the susceptibility is equally important in developing a measured response to a growing clinical problem.

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References 

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PII: S0168-8278(07)00194-8

doi:10.1016/j.jhep.2007.03.017

Journal of Hepatology
Volume 46, Issue 6 , Pages 995-998, June 2007

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