Diagnosing Wilson Disease in Acute Liver Failure: Comparison of Existing and Experimental Biomarkers

In acute liver failure due to Wilson disease (ALF-WD), early and correct diagnosis is critical. Readily available biochemical parameters, e.g., ALT:AST ratio provide acceptable diagnostic accuracy. Recently, accurate nonceruloplasmin bound copper (ANCC), reflecting bioavailable serum copper and relative-ANCC (RelANCC) were developed. We investigated the diagnostic use of ANCC and RelANCC, and the validity of current diagnostic markers in ALF-WD.

Serum samples and data were collected through the US ALF Study Group registry. Etiologies included ALF-WD (n = 23), acetaminophen (n = 11), autoimmune (n = 10), drug induced liver injury (n = 13), HBV/HDV (n = 10), and other (n = 3). Standard clinical and biochemical parameters, serum copper (s-Cu), ANCC, and RelANCC were measured. Receiver operating characteristic analysis was performed.

Both ANCC (cut-off ≥483 μg/L) and s-Cu (≥1369 μg/L) provided excellent diagnostic information for ALF-WD (area under the receiver operating curve [AUROC] 0.94 and 0.89). Low ALP (≤45 U/L), and ALT (≤52 U/L) individually provided diagnostic information for ALF-WD (AUROC's > 0.89). Combining ALT with either s-Cu or ANCC further improved diagnostic accuracy, with the ANCC-ALT score being more accurate, AUROC 0.99, sensitivity 91% and specificity 100%. Adding ALP:total bilirubin ratio, AST:ALT ratio or serum zinc to ANCC did not improve accuracy. Median RelANCC was significantly higher in patients with WD (64%) than in non-WD ALF patients (22%) ( P = 0.0001).

Standard biochemistry provides excellent diagnostic information for identifying WD in the setting of ALF. Combining ALT with specific copper measurements significantly improved diagnostic use, with ANCC outperforming s-Cu. RelANCC may also be useful for WD diagnosis. We suggest adding s-Cu to the clinical algorithm in ALF.