Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests

Jessica D Korman, Irene Volenberg, Jody Balko, Joe Webster, Frank V Schiodt, Robert H Squires Jr, Robert J Fontana, William M Lee, Michael L Schilsky, Pediatric and Adult Acute Liver Failure Study Groups, William M Lee, Julie Polson, Carla Pezzia, Ezmina Lalani, Linda S Hynan, Joan S Reisch, Anne M Larson, Hao Do, Jeffrey S Crippin, Laura Gerstle, Timothy J Davern, Katherine Partovi, Sukru Emre, Timothy M McCashland, Tamara Bernard, J Eileen Hay, Cindy Groettum, Natalie Murray, Sonnya Coultrup, A Obaid Shakil, Diane Morton, Andres T Blei, Jeanne Gottstein, Atif Zaman, Jonathan Schwartz, Ken Ingram, Steven Han, Val Peacock, Robert J Fontana, Suzanne Welch, Brendan McGuire, Linda Avant, Raymond Chung, Deborah Casson, Robert Brown Jr, Michael Schilsky, Laren Senkbeil, M Edwyn Harrison, Rebecca Rush, Adrian Reuben, Nancy Huntley, Santiago Munoz, Chandra Misra, Todd Stravitz, Jennifer Salvatori, Lorenzo Rossaro, Colette Prosser, Raj Satyanarayana, Wendy Taylor, Raj Reddy, Mical Campbell, Tarek Hassenein, Fatma Barakat, Alistair Smith, Jessica D Korman, Irene Volenberg, Jody Balko, Joe Webster, Frank V Schiodt, Robert H Squires Jr, Robert J Fontana, William M Lee, Michael L Schilsky, Pediatric and Adult Acute Liver Failure Study Groups, William M Lee, Julie Polson, Carla Pezzia, Ezmina Lalani, Linda S Hynan, Joan S Reisch, Anne M Larson, Hao Do, Jeffrey S Crippin, Laura Gerstle, Timothy J Davern, Katherine Partovi, Sukru Emre, Timothy M McCashland, Tamara Bernard, J Eileen Hay, Cindy Groettum, Natalie Murray, Sonnya Coultrup, A Obaid Shakil, Diane Morton, Andres T Blei, Jeanne Gottstein, Atif Zaman, Jonathan Schwartz, Ken Ingram, Steven Han, Val Peacock, Robert J Fontana, Suzanne Welch, Brendan McGuire, Linda Avant, Raymond Chung, Deborah Casson, Robert Brown Jr, Michael Schilsky, Laren Senkbeil, M Edwyn Harrison, Rebecca Rush, Adrian Reuben, Nancy Huntley, Santiago Munoz, Chandra Misra, Todd Stravitz, Jennifer Salvatori, Lorenzo Rossaro, Colette Prosser, Raj Satyanarayana, Wendy Taylor, Raj Reddy, Mical Campbell, Tarek Hassenein, Fatma Barakat, Alistair Smith

Abstract

Acute liver failure (ALF) due to Wilson disease (WD) is invariably fatal without emergency liver transplantation. Therefore, rapid diagnosis of WD should aid prompt transplant listing. To identify the best method for diagnosis of ALF due to WD (ALF-WD), data and serum were collected from 140 ALF patients (16 with WD), 29 with other chronic liver diseases and 17 with treated chronic WD. Ceruloplasmin (Cp) was measured by both oxidase activity and nephelometry and serum copper levels by atomic absorption spectroscopy. In patients with ALF, a serum Cp <20 mg/dL by the oxidase method provided a diagnostic sensitivity of 21% and specificity of 84% while, by nephelometry, a sensitivity of 56% and specificity of 63%. Serum copper levels exceeded 200 microg/dL in all ALF-WD patients measured (13/16), but were also elevated in non-WD ALF. An alkaline phosphatase (AP) to total bilirubin (TB) ratio <4 yielded a sensitivity of 94%, specificity of 96%, and a likelihood ratio of 23 for diagnosing fulminant WD. In addition, an AST:ALT ratio >2.2 yielded a sensitivity of 94%, a specificity of 86%, and a likelihood ratio of 7 for diagnosing fulminant WD. Combining the tests provided a diagnostic sensitivity and specificity of 100%.

Conclusion: Conventional WD testing utilizing serum ceruloplasmin and/or serum copper levels are less sensitive and specific in identifying patients with ALF-WD than other available tests. More readily available laboratory tests including alkaline phosphatase, bilirubin and serum aminotransferases by contrast provides the most rapid and accurate method for diagnosis of ALF due to WD.

Figures

Figure 1
Figure 1
Serum Copper in ALF. Results are shown for patients with ALF due to acetaminophen injury, non-acetaminophen injury and for patients with WD.
Figure 2
Figure 2
Alkaline Phosphatase to Total Bilirubin Ratio in ALF. Results are shown for patients with ALF due to acetaminophen injury, non-acetaminophen injury and for patients with WD.
Figure 3
Figure 3
AST:ALT Ratio in ALF. Results are shown for patients with ALF due to acetaminophen injury, non-acetaminophen injury and for patients with WD.
Figure 4
Figure 4
Hemoglobin in ALF. Results are shown for patients with ALF due to acetaminophen injury, non-acetaminophen injury and for patients with WD.
Figure 5
Figure 5
a. Receiver Operating Characteristics for Ceruloplasmin Measured by Nephelometry and by Oxidase Methods in 140 patients with ALF. The area under the curve is 0.60 and 0.70, respectively. b. Receiver Operating Characteristics for Ceruloplasmin Measured by Nephelometry and by Oxidase in 17 chronic Wilson Disease patients. The area under the curve is 0.87 and 0.89, respectively. c. Receiver Operating Characteristics for Alkaline Phosphatase to Total Bilirubin Ratio and Hemoglobin (g/dL) and the diagnosis of Wilson Disease in ALF (ALF-WD). The area under the curve is 0.98 and 0.94, respectively. d. Receiver Operating Characteristics for AST to ALT Ratio and Serum Copper (μg/dL) and the diagnosis of Wilson Disease in ALF. The area under the curve is 0.98 and 0.95, respectively.
Figure 5
Figure 5
a. Receiver Operating Characteristics for Ceruloplasmin Measured by Nephelometry and by Oxidase Methods in 140 patients with ALF. The area under the curve is 0.60 and 0.70, respectively. b. Receiver Operating Characteristics for Ceruloplasmin Measured by Nephelometry and by Oxidase in 17 chronic Wilson Disease patients. The area under the curve is 0.87 and 0.89, respectively. c. Receiver Operating Characteristics for Alkaline Phosphatase to Total Bilirubin Ratio and Hemoglobin (g/dL) and the diagnosis of Wilson Disease in ALF (ALF-WD). The area under the curve is 0.98 and 0.94, respectively. d. Receiver Operating Characteristics for AST to ALT Ratio and Serum Copper (μg/dL) and the diagnosis of Wilson Disease in ALF. The area under the curve is 0.98 and 0.95, respectively.
Figure 5
Figure 5
a. Receiver Operating Characteristics for Ceruloplasmin Measured by Nephelometry and by Oxidase Methods in 140 patients with ALF. The area under the curve is 0.60 and 0.70, respectively. b. Receiver Operating Characteristics for Ceruloplasmin Measured by Nephelometry and by Oxidase in 17 chronic Wilson Disease patients. The area under the curve is 0.87 and 0.89, respectively. c. Receiver Operating Characteristics for Alkaline Phosphatase to Total Bilirubin Ratio and Hemoglobin (g/dL) and the diagnosis of Wilson Disease in ALF (ALF-WD). The area under the curve is 0.98 and 0.94, respectively. d. Receiver Operating Characteristics for AST to ALT Ratio and Serum Copper (μg/dL) and the diagnosis of Wilson Disease in ALF. The area under the curve is 0.98 and 0.95, respectively.
Figure 5
Figure 5
a. Receiver Operating Characteristics for Ceruloplasmin Measured by Nephelometry and by Oxidase Methods in 140 patients with ALF. The area under the curve is 0.60 and 0.70, respectively. b. Receiver Operating Characteristics for Ceruloplasmin Measured by Nephelometry and by Oxidase in 17 chronic Wilson Disease patients. The area under the curve is 0.87 and 0.89, respectively. c. Receiver Operating Characteristics for Alkaline Phosphatase to Total Bilirubin Ratio and Hemoglobin (g/dL) and the diagnosis of Wilson Disease in ALF (ALF-WD). The area under the curve is 0.98 and 0.94, respectively. d. Receiver Operating Characteristics for AST to ALT Ratio and Serum Copper (μg/dL) and the diagnosis of Wilson Disease in ALF. The area under the curve is 0.98 and 0.95, respectively.

Source: PubMed

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