Diagnostic Challenges of Wilson Disease in Early Childhood

Yıl 2020, Cilt: 18 Sayı: 1, 41 - 52, 15.04.2020

Fatma Demirbaş , Ayça Efendioğlu Ağayev Gönül Çaltepe Ayhan Gazi Kalaycı

Öz

INTRODUCTION: Wilson's Disease (WD) is an autosomal recessive inherited copper metabolism disorder caused by mutations in the ATP7B gene. The aim of this study was to retrospectively evaluate the patients diagnosed prior to the age of five.

MATERIALS and METHODS: Between January 2005 and December 2018, the clinical and laboratory characteristics, treatment and prognostic features of 64 WD patients, 13 of whom were ≤ 5 years old, were analyzed retrospectively.

RESULTS: Of the 64 patients in this study, 33 were male and the mean age at the time of diagnosis was 9.38 ± 3.37 years (3yr 5mo-16yr 3mo). Thirteen (20.3%) of these patients were ≤ 5 years of age (7 girls, 4.1 ± 0.6 years).
Of patients ≤ 5 years of age 38.4% presented with hepatomegaly, 53.8% with similar family history, 76.9% with elevated AST and ALT levels, 76.9% with low ceruloplasmin level, 53.8% with increased urinary copper excretion, and 50% with an increased liver copper quantification. When patients ≤ 5 years of age compared with < 5 years of age patients at the time of admission, there was a statistically significant increment on AST levels but decrement in the levels of total bilirubin, direct bilirubin, and urinary copper (p=0.023, 0.009, p=0.040, p=0.011, respectively). Of patients ≤ 5 years of age (n =10) who underwent liver biopsy, mononuclear inflammatory cell infiltration (80%), macro-vesicular steatosis (50%), and parenchymal necrosis were observed in portal areas. While liver copper quantification was 405 ± 101.3 µg / gr in patients ≤ 5 years of age, that value evaluated as 615.9 ± 56,4 μg / g in patients > 5 years of age. The amount of liver copper quantification, framework distortion and bridging necrosis on liver biopsy were statistically at increased levels in patients > 5 years of age (p = 0.03, p = 0.01, p = 0.005, respectively).

RESULTS: As seen in this study, the chance of early diagnosis of patients with WD increasing steadily. In countries like Turkey where consanguineous marriages are common, it is difficult to diagnose WD with a single test and many tests should be performed jointly

CONCLUSIONS: . Early diagnosis and treatment having a great impact on prognosis.

Anahtar Kelimeler

Copper, Early onset, Wilson disease

Erken Çocukluk Çağında Wilson Hastaların Tanısal Zorlukları

Öz

GİRİŞ ve AMAÇ: Wilson Hastalığı (WH), ATP7B genindeki mutasyonlardan kaynaklanan otozomal resesif geçişli, bakır metabolizması bozukluğudur. Bu çalışmada beş yaşından önce tanı alan hastaların geri dönük incelemesi amaçlanmıştır.

YÖNTEM ve GEREÇLER: Ocak 2005-Aralık 2018 tarihleri arasında bölümümüzde 13’ü ≤ 5 yaş olan 64 WH’nin klinik ve laboratuar özellikleri, tedavi ve prognozları açısından retrospektif olarak analiz edildi.

BULGULAR: Çalışmamızdaki 64 hastanın 33’ü erkek ve ortalama tanı yaşı 9,38±3,37 yıl (3y5a-16,3 yıl) idi. Bu hastaların 13’ü (% 20,3) ≤5 yaş altı hastadan (7 kız, 4,1±0,6 yıl) oluşmaktaydı.
Beş yaş altı hastaların başvuru anında %38,4’inde hepatomegali, % 53,8’inde ailede benzer hikaye, %76,9’unda AST ve ALT yüksekliği %76,9’unda seruloplazmin düşüklüğü,%53,8’inde idrarda bakır atılımı, %50’sinde artmış karaciğer bakırı mevcuttu. İstattiksel olarak anlamlı düzeyde > 5 yaş hastalar ile kıyaslandığında ≤5 yaş olan hastaların başvuru anındaki AST değeri yüksek, total billubin, direk billuribin, idrar bakırı düzeyleri düşük saptandı (sırasıyla p=0,023, 0,009, p=0,040, p=0,011). Karaciğer biyopsisi yapılan ≤5 yaş hastaların (n: 10) portal alanda mononükleer iltihabi hücre infiltrasyonu (%80), makrovesiküler yağlanma (%50) ve parankim nekrozu (%50) olduğu görüldü. Karaciğer kuru bakır ağırlığı ortalaması ≤5 yaş hastaların 405 ±101,3 µg/gr iken >5 yaş hastaların 615,9±56,4µg/gr saptandı. İstattiksel olarak anlamlı düzeyde 5 yaş üstü hastalarda karaciğer kuru bakır ağırlığı, karaciğer biyopsisinde çatı bozulması ve köprüleşme nekrozu daha fazlaydı (sırasıyla p=0,03, p=0,01, p=0,005).

TARTIŞMA ve SONUÇ: Çalışmamızda da görüldüğü gibi hastaların erken dönemde tanı alma şansı gün geçtikçe artmaktadır. Akraba evliliğinin sık olduğu ülkemiz gibi ülkelerde WH tanısında tek bir testle tanı koymak zorlaşmakta birçok testin bir arada yapılması gerekmektedir. Erken tanı ve tedavi prognoz üzerinde etkilidir

Anahtar Kelimeler

Bakır, Erken çocukluk çağı, Wilson hastalığı

Kaynakça

• 1.Ranucci G, Socha P, Iorio R. Wilson disease: what is still unclear in pediatric patients? Clin Res Hepatol Gastroenterol 2014; 38: 268-72.
• 2.Sternlieb I. Perspectives on Wilson's disease. Hepatology 1990;12:1234-9.
• 3.Scheinberg IH, Sternlieb I. Wilson's disease in: R Wright, KGM Alberti, S Karran eds, Liver and Biliary Disease. Bailliere Tindall, London 1985:949-61.
• 4.Park R, McCabe P, Fell G, Russell R. Wilson's disease in Scotland. Gut 1991;32:15415.
• 5.Dedoussis GV, Genschel J, Sialvera TE, et al. Wilson disease: high prevalence in a mountainous area of Crete. Ann Hum Genet 2005; 69:268.
• 6.https://www.uptodate.com/contents/wilson-disease-clinical-manifestations-diagnosis-andnaturalhistory?search=wilson%20disease&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1.
• 7.https://www.uptodate.com/contents/wilson-disease-treatment-and prognosis?search=wilson%20disease&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2.
• 8.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 Transplantion 2005;11:441-8.
• 9.Arikan Ç. 46 olgunun klinik, laboratuvar ve histopatolojik özellikleri ile birlikte tedavi sonuçlarının değerlendirilmesi. Ege Pediatri Bülteni 2007;14:157-65.
• 10. orio R, D’Ambrosi M, Mazzarella G, et al. Early occurrence of hypertransaminasemia in a 13-month-old child with Wilson disease. J Pediatr Gastroenterol Nutr 2003;36:637-8.
• 11. Merle U, Schaefer M, Ferenci P, et al. Clinical presentation, diagnosis and long-term outcome of Wilson disease: a cohort study. Gut 2007;56:115-20.
• 12.O’Connor JA, Sokol RJ. Copper metabolism and copper storage disorders. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Diseases in Children. New York, NY USA: Cambridge University Press; 2007:626-59.
• 13.Wiernicka A, Dądalski M, Jańczyk W, et al. Early Onset of Wilson Disease: Diagnostic Challenges. J Pediatr Gastroenterol Nutr 2017; 6:555-60
• 14.8th international conference on Wilson disease and Menkes disease. Leipzig, Germany, April 16-18, 2001. Z Gastroenterol 2001; 3:245-60.
• 15. Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int 2003; 23:139-42.
• 16.Nicastro E, Loudianos G, Zancan L, et al. Genotype-phenotype correlation in Italian children with Wilson’s disease. J Hepatol 2009; 50:555-61.
• 17.Rosencrantz R, Schilsky M. Wilson Disease: Pathogenesis and Clinical Considerations in Diagnosis and Treatment. Semin Liver Dis 2011; 31:245-59.
• 18.Perman JA, Werlin SL, Grand RJ, et al. Laboratory measures of copper metabolism in the differentiation of chronic active hepatitis and Wilson disease in children. J Pediatr 1979; 94:564-8.
• 19.Liver EAFTSOT. EASL clinical practice guidelines: Wilson’s disease. Journal of Hepatology 2012; 56:671-85.
• 20.The Human Gene Mutation Database of the Institute of Medical Genetics in Cardiff. http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ATP7B. Accessed November 2018.
• 21.Aggarwal A, Chandhok G, Todorov T, et al. Wilson disease mutation pattern with genotype phenotype correlations from Western India: confirmation of C271* as a common indian mutation and identification of 14 novel mutations. Ann Hum Genet 2013; 77:299-307.
• 22.Brage A, Tomé S, García A, et al. Clinical and molecular characterization of Wilson disease in Spanish patients. Hepatol Res 2007; 37:18-26.
• 23.Stromeyer FW, Ishak KG. Histology of the liver in Wilson’s disease: a study of 34 cases. Am J Clin Pathol 1980; 73: 12-24.
• 24.European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol 2012; 56:671.
• 25.Lin LJ, Wang DX, Ding NN, et al. Comprehensive analysis on clinical features of Wilson's disease: an experience over 28 years with 133 cases. Neurol Res 2014; 36:157.
• 26.Ranucci G, Di Dato F, Spagnuolo MI, et al. Zinc monotherapy is effective in Wilson’s disease patients with mild liver disease diagnosed in childhood: a retrospective study. Orphanet J Rare Dis 2014; 9: 1.
• 27.Weiss KH, Gotthardt DN, Klemm D, et al. Zinc monotherapy is not as effective as chelating agents in treatment of Wilson disease. Gastroenterology 2011; 140: 1189-98.
• 28.Schilsky ML. Treatment of Wilson’s disease: what are the relative roles of penicillamine, trientine, and zinc supplementation? Current gastroenterology Reports 2001; 3: 54-9.