Re-evaluation of the penicillamine challenge test in the diagnosis of Wilson’s disease in children

Backgrounds/Aims

A urinary copper (Cu) >25 μmol/24 h following penicillamine had a reported specificity of 98.2% and sensitivity of 88.2% in diagnosing Wilson’s disease (WD). We have re-evaluated this test. Ninety-eight subjects were studied at presentation.

Methods

Thirty-eight (19 girls, 19 boys; median age 10.3 years; range 5–16 years) had an ultimate diagnosis of WD. Sixty (24 girls, 36 boys; median age 10.1, range 2.3–15 years) had other liver disorders. Urinary Cu was estimated for 24 h before (basal Cu) and for 24 h whilst giving penicillamine 500 mg orally 12 hourly × 2 (post-penicillamine Cu).

Results

Both basal Cu and post-penicillamine Cu differed significantly between WD patients and controls (basal Cu: median 6.5 μmol/24 h, range 0.9–109 μmol/24 h, versus median: 0.8 μmol/24 h, range 0.1–19.5, p < 0.0001; post-penicillamine Cu: median 36.9 μmol/24 h, range 1.98–219 μmol/24 h, versus median 12.35 μmol/24 h, range 0.5–49.8 μmol/24 h, p < 0.0001). A post-penicillamine Cu >25 μmol/24 h was observed in 29/38 patients with WD and in 4/60 controls. 25/38 WD patients were symptomatic. Twenty-three of these and 6/13 asymptomatic siblings had a positive test. The test had a sensitivity of 76% (95% confidence interval [CI], 59.8–88.6%) and a specificity of 93% (95% CI, 83.8–98.2%). Sensitivity was better in symptomatic patients (92%, [95% CI; 74–99%]) than asymptomatic (46%, [95% CI; 19.2–74.9%]).

Conclusions

This test is valuable in the diagnosis of WD with active liver disease, but is unreliable to exclude the diagnosis in asymptomatic siblings.

Introduction

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by mutations within the ATP7B gene which cause impaired biliary copper excretion resulting in hepatic copper toxicity and subsequent multisystem disease involving the liver, brain, cornea, skeleton and rarely the heart [1], [2]. In childhood hepatic manifestations predominate with a highly variable spectrum ranging from self-limiting hepatitis to fulminant hepatic failure (FHF). Symptomatic patients usually present after 4 years of age with acute hepatitis, FHF, clinical or biochemical signs of chronic liver disease or decompensated cirrhosis [3], [4]. Pre- or asymptomatic patients may accidentally be identified at any age by detecting elevated serum aminotransferase levels during routine laboratory tests done for unrelated reasons or by family screening after a first degree relative has been diagnosed with WD.

Establishing the diagnosis of WD may be problematic because Kayser–Fleischer (KF) rings may be absent and because there is no single reliable biochemical test [5], [6]. The limitations of serum copper, serum ceruloplasmin and basal urinary copper excretion estimations have been reported in several studies (for reference see [6]). Mutational analysis is particularly helpful for primary diagnosis in geographical areas where one mutation predominates, but in Northern Europe and the USA many mutations are found and most patients are compound heterozygotes [7]. Although quantitative hepatic copper analysis is still considered the gold standard [6], in a series of adults 19/114 had liver copper values less than 250 μg/g dry weight [8]. In a series of 17 pediatric WD cases, a urinary copper excretion >25 μmol/24 h following penicillamine was reported to have a specificity of 98.2% and sensitivity of 88.2% [9]. However, the diagnostic value of this penicillamine challenge test (PCT) was discounted by several authorities and different cut-off levels have been proposed [10]. Furthermore, the diagnostic accuracy of PCT has not been ascertained among genotypically confirmed patients. Thus, we re-evaluated this test in a larger series of 38 pediatric patients with WD, 50% of whom had ascertainment of ATP7B genotype, and 60 age-matched controls with non-Wilsonian liver disease.