When you take an antifungal pill for a stubborn nail infection or a systemic fungal illness, you’re trusting it to kill the fungus-not your liver. But here’s the hard truth: antifungals are among the most common culprits behind drug-induced liver injury. Not all of them are equally risky, and not everyone knows the signs until it’s too late.
Not All Antifungals Are Created Equal
There are four main classes of antifungals: azoles, polyenes, echinocandins, and allylamines. Each has a different profile when it comes to liver safety. The azoles-fluconazole, itraconazole, voriconazole, posaconazole, and ketoconazole-are the most widely used. But they’re also the most dangerous to your liver. Ketoconazole is the worst offender. The FDA pulled its oral form from the European market in 2013 and restricted its use in the U.S. to only the most extreme cases, like rare fungal infections where nothing else works. Why? Because about 1 in 500 people taking it develop serious liver damage. Some patients have seen their liver enzymes spike to over 1,200 U/L-normal is under 56. That’s not a lab anomaly; that’s a medical emergency. Voriconazole and itraconazole aren’t far behind. Studies show they cause liver injury more often than fluconazole. Voriconazole, especially, is tricky because it’s metabolized by a liver enzyme called CYP2C19. If you have a genetic variation in that enzyme, your risk of liver damage jumps nearly fourfold. That’s not rare-it affects about 15% of people of European descent. Most doctors don’t test for it. They should. Fluconazole is safer, but not risk-free. If you’re on it for more than two weeks, especially if you’re older or already have liver problems, you need monitoring. A 2020 study found that nearly two-thirds of primary care doctors didn’t check liver enzymes at all during long-term fluconazole therapy. Then there’s terbinafine. It’s the go-to for athlete’s foot and toenail fungus. It’s cheaper, effective, and has a lower overall risk-only about 0.1% of users get liver injury. But here’s the catch: when it does happen, it can be sudden and severe. The FDA added a black box warning in 2015. One patient on Healthline reported jaundice at week five, with bilirubin levels over ten times normal. It took three weeks in the hospital to recover. Echinocandins-caspofungin, micafungin, anidulafungin-are newer and often used in hospitals for life-threatening infections. You’d think they’re safer because they’re not metabolized by the liver. But real-world data from 2022 shows they’re linked to liver injury just as often as azoles. Anidulafungin had the highest death rate among DILI cases-50%. That doesn’t mean it kills half the people who take it. It means among the rare cases where liver injury happened, half died. Why? Because it’s usually given to the sickest patients-those already in liver failure. That’s not the drug’s fault; it’s the patient’s condition.Who’s at Highest Risk?
Age matters. People over 65 are nearly eight times more likely to develop antifungal-induced liver injury than younger adults. That’s not because the drugs are more toxic-it’s because older livers process drugs slower and have less reserve. Women are more vulnerable than men, especially with azoles. Why? Hormonal differences affect how liver enzymes break down these drugs. There’s also a higher risk if you’re taking other medications that stress the liver-like statins, antibiotics, or even common painkillers like acetaminophen. People with existing liver disease should avoid ketoconazole entirely. The FDA says so. The European Association for the Study of the Liver says the same. But in some clinics, it’s still prescribed by mistake. And don’t assume that because you’re healthy, you’re safe. One Reddit user, 32, no history of liver problems, took ketoconazole for a skin infection. Three weeks later, he was in the ER with vomiting, dark urine, and confusion. His ALT was 1,200. He needed a liver transplant evaluation.What You Need to Watch For
Liver injury from antifungals doesn’t always show up on a blood test before you feel sick. The first signs are often vague: fatigue, nausea, loss of appetite, or a dull ache under your right ribs. Jaundice-yellowing of the skin or eyes-is a late sign. By then, damage may already be serious. The timing varies by drug:- Ketoconazole: injury can show up in 1-2 weeks
- Voriconazole and itraconazole: usually 2-8 weeks
- Terbinafine: often after 4-6 weeks, sometimes later
- Echinocandins: unpredictable, but often during prolonged hospital stays
Monitoring: What Doctors Should Do (But Often Don’t)
The Infectious Diseases Society of America says: baseline liver tests before starting any systemic antifungal. Then:- Weekly for the first month if you’re on ketoconazole, itraconazole, or voriconazole
- Every two weeks after that
- For terbinafine: test at 4-6 weeks, then every 4-6 weeks if treatment goes beyond 8 weeks
- For fluconazole: only if you’re on it longer than two weeks or have risk factors
Drug Interactions: The Silent Killer
Antifungals don’t just hurt your liver on their own. They play dirty with other drugs. Azoles block liver enzymes (CYP3A4, CYP2C9, CYP2C19) that break down dozens of common medications. That means:- Statins (like simvastatin) can build up to toxic levels, causing muscle damage
- Blood thinners (warfarin) can spike, leading to dangerous bleeding
- Anti-seizure drugs (phenytoin) can drop, triggering seizures
- Immunosuppressants (cyclosporine) can become deadly
What’s Changing Now?
The tide is turning. The FDA’s Sentinel Initiative now tracks antifungal liver injury in real time across millions of patient records. In 2022, researchers identified a genetic marker (CYP2C19) that predicts voriconazole toxicity. Soon, we may see pre-treatment genetic testing before prescribing it. New antifungals like olorofim and ibrexafungerp are in development-and liver safety is their top design goal. Early trials show 78% fewer liver enzyme spikes than old azoles. Hospitals have cut ketoconazole use by over 90% since 2013. That’s progress. But community use? Still risky. People buy terbinafine over the counter for nail fungus and take it for months without a single blood test.What You Should Do
If you’re prescribed an antifungal:- Ask: "Which one are you prescribing, and why? Is it the safest option for my liver?"
- Insist on a baseline liver test before starting
- Know your monitoring schedule-don’t wait for your doctor to remind you
- Track symptoms: fatigue, nausea, dark urine, yellow eyes
- Never mix with alcohol or other liver-stressing meds without checking
- If you’re on terbinafine for nail fungus, get tested at week 6
Can antifungals cause permanent liver damage?
Yes, in rare cases. While most people recover fully after stopping the drug, some develop acute liver failure requiring transplant. Ketoconazole and voriconazole have the highest rates of severe injury. Early detection and stopping the drug are the best ways to prevent permanent damage.
Is terbinafine safe for long-term use?
Terbinafine is generally safe for short courses (6-12 weeks for nail fungus), but long-term use increases liver risk. The FDA recommends liver enzyme checks at 4-6 weeks and then every 4-6 weeks if treatment continues past 8 weeks. Never take it for months without monitoring.
Why is ketoconazole still available if it’s so dangerous?
Oral ketoconazole is restricted in the U.S. and banned in Europe for most uses. It’s only approved for rare, life-threatening fungal infections when no other antifungal works. Topical versions (creams, shampoos) are still safe and widely used because they don’t enter the bloodstream significantly.
Can I take antifungals if I have hepatitis C?
You can, but with extreme caution. People with chronic liver disease, including hepatitis C, are at much higher risk of antifungal-induced liver injury. Fluconazole is often preferred over azoles like voriconazole. Always get liver tests before and during treatment. Avoid ketoconazole entirely.
Do I need a liver test before getting a prescription for antifungals?
Yes-for all systemic antifungals (pills or IV). Even if you feel fine, a baseline liver test is essential. It’s the only way to know if the drug is harming your liver. For topical antifungals (creams, sprays), testing isn’t needed because they don’t enter your bloodstream in meaningful amounts.
