Michael L. Schilsky

Screening for Wilson disease in acute liver failure: A comparison of currently available diagnostic tests Potential conflict of interest: Nothing to report.

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 μg/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. (HEPATOLOGY 2008.)

Prognosis of Wilsonian chronic active hepatitis

Twenty of 320 patients with Wilsons disease initially presented with chemical and laboratory features of chronic active hepatitis, confirmed histologically in 17. When first seen, cirrhosis was present in all 20 and was complicated by ascites and/or jaundice in 11. Within 1 week to 8 years of the onset of over liver disease the diagnosis of Wilsons disease was established, and treatment with D-penicillamine was promptly initiated in 19 patients. One man refused treatment and died 4 months later. Treated patients received D-penicillamine or trientine for a total of 264 patient-years (median, 14 patient-years). Abnormal water retention, for which salt restriction and diuretics were added to penicillamine or trientine, disappeared in all but 1 of the patients so affected. Symptomatic improvement and virtually normal levels of serum albumin, bilirubin, aspartate aminotransferase, and alanine aminotransferase followed within 1 year in the majority of subjects. One woman died after 9 months of treatment. Two patients, who became noncompliant with the therapeutic regimen after 9 and 17 years of successful pharmacological treatment, required liver transplants. These results indicate that the prognosis of specifically treated Wilsonian chronic active hepatitis is very good in spite of the presence of cirrhosis.

ATP7B (WND) protein

Wilsons disease is a genetic disorder of copper metabolism characterized by the excessive accumulation of this metal in the liver. The gene for Wilsons disease, designated ATP7B, encodes a copper transporting P-type ATPase expressed predominantly in the liver. Over 60 disease specific mutations of ATP7B have now been reported in patients with Wilsons disease. The gene for ATP7B is approximately 80 kb and contains 21 exons that encode an approximately 7.5 kb transcript. Recent studies that focus on the structure and expression of the ATP7B protein support its role as a copper transporter involved in the intracellular trafficking of copper in hepatocytes. The introduction of functional ATP7B protein by recombinant adenovirus mediated gene delivery will be a potential approach for correcting Wilsons disease.

Biliary copper excretion capacity in intact animals: Correlation between ATP7B function, hepatic mass, and biliary copper excretion

Copper toxicosis can occur in the absence of biliary copper excretion. To demonstrate whether biliary copper excretion capacity is correlated with hepatic mass and ATP7B function, we undertook studies in intact animals. Copper‐histidine was injected intrasplenically after baseline bile collection, followed by measurement of copper excretion in Long‐Evans Cinnamon (LEC) rats lacking atp7b function and in normal, syngeneic Long‐Evans Agouti (LEA) rats. The basal biliary copper excretion was very low in LEC rats compared with LEA rats, 8 ± 4 and 37 ± 18 ng copper/min, respectively; p < 0.05. After addition of copper, copper excretion increased significantly (by two‐ to five‐fold) in LEA rats during the 30 minute study period, whereas LEC rats showed only a slight and transient increase in copper excretion. After one‐third and two‐thirds partial hepatectomy immediately before copper loading, copper excretion decreased progressively. The studies indicate that biliary copper excretion depends on hepatocyte mass and ATP7B gene function. Analysis of copper excretion with our nonradioactive method will facilitate testing of novel therapies and pathophysiological mechanisms in copper toxicity.