What are the manifestations of Methotrexate (MTX) toxicity?

Manifestations of Methotrexate (MTX) Toxicity

Methotrexate toxicity can manifest as multiple serious adverse effects including hematologic toxicity, hepatotoxicity, nephrotoxicity, pulmonary toxicity, mucocutaneous reactions, and neurotoxicity, with severity depending on dosage, administration route, and patient risk factors. 1

Hematologic Toxicity

• Presentation: Pancytopenia, anemia, leukopenia, neutropenia, thrombocytopenia
• Risk factors: Renal insufficiency, advanced age, dosing errors, drug interactions, hypoalbuminemia, excessive alcohol intake 1
• Timing: Can occur after even a single dose and at any time during treatment, potentially as late as 6 weeks after dose increase 1
• Severity: Can range from mild to severe, potentially fatal myelosuppression requiring immediate intervention 2

Hepatotoxicity

• Acute manifestations: Elevated transaminases (typically transient and asymptomatic)
• Chronic manifestations: Fibrosis and cirrhosis (after prolonged use, generally after 2+ years or cumulative dose ≥1.5 grams) 2
• Risk factors: Obesity (BMI ≥40 kg/m²), diabetes, hyperlipidemia, non-alcoholic fatty liver disease, excessive alcohol use, chronic hepatitis B/C, prior hepatotoxic drug exposure 1
• Warning signs: Persistent abnormal liver function tests, decline in serum albumin below normal range 1

Nephrotoxicity

• Mechanism: Crystallization of MTX in renal tubular lumen leading to tubular toxicity 3
• Manifestations: Acute kidney injury, elevated creatinine, decreased urine output
• Warning sign: Severe loin pain within hours of injection (may predict subsequent renal toxicity) 4
• Incidence: 2-12% of patients receiving high-dose MTX (>500 mg/m²) 3

Pulmonary Toxicity

• Presentation: Dry nonproductive cough, dyspnea, fever, hypoxemia, infiltrates on chest X-ray
• Severity: Potentially dangerous and not always fully reversible; fatalities reported 2
• Types: Acute or chronic interstitial pneumonitis, Pneumocystis carinii pneumonia (opportunistic infection) 1, 2
• Timing: Can occur acutely at any time during therapy, even at low doses 2

Mucocutaneous Reactions

• Common manifestations: Stomatitis, oral ulcers, dermatitis
• Severe reactions: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme 2
• Timing: Can occur within days of administration by any route (oral, IM, IV, intrathecal) 2
• Severity: Potentially fatal in severe cases 2

Neurotoxicity

• Acute manifestations: Confusion, hemiparesis, transient blindness, seizures, coma (stroke-like encephalopathy) 2
• Chronic manifestations: Leukoencephalopathy (especially with high-dose regimens or intrathecal administration)
• Risk factors: Prior craniospinal irradiation, concomitant nitrous oxide anesthesia 2
• Special concern: Higher frequency of seizures reported in pediatric patients with acute lymphoblastic leukemia receiving intermediate-dose IV MTX 2

Gastrointestinal Toxicity

• Common manifestations: Nausea, vomiting, anorexia, diarrhea
• Severe complications: Hemorrhagic enteritis, intestinal perforation (can be fatal) 2
• Timing: Often occurs shortly after medication initiation 1

Early Warning Signs of Toxicity

• Fatigue and malaise
• Oral ulcers and stomatitis (early indicator)
• Nausea and anorexia
• Unexplained fever
• Dry cough
• Skin rash
• Loin pain (potential early sign of renal toxicity) 4

High-Risk Patient Factors

• Renal insufficiency (eGFR <60 mL/min)
• Advanced age
• Drug interactions (especially NSAIDs, proton pump inhibitors, penicillins)
• Hypoalbuminemia
• Excessive alcohol intake
• Third-space fluid accumulations (pleural effusions, ascites)
• MTHFR gene mutations 5, 6
• Dehydration or volume depletion
• Acidic urine 3

Monitoring Recommendations

• Complete blood count, liver function tests every 3-6 months (more frequently after dose increases)
• Renal function monitoring, especially in patients with poor baseline function
• Methotrexate levels at 24,48, and 72 hours after high-dose administration 5
• Close monitoring for early signs of toxicity, particularly after dose increases

Early recognition of these manifestations is crucial for prompt intervention to prevent progression to severe, potentially life-threatening toxicity.