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Pseudohyperaldosteroism during itraconazole treatment: a hitherto neglected clinically significant side effect
  1. Sandra L Brandi1,
  2. Claus L Feltoft1,
  3. Jørgen Serup2 and
  4. Ebbe Eldrup1
  1. 1Department of Endocrinology, Copenhagen University Hospital, Herlev Hospital, 2730 Herlev, Denmark
  2. 2Department of Dermatology, Bispebjerg Hospital, Kobenhavn, Denmark
  1. Correspondence to Dr Ebbe Eldrup; Ebbe.Eldrup{at}regionh.dk

Abstract

We describe a married couple who both presented with hypertension and hypokalaemia. Both patients were diagnosed with pseudohyperaldosteronism triggered by the widely used antifungal drug itraconazole. This effect appears to be dose-dependent, where a daily intake of 100 mg itraconazole is enough to induce pseudohyperaldosteronism. Clinicians should be aware of pseudohyperaldosteronism as a possible adverse effect of itraconazole, and we recommend monitoring potassium levels and blood pressure in all patients receiving this drug over a longer period of time. Voriconazole is probably an alternative antifungal treatment to itraconazole but also with this drug potassium levels should be monitored.

  • hypertension
  • unwanted effects / adverse reactions
  • endocrinology
  • drugs: infectious diseases
  • dermatology

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Background

Hypertension is a common disease, and for 90%–95% of the people suffering from this, an underlying causality cannot be identified.1 Many secondary reasons for hypertension do however exist, including primary hyperaldosteronism and adverse effects to different types of medication.2

Patients suffering from primary hyperaldosteronism have abnormally high levels of aldosterone, which induces hypertension and hypokalaemia through its binding to the mineralocorticoid receptor along with a suppression of plasma renin levels.3 Aldosterone and cortisol are both able to bind and activate the mineralocorticoid receptor in the kidneys, but cortisol’s activation is normally inhibited by the 11-β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzyme, which converts cortisol into cortisone (see figure 1). Reduced activity of the 11β-HSD2 enzyme may cause cortisol activating the mineralocorticoid receptor. This causes a state of apparent mineralocorticoid excess,4 and results in patients presenting with clinical features resembling primary hyperaldosteronism.

Figure 1

The steroid synthesis. Itraconazole inhibits the 11β-HSD2 (11-beta-hydroxysteroid dehydrogenase type 2) enzyme causing an increased level of cortisol thereby changing the cortisol-to-cortisone ratio. Cortisol activates the mineralocorticoid receptor in the kidney causing a state of apparent mineralocorticoid excess.

We report two cases of itraconazole induced pseudohyperaldosteronism, an association that has only recently and very sparsely been reported.5–7 Due to the marital relationship between the two cases, the patients will be referred to as ‘wife’ and ‘husband’ in the following sections.

Case presentation

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.

Figure 2

Onychomycosis of toenails, the wife (A) and her husband (B). The distal nail plate was undermined by a layer of keratotic debris, and the treatments were not curative.

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.

Investigations

Wife

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

Table 1

Results for the 66-year-old female patient

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.

Table 2

Results for the 65-year-old male patient

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.

Differential diagnosis

Initially, plasma aldosterone and renin levels in the wife were both low despite hypertension and hypokalaemia indicating pseudohyperaldosteronism. Both BP, K+ levels and ARR normalised after she stopped taking itraconazole, excluding primary hyperaldosteronism. Also, treatment with verapamil and KCl was no longer necessary and urine test for steroid metabolites was normal.

Initial investigations of secondary hypertension in the husband were normal and showed no signs of pseudo or primary hyperaldosteronism. After increasing the itraconazole dose, his steroid metabolism became abnormal: urine steroid metabolites showed a subnormal excretion of cortisol-metabolites and an increased urinary cortisol-to-cortisone ratio, indicating a reduced inactivation of cortisol by the 11β-HSD2 enzyme. Also, aldosterone and renin decreased to the low end of the normal range indicating a negative feedback mechanism, supporting the pseudohyperaldosteronism diagnosis. At follow-up, 2 months after itraconazole treatment had ended, the husband was still suffering from mild hypertension with a BP of 140/86 mm Hg, now with normal K+ levels (4.1 mmol/L), indicating that he originally was suffering from both idiopathic hypertension as well as pseudohyperaldosteronism induced by itraconazole. The wife also most likely suffered from pseudohyperaldosteronism induced by itraconazole.

Outcome and follow-up

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.

Discussion

Itraconazole is widely used by GPs and dermatologists to treat local fungal infections such as onychomycosis, but currently there exist no recommendations regarding patient monitoring during treatment.

One other case-report has described 11β-HSD2 inhibition by itraconazole in patients presenting with hypertension, hypokalaemia and suppressed renin and aldosterone levels.6 Beck et al have examined the molecular mechanisms of itraconazole induced pseudohyperaldosteronism.8 They found that itraconazole inhibits the 11β-HSD2 enzyme potently and the 11β-hydroxylase enzyme (also known as CYP11B1) moderately, thereby inducing elevated levels of the mineralocorticoid receptor agonists cortisol and 11-deoxycorticosterone respectively (see figure 1). However, they conclude that the primary mechanism for inducing pseudohyperaldosteronism is through the cortisol dependent mineralocorticoid receptor activation that results from 11β-HSD2 inhibition. This is also the conclusion of a review on drug-induced endocrine BP elevation published in 2020.2 Partial 11-deoxycorticosterone induced pseudohyperaldosteronism caused by itraconazole inhibiting adrenal 11β-hydroxylase, cannot be ruled out in the wife’s case since urine steroid metabolites were not measured while taking itraconazole.

Beck et al state that 11β-HSD2 deficiency can be detected by an increased urinary cortisol-to-cortisone ratio, corresponding well with our findings, and they hypothesise a dose-dependent occurrence of itraconazole induced pseudohyperaldosteronism.8 Our data support this hypothesis, where abnormal steroid metabolism occurred in the husband’s case when the dose of itraconazole was increased to 100 mg/day.

Only three publications have been found describing patients presenting with hypertension and hypokalaemia following treatment with itraconazole in varying doses of 200 mg/day,7 300 mg two times per day6 and 600 mg/day.5 We find that a dose of only 100 mg/day is enough to induce pseudohyperaldosteronism in both our patients. Knowledge of this side effect is therefore highly relevant to all clinicians initiating treatment with this drug and potassium levels and BP should be monitored when prescribing long term treatment. Voriconazole does not appear to induce the same pseudohyperaldosteronism as itraconazole,2 6 8 and should therefore be considered an alternative in patients experiencing this adverse effect to itraconazole. A recent report, however, has suggested that voriconazole under certain conditions and dosages may cause hypoaldosteronism and hyperkalaemia.9 Thus, serum potassium should also be monitored when treating with this drug.

We found itraconazole induced pseudohyperaldosteronism randomly in two spouses, indicating this side effect being much more common, than what is described in current literature. Further studies are needed to examine the exact prevalence, but it is a side effect that all clinicians should keep in mind when commencing treatment with itraconazole.

Learning points

  • Itraconazole in therapeutic doses can cause pseudohyperaldosteronism by inhibition of the 11-β-hydroxysteroid dehydrogenase type 2 enzyme and potassium levels and blood pressure should be monitored in long-term treatment.

  • Itraconazole-induced pseudohyperaldosteronism should be suspected in patients receiving itraconazole treatment presenting with hypertension and hypokalaemia.

  • Low aldosterone and renin levels and an increased urinary cortisol-to-cortisone ratio supports the diagnosis of itraconazole-induced-pseudohyperaldosteronism.

Ethics statements

References

Footnotes

  • Contributors All four authors SLB, CLF, JS and EE have contributed to the case description. EE and JS have conducted the clinical investigations and treatments of the two patients. All authors have approved the final manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.