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Requests for reprints should be addressed to Anne-Kathrin Tausche, MD, Department of Internal Medicine, Section of Endocrinology and Rheumatology, University Hospital Carl Gustav Carus, Technical University of Dresden, Fetscherstrasse 74, Dresden D-01307, Germany.
Department of Internal Medicine, Section of Endocrinology and Rheumatology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany
Department of Internal Medicine, Section of Endocrinology and Rheumatology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany
Department of Internal Medicine, Section of Endocrinology and Rheumatology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany
Department of Internal Medicine, Section of Endocrinology and Rheumatology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany
Hyperuricemia is one of the most common metabolic disorders. There is international consensus that antihyperuricemic therapy is indicated in gouty arthritis, tophi, and uric acid overproduction. Regardless of the cause of hyperuricemia, allopurinol is the most commonly prescribed drug and is normally well tolerated.
Case Report
A 69-year-old white woman suffering from a complete metabolic syndrome was admitted for treatment of a decompensated arterial hypertension. The creatinine clearance was impaired (44.4 mL/min) with slight increases in serum creatinine (120 μmol/L, 1.3 mg/dL). The patient received thiazide diuretics.
Because of constantly raised values for serum uric acid (>480 μmol/L, >8.0 mg/dL), the patient was administered 300 mg allopurinol daily for antihyperuricemic therapy. After 3 months the patient complained of generalized itching; 8 weeks later an erythema with disseminated exfoliative dermatitis developed (Figure, A-C). At readmission, the patient was characterized by fever, malaise, and general fatigue. Severe erythrodermia, diffuse alopecia, and nail onycholysis were apparent.
Laboratory findings revealed the following signs of inflammation: leukocytosis (12.3 Gpt/L) with eosinophilia (1.23 Gpt/L), erythrocyte sedimentation rate of 45 mm/1st hour, and C-reactive protein of 10.1 mg/L. Markedly increased eosinophilic cationic protein concentration of 61 g/L (normal: <18 g/L) gave further evidence of eosinophil granulocyte activation. Normal total immunoglobulin E levels (18.5 kU/L) confirmed the patient’s otherwise allergy-free record. Apart from emerging renal insufficiency with creatinine clearance at 30.8 mL/min, liver damage was demonstrated by a 10-fold elevated serum transaminase. After diagnosis of an allopurinol hypersensitivity syndrome, allopurinol was stopped immediately. Under treatment with heavily dosed steroids and antihistamines, the liver enzymes and renal function returned to normal ranges during the next weeks. The extensive efflorescence started to heal gradually, the hair and nails started to develop normally around 8 weeks later.
Discussion
To date, only a few cases of a syndrome characterized by exfoliative dermatitis with blood eosinophilia complicated by hepatitis and interstitial nephritis due to allopurinol therapy have been described in the literature. The clinical diagnosis of the allopurinol hypersensitivity syndrome is challenging because it usually starts delayed (eg, weeks or months) with various cutaneous manifestations, together with fever and fatigue (Table).
Extensive itching develops as a prodrome mostly after 4-6 weeks, which precedes the visible cutaneous changes. Depending on the affected skin compartment, symmetric epidermal, dermal, or primary vasculitic reactions appear in varying extent and severity. Usually, an impairment of the liver and renal function is evident. If allopurinol is not discontinued at this point, the medical condition may progress to a multiorgan failure.
TableDiagnostic Criteria of Allopurinol Hypersensitivity Syndrome
Explicit connection with the intake of allopurinol
Clinical image
Either:
At least 2 of the following main criteria
Deterioration of renal function
Acute liver damage
Cutaneous changes such as diffuse erythematous or exfoliative dermatitis, erythema exudativum multiforme (EEM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)
Or:
With one of the main criteria and one of the following secondary criteria:
Fever
Eosinophilia
Leukocytosis
Absence of exposure to another drug that may have caused a similar clinical image
The pathogenesis of the allopurinol hypersensitivity syndrome is not entirely clear, but it seems to involve the accumulation of one of the allopurinol metabolites, oxipurinol, so patients with renal insufficiency are especially prone to develop allopurinol hypersensitivity syndrome.
Further risk factors seem to be the comedication with thiazide diuretics. Recent analyses revealed that allopurinol was often prescribed in doses up to 300 mg daily—sometimes in patients with asymptomatic hyperuricemia. In order to avoid the allopurinol hypersensitivity syndrome with potentially lethal consequences, the dose adaptation to renal function is mandatory.
As a new therapeutic option, febuxostat—a nonpurine, selective inhibitor of xanthine oxidase—seems to be a promising alternative in cases with contraindication against allopurinol.
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