Antifungals and Liver Risks: What You Need to Know About Drug Interactions and Toxicity

When you take an antifungal to treat a stubborn nail infection or a systemic yeast problem, you’re trusting that the medicine will kill the fungus - not harm your liver. But for many antifungals, that’s not a guarantee. Liver damage from these drugs isn’t rare. It’s well-documented, predictable, and often overlooked until it’s too late.

Some antifungals carry black box warnings. Others have been pulled from the market. And many patients - even those taking them for minor infections - never get their liver checked. That’s a problem.

Which Antifungals Are Most Dangerous for Your Liver?

The biggest red flags come from the azole class. Among them, ketoconazole is a systemic antifungal once widely used for fungal infections but now restricted due to severe liver toxicity and drug interactions. The FDA issued a safety alert in 2013 after reports of acute liver failure. In one UK study, about 1 in 500 patients developed serious liver injury. Some cases led to liver transplants. Today, ketoconazole is banned in Europe and only used in the U.S. as a last-resort option for rare fungal infections when nothing else works.

But ketoconazole isn’t the only risky one. Itraconazole is an oral azole antifungal used for fungal infections like aspergillosis and histoplasmosis, with a high risk of drug-induced liver injury and Voriconazole is a broad-spectrum azole antifungal commonly used in immunocompromised patients, associated with elevated liver enzymes and hepatotoxicity in up to 20% of users also carry heavy warnings. Data from the FDA’s adverse event database (2004-2021) shows they cause more reports of liver injury than any other antifungal class except ketoconazole. Voriconazole, in particular, is notorious for causing liver enzyme spikes - sometimes within just a few weeks of starting treatment.

Fluconazole, another azole, is safer - but not risk-free. It’s often used for yeast infections, including vaginal candidiasis. For short courses (under two weeks), liver monitoring isn’t usually needed. But if you’re on it for months - say, for chronic fungal nail infection or recurrent thrush - your doctor should check your liver enzymes every few weeks.

Then there’s Terbinafine is an allylamine antifungal used primarily for dermatophyte infections like athlete’s foot and nail fungus, with a low but serious risk of hepatotoxicity. It’s the go-to for nail fungus. The risk of liver injury is low - about 0.1% based on a 1996 study of nearly 10,000 patients. But that doesn’t mean it’s harmless. A single case of liver failure can be devastating. That’s why it carries a black box warning. Most liver issues show up within the first six weeks. If you feel unusually tired, your skin turns yellow, or your urine darkens, stop taking it and get tested immediately.

Echinocandins - Caspofungin is a parenteral echinocandin antifungal used for invasive candidiasis and aspergillosis, with a generally favorable hepatic safety profile, Micafungin is an echinocandin antifungal with lower rates of liver enzyme elevation compared to other agents in its class, and Anidulafungin is an echinocandin antifungal associated with the highest mortality rate among DILI cases despite its use in patients with severe infections - are given intravenously in hospitals. They’re often used for serious infections in ICU patients. On paper, they seem safer than azoles. But real-world data tells a different story. Anidulafungin was linked to a 50% mortality rate in patients who developed liver injury. That sounds terrifying, but it’s likely because these patients were already critically ill with multiple organ failures. Micafungin, on the other hand, shows the cleanest liver safety profile among echinocandins.

Why Do These Drugs Hurt the Liver?

Antifungals don’t attack the liver on purpose. But they’re processed there. Your liver uses enzymes - especially the CYP450 family - to break down these drugs. Some antifungals interfere with these enzymes. Others are toxic byproducts of that breakdown.

For example, voriconazole is metabolized by CYP2C19. If you have a genetic variation that makes this enzyme work too slowly, the drug builds up in your system. A 2022 study found that people with certain CYP2C19 mutations had a 3.7 times higher risk of liver injury. That’s why genetic testing is now being considered before starting voriconazole in high-risk patients.

Ketoconazole is even worse. It blocks multiple liver enzymes, including those needed to make cortisol and other hormones. That’s why it can cause adrenal problems too. It also interacts with dozens of other drugs - statins, blood thinners, antidepressants - all of which are also processed by the liver. When you stack them, the liver gets overwhelmed.

Terbinafine is different. It doesn’t interfere with enzymes as much. But in rare cases, it triggers an immune reaction in the liver. That’s why the damage can be sudden and severe - even if you’ve been taking it for weeks without issues.

What Do Doctors Actually Do to Protect You?

Good doctors don’t just write a prescription. They monitor.

The Infectious Diseases Society of America (IDSA) recommends baseline liver tests before starting any systemic antifungal. For high-risk drugs like ketoconazole, itraconazole, and voriconazole, they want weekly blood tests for the first month. After that, every two weeks. For fluconazole and terbinafine, testing is less frequent - but still needed if you’re on it longer than 8 weeks.

Here’s what they look for:

• ALT and AST: These enzymes leak into the blood when liver cells are damaged. If they’re more than 3 times the normal level AND you have symptoms (nausea, fatigue, dark urine), stop the drug.
• Bilirubin: If it’s elevated along with ALT/AST, that’s a sign of serious liver trouble.
• ALP and GGT: These help tell if the problem is in the liver cells (hepatocellular) or the bile ducts (cholestatic).

Many primary care providers don’t follow these rules. A 2020 study found only 37% of doctors ordered liver tests for patients on terbinafine for nail fungus. That’s a gap. And it’s dangerous.

Real Patient Stories - What Went Wrong?

On Reddit, one user shared: "I took ketoconazole for 3 weeks. My ALT hit 1,200 U/L (normal is under 56). I was hospitalized. My liver was nearly shut down. I had no symptoms until I collapsed."

Another on Healthline wrote: "I was on terbinafine for 5 weeks. I got tired, then my eyes turned yellow. My doctor said it was the drug. I stopped. Two months later, I was fine. But I almost didn’t make it."

These aren’t outliers. The FDA’s database has over 1,800 reports of ketoconazole-related liver injury between 2004 and 2021. Voriconazole? Nearly 1,000. And those are just the ones reported. Many go unnoticed.

Patients often don’t connect fatigue or nausea to their antifungal. They assume it’s a cold, stress, or aging. By the time jaundice appears - the yellowing of the skin - it’s often too late.

What Should You Do If You’re Taking an Antifungal?

If you’re prescribed an antifungal - especially for anything longer than two weeks - here’s what to do:

1. Ask your doctor: "Which one are you prescribing, and why? Is there a safer option?"
2. Request a baseline liver test before you start.
3. Ask if you need follow-up tests - and when.
4. Know the warning signs: fatigue, nausea, loss of appetite, dark urine, pale stools, yellow eyes or skin, pain under your right ribs.
5. If you have liver disease, alcohol use, or take other meds (statins, antidepressants, seizure drugs), tell your doctor. You may need a different drug.
6. Don’t skip blood tests. Even if you feel fine.

For nail fungus, terbinafine is still the best option - if you’re monitored. For systemic infections, echinocandins are often preferred in hospitals. But for outpatients, fluconazole is usually the safest azole - if used properly.

The Bigger Picture: How Prescribing Is Changing

Since the 2013 FDA warning, ketoconazole use has dropped by over 90%. Hospitals now avoid it entirely. Echinocandins have become the first-line for invasive candidiasis - not because they’re perfect, but because they’re less likely to interact with other drugs.

New antifungals are in development. Drugs like olorofim and ibrexafungerp are being tested with liver safety as a top priority. Early trials show 78% fewer liver enzyme spikes than older azoles. That’s promising.

But until those are widely available, we’re stuck with what we have. And that means vigilance.

The bottom line? Antifungals save lives. But they can also end them - if you don’t pay attention to the liver.

If you’re on an antifungal, don’t assume it’s harmless. Ask questions. Get tested. Pay attention to your body. Your liver can’t speak - but it can fail silently. Don’t let it.