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Mihaela Horumba1, Raluca Ciomag1,2, Ana-Maria Vintila1,2

1 Department of Internal Medicine and Cardiology, Coltea Clinical Hospital, Bucharest, Romania
2 Department of Internal Medicine, „Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

Abstract: Dysgeusia, the alteration of taste perception, may occur in the setting of various pathologies and is a relatively common adverse drug reaction. Dysgeusia may lead to changes in dietary intake resulting in malnutrition or weight gain. Older patients seem to be at an increased risk of developing dysgeusia and consequently, malnutrition and severe dehy-dration. Angiotensin-converting enzyme inhibitor-induced dysgeusia has been reported in up to 4% of patients undergoing ACEi treatment but is self-limiting despite continued use and resolves within a couple of months. The defi nite cause of ACEi-induced dysgeusia is yet to be settled, though salivary gland zinc ion chelation has been incriminated; more research is required. We present the case of a patient who developed dysgeusia after initiation of treatment with perindopril, which led to severe dehydration and acute kidney injury.

Keywords: dysgeusia, taste disturbances, ACEi-induced adverse drug reactions, acute kidney injury, ADRs.

INTRODUCTION
Dysgeusia, the alteration of taste perception, may occur in the setting of various pathologies and is a relatively common adverse drug reaction. Frequently cited dysgeusia-inducing drugs are angiotensin-conver-ting enzyme inhibitors (ACEi). Historically, patients treated with captopril were so likely to develop side effects, including dysgeusia or cough that treatment discontinuation lead to development of new ACEi. Though the European Medicines Agency (EMA) warns about dysgeusia as a common adverse effect of perin-dopril treatment, there are no case reports documen-ting the association
We present the case of a patient who developed dysgeusia after initiation of treatment with perindo-pril, which led to severe dehydration and acute kidney injury.

CASE PRESENTATION
A 66-year-old man with hypertension and diabetes mellitus is admitted for anorexia, 3-kg weight loss and oligoanuria, as well as a persistent and unpleasant swe-et taste in his mouth. He had been hospitalized three weeks before for heart failure, severe hypertension and left lower lobe pneumonia. Since he had had no prior antihypertensive treatment, in this setting, he was started on perindopril 10 mg o.d., amlodipine 10 mg o.d and indapamide 2.5 mg o.d., bisoprolol 5 mg o.d. and spironolactone 25 mg o.d. for heart failure and a 7 day course of ceftriaxone 1 g every 12 hours for the pulmonary infection. Shortly after discharge, alteration of his sense of taste developed, which was significant enough that the patient limited his oral in-take in terms of food as well as liquids, but continued taking the recommended medication.
On examination, he appeared unwell, afebrile, with a BP of 140/100 mmHg, HR 70 bpm and SatO₂ 98% on breathing ambient air. Though he was severely dehy-drated, the remainder of the examination, including neurological and otorhinolaryngology (ENT) exam, was unremarkable.
Investigations reveled leucocytes (WBC): 12 x 109/L with a neutrophil count 8.7 x 109/L, hemoglobin (Hgb): 14 g/dL, platelets 329 x 109/L, C-reactive pro-tein (CRP) 2.8 mg/dL (ULN: 0.3 mg/dL), blood urea nitrogen (BUN) 48.5 mg/dL (ULN: 22.9 mg/dL), crea-tinine 2.46 mg/dL (two-fold increase since hospital dis-charge) and NT-proBNP 3580 pg/mL (Table 1). Liver and thyroid function tests as well as electrolytes were within normal range. The tongue and throat swab cultures were negative for fungal or bacterial pathogens. Computed tomography of the brain failed to show evi-dence of stroke, brain injury or tumor. Acute kidney injury in a patient with cardiovascular risk factors, as well as severe hypertension on presentation and a de-cline in renal function after ACEi initiation prompted the search for bilateral renal artery stenosis. Howe-ver, the renal Doppler examination was unremarkable (see Figure 1).
Since the patient started complaining of dysgeusia promptly after treatment initiation with ACEi, beta-blocker, diuretics (thiazide and potassium-sparing) and cephalosoporin, we assumed that the taste disturbance may be an adverse drug reaction. Hence, we decided on a sequential discontinuation starting with perindo-pril, an agent from a class frequently associated with dysgeusia, which was replaced with rilmenidine 1 mg o.d. Dysgeusia resolved within 2 days of perindopril discontinuation. A diagnosis of acute kidney injury due to severe dehydration owing to initiation of angioten-sin-converting-enzyme inhibitor was established and the patient was discharged from hospital. At follow-up he had adequate renal function and no dysgeusia.

Figure 1. Color Doppler of the intrarenal vasculature corresponding to the right (panel A) and left (panel B) kidney. Renal Doppler ultrasound showed normal velocities and waveform envelopes of both renal arteries.

DISCUSSIONS
Taste disturbances (dysgeusia) include alterations in the ability to grade taste: ageusia (complete loss), hypogeusia (loss of acuity), hypergeusia (increased acuity) or perceive its quality: parageusia (inadequate perception of stimuli) and phantogeusia (perception despite absence of stimuli)1.
In a large US study, prevalence of self-reported dysgeusia ranged from 5% in the general population to as much as 27% in patients aged >80 years2. Dysgeusia may lead to changes in dietary intake resulting in ei-ther malnutrition or weight gain. Older patients seem to be at an increased risk of developing dysgeusia1 and consequently, malnutrition and severe dehydration3.
Dysgeusia etiology is varied and ranges from infec-tion (sinusitis, pharyngitis, tonsillitis, upper respirato-ry tract infection) to oral pathology (glossitis, gingivitis), xerostomia (salivary gland dysfunction, Sjögren’s syndrome), depression, smoking, diabetes mellitus, stroke or nerve damage (facial, vagus or glossopharyn-geal), liver and kidney failure, Parkinson’s disease, and hypothyroidism. Drugs and radiation therapy have also been reported to produce disorders of taste per-ception3,4.
A wide array of frequently used drugs have been cited in relation to taste disturbance including angi-otensin-converting enzyme inhibitors (ACEi), antibio-tics and chemotherapics (see Table 2)5. In a study by Smith et al., among patients who report oral adverse drug reactions to the 200 most commonly prescribed drugs in the US, up to 47.5% complain of dysgeusia5.
Drug-induced dysgeusia has two mechanisms: con-tact injury (alteration of saliva composition/ flow or chemoreceptor failure, both preventing the stimulant from coming into contact with the receptor) and ne-ural injury (signal transduction dysfunction, nerve da-mage or brain lesions involving taste centers in the orbitofrontal cortex)4-6.
Angiotensin-converting enzyme inhibitor-induced dysgeusia has been reported in up to 4% of patients undergoing ACEi treatment but is self-limiting despite continued use and resolves in 2-3 months5. Though the definite cause of ACEi induced dysgeusia is yet to be settled7, salivary gland zinc ion chelation has been incriminated8,9. Captopril is the ACEi most commonly cited as the cause of taste disturbances and the mecha-nism has been explained by interactions between its thiol radical and zinc. Sekimoto et al. revealed the cap-topril-zinc chelate to be highly soluble which leads to increased urinary zinc excretion and ultimately zinc deficiency and thus, dysgeusia10-14. Papers proving tas-te improvement after zinc supplementation have been published, however none in relation to drug-induced dysgeusia.
Though no case reports have been published to date, the European Medicines Agency (EMA) includes dysgeusia as a common (>1/100, <1/10) undesirable effect of perindopril15. Moreover, Tsuruoka et al. showed that perindopril subclinically worsened taste perception in healthy subjects and hypothesized that a preexisting, slight taste disturbance may be enhan-ced by administration of perindopril in hypertensive patients16.

CONCLUSION
The acute development of dysgeusia in a patient with probable subclinical taste alteration due to preexisting diabetes mellitus, as well as its complete reversibility after perindopril discontinuation, point to a drug-in-duced taste alteration with consequent dehydration as the cause of the acute kidney injury.

Conflict of interest: none declared.

List of abbreviations used
ACEi – angiotensin converting enzyme inhibitor ADR – adverse drug reaction
BP – blood pressure
CRP – C-reactive protein
EMA – European Medicines Agency ENT – otorhinolaryngology HR – heart rate
IRA – insuficienţă renală acută o.d. – once daily
ULN – upper limit of normal

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