What are the potential side effects of Methotrexate, especially in patients with pre-existing liver or kidney disease?

Methotrexate Side Effects in Patients with Pre-existing Liver or Kidney Disease

Methotrexate is absolutely contraindicated in patients with end-stage kidney disease (eGFR <30 mL/min) and should be avoided in those with cirrhosis or chronic liver disease due to severe and potentially fatal toxicity. 1, 2

Critical Contraindications and High-Risk Populations

Renal Disease

• Methotrexate is contraindicated in patients with creatinine clearance <20 mL/min-1 or those on dialysis 3
• Dose must be reduced by 50% in patients with creatinine clearance between 20-50 mL/min-1 3
• Renal impairment is the primary risk factor for methotrexate toxicity because 85% of the drug is renally excreted 1, 4
• Myelosuppression is the most lethal complication and increases significantly with renal dysfunction 3, 1

Hepatic Disease

• Methotrexate is absolutely contraindicated in patients with alcoholism, alcoholic liver disease, or other chronic liver disease 1
• Patients with cirrhosis should not receive methotrexate due to risk of fatal hepatic necrosis 3
• Pre-existing liver damage requires extreme caution or complete avoidance 4

Major Side Effects by Organ System

Hematologic Toxicity (Most Lethal)

• Myelosuppression accounts for the majority of methotrexate-associated fatalities (67 of 164 reported deaths) 1
• Pancytopenia, leukopenia, neutropenia, thrombocytopenia, and aplastic anemia can occur even after single doses 1, 4
• Risk is highest in patients with renal impairment, advanced age (>70 years), lack of folate supplementation, and concurrent use of trimethoprim-sulfamethoxazole or NSAIDs 1

Hepatotoxicity

• Ranges from asymptomatic transaminase elevations to fibrosis, cirrhosis, and fatal hepatic necrosis 1, 4
• Risk factors include alcohol consumption, obesity, diabetes mellitus, pre-existing liver disease, hyperlipidemia, and history of hepatotoxic drug exposure 1
• Chronic toxicity generally occurs after prolonged use (≥2 years) and total cumulative dose of at least 1.5 grams 4
• Modern studies show approximately doubling of relative risk for elevated transaminases but no increased risk of symptomatic or severe liver events with current dosing regimens 5

Pulmonary Toxicity

• Pulmonary toxicity accounts for 30 of 164 methotrexate-associated fatalities 1
• Presents with dry nonproductive cough, dyspnea, fever, and infiltrates on chest X-ray 3, 1
• Incidence estimated at 0.03% of patients 3
• Pre-existing lung disease, psoriatic arthritis, and cigarette smoking are risk factors 3

Renal Toxicity

• Can cause severe nephropathy, acute renal failure, and azotemia, particularly with high doses 1
• Due primarily to precipitation of methotrexate and 7-hydroxymethotrexate in renal tubules 4
• Serum creatinine measurements may overestimate renal function in elderly patients 4

Gastrointestinal Effects

• Nausea occurs in up to 25% of patients, typically within 12-24 hours of consumption 3
• Ulcerative stomatitis, anorexia, vomiting, diarrhea, and gastrointestinal ulceration are common 4
• Folic acid supplementation up to 5 mg daily reduces nausea 3

Other Common Side Effects

• Malaise, undue fatigue, chills, fever, dizziness, and decreased resistance to infection 4
• Hair loss (rare), photosensitivity (rare) 3
• Severe dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (rare but potentially fatal) 4

Critical Drug Interactions

Absolutely Contraindicated

• Trimethoprim-sulfamethoxazole is absolutely contraindicated with methotrexate due to severe bone marrow suppression risk from dual folate antagonism 1

Use with Extreme Caution

• NSAIDs reduce renal elimination and are particularly dangerous at any methotrexate dose 1
• Salicylates, sulfonamides, penicillins, probenecid, and colchicine decrease methotrexate binding to albumin or reduce renal tubular excretion 1

Essential Monitoring Requirements

Baseline Testing

• Complete blood count with differential, liver function tests, renal function tests 3, 1
• Chest X-ray to establish baseline pulmonary status 1
• Non-invasive liver fibrosis assessment (FIB-4 Index, vibration-controlled transient elastography) before starting treatment 3
• Hepatitis B and C screening in patients with risk factors 1

Regular Monitoring Schedule

• First 3 months: CBC, liver function tests, and creatinine at least monthly 1
• After stabilization: CBC and liver function tests every 3-6 months 1
• Patients with risk factors require enhanced monitoring every 2-4 weeks initially 1

When to Hold or Discontinue

• Hold methotrexate if WBC <3.5×10⁹/L, neutrophils <2×10⁹/L, or platelets <100×10⁹/L 1
• Stop if transaminases exceed 2× upper limit of normal on repeat testing 1
• Discontinue immediately if significant thrombocytopenia (platelet count <100,000/mm³) is detected 1

Mandatory Prevention Strategies

Folic Acid Supplementation

• All patients on methotrexate must receive folic acid supplementation (1-5 mg daily, except on the day of methotrexate administration) 1
• Reduces gastrointestinal, hepatic, and hematologic toxicity without compromising efficacy 1

Lifestyle Modifications

• Limit alcohol consumption to well below moderate levels (women: <1 drink/day, men: <2 drinks/day) 1
• Ensure adequate hydration 1

Management of Acute Toxicity

Immediate Antidote

• Leucovorin (folinic acid) is the life-saving antidote for methotrexate toxicity and must be administered immediately upon suspicion 1
• Initial dosing: 10-15 mg/m² (approximately 15 mg for average adult) IV or orally, repeated every 6 hours until toxicity resolves 1
• Efficacy diminishes dramatically after 24 hours 1

Common Pitfalls to Avoid

• Do not confuse folic acid with folinic acid (leucovorin)—only leucovorin bypasses methotrexate's metabolic block 1
• Do not delay leucovorin administration; efficacy is doubtful if initiated >24 hours after last methotrexate dose 1
• Do not assume low serum levels exclude toxicity; treat based on clinical presentation 1

Special Populations

Pregnancy and Lactation

• Methotrexate is absolutely contraindicated during pregnancy 3
• Women must use contraception while taking methotrexate 3
• Wait at least 3-6 months after discontinuation before attempting conception 3, 1

Elderly Patients

• Advanced age (>70 years) is a major risk factor for toxicity 1, 4
• Elderly patients have greater frequency of decreased hepatic and renal function, decreased folate stores 4
• Post-marketing experience suggests increased occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis with age 4