Hepatotoxic potentials of methotrexate: Understanding the possible toxicological molecular mechanisms

Psoriasis can be paradoxically associated with human immunodeficiency virus (HIV) infection, having a prevalence similar to the general population but with a more severe evolution. In the genetically predisposed patients with the CW * 0602 haplotype, HIV infection can be a triggering factor and a first sign of infection, and lesions can spontaneously remit with immune reconstruction after antiretroviral therapy. Our patient is a 34 year-old male with recent HIV infection, in spite of being for over 10 years the partner of an HIV-positive patient with whom the patient has two HIV-positive children. The patient was diagnosed with psoriasis 7 years ago and was treated topically. The physical examination at HIV diagnosis was overall favorable, with skin findings compatible with disseminated vulgar psoriasis. Following antiretroviral treatment with Triumeq the patient had a favorable viral response, with complete viral suppression after 12 weeks, but the pre-existent psoriasis lesions worsened. Methotrexate (MTX) treatment followed for 12 weeks, with partial improvement of psoriatic dermatitis. This medication was continued for 1 year, but the lesions reappeared, possibly due to treatment resistance. MTX treatment for psoriasis in the HIV-infected patient was beneficial, but limited to one year, leaving biologics as possible treatment following therapy under strict monitoring for adverse effects, T-lymphocyte CD4 + and viral levels.

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“…MTX is an immune suppressive drug frequently used in autoimmune and inflammatory dermatological diseases ( 17 , 18 ).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic challenges of psoriasis in the HIV‑infected patient: A case report

Arbune

Niculeț

et al. 2021

Exp Ther Med

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“…Methotrexate (MTX) is commonly used for the treatment of autoimmune diseases and skin diseases, but rheumatoid arthritis and psoriasis patients who receive MTX therapy for a long time are at high risk of developing liver damage. MTX-PG, a metabolite of MTX, inhibits 5-aminoimidazole-4-carboxamide ribonucleotide transformylase enzyme, leading to intracellular adenosine accumulation, which in turn leads to HSC activation, ECM accumulation and liver fibrosis [59]. Acetaminophen (APAP) is one of the quantitively most consumed drugs worldwide, but overdosing often results in severe liver damage and even liver failure [60].…”

Section: Other Factorsmentioning

confidence: 99%

Extra- and Intra-Cellular Mechanisms of Hepatic Stellate Cell Activation

et al. 2021

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Hepatic fibrosis is characterized by the pathological accumulation of extracellular matrix (ECM) in the liver resulting from the persistent liver injury and wound-healing reaction induced by various insults. Although hepatic fibrosis is considered reversible after eliminating the cause of injury, chronic injury left unchecked can progress to cirrhosis and liver cancer. A better understanding of the cellular and molecular mechanisms controlling the fibrotic response is needed to develop novel clinical strategies. It is well documented that activated hepatic stellate cells (HSCs) is the most principal cellular players promoting synthesis and deposition of ECM components. In the current review, we discuss pathways of HSC activation, emphasizing emerging extra- and intra-cellular signals that drive this important cellular response to hepatic fibrosis. A number of cell types and external stimuli converge upon HSCs to promote their activation, including hepatocytes, liver sinusoidal endothelial cells, macrophages, cytokines, altered ECM, hepatitis viral infection, enteric dysbiosis, lipid metabolism disorder, exosomes, microRNAs, alcohol, drugs and parasites. We also discuss the emerging signaling pathways and intracellular events that individually or synergistically drive HSC activation, including TGFβ/Smad, Notch, Wnt/β-catenin, Hedgehog and Hippo signaling pathways. These findings will provide novel potential therapeutic targets to arrest or reverse fibrosis and cirrhosis.

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“…Perhaps the most substantive evidence, and concern, regarding potential hepatotoxicity relates to methotrexate. [65][66][67][68][69][70] Early signs of negative effects of methotrexate on liver function include elevated hepatic 71,72 These more serious adverse hepatic effects have been reported to occur in about 5% of patients treated with chronic, low-dose methotrexate, although rarely in patients without additional clinical risk factors for hepatotoxicity, such as pre-existing liver disease, excessive alcohol abuse, hepatitis B or C, central obesity and type 2 diabetes. 71 Given the hepatotoxic concerns, use of methotrexate is preferably avoided in these high-risk psoriasis patient groups, including those with established NAFLD, and methotrexate is contraindicated if bilirubin values are > 5 mg/dl.…”

Section: Hepatotoxic Effects Of Systemic Psoriasis Treatmentmentioning

confidence: 99%

Non-Alcoholic Fatty Liver Disease (NAFLD) in Patients with Psoriasis: A Review of the Hepatic Effects of Systemic Therapies

Balak¹,

Piaserico²,

Kasujee³

2021

PTT

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There is increasing interest in the association between psoriasis and non-alcoholic fatty liver disease (NAFLD), which is a prevalent liver disease characterized by excessive fat storage and inflammation that can progress to fibrosis and cancer. Patients with psoriasis have a two-fold higher risk to develop NAFLD and a higher risk to progress to more severe liver disease. Psoriasis and NAFLD share common risk factors such as smoking, alcohol consumption, and the presence of metabolic syndrome and its component disorders. In addition, both psoriasis and NAFLD hinge upon a systemic low-grade inflammation that can lead to a vicious cycle of progressive liver damage in NAFLD as well as worsening of the underlying psoriasis. Other important shared pathophysiological pathways include peripheral insulin resistance and oxidative stress. NAFLD should receive clinical awareness as important comorbidity in psoriasis. In this review, we assess the recent literature on the epidemiological and pathophysiological relationship of psoriasis and NAFLD, discuss the clinical implications of NAFLD in psoriasis patients, and summarize the hepatotoxic and hepatoprotective potential of systemic psoriasis therapies.

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Hepatotoxic potentials of methotrexate: Understanding the possible toxicological molecular mechanisms

Cited by 95 publications

References 87 publications

Therapeutic challenges of psoriasis in the HIV‑infected patient: A case report

Therapeutic challenges of psoriasis in the HIV‑infected patient: A case report

Extra- and Intra-Cellular Mechanisms of Hepatic Stellate Cell Activation

Non-Alcoholic Fatty Liver Disease (NAFLD) in Patients with Psoriasis: A Review of the Hepatic Effects of Systemic Therapies

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