Wilson's Disease: Monocentric Experiences Over a Period of 16 Years

Abstract

Background: Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism. The objective of this study is to present diagnostic pitfalls and long time follow-up data in Wilson disease.

Patients/Methods: We studied 21 WD patients and 14 heterozygote carriers aged 2–43 years, retrospectively. 18 WD patients presented liver disease, three had mixed neurological and hepatic involvement and 9 patients underwent orthotopic liver transplantation (OLT).

Results: The median age at diagnosis of WD children without OLT was 10.16±3.8 (range, 5–16). All of females and younger age categories of patients prevailed in acute liver failure group. Serum ceruloplasmine levels were below 0.2 g/l in about ⅓ of WD carriers (X¯=0.27±0.09 g/l) and nearly ⅔ of children with WD (X¯= 0.21±0.13 g/l). A statistically significant difference (p<0.05) in the 24-h excretion of copper in urine was noticed between healthy controls, children with WD and WD heterozygote carriers. As diagnostic important proved the copper content of more than 250 μg/g hepatic dry weight. The Kayser-FleischerŽs ring was not observed in children. Ceruloplasmine, haemoglobin, ALT, ALP and plasma albumin were significantly different between fulminant and non-fulminant WD and could be used as indirect markers in evaluation of urgent OLT.

Conclusion: Detection of WD in children remains very difficult. The most important investigation is liver biopsy with the assessment of liver copper. Genetic analysis may help in doubtful cases.

Zusammenfassung

Hintergrund: Morbus Wilson (MW) ist eine autosomal-rezessive Störung des Kupferstoffwechsels. Das Ziel dieser Studie ist es, klinische Probleme bei der Diagnostik und die Daten der Langzeitbeobachtung von Morbus Wilson zu präsentieren.

Patienten und Methoden: Wir haben 21 MW-Patienten und 14 heterozygote Träger im Alter von 2 bis 43 Jahren retrospektiv analysiert. Von den MW-Patienten haben 18 an einer isolierten Lebererkrankung und 3 an einer gemischt-neurologisch-hepatischen Störung gelitten; insgesamt 9 Patienten haben sich einer orthotopen Lebertransplantation (OLT) unterzogen.

Ergebnisse: Das Durchschnittsalter bei Diagnose der MW-Patienten ohne OLT war 10,16±3,8 Jahre (Bereich 5–16). Alle jungen Frauen und Mädchen gehören in die Gruppe von Patienten mit akuten Leberstörungen. Bei ca ⅓ von MW-Trägern (X¯ 0,27±0,09 g/l) und fast ⅔ von Kindern mit MW (X¯ 0,21±0,13 g/l) waren die Werte des Ceruloplasmins im Serum <0,2 g/l. Bei gesunden Kontrollpersonen, Kindern mit MW und heterozygoten MW-Trägern wurde eine statistisch signifikante Differenz (p<0,05) in der 24-Stunden-Kupferausscheidung im Urin beobachtet. Als wichtiges Untersuchungsmerkmal hat sich ein Kupfergehalt von > 250 μg/g im Lebertrockengewicht erwiesen. Der Kayser-Fleischer-Ring wurde bei Kindern nicht beobachtet. Ceruloplasmin, Hämoglobin, ALT, ALP und Plasmaalbumin haben bei fulminantem und nicht-fulminantem MW signifikante Unterschiede aufgewiesen und könnten als indirekte Marker für die Entscheidung für eine dringliche OLT verwendet werden.

Schlussfolgerung: Die Diagnose des MW bei Kindern bleibt kompliziert. Die wichtigste Untersuchungsmethode ist die Leberbiopsie mit Bestimmung des Kupfergehaltes in der Leber. Die genetische Analyse kann in unklaren Fällen behilflich sein.

Keywords

Wilson disease - copper metabolism - orthotopic liver transplantation - children

Schlüsselwörter

Morbus Wilson - Kupferstoffwechsel - orthotope Lebertransplantation - Kinder

References

• 1 Arnon R. et al . Wilson Disease in Children: Serum Aminotransferases and Urinary Copper on Triethylene Tetramine Dihydrochloride (Trientine) Treatment.  J Pediatr Gastr Nutr. 2007;  44 596-602
• 2 Brewer G-J. et al . Treatment of Wilson's disease with zinc XVI: treatment during the pediatric years.  J Lab Clin Med. 2001;  137 191-198
• 3 Caca K. et al . High prevalence of H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis.  J Hepatol. 2002;  35 575-581
• 4 Caprai S. et al . Direct diagnosis of Wilson disease by molecular genetics.  The Journal of Pediatrics. 2006;  148 138-140
• 5 Czlonkowska A. et al . Very high frequency of the His1069Gln mutation in Polish Wilson disease patients.  J Neurol. 1997;  244 591-592
• 6 Dhawan A. et al . Wilson's disease in children: 37-year experience and revise King's College Score for liver transplantation.  Liver Transplant. 2005;  11 441-448
• 7 Eisenbach C. et al . Diagnostic criteria for acute liver failure due to Wilson disease.  World J Gastroenterol. 2007;  13 1711-1714
• 8 Eghtesad B. et al . Liver transplantation for Wilson's disease: a single-centre experience.  Liver Transplant Surg. 1999;  5 467-474
• 9 Ferenci P. et al . Diagnosis and phenotypic classification of Wilson's disease.  Liver Int. 2003;  23 139-142
• 10 Ferenci P. Regional distribution of mutations of ATP7B gene in patients with Wilson disease: impact on genetic testing.  Hum Genet. 2006;  120 151-159
• 11 Fiernicz G. et al . Common mutations of ATP7B in Wilson disease patients from Hungary.  Am J Med Genet. 2002;  108 23-28
• 12 Gojova L. et al . Genotyping microarray as a novel approach for the detection of ATP7B gene mutations in patients with Wilson disease.  Clin Genet. 2008;  73 441-452
• 13 Gromadzka G. et al . Frameshift and nonsense mutations in the gene for ATP-ase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson's disease.  Clin Genet. 2005;  68 524-532
• 14 Grünmayer E-R, Weippl G. Hemolysis and Liver Cirrhosis Featuring a case of Wilson's Disease in Childhood.  Klin Padiatr. 1983;  195 355-357
• 15 Hillebrand P. et al . Significance of intravascular coagulation and fibrinolysis in acute hepatic failure.  Scand J Gastroenterol Suppl. 1973;  19 133-134
• 16 Hoshino T. et al . Low alkaline phosphatase activity associated with severe Wilson's disease. Is the breakdown of alkaline phosphatase molecules caused by reactive oxygen species?.  Clin Chim Acta. 1995;  238 91-100
• 17 Ibel H. et al . D-Penicillamine – Induced IgA Deficiency in Treatment of Wilson's Disease.  Klin Padiatr. 1990;  202 427-429
• 18 Ivanova-Smolenskaya I-A. et al . The His1069Gln mutation in the ATP7B gene in Russian patients with Wilson disease.  J Med Genet. 1999;  36 174
• 19 Kumar S. et al . Identification and molecular characterization of 18 novel mutations in the ATP7B gene from Indian Wilson disease patients genotype.  Clin Genet. 2005;  67 443-445
• 20 McCullough A-J. et al . Diagnosis of Wilson's disease presenting as fulminant hepatic failure.  Gastroenterology. 1983;  84 161-167
• 21 Merle U. et al . Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study.  Gut. 2007;  56 115-120
• 22 Müller T. et al . Re-evaluation of the penicillamine challenge test in the diagnosis of Wilson's disease in children.  J Hepatol. 2007;  47 270-276
• 23 Nazer H. et al . Wilson's disease: clinical presentation and use of prognostic index.  Gut. 1986;  27 1377-1381
• 24 Ohura T. et al . Pilot study of screening for Wilson disease using dried blood spots obtained from children seen at outpatient clinics.  J Inher Metab Dis. 1999;  22 74-80
• 25 Okada T. et al . Mutational analysis of ATP7B and genotype-phenotype correlation in Japanese with Wilson's disease.  Human Mutation. 2000;  15 454-462
• 26 Olivarez L. et al . Estimate of the frequency of Wilson's disease in the US Caucasian population: a mutation analysis approach.  Ann Hum Genet. 2001;  65 459-463
• 27 Petrukhin K. et al . Mapping, cloning and genetic characterization of the region containing the Wilson's disease gene.  Nat Genet. 1993;  5 338-343
• 28 Scheffe H. The analysis of variance. Wiley and Sons, Inc. New York 1959: 479
• 29 Shah A-B. et al . Identification and analysis of mutations in the Wilson disease (ATP7B): population frequencies, genotype-phenotype correlation, and functional analysis.  Am J Human Genet. 1997;  61 317-328
• 30 Snedecor G, Cochran W-G. Statistical methods. The Iowa State University Press, AMES, Iowa 50014, eight editions 1989: 503
• 31 Tissieres P. et al . Fulminant Wilson's disease in children: appraisal of a critical diagnosis.  Pediatr Crit Care Med. 2003;  4 338-343
• 32 Vrabelova S. et al . Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease.  Mol Genet Metab. 2005;  86 277-285
• 33 Yûce A. et al . Wilson's disease with hepatic presentation in childhood.  Indian Pediatr. 2000;  37 31-36

Correspondence