Methotrexate Hepatotoxicity and the Impact of Nonalcoholic Fatty Liver Disease

doi:10.1016/j.amjms.2017.03.014

The American Journal of the Medical Sciences

Volume 354, Issue 2, August 2017, Pages 172-181

https://doi.org/10.1016/j.amjms.2017.03.014 Get rights and content

Abstract

Methotrexate (MTX) is commonly used to treat individuals with rheumatological and dermatologic disorders. Current American College of Rheumatology (ACR) and American Association of Dermatology (AAD) guidelines identify diabetes and obesity as risk factors for MTX-induced liver injury. Both diabetes and obesity are components of the metabolic syndrome, and are also risk factors for nonalcoholic fatty liver disease (NAFLD). NAFLD affects approximately 40% of the U.S. population, and those with more advanced NAFLD (i.e., nonalcoholic steatohepatitis with or without fibrosis) are likely to develop progressive liver disease. As such, individuals who are treated with MTX may need to be screened for advanced NAFLD, as this may put them at an increased risk of MTX-induced liver injury. In this mini-review, we review the current ACR and AAD guidelines on MTX hepatotoxicity, discuss the evidence (or lack thereof) of the impact of metabolic risk factors on MTX-induced liver injury and highlight the areas that need further research.

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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Methotrexate (MTX), a folic acid antagonist, is commonly prescribed as a cytotoxic drug to treat several conditions such as leukemia and inflammation-related diseases, including rheumatoid arthritis and psoriasis. However, its use in clinical practice has been limited due to its fatal side effects, especially hepatotoxicity. Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has recently been reported to exhibit anti-inflammatory and anti-oxidative properties. This study was aimed to evaluate the effect of Empagliflozin on liver injury induced by MTX in rats. The rats were divided into five groups as control, MTX (20 mg/kg; i.p.), Empagliflozin (30 mg/kg/day; i.p.), MTX and Empagliflozin (10 and 30 mg/kg/day; i.p.). Histopathologic alterations were examined for assessment of the liver injury. Furthermore, the levels of tissue malondialdehyde (MDA) and activity of anti-oxidative enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase, as well as serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were evaluated. Our results revealed that treatment with Empagliflozin significantly improved histopathologic alterations, and elevated levels of AST and ALT induced by MTX administration. Additionally, altered activities of SOD, GPx, and catalase were significantly improved followed by Empagliflozin treatment. However, the higher dose of Empagliflozin was observed to have several benefits compared to the lower dose. Our data suggest that Empagliflozin might possess a protective role against MTX-induced hepatotoxicity by inhibiting oxidative stress in liver tissue.
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There are many approved therapeutic options for treating patients with PsA, and additional emerging treatment options are in the pipeline. Individualized treatment decisions for each patient, depending on the leading disease phenotype, underlying comorbidities, and patient preferences, should be made based on shared decision-making.
[Translated article] Common Approach to Metabolic-Associated Fatty Liver Disease in Patients With Psoriasis: Consensus-Based Recommendations From a Multidisciplinary Group of Experts
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Recent years have seen concerted efforts to understand the relation between psoriasis and metabolic-associated fatty liver disease (MAFLD). Not only is MALFD diagnosed more often in patients with psoriasis, but its clinical course is also more aggressive. A common approach is therefore needed to enable early detection of liver disease coincident with psoriasis. Especially important is an analysis of risks and benefits of potentially hepatotoxic treatments. This consensus paper presents the recommendations of a group of experts in dermatology and hepatology regarding screening for MALFD as well as criteria for monitoring patients and referring them to hepatologists when liver disease is suspected.
En los últimos años se están haciendo notables esfuerzos para entender la relación existente entre la psoriasis y la esteatosis hepática metabólica (EHmet). Este trastorno no solo se presenta con una mayor prevalencia en pacientes psoriásicos, sino que además se acompaña de una mayor gravedad. Con este precedente se evidencia la necesidad de establecer un protocolo de abordaje precoz de la enfermedad hepática en los pacientes con psoriasis. Asimismo, es de especial relevancia la evaluación del riesgo y del beneficio en referencia al uso de tratamientos con potencial hepatotóxico. En el presente manuscrito se exponen las recomendaciones de un panel de expertos en dermatología y hepatología para el cribado, el diagnóstico, la monitorización y los criterios de derivación en pacientes con psoriasis, en caso de sospecha de esteatosis hepática metabólica.
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Citation Excerpt :
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2022, Current Opinion in Pharmacology
For the last several decades, the standard of care for the initial management of rheumatoid arthritis (RA) has been methotrexate. Methotrexate is effective as monotherapy and in combination with conventional, biologic, and targeted-synthetic therapies. Methotrexate is generally well-tolerated, but has important, albeit uncommon, potential side-effects including a risk of liver toxicity and cytopenias. Some studies suggest that more active monitoring in patients with fatty liver disease may be appropriate. With reassuring safety data, more rapid dose escalation and use of subcutaneous therapy may provide even greater success. Some off-target benefits such as a reduction in cardiovascular disease risk have also been demonstrated, though these studies may suffer from confounding. Recent published guidelines continue to endorse methotrexate as first-line therapy. Methotrexate is a low-cost, safe, and effective therapy for RA that should not be overlooked nor too quickly abandoned.

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^☆: The authors have no financial or other conflicts of interest to disclose.

^☆: Co-first authorship.

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Review ArticleMethotrexate Hepatotoxicity and the Impact of Nonalcoholic Fatty Liver Disease☆,☆

Abstract

Introduction

Section snippets

History of Baseline Liver Biopsy

MTX Monitoring in Psoriasis

Metabolic Syndrome

Alcohol

Recommendations

Future Research

The mechanism of action of the folate antagonists in man

Cancer Res

The pharmacology and clinical use of methotrexate

N Engl J Med

Methotrexate in psoriasis: consensus conference

J Am Acad Dermatol

Prevalence of metabolic syndrome in patients with psoriasis: a hospital-based case-control study

Br J Dermatol

Age and gender differences in Framingham risk score and metabolic syndrome in psoriasis patients: a cross-sectional study in the Turkish population

Anatol J Cardiol

Prevalence of metabolic syndrome in patients with psoriasis: a population-based study in the United Kingdom

J Invest Dermatol

Increased prevalence of the metabolic syndrome in patients with moderate to severe psoriasis

Arch Dermatol Res

Metabolic syndrome: nonalcoholic fatty liver disease

FP Essent

Extrahepatic complications of nonalcoholic fatty liver disease

Hepatology

Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity

Gastroenterology

Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study

Gastroenterology

Nonalcoholic fatty liver disease

N Engl J Med

Hepatic fibrosis in children with acute leukemia after therapy with folic acid antagonists

AMA Arch Pathol

Drug use and toxicity in psoriatic disease: focus on methotrexate

J Rheumatol

Use of methotrexate in psoriasis

Arch Dermatol

Methotrexate in psoriasis: revised guidelines

J Am Acad Dermatol

Sequential liver biopsies during long-term methotrexate treatment for psoriasis: a reappraisal

Br J Dermatol

Methotrexate and liver toxicity: role of surveillance liver biopsy. Conflict between guidelines for rheumatologists and dermatologists

Ann Rheum Dis

Light and electron microscopic analysis of sequential liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy. Followup over long treatment intervals and correlation with clinical and laboratory variables

Arthritis Rheum

Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up

Can J Gastroenterol

Methotrexate hepatotoxicity in psoriatic patients submitted to long-term therapy

Acta Derm Venereol

Methotrexate induced liver cirrhosis. Studies including serial liver biopsies during continued treatment

Br J Dermatol

A prospective analysis of liver biopsies in rheumatoid arthritis patients receiving long term methotrexate therapy

Rheum Int

Methotrexate-induced liver cirrhosis. Clinical, histological and serological studies—a further 10-year follow-up

Methotrexate hepatotoxicity in psoriasis. Consideration of liver biopsies at regular intervals

Arch Dermatol

Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology

Arthritis Rheum

Monitoring liver function during methotrexate therapy for psoriasis: are routine biopsies really necessary?

Am J Clin Dermatol

Monitoring methotrexate-induced hepatic fibrosis in patients with psoriasis: are serial liver biopsies justified?

Aliment Pharmacol Ther

Histological grading and staging of chronic hepatitis

J Hepatol.

Classification of chronic viral hepatitis: a need for reassessment

J Hepatol.

Psoriasis patients with diabetes type 2 are at high risk of developing liver fibrosis during methotrexate treatment

J Hepatol

Design and validation of a histological scoring system for nonalcoholic fatty liver disease

Hepatology

Liver injury in long-term methotrexate treatment in psoriasis is relatively infrequent

Aliment Pharmacol Ther

Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference

J Am Acad Dermatol

Review Article
Methotrexate Hepatotoxicity and the Impact of Nonalcoholic Fatty Liver Disease☆,☆