Terbinafine used safely in autoimmune hepatitis for treatment of tinea corporis

Abstract

Terbinafine is often considered contraindicated in those with liver disease, as one of the known side effects is hepatotoxicity. We report the first case documenting the safe use of oral terbinafine in a 77-year-old woman with stable autoimmune hepatitis presenting with extensive tinea corporis. Precautions were carried out to minimise the risk of worsening hepatotoxicity, including consultation with the patient’s hepatologist, limiting terbinafine exposure to less than 6 weeks, monitoring of liver function tests, and patient education. The patient’s fungal infection cleared without any signs or symptoms of worsening liver disease. The rash had not recurred 6 months after treatment. When terbinafine must be used in a patient with pre-existing liver disease, we recommend considering a short course of oral terbinafine after consultation with their hepatologist, obtaining baseline liver function tests with consideration of further monitoring during treatment course, and patient education on the signs and symptoms of liver injury.

Background

Terbinafine is an oral medication with activity against fungal species such as dermatophytes that cause infections of the fingernails, toenails, and skin. The medication concentrates in keratin where it inhibits fungal squalene epoxide, an enzyme crucial for fungal cell wall development, leading to subsequent fungal death.¹ Common side effects of terbinafine include headaches, gastrointestinal upset, rash and taste abnormalities. Serious but rare side effects include hepatotoxicity and liver failure.^{2 3} For this reason, terbinafine is contraindicated in patients with acute or chronic liver disease or impairment due to the increased incidence and severity of liver side effects in these patients.² To the best of our knowledge, we report the first successful treatment of diffuse tinea corporis using oral terbinafine in a patient with a history of autoimmune hepatitis.

Case presentation

A 77-year-old woman with a medical history significant for autoimmune hepatitis diagnosed in 2017 and well controlled on azathioprine and prednisone presented to the dermatology clinic for pruritic rash. The rash initially appeared on the medial thighs and progressively spread to the buttocks, flanks, arms, face and chest over the following 8 months. She had tried topical betamethasone and clobetasol without improvement. On physical examination, there were many well demarcated, erythematous nummular to annular scaly papules and plaques distributed over the chest, right upper extremity, face, scalp, inner thighs and flanks. Many of the plaques demonstrated trailing scale (figure 1).

Figure 1.

Tinea corporis on the right lower back.

Investigations

Given strong clinical suspicion for superficial fungal infection, potassium hydroxide scraping was performed, and florid hyphae were noted. Fungal culture later grew trichophyton species, confirming the diagnosis of severe tinea corporis and tinea cruris with a component of tinea incognito exacerbated by topical corticosteroids.

Treatment

Due to the patient’s history of autoimmune hepatitis, she was initially treated with topical butenafine cream until her hepatologist was contacted to discuss the safe use of oral terbinafine. In conjunction with her hepatologist, she was started on a 14-day course of terbinafine 250 mg/day by mouth. Baseline liver function tests (LFTs) obtained from her hepatologist were within normal limits. The patient was counselled to discontinue the drug if she developed signs or symptoms of liver disease and after discussion opted to repeat LFTs after finishing her 2-week course of oral terbinafine.

Outcome and follow-up

On follow-up, the patient’s rash had completely resolved with minimal residual erythema, and her LFTs remained within normal limits. Six months following treatment, her skin remained clear and the patient was counselled to apply topical terbinafine cream as needed to treat any acute flares.

Discussion

Although liver disease is considered by many resources a relative contraindication for terbinafine use,² our patient with controlled autoimmune hepatitis was treated successfully without side effects. We considered topical treatment only but, given her extensive body surface area involved and immunocompromised state, topical treatments alone were unlikely to be successful. We also considered the use of other oral antifungal agents. We chose terbinafine based on efficacy, duration of course and price.^4–6

Worsening of hepatotoxicity with administration of oral terbinafine appears rare. The reported incidence of worsening liver injury in those with underlying liver disease is not fully known. However, on retrospective cohort study of 255 patients found the incidence of terbinafine-induced liver injury in those with underlying liver disease to be similar to the incidence in healthy adults, between 3.1% and 3.5% of the population.^{3 7 8}

Drug-induced liver injury (DILI) caused by terbinafine is currently thought to be idiosyncratic, meaning healthcare professionals are unable to predict who will develop severe liver damage and who will not.⁹ The risk factors associated with these idiosyncratic reactions are not fully understood. HLA classes, specifically HLA-A*33:01, appear to correlate with terbinafine induced DILI in addition to environmental factors.¹⁰ Considering we could not alter our patient’s genetic factors, we attempted to limit our patient’s environmental factors by limiting the course of terbinafine, monitoring LFTs, and providing patient education about DILI.

There are a number of proposed mechanisms to reduce the risk of DILI in patients with underlying liver disease treated with terbinafine. One recommendation includes treatment with a limited course of 2–6 weeks, although occasionally longer courses of up to 3 months are required in the use of onychomycosis.² A review of 20 patients with terbinafine associated DILI determined patients treated with a longer duration of terbinafine, defined as greater than 4–6 weeks, were more likely to require medical treatment to recover from DILI.⁷ Additionally, multiple case reports document the prolonged use of 250 mg terbinafine daily contributing to DILI requiring medical intervention, and Kramer et al determined the majority of DILI presented within the first 6 weeks of treatment.^11–14 Yan et al noted patients treated for 2 weeks or less recovered from liver injury with mere cessation of the drug and no further interventions.⁷

Another recommendation to prevent DILI is monitoring LFTs; however, this is controversial. Originally, physicians obtained LFTs at baseline and again at 4–6 weeks after terbinafine use, the latency period to the development of DILI.^{3 12 14} However, one systematic review found no benefit to monitoring, as the progression from normal LFTs to DILI is rapid and difficult to catch on routine testing,¹⁴ while a second retrospective study that excluded those with underlying liver disease found LFT elevations that were captured on routine monitoring were transient and benign.¹⁵ The utility of baseline testing in patients without underlying liver disease is also unclear, but in those with known liver dysfunction baseline LFT monitoring is recommended.^{8 14} Although monitoring LFTs may no longer be recommended in healthy individuals, physicians may need to take a case-based approach when determining if monitoring LFTs is necessary in individuals with underlying liver disease.

Patient counselling is another critical practice required to reduce DILI, as predetermined liver monitoring may not capture the rapid progression to DILI.^{3 14} Kramer et al cautions that monitoring LFTs provided a false sense of security to patients and thus delays presentation to medical professionals.¹⁴ Educating patients on the signs and symptoms of DILI (anorexia, pruritus, fatigue, jaundice, abdominal pain, pale stool and dark urine) and to discontinue terbinafine and seek medication attention at these initial signs is considered one of the most important steps in preventing DILI, as most cases resolve with medication cessation.3 8 11 12

In our patient’s case, we limited her exposure to terbinafine to a short course of 2 weeks, monitored LFTs at baseline and at the end of the terbinafine course, and counselled the patient to discontinue the drug and seek medical attention at the first signs or symptoms of further liver damage. Other protective measures include limiting exposure to other liver toxins (eg, acetaminophen, alcohol) and continuing medication for the underlying liver disease. By following these recommendations, we safely administered terbinafine in the setting of autoimmune hepatitis. Although we were able to safely treat our patient with oral terbinafine, we advise using caution when considering oral terbinafine in patients with underlying liver disease because of the risk of developing severe hepatotoxicity among these patients.

Learning points.

• Our case reports the safe use of oral terbinafine in a patient with chronic liver disease to treat severe tinea corporis.

• One way to reduce the risk of drug-induced liver injury (DILI) is by administering a short course of medication (6 weeks or less).

• The most important way to reduce the risk of DILI is by patient education and to discontinue the drug on the first signs and symptoms of DILI.

• Routine monitoring of liver function tests is controversial, and patients may benefit from a case-based approach.