Review ArticleMethotrexate Hepatotoxicity and the Impact of Nonalcoholic Fatty Liver Disease☆,☆
Introduction
Methotrexate (MTX) is an inhibitor of the enzyme dihydrofolate reductase, and it reduces the levels of folate cofactors necessary for nucleic acid synthesis.1 Initially used to treat childhood leukemia, it has since gained popularity in the treatment of various dermatologic, rheumatological, oncological and inflammatory bowel diseases.2 Since its inception into the treatment armamentarium for rheumatoid arthritis (RA) and psoriasis, MTX has continued to be the most favored steroid-sparing immunosuppressant.3 The introduction of MTX preceded the era of randomized control trials; therefore, limited safety data existed before the initiation of MTX use. However, with the continued use of MTX, recognition of its adverse effects has grown. One important adverse effect is liver injury, and MTX-associated–induced liver injury has been noted to be more prevalent in patients with psoriasis than those with RA. The reasons for this apparent disparity is not known, but there is a much higher prevalence of metabolic syndrome, including nonalcoholic fatty liver disease (NAFLD), in patients with psoriasis compared with the general population.4, 5, 6, 7
Nonalcoholic fatty liver disease is a leading cause of chronic liver disease in the United States and is strongly associated with metabolic risk factors such as type 2 diabetes mellitus (T2DM) and obesity. It is considered the hepatic manifestation of metabolic syndrome8 and affects nearly 40% of the U.S. population, mirroring both the obesity and T2DM epidemics.9, 10, 11 NAFLD encompasses a wide spectrum of histopathological states, ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular cancer.12 Among patients treated with MTX, those with metabolic syndrome are at an increased risk of MTX hepatotoxicity. Nevertheless, it is unclear if these individuals have underlying NAFLD that predisposes them to liver injury.
We will review the association between metabolic syndrome and MTX-associated liver injury, discuss the current clinical practice guidelines for monitoring MTX-associated liver injury, examine their limitations and highlight the areas for future research.
Section snippets
History of Baseline Liver Biopsy
Methotrexate hepatotoxicity was first reported in 1955 when 5 children who achieved remission from acute leukemia after treatment with MTX developed liver cirrhosis.13 Over the ensuing 3 decades, despite increasing recognition of MTX-associated liver injury, which includes hepatic steatosis followed by hepatic fibrosis and, rarely, cirrhosis,14 the underlying mechanism for hepatotoxicity has remained poorly understood. As such, MTX-associated liver injury continued to be the primary concern for
MTX Monitoring in Psoriasis
Histological assessment of liver biopsies in numerous studies19, 21, 22, 23, 24, 25, 19, 21, 22, 23, 24, 25 lacked conformity in using an established histological scale.18, 27 The Roenigk scale (Table 1), which was previously advocated by the AAD, and an ad hoc scale (described in the study itself) were used for the histological assessment of MTX-associated liver toxicity in these studies, but neither the Roenigk scale nor the ad hoc scale was ever validated for evaluation in any other liver
Metabolic Syndrome
Risk factors associated with NAFLD include obesity, T2DM, hyperlipidemia (HLD), hypertension, obstructive sleep apnea, polycystic ovarian syndrome and gout, all of which constitute the metabolic syndrome and are summarized further in Table 5.12, 40, 41, 42, 40, 41, 42 The apparent disparity between MTX-associated hepatotoxicity, specifically fibrosis, in patients with psoriasis and RA is likely related to the differences in the prevalence of metabolic risk factors. Cross-sectional studies
Alcohol
Excess alcohol consumption is a well-established risk factor for both alcohol-related liver injury and MTX-associated livery injury, with the quantity of alcohol consumed being a major predictor. In a meta-analysis by the Whiting-O׳Keefe group,37 heavy alcohol consumption (>100 g/week) was associated with an increased risk of developing MTX-associated liver fibrosis, up to 5 times higher, and this risk is observed even with lower doses of MTX therapy.28, 31 Although there is no consensus
Recommendations
Evaluation of a patient at risk for hepatotoxicity from MTX should therefore include assessment for risk factors for metabolic syndrome, as listed in Table 5, and the above discussed MTX-associated liver injury risk factors, summarized in Table 7. The risk of hepatotoxicity in long-term use of low-dose MTX dosed weekly is low in patients without risk factors. The risk of MTX-associated liver injury increases when the cumulative dose exceeds 4,000 mg. In this patient population, it is reasonable
Future Research
The metabolic syndrome comprises a constellation of medical disorders and pathophysiological states, ranging from central obesity and insulin resistance to nocturnal hypoxia and disruption of the circadian clock. We have highlighted the association of obesity, T2DM, HLD and NAFLD to MTX-associated liver injury, but the effect of other metabolic risk factors (described in Table 5) on MTX-associated liver injury is unknown, and needs to be better understood. Importantly, whether NAFL, NASH or
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