Wilson Disease in Children: Analysis of 21 Patients

Yıl 2022, Cilt: 44 Sayı: 6, 873 - 880, 28.11.2022

Yusuf Aydemir Meral Barış Zeren Barış

https://doi.org/10.20515/otd.1127755

Öz

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. Affected children may be asymptomatic, makes the diagnosis more difficult. In this study, we aimed to evaluate the clinical, laboratory, histopathological and genetic characteristics, and outcomes of the patients with WD. Our study includes patients who were diagnosed with WD between January 2010 and December 2020. The presenting complaints, physical examination findings, consanguinity and family history, laboratory, genetic, histopathological evaluation results, treatment and outcomes were all recorded. A total of 21 patients from 18 families [median age 9.5 (1-14) years, 10 girls] were included. Kayser-Fleischer ring was detected in 11 (52.4%) patients. Serum ceruloplasmin (<20 mg/dl) was low in 15 patients. Urinary copper excretion was >100 µg/day in 17 patients. Copper was positively stained with rhodanine in 9 of the18 liver biopsies. Liver copper content was >50 µg/g dry weight in all patients, 50-250 µg/g in 3 patients and >250 µg/g in 15 patients. Genetic evaluation was available in 18 patients and revealed heterozygous mutations in the ATP7B gene in 4 patients, combined heterozygous mutations in 6, and homozygous mutations in 8. Except for two patients with neurological findings and three asymptomatic patients who were diagnosed by family screening, all were presented with liver findings. Neurological involvement was also detected in 2 patients during follow up. D-Penicillamine and zinc sulfate combined treatments were used in 16 patients, zinc sulfate monotherapy was given to a presymptomatic patient diagnosed with family screening, and trientine and zinc sulfate combined therapies were used in four patients with neurological involvement. Transaminase values returned to normal in a median of 8.3 (4-23) months in 15 patients. The Kayser-Fleischer ring disappeared in a median of 32.8 months (10-81) in seven out of eleven patients. While liver transplantation was performed in one of the two patients who presented with fulminant hepatic failure at admission, the other was followed up with plasmapheresis and chelation therapy without the need for transplantation. Wilson disease should be considered in the differential diagnosis of all kinds of liver diseases ranging from asymptomatic elevation of transaminases to acute liver failure. Since early diagnosis and treatment are very important, family screening should definitely be recommended in diagnosed patients.

Anahtar Kelimeler

Copper, Kayser-Fleischer ring, Ceruloplasmin, Wilson disease

Çocuklarda Wilson Hastalığı: 21 Hastanın Analizi

Öz

Wilson hastalığı (WH), bakır metabolizmasının otozomal resesif geçişli bir bozukluğudur. Etkilenen çocuklar asemptomatik olabilir ve bu tanı koymayı zorlaştırır. Bu çalışmada WH'li hastaların klinik, laboratuvar, histopatolojik ve genetik özellikleri ve izlem sonuçlarını değerlendirmeyi amaçladık. Çalışmamıza Ocak 2010-Aralık 2020 tarihleri arasında WH tanısı konulan hastalar dahil edilmiştir. Başvuru şikayetleri, fizik muayene bulguları, akrabalık ve aile öyküsü, laboratuvar, genetik, histopatolojik değerlendirme sonuçları, tedavi ve izlem sonuçları kayıt altına alındı.18 aileden toplam 21 hasta [ortanca yaş 9,5 (1-14) yıl, 10 kız] dahil edildi. 11 (%52,4) hastada Kayser-Fleischer halkası tespit edildi. 15 hastada serum seruloplazmin (<20 mg/dl) düşüktü. 17 hastada üriner bakır atılımı >100 µg/gün idi. Bakır, 18 karaciğer biyopsisinin 9'unda rhodanin ile pozitif olarak boyandı. Karaciğer bakır içeriği tüm hastalarda >50 µg/g olup, 3 hastada 50-250 µg/g ve 15 hastada > 250 µg/g idi. 18 hastada genetik değerlendirme yapıldı ve 4 hastada ATP7B geninde heterozigot mutasyonlar, 6 hastada kombine heterozigot mutasyonlar ve 8 hastada homozigot mutasyonlar saptandı. Nörolojik bulguları olan iki hasta ve aile taraması ile tanı konulan üç asemptomatik hasta dışında, tümü karaciğer bulguları ile başvurdu. Takiplerde 2 hastada nörolojik tutulum saptandı. 16 hastada D-penisilamin ve çinko sülfat kombine tedavileri, aile taraması ile tanı konan presemptomatik bir hastaya çinko sülfat monoterapisi, nörolojik tutulumu olan dört hastada trientin ve çinko sülfat kombine tedavileri uygulandı. 15 hastada ortalama 8,3 (4-23) ayda transaminaz değerleri normale döndü. Kayser-Fleischer halkası, on bir hastanın yedisinde medyan 32,8 ayda (10-81) kayboldu. Başvuru anında fulminan karaciğer yetmezliği ile başvuran iki hastadan birine karaciğer nakli yapılırken, diğerine transplantasyona gerek kalmadan plazmaferez ve şelasyon tedavisi uygulandı. Asemptomatik transaminaz yükselmesinden akut karaciğer yetmezliğine kadar her türlü karaciğer hastalığının ayırıcı tanısında Wilson hastalığı düşünülmelidir. Erken tanı ve tedavi çok önemli olduğundan tanı konulan hastalarda aile taraması mutlaka önerilmelidir.

Anahtar Kelimeler

Bakır, Kayser-Fleischer halkası, Seruloplazmin, Wilson hastalığı

Kaynakça

• 1. Bandmann O, Weiss KH, Kaler SG. Wilson’s disease and other neurological copper disorders. Lancet Neurol. 2015;14:103-13.
• 2. Ferenci P. Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing. Hum Genet. 2006;120:151-59.
• 3. Scheinberg IH, Sternlieb I. Wilson’s disease (a volume in the major problems in internal medicine series). Ann Neurol. 1984;16: 626-36.
• 4. Członkowska A, Litwin T, Dusek P, et al. Wilson disease. Nat Rev Dis Primers. 2018;4:21.
• 5. Riordan SM, Williams R. The Wilson’s disease gene and phenotypic diversity. J Hepatol. 2001;34:165-71.
• 6. Boga S, Ala A, Schilsky ML. Hepatic features of Wilson disease. Handb Clin Neurol. 2017;142: 91-9.
• 7. Lorincz MT. Neurologic Wilson’s disease. Ann NY Acad Sci 2009;1184:173-87.
• 8. European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol. 2012;56:671‐85.
• 9. Socha P, Janczyk W, Dhawan A, et al. Wilson's Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatri Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018;66:334-44.
• 10. Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int. 2003;23:139-42.
• 11. Gromadzka G, Schmidt HH, Genschel J, et al. Frameshift and nonsense mutations in the gene for ATPase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson’s disease. Clin Genet. 2005;68:524-32.
• 12. Merle U, Eisenbach C, Weiss KH, et al. Serum ceruloplasmin oxidase activity is a sensitive and highly specific diagnostic marker for Wilson’s disease. J Hepatol. 2009;51:925-30.
• 13. Roberts, E. A. & Schilsky, M. L. Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008; 47:2089–2111.
• 14. Nicastro E, Ranucci G, Vajro P, et al. Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease. Hepatology. 2010;52:1948-56.
• 15. 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.
• 16. Johncilla M, Mitchell KA. Pathology of the liver in copper overload. Semin Liver Dis. 2011;31:239-44.
• 17. Ferenci P, Steindl-Munda P, Vogel W, et al. Diagnostic value of quantitative hepatic copper determination in patients with Wilson’s disease. Clin Gastroenterol Hepatol. 2005;3:811-18.
• 18. Liggi M, Mais C, Demurtas M, et al. Uneven distribution of hepatic copper concentration and diagnostic value of double-sample biopsy in Wilson’s disease. Scand J Gastroenterol. 2013;48:1452-8.
• 19. Cooper, D. N. et al. The Human Gene Mutation Database. QIAGEN http://www.hgmd.cf.ac.uk/ac/ index.php (2018).
• 20. Caca K, Ferenci P, Kuhn HJ, et al. High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis. J Hepatol. 2001;35:575-81.
• 21. Loudianos G, Dessi V, Lovicu M, et al. Molecular characterization of Wilson disease in the Sardinian population—evidence of a founder effect. Hum Mutat. 1999;14:294-303.
• 22. Simsek Papur O, Akman SA, Cakmur R, Terzioglu O. Mutation analysis of ATP7B gene in Turkish Wilson disease patients: identification of five novel mutations. Eur J Med Genet. 2013;56(4):175‐179.
• 23. Glenn TC. Field guide to next-generation DNA sequencers. Mol Ecol Resour. 2011;11:759-69.
• 24. Koppikar S, Dhawan A. Evaluation of the scoring system for the diagnosis of Wilson’s disease in children. Liver Int. 2005;25:680–1.
• 25. Taylor RM, Chen Y, Dhawan A. Triethylene tetramine dihydrochloride (trientine) in children with Wilson disease: experience at King’s College Hospital and review of the literature. Eur J Pediatr. 2009;168:1061–8.
• 26. Mizuochi T, Kimura A, Shimizu N, et al. Zinc monotherapy from time of diagnosis for young pediatric patients with presymptomatic Wilson disease. J Pediatr Gastroenterol Nutr. 2011;53:365–7.
• 27. Ranucci G, Di Dato F, Spagnuolo MI, et al. Zinc monotherapy is effective inWilson’s disease patients with mild liver disease diagnosed in childhood: a retrospective study. Orphanet J Rare Dis. 2014;9:41.
• 28. Weiss KH, Thurik F, Gotthardt DN, et al. Efficacy and safety of oral chelators in treatment of patients with Wilson disease. Clin Gastroenterol Hepatol. 2013;11:1028 35.e1-2.
• 29. Santos Silva EE, Sarles J, Buts JP, et al. Successful medical treatment of severely decompensatedWilson disease. J Pediatr. 1996;128:285–7.
• 30. Dhawan A, Taylor RM, Cheeseman P, et al. Wilson’s disease in children: 37-year experience and revised King’s score for liver transplantation. Liver Transpl. 2005;11:441–8.
• 31. Guillaud O, Dumortier J, Sobesky R, et al. Long term results of liver transplantation for Wilson’s disease: experience in France. J Hepatol. 2014;60:579–89.