Acute Hepatic Phenotype of Wilson Disease: Clinical Features of Acute Episodes and Chronic Lesions Remaining in Survivors

Background and Aims:Wilson disease(WD)is an inherited disorder of copper metabolism,and an international group for the study of WD(IGSW)has proposed three phenotypes for its initial presentation:acute hepatic,chronic hepatic,and neurologic phenotypes.Characterization of the acute hepatic phenotype may improve our understanding of the disease.Methods:Clinical features of 10 WD patients with the acute hepatic phenotype and characteristics of chronic lesions remaining in survivors were assessed by the European Association for the Study of the Liver(EASL)guide-lines.Results:All six patients younger than 30 years had survived an acute episode of hemolytic anemia with residual liver disease of cirrhosis or chronic hepatitis.The acute episode was self-limiting in two of the four patients over the age of 30 years and progressed to acute liver failure in the other two patients.One of the two survivors had residual liver disease of chronic hepatitis,while the other had chronic hepatitis and neurologic disease.Neurologic disease remained in a patient who successfully received a liver transplantation.During acute episodes,serum levels of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)changed rapidly along with anemia.Liver-specific ALT levels were age-dependently correlated with hemoglobin(Hb)concentrations.Enzyme reduction was milder for AST than ALT which resulted in a high AST/ALT ratio in the anemic stage.The anemic stage in two patients transformed to acute liver failure.Conclusions:All survivors of an acute episode of the acute hepatic phenotype had residual liver disease or both liver and neurologic diseases.The rapid changes in liver enzymes during the acute episode and the liver and neurologic diseases remaining in survivors may provide a better understanding of WD.

Phenotypes and Chronic Organ Damage May Be Different among Siblings with Wilson's Disease

Background and Aims:Cloning of ATP7B provided evidence that Wilson's disease is a hepatic copper toxicosis with a variety of extrahepatic complications.Affected siblings with the same genetic background and exposure to similar environmental factors may be a good model for the study of genotype-phenotype correlation.Methods:Twenty-three affected siblings in 11 families were selected from a database.The first phenotypes were determined according to the international proposal.The final types of chronic organ damage were re-evaluated for life-long management.Results:Phenotypes were identical in 5 of the families and different in 6 of the families.The acute hepatic phenotype H1 was found in 3 younger siblings and 1 older sibling.All survived an acute episode of hemolysis with underlying chronic liver disease.One also presented complication with neurological disease.The neurological phenotype N1 with neuropsychiatric symptoms and hepatic disease was found in 2 aged siblings of 1 family,in an older sibling in 3 families and in the oldest sibling in 1 family.Phenotypes in siblings were mainly split by either H1 occurring in random order or age-dependent N1.Types of chronic organ damage were identical in 8 of the families and different in 3 of the families.The same combination of chronic liver disease was found in 6 families and chronic liver disease complicated with neurological disease in 2 families.Split organ damage in siblings was found when an older sibling was complicated by neurological disease.There was no reverse combination of a younger sibling being complicated by neurological disease in any of the families.Conclusion:Phenotype combinations of siblings were mainly modified by externally-induced hemolytic episodes,while chronic organ damage in siblings was split by age-dependent neurological complications.

Alanine Aminotransferase as the First Test Parameter for Wilson's Disease

Background and Aims: The liver is the first organ affected by toxic copper in the classical and severe hepatic forms of Wilson's disease(WD).Because their associated chronic liver damage is mostly asymptomatic,an intervention using a special test including serum alanine aminotransferase(ALT)activity is needed for detecting WD.Methods: Using the modified international criteria for the diagnosis of WD,45 patients were selected from the collective databases of our institutions,and 7 infants were reviewed from the literature.Two patients had the severe hepatic form,with nor-moceruloplasminemia and no mutations in ATP7B.The rapid ALT change during hemolytic anemia was adjusted for a baseline.The diagnostic potential of the ALT test was assessed from the age-dependent natural course of the liver damage of WD.Results: The natural course had three stages.ALTs were still low in some infants younger than 4 years-old.They were high in all children between the ages of 4 and 8 years-old;then,they reduced to low levels in some patients over 9 years of age.The high ALT stage represents chronic active hepatitis,and the sub-sequent low ALT stage is due to silent cirrhosis.The hepatic cop-per content is a reliable but invasive test,while urinary copper secretion is an alternative,non-invasive test for copper toxicosis of WD.The serum ceruloplasmin and ATP7B analyses are sub-type tests of WD.The response to anti-copper regimens is the final test result.Conclusions: ALTcould be the first parameter to test to detect WD in children between the ages of 4 and 8 years.