Pseudohyperaldosteroism during itraconazole treatment: a hitherto neglected clinically significant side effect

Wife

In the beginning of April 2020, a 66-year-old woman was admitted to the emergency department (ED) with hypokalaemia and hypertension. She had suffered from onychomycosis of her toenails (figure 2) for the past 10 years, but was otherwise known to be a healthy woman, including potassium (K⁺) levels within the normal range. She had no abnormal use of artificial sweeteners or liquorice that could imply syndrome of apparent mineralocorticoid excess. She had received treatment with oral terbinafine for the onychomycosis with no effect, followed by repeated 3 months treatment courses with oral itraconazole 200 mg/day, supplemented with continuous amorolfine nail varnish with some effect, though reoccurring after a few months. Trichophyton rubrum was cultured, confirmed by PCR. Fungus was found resistant to terbinafine, and less sensitive to itraconazole. She had been taking itraconazole 100 mg two times per day since September 2019.

During the week prior to admission, the patient suffered from headaches. Her general practitioner (GP) discovered that she had hypokalaemia and hypertension and admitted her to hospital. In the ED, blood pressure (BP) was 196/100 mm Hg and K⁺ was 2.6 mmol/L. Hypokalaemia was corrected with potassium chloride (KCl) and she received verapamil 120 mg/day. She was discharged the next day and scheduled for further follow-up in our outpatient clinic.

In the end of April, the patient stopped taking itraconazole on her own initiative. At the following outpatient visit, she presented with dizziness, systolic BP around 105–110 mm Hg and slightly elevated K⁺ (4.4 mmol/L). Treatment with verapamil and KCl was stopped. Afterwards both BP and K⁺ levels stayed within the normal range.

Husband

In May 2020, the husband of the previously described patient, a 65-year-old man, was seen in our endocrine outpatient clinic for further investigations of hypertension and hypokalaemia. He had received treatment for hypertension and hypokalaemia since 2019, where he presented with BP 151/106 mm Hg and K⁺ 3.3 mmol/L. No further investigations were performed at that time. In addition, he was suffering from hypercholesterolaemia, treated with ezetimibe 10 mg and simvastatin 40 mg.

For 13 years he had suffered from onychomycosis of his toenails (figure 2). He was initially treated with oral itraconazole 200 mg/day in 3 months courses, supplemented with amorolfine nail varnish, with moderate effect, followed by itraconazole 100 mg two times per week for maintenance. As shown in figure 2, itraconazole had no curative effect; the aim of therapy was to keep the infection under acceptable control, thus, avoiding cumbersome nail dystrophy.

On his first visit, the antihypertensive medication was changed from amlodipine 5 mg, losartan 100 mg and furosemide 80 mg to verapamil 120 mg two times per day and the KCl dose was adjusted from 5 to 3 tablets per day. Treatment with itraconazole and cholesterol-lowering drugs was continued without any changes. At the next follow-up, blood and urine samples were normal. Despite these findings, itraconazole was still suspected to be the cause of the initial hypertension and hypokalaemia. It was hypothesised that the normal results could be due to the low dose of itraconazole (100 mg two times per week). The patient agreed to return to an earlier received higher dose of 100 mg itraconazole daily for 2 weeks to see how this would affect the lab results. Administering higher doses of itraconazole was considered unethical.

After the 2 weeks, a decrease in aldosterone and renin levels were seen along with a changed urine steroid metabolite excretion. Then treatment with itraconazole was stopped. Both verapamil and the KCl substitution were stopped and treatment with losartan 100 mg recommenced.

At follow-up, 2 months later (October 2020), the patient still presented with mild hypertension (140/86 mm Hg) but with normal K⁺ levels (4.1 mmol/L). Losartan treatment continued.

Wife

The results from the investigations have been summarised in table 1.

Unfortunately, the aldosterone renin ratio (ARR) was only measured under hypokalaemia while ARR and urine steroid metabolites were not measured under standardised conditions, before she stopped taking itraconazole.

September 2020 (after itraconazole treatment—as well as treatment with verapamil and KCl—had ended): BP, K⁺ levels, as well as ARR were normal under normokalaemic conditions. There was a normal excretion of all urine steroid metabolites. The kidney function was normal.

Husband

The results from the investigations have been summarised in table 2.

Beginning of June 2020 (first investigation for secondary hypertension): all investigations were normal.

End of June 2020 (2 weeks after an increased itraconazole dose of 100 mg/day): Stable levels of K⁺ and sodium. Decrease in aldosterone and renin to the low end of the normal range. Subnormal excretion of urinary cortisol-metabolites with an increased urinary cortisol-to-cortisone ratio. Other urine metabolites were not affected. The kidney function was normal.

Wife

After seeing the patient in September 2020 with normal BP (110/70 mm Hg) and K⁺ level within normal range (4.0 mmol/L) without taking any medication, the patient was considered to be healthy and no further follow-ups were planned. The patient was informed that she should avoid itraconazole in the future. To treat her onychomycosis, she was recommended treatment with voriconazole.

Husband

In October 2020, he was seen in our outpatient clinic. His K⁺ level was normal (4.1 mmol/L) without any potassium supplements and BP was 140/86 mm Hg when taking 100 mg losartan. Though stopping the itraconazole treatment did not completely normalise his BP, it reduced his need of medication from amlodipine, losartan and furosemide to losartan only. He was also recommended voriconazole to treat his onychomycosis.