검색
검색 팝업 닫기

Ex) Article Title, Author, Keywords

Articles

Split Viewer

Review Article

Ann Liver Transplant 2023; 3(2): 80-85

Published online November 30, 2023 https://doi.org/10.52604/alt.23.0019

Copyright © The Korean Liver Transplantation Society.

Pediatric liver transplantation for Wilson disease

Jeong-Ik Park1 , Bo Hyun Jung2

1Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
2Department of Surgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea

Correspondence to:Jeong-Ik Park
Department of Surgery, Ulsan University Hospital, 877 Bangeojinsunhwando-ro, Dong-gu, Ulsan 44033, Korea
E-mail: jipark@uuh.ulsan.kr
https://orcid.org/0000-0002-1986-9246

Received: November 6, 2023; Revised: November 7, 2023; Accepted: November 9, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Wilson disease (WD) stands as an autosomal recessive disorder primarily brought about by genetic mutations affecting the ATP7B gene, yielding a prevalence rate estimated at 1:30,000 to 50,000 individuals. The ATP7B gene codes for an enzyme known as transmembrane copper-transporting ATPase, a crucial factor in the incorporation of copper into ceruloplasmin and its elimination through bile excretion. The malfunction or absence of this enzyme leads to the progressive buildup of copper within various organs, particularly the liver, nervous system, corneas, kidneys, and heart. Children afflicted with WD may manifest with asymptomatic liver issues, cirrhosis, or even acute liver failure, accompanied by or without neurological and psychiatric symptoms. Approximately 20% to 30% of WD patients experience acute liver failure, while the majority of others develop chronic progressive hepatitis or cirrhosis when left untreated. While genetic testing has gained significance in diagnosing WD, the diagnosis still relies on a combination of clinical observations and laboratory tests. In cases of liver failure and encephalopathy, liver transplantation emerges as a life-saving option for WD patients. This review addresses specific concerns pertinent to liver transplantation for pediatric WD patients.

Keywords: Wilson disease, Acute liver failure, Copper metabolism, Genetic disorder, Liver transplantation

Wilson disease (WD) is a hereditary autosomal recessive disorder attributed to mutations occurring within the ATP7B gene, and it exhibits a documented prevalence ranging between 1 in 30,000 to 1 in 50,000 individuals [1-5]. The ATP7B gene carries the genetic code for an enzyme termed transmembrane copper-transporting ATPase, which plays a crucial role in facilitating the integration of copper into ceruloplasmin and the subsequent excretion of copper into the bile. A deficiency or malfunction of this enzyme leads to the gradual accumulation of copper in multiple organs, particularly in the liver, nervous system, corneas, kidneys, and heart.

Children diagnosed with WD may present with various clinical manifestations, including asymptomatic liver disease, cirrhosis, or acute liver failure, with or without accompanying neurological and psychiatric symptoms [1]. It is noteworthy that approximately 20% to 30% of WD patients experience acute liver failure, while the majority of untreated individuals progress to develop chronic progressive hepatitis or cirrhosis [6].

ATP7B gene mutations on chromosome 13, including missense and nonsense types, can be homozygous or compound heterozygous. H1069Q is the most common mutation in European and American populations (50%–80%), while R778L prevails in Far East Asian countries (14%–49%) [7-10]. Various ATP7B variants result in distinct disease phenotypes [11-16]. Homozygous H1069Q patients show delayed-onset neurological symptoms, differing from compound heterozygous cases [12,13]. Truncating mutations often lead to acute liver failure [15]. Genotype/phenotype correlation in WD is inconclusive, suggesting a potential role of epigenetics influenced by environmental and nutritional factors [17].

Copper, vital for mitochondrial respiration, enters the body through ATP7A in the intestines, then travels to the liver via the portal system, with a portion excreted through urine and sweat. Within hepatocytes, copper uses CTR1 to reach the trans Golgi network via ATP7B. It incorporates into apoceruloplasmin to form holoceruloplasmin, a major copper-containing protein, and is released into circulation [18]. ATP7B also expels copper into bile via vesicles that reach biliary canaliculi, later excreted in stool. Mutations in ATP7B lead to copper accumulation in the liver and bloodstream, affecting other tissues, causing oxidative stress and cellular damage. Hepatic injury predominates in WD due to the liver’s role in copper homeostasis. Copper initially binds with metallothionein, detected in liver histology with special staining. Over time, copper accumulates in lysosomes, causing hepatic issues and subsequent copper buildup in other tissues. In the brain, copper toxicity leads to damage, particularly in the basal ganglia, thalamus, cerebellum, and brainstem. In the bloodstream, excess copper triggers oxidative damage and Coombs-negative hemolysis. Muscle, kidney, and other tissues also experience adverse effects from copper overload [19-21].

In children, WD can appear at various ages, with a median age of 13 years, but symptomatic cases are rare before age of 3 years [20-23]. Hepatic issues are more frequent in children, but around 4% to 6% may exhibit subtle neurological symptoms. Older children and young adults, typically aged 20 to 30 years, are more likely to display neurological or psychiatric symptoms, with or without liver involvement.

Hepatic Manifestation

Hepatic symptoms in WD range from asymptomatic or incidentally discovered abnormal liver tests to complications like acute liver failure [1]. Early stages may show no symptoms but could include elevated liver enzymes or abnormal ultrasound findings. As the disease progresses, patients may display signs of chronic liver disease or cirrhosis complications. WD should always be considered when a child or young adult presents with abnormal liver tests or clinical features resembling non-alcoholic fatty liver disease or autoimmune liver disease [24,25].

Acute liver failure in WD is a severe form marked by jaundice, hepatitis, hepatomegaly, and coagulopathy, with or without encephalopathy. Acute liver failure is defined as international normalized ratio (INR) ≥1.5 with encephalopathy or INR ≥2.0 regardless of encephalopathy [26]. Some children may have a history of acute self-limited hepatitis-like illness, recurrent jaundice, hemolytic anemia, or elevated transaminases. Some clinicians consider this presentation as acute-on-chronic liver failure, often showing preexisting chronic liver damage on histology. Acute-on-chronic liver failure is defined as acute hepatitis causing jaundice (total bilirubin >5 mg/dL or 85 µmol/L) and coagulopathy (INR>1.5) with ascites and/or hepatic encephalopathy within 4 weeks [27].

Differentiating WD from other causes of hepatic failure involves relatively milder elevation of liver enzymes, high total bilirubin, and low alkaline phosphatase [20,28]. Associated hemolysis due to free copper can contribute to elevated total bilirubin.

Neurological Manifestation

Neuropsychiatric symptoms in children are rare, especially in those under 10 years old, but about 5% to 15% of children with liver issues may experience neurological symptoms [17,29]. These symptoms include incoordination, declining school performance, mild cognitive impairment, language difficulties, or movement disorders like tremors. Psychiatric symptoms can range from behavioral and personality problems to mood disorders, and even psychosis. Brain magnetic resonance imaging is a valuable diagnostic tool for patients with neurological signs/symptoms, revealing hyperintensity lesions in the basal ganglia, thalamus, midbrain, and pontine white matter [30,31]. These findings indicate cerebral involvement in WD. Conversely, high signal intensity lesions in the basal ganglia on T1-weighted images may result from chronic liver disease and may suggest WD with hepatic involvement [17,20].

WD diagnosis relies on clinical features and lab tests. A WD diagnostic score (Table 1) created in 2001 is widely adopted for its diagnostic accuracy and incorporated into the European Association for Study of Liver guidelines [32,33]. Validation studies in children and young adults by Koppikar and Dhawan [34] confirmed its diagnostic value.

Table 1 The scoring system for the diagnosis of Wilson disease (WD) [32,43]

Score−10124
Kayser-Fleischer ringsAbsentPresent
Neuropsychiatric symptoms suggestive of WD (or typical brain MRI)AbsentPresent
Coombs-negative hemolytic anemia+high serum copperAbsentPresent
Urinary copper (in the absence of acute hepatitis)Normal1-2 ULN>2×ULN or normal, but >5 ×ULN day after challenge with 2×0.5 g D-penicillamine
Liver copper quantitativeNormal<5×ULN (<250 µg/g)>5×ULN (>250 µg/g)
Rhodanine positive hepatocytes (only if quantitative Cu measurement is not available)AbsentPresent
Serum ceruloplasmin (nephelometric assay)>0.2 g/L0.1–0.2 g/L<0.1 g/L
Disease-causing mutations detectedNone12

Assessment of the WD diagnostic score: 0–1, unlikely; 2–3, probable; 4 or more, highly likely.

ULN, upper limit of normal.



Mutational analysis is crucial for WD diagnosis, distinguishing carriers from affected presymptomatic patients [7]. However, accessibility and time for genetic tests can vary. Some cases may need additional analysis for large gene defects. Approximately 900 ATP7B mutations have been identified, and most patients have compound heterozygous mutations [20,35]. If only one mutation is found, it could indicate either a carrier or a WD patient awaiting a second mutation. Comprehensive genetic analysis can yield detection rates of 77% to 98% [36,37], allowing for cases with one or no ATP7B variants [35]. In such cases, diagnosis may rely on suggestive laboratory tests and the WD diagnostic score. A recent study proposed measuring ATP7B peptides for direct evidence of variant consequences, even without a second mutation [38].

Indications for liver transplantation (LT) in WD include acute liver failure with severe hepatic insufficiency, coagulopathy, and hepatic encephalopathy, as well as acute-on-chronic liver failure [1,17,39]. LT in neurologic WD cases remains controversial. Children with acute liver failure but without hepatic encephalopathy can be treated with chelation agents, but response may be delayed, taking at least 1 month for prothrombin time improvement and 3 to 12 months for normalization [40]. Deciding when to opt for LT can be challenging. The revised King’s prognostic WD Index helps identify those at risk of failing chelation or facing mortality without LT (Table 2). An index score of ≥11 strongly predicts mortality without LT, with high sensitivity and specificity (93% and 97%, respectively), along with high positive and negative predictive values (92% and 97%, respectively) [41].

Table 2 The revised King’s prognostic Wilson Index [41,43]

ScoreBilirubin (µmol/L)INRAST (IU/L)WBC (×109/L)Albumin (g/L)
01–1000–1.290–1000–6.7>45
1101–1501.3–1.6101–1506.8–8.332–44
2151–2001.7–1.9151–3008.4–10.325–33
3201–3002.0–2.4301–40010.4–15.321–24
4>301>2.5>401>15.4<20

INR, international normalized ratio; AST, aspartate transaminase; WBC, white blood cell.



In patients without advanced liver or brain damage, liver function can improve in over 90% of cases within 2 to 6 months. Neurological improvement occurs in 50% to 60% of patients over 1 to 3 years with early and proper pharmacological treatment [39]. Adherence to therapy is crucial for long-term success, and 24-hour urinary copper excretion has been proposed as a monitoring tool in children with WD [42].

In WD, LT is primarily indicated for two conditions: acute liver failure and chronic liver disease. There is also emerging consideration for LT in cases of uncontrolled neurological disease without liver deficiency [43-45]. While acute liver failure is the initial presentation in 5% of WD patients, the rate has been reported as 4% to 6% in the United States [46]. It has been suggested that mortality in these acute liver failure cases reaches 100% without LT [45,46].

Diagnosing WD in cases of acute liver failure remains challenging due to associated difficulties. Key diagnostic tools include 24-hour urine copper levels, hepatic copper concentration, ATP7B gene mutations, the presence of Kayser–Fleischer rings, neurological symptoms, cranial magnetic resonance imaging findings, serum ceruloplasmin and copper levels, and the presence of hemolytic anemia. However, it is important to note that Kayser–Fleischer rings are only observed in about 50% of patients [23]. Serum and urine copper levels are unreliable markers, as they can fluctuate not only in WD but also in other acute liver failure cases [47,48]. These complexities underscore the importance of a thorough and precise differential diagnosis.

Supportive treatments play a crucial role in patients diagnosed with acute liver failure, particularly when there is severe encephalopathy, during living donor preparation, or while waiting for a deceased donor. These treatments encompass various approaches, including exchange transfusion, plasmapheresis, the molecular adsorbent recycling system, therapeutic plasma exchange, and renal replacement therapies [49,50]. Plasma exchange treatments have shown a beneficial effect, particularly in improving serum copper levels, liver function, and kidney function [51].

The decision for LT in cases of chronic liver disease related to WD have received limited attention. It is worth considering that in countries primarily reliant on deceased donor operations, LT decisions are typically based on the Model for End-Stage Liver Disease score, allowing patients to become eligible only as their Model for End-Stage Liver Disease score increases. On the contrary, living donor LT offers an opportunity for WD patients with chronic liver disease in better clinical condition to access LT by preparing suitable living donors under elective circumstances.

Lately, there have been documented cases of central nervous system involvement without concurrent liver failure as a potential third indication for LT in WD [52]. The topic of LT in the context of central nervous system involvement remains a subject of debate, particularly in patients with advanced neurological complications. Nevertheless, reports indicate that LT can either ameliorate or halt the progression of neurological issues [46,53]. Survival rates are notably poor in patients with chronic liver disease and severe neurological involvement [46,54].

In conclusion, LT is an effective treatment approach with a high rate of success in addressing WD-related acute or chronic liver failure.

Conceptualization: All. Data curation: JIP. Investigation: BHJ. Methodology: JIP. Project administration: JIP. Resources: JIP. Writing – original draft: All. Writing – review & editing: All.

  1. Socha P, Janczyk W, Dhawan A, Baumann U, D'Antiga L, Tanner S, et al. Wilson's disease in children: a position paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018;66:334-344.
    Pubmed CrossRef
  2. Reilly M, Daly L, Hutchinson M. An epidemiological study of Wilson's disease in the Republic of Ireland. J Neurol Neurosurg Psychiatry 1993;56:298-300.
    Pubmed KoreaMed CrossRef
  3. Poujois A, Woimant F, Samson S, Chaine P, Girardot-Tinant N, Tuppin P. Characteristics and prevalence of Wilson's disease: a 2013 observational population-based study in France. Clin Res Hepatol Gastroenterol 2018;42:57-63.
    Pubmed CrossRef
  4. Cheung KS, Seto WK, Fung J, Mak LY, Lai CL, Yuen MF. Epidemiology and natural history of Wilson's disease in the Chinese: a territory-based study in Hong Kong between 2000 and 2016. World J Gastroenterol 2017;23:7716-7726.
    Pubmed KoreaMed CrossRef
  5. Gao J, Brackley S, Mann JP. The global prevalence of Wilson disease from next-generation sequencing data. Genet Med 2019;21:1155-1163.
    Pubmed CrossRef
  6. Steindl P, Ferenci P, Dienes HP, Grimm G, Pabinger I, Madl C, et al. Wilson's disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology 1997;113:212-218.
    Pubmed CrossRef
  7. Seo JK. Diagnosis of Wilson disease in young children: molecular genetic testing and a paradigm shift from the laboratory diagnosis. Pediatr Gastroenterol Hepatol Nutr 2012;15:197-209.
    Pubmed KoreaMed CrossRef
  8. Kluska A, Kulecka M, Litwin T, Dziezyc K, Balabas A, Piatkowska M, et al. Whole-exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson's disease phenotype. Liver Int 2019;39:177-186.
    Pubmed CrossRef
  9. Ferenci P. Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing. Hum Genet 2006;120:151-159.
    Pubmed CrossRef
  10. Gomes A, Dedoussis GV. Geographic distribution of ATP7B mutations in Wilson disease. Ann Hum Biol 2016;43:1-8.
    Pubmed CrossRef
  11. Huster D, Kühne A, Bhattacharjee A, Raines L, Jantsch V, Noe J, et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology 2012;142:947-956.e5.
    Pubmed KoreaMed CrossRef
  12. Ferenci P, Roberts EA. Defining Wilson disease phenotypes: from the patient to the bench and back again. Gastroenterology 2012;142:692-696.
    Pubmed CrossRef
  13. Caca K, Ferenci P, Kühn HJ, Polli C, Willgerodt H, Kunath B, 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;35:575-581.
    Pubmed CrossRef
  14. Ferenci P. Phenotype-genotype correlations in patients with Wilson's disease. Ann N Y Acad Sci 2014;1315:1-5.
    Pubmed CrossRef
  15. Merle U, Weiss KH, Eisenbach C, Tuma S, Ferenci P, Stremmel W. Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease. BMC Gastroenterol 2010;10:8.
    Pubmed KoreaMed CrossRef
  16. Okada T, Shiono Y, Kaneko Y, Miwa K, Hasatani K, Hayashi Y, et al. High prevalence of fulminant hepatic failure among patients with mutant alleles for truncation of ATP7B in Wilson's disease. Scand J Gastroenterol 2010;45:1232-1237.
    Pubmed CrossRef
  17. Członkowska A, Litwin T, Dusek P, Ferenci P, Lutsenko S, Medici V, et al. Wilson disease. Nat Rev Dis Primers 2018;4:21.
    Pubmed KoreaMed CrossRef
  18. Gitlin D, Janeway CA. Turnover of the copper and protein moieties of ceruloplasmin. Nature 1960;185:693.
    Pubmed CrossRef
  19. Mounajjed T, Oxentenko AS, Qureshi H, Smyrk TC. Revisiting the topic of histochemically detectable copper in various liver diseases with special focus on venous outflow impairment. Am J Clin Pathol 2013;139:79-86.
    Pubmed CrossRef
  20. Fernando M, van Mourik I, Wassmer E, Kelly D. Wilson disease in children and adolescents. Arch Dis Child 2020;105:499-505.
    Pubmed CrossRef
  21. Walshe JM. The acute haemolytic syndrome in Wilson's disease--a review of 22 patients. QJM 2013;106:1003-1008.
    Pubmed CrossRef
  22. Lin LJ, Wang DX, Ding NN, Lin Y, Jin Y, Zheng CQ. Comprehensive analysis on clinical features of Wilson's disease: an experience over 28 years with 133 cases. Neurol Res 2014;36:157-163.
    Pubmed CrossRef
  23. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology 2008;47:2089-2111.
    Pubmed CrossRef
  24. Roberts EA, Yap J. Nonalcoholic Fatty Liver Disease (NAFLD): approach in the adolescent patient. Curr Treat Options Gastroenterol 2006;9:423-431.
    Pubmed CrossRef
  25. Yener S, Akarsu M, Karacanci C, Sengul B, Topalak O, Biberoglu K, et al. Wilson's disease with coexisting autoimmune hepatitis. J Gastroenterol Hepatol 2004;19:114-116.
    Pubmed CrossRef
  26. Squires RH Jr, Shneider BL, Bucuvalas J, Alonso E, Sokol RJ, Narkewicz MR, et al. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr 2006;148:652-658.
    Pubmed KoreaMed CrossRef
  27. Zaccherini G, Weiss E, Moreau R. Acute-on-chronic liver failure: definitions, pathophysiology and principles of treatment. JHEP Rep 2020;3:100176.
    Pubmed KoreaMed CrossRef
  28. Berman DH, Leventhal RI, Gavaler JS, Cadoff EM, Van Thiel DH. Clinical differentiation of fulminant Wilsonian hepatitis from other causes of hepatic failure. Gastroenterology 1991;100:1129-1134.
    Pubmed CrossRef
  29. Rukunuzzaman M. Wilson's disease in Bangladeshi children: analysis of 100 cases. Pediatr Gastroenterol Hepatol Nutr 2015;18:121-127.
    Pubmed KoreaMed CrossRef
  30. Kim TJ, Kim IO, Kim WS, Cheon JE, Moon SG, Kwon JW, et al. MR imaging of the brain in Wilson disease of childhood: findings before and after treatment with clinical correlation. AJNR Am J Neuroradiol 2006;27:1373-1378.
  31. Zhong W, Huang Z, Tang X. A study of brain MRI characteristics and clinical features in 76 cases of Wilson's disease. J Clin Neurosci 2019;59:167-174.
    Pubmed CrossRef
  32. Ferenci P, Caca K, Loudianos G, Mieli-Vergani G, Tanner S, Sternlieb I, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int 2003;23:139-142.
    Pubmed CrossRef
  33. Nicastro E, Ranucci G, Vajro P, Vegnente A, Iorio R. Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease. Hepatology 2010;52:1948-1956.
    Pubmed CrossRef
  34. Koppikar S, Dhawan A. Evaluation of the scoring system for the diagnosis of Wilson's disease in children. Liver Int 2005;25:680-681. Erratum in: Liver Int 2005;25:1078.
    Pubmed CrossRef
  35. Espinós C, Ferenci P. Are the new genetic tools for diagnosis of Wilson disease helpful in clinical practice? JHEP Rep 2020;2:100114.
    Pubmed KoreaMed CrossRef
  36. Ferenci P, Stremmel W, Członkowska A, Szalay F, Viveiros A, Stättermayer AF, et al. Age and sex but not ATP7B genotype effectively influence the clinical phenotype of Wilson disease. Hepatology 2019;69:1464-1476.
    Pubmed CrossRef
  37. Mukherjee S, Dutta S, Majumdar S, Biswas T, Jaiswal P, Sengupta M, et al. Genetic defects in Indian Wilson disease patients and genotype-phenotype correlation. Parkinsonism Relat Disord 2014;20:75-81.
    Pubmed CrossRef
  38. Collins CJ, Yi F, Dayuha R, Duong P, Horslen S, Camarata M, et al. Direct measurement of ATP7B peptides is highly effective in the diagnosis of Wilson disease. Gastroenterology 2021;160:2367-2382.e1.
    Pubmed KoreaMed CrossRef
  39. European Association for Study of Liver. EASL clinical practice guidelines: Wilson's disease. J Hepatol 2012;56:671-685.
    Pubmed CrossRef
  40. Santos Silva EE, Sarles J, Buts JP, Sokal EM. Successful medical treatment of severely decompensated Wilson disease. J Pediatr 1996;128:285-287.
    Pubmed CrossRef
  41. Dhawan A, Taylor RM, Cheeseman P, De Silva P, Katsiyiannakis L, Mieli-Vergani G. Wilson's disease in children: 37-year experience and revised King's score for liver transplantation. Liver Transpl 2005;11:441-448.
    Pubmed CrossRef
  42. Chanpong A, Dhawan A. Long-term urinary copper excretion on chelation therapy in children with Wilson disease. J Pediatr Gastroenterol Nutr 2021;72:210-215.
    Pubmed CrossRef
  43. Chanpong A, Dhawan A. Wilson disease in children and young adults - state of the art. Saudi J Gastroenterol 2022;28:21-31.
    Pubmed KoreaMed CrossRef
  44. Dal MB, Alim A, Acarli K. The advantage of early liver transplantation for Wilson's disease using living donors. Prz Gastroenterol 2021;16:213-218.
    Pubmed KoreaMed CrossRef
  45. Catana AM, Medici V. Liver transplantation for Wilson disease. World J Hepatol 2012;4:5-10.
    Pubmed KoreaMed CrossRef
  46. Guillaud O, Dumortier J, Sobesky R, Debray D, Wolf P, Vanlemmens C, et al. Long term results of liver transplantation for Wilson's disease: experience in France. J Hepatol 2014;60:579-589.
    Pubmed CrossRef
  47. McCullough AJ, Fleming CR, Thistle JL, Baldus WP, Ludwig J, McCall JT, et al. Diagnosis of Wilson's disease presenting as fulminant hepatic failure. Gastroenterology 1983;84:161-167.
    Pubmed CrossRef
  48. Schilsky ML, Sternlieb I. Overcoming obstacles to the diagnosis of Wilson's disease. Gastroenterology 1997;113:350-353.
  49. Sen S, Felldin M, Steiner C, Larsson B, Gillett GT, Olausson M, et al. Albumin dialysis and Molecular Adsorbents Recirculating System (MARS) for acute Wilson's disease. Liver Transpl 2002;8:962-967.
    Pubmed CrossRef
  50. Collins KL, Roberts EA, Adeli K, Bohn D, Harvey EA. Single pass albumin dialysis (SPAD) in fulminant Wilsonian liver failure: a case report. Pediatr Nephrol 2008;23:1013-1016.
    Pubmed CrossRef
  51. Jhang JS, Schilsky ML, Lefkowitch JH, Schwartz J. Therapeutic plasmapheresis as a bridge to liver transplantation in fulminant Wilson disease. J Clin Apher 2007;22:10-14.
    Pubmed CrossRef
  52. Walker G, Hussaini T, Stowe R, Cresswell S, Yoshida EM. Liver transplant can resolve severe neuropsychiatric manifestations of Wilson disease: a case report. Exp Clin Transplant 2018;16:620-624.
  53. Stracciari A, Tempestini A, Borghi A, Guarino M. Effect of liver transplantation on neurological manifestations in Wilson disease. Arch Neurol 2000;57:384-386.
    Pubmed CrossRef
  54. Ostapowicz G, Fontana RJ, Schiødt FV, Larson A, Davern TJ, Han SH, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137:947-954.
    Pubmed CrossRef

Article

Review Article

Ann Liver Transplant 2023; 3(2): 80-85

Published online November 30, 2023 https://doi.org/10.52604/alt.23.0019

Copyright © The Korean Liver Transplantation Society.

Pediatric liver transplantation for Wilson disease

Jeong-Ik Park1 , Bo Hyun Jung2

1Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
2Department of Surgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea

Correspondence to:Jeong-Ik Park
Department of Surgery, Ulsan University Hospital, 877 Bangeojinsunhwando-ro, Dong-gu, Ulsan 44033, Korea
E-mail: jipark@uuh.ulsan.kr
https://orcid.org/0000-0002-1986-9246

Received: November 6, 2023; Revised: November 7, 2023; Accepted: November 9, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Wilson disease (WD) stands as an autosomal recessive disorder primarily brought about by genetic mutations affecting the ATP7B gene, yielding a prevalence rate estimated at 1:30,000 to 50,000 individuals. The ATP7B gene codes for an enzyme known as transmembrane copper-transporting ATPase, a crucial factor in the incorporation of copper into ceruloplasmin and its elimination through bile excretion. The malfunction or absence of this enzyme leads to the progressive buildup of copper within various organs, particularly the liver, nervous system, corneas, kidneys, and heart. Children afflicted with WD may manifest with asymptomatic liver issues, cirrhosis, or even acute liver failure, accompanied by or without neurological and psychiatric symptoms. Approximately 20% to 30% of WD patients experience acute liver failure, while the majority of others develop chronic progressive hepatitis or cirrhosis when left untreated. While genetic testing has gained significance in diagnosing WD, the diagnosis still relies on a combination of clinical observations and laboratory tests. In cases of liver failure and encephalopathy, liver transplantation emerges as a life-saving option for WD patients. This review addresses specific concerns pertinent to liver transplantation for pediatric WD patients.

Keywords: Wilson disease, Acute liver failure, Copper metabolism, Genetic disorder, Liver transplantation

INTRODUCTION

Wilson disease (WD) is a hereditary autosomal recessive disorder attributed to mutations occurring within the ATP7B gene, and it exhibits a documented prevalence ranging between 1 in 30,000 to 1 in 50,000 individuals [1-5]. The ATP7B gene carries the genetic code for an enzyme termed transmembrane copper-transporting ATPase, which plays a crucial role in facilitating the integration of copper into ceruloplasmin and the subsequent excretion of copper into the bile. A deficiency or malfunction of this enzyme leads to the gradual accumulation of copper in multiple organs, particularly in the liver, nervous system, corneas, kidneys, and heart.

Children diagnosed with WD may present with various clinical manifestations, including asymptomatic liver disease, cirrhosis, or acute liver failure, with or without accompanying neurological and psychiatric symptoms [1]. It is noteworthy that approximately 20% to 30% of WD patients experience acute liver failure, while the majority of untreated individuals progress to develop chronic progressive hepatitis or cirrhosis [6].

PATHOPHYSIOLOGY

ATP7B gene mutations on chromosome 13, including missense and nonsense types, can be homozygous or compound heterozygous. H1069Q is the most common mutation in European and American populations (50%–80%), while R778L prevails in Far East Asian countries (14%–49%) [7-10]. Various ATP7B variants result in distinct disease phenotypes [11-16]. Homozygous H1069Q patients show delayed-onset neurological symptoms, differing from compound heterozygous cases [12,13]. Truncating mutations often lead to acute liver failure [15]. Genotype/phenotype correlation in WD is inconclusive, suggesting a potential role of epigenetics influenced by environmental and nutritional factors [17].

Copper, vital for mitochondrial respiration, enters the body through ATP7A in the intestines, then travels to the liver via the portal system, with a portion excreted through urine and sweat. Within hepatocytes, copper uses CTR1 to reach the trans Golgi network via ATP7B. It incorporates into apoceruloplasmin to form holoceruloplasmin, a major copper-containing protein, and is released into circulation [18]. ATP7B also expels copper into bile via vesicles that reach biliary canaliculi, later excreted in stool. Mutations in ATP7B lead to copper accumulation in the liver and bloodstream, affecting other tissues, causing oxidative stress and cellular damage. Hepatic injury predominates in WD due to the liver’s role in copper homeostasis. Copper initially binds with metallothionein, detected in liver histology with special staining. Over time, copper accumulates in lysosomes, causing hepatic issues and subsequent copper buildup in other tissues. In the brain, copper toxicity leads to damage, particularly in the basal ganglia, thalamus, cerebellum, and brainstem. In the bloodstream, excess copper triggers oxidative damage and Coombs-negative hemolysis. Muscle, kidney, and other tissues also experience adverse effects from copper overload [19-21].

CLINICAL PRESENTATION

In children, WD can appear at various ages, with a median age of 13 years, but symptomatic cases are rare before age of 3 years [20-23]. Hepatic issues are more frequent in children, but around 4% to 6% may exhibit subtle neurological symptoms. Older children and young adults, typically aged 20 to 30 years, are more likely to display neurological or psychiatric symptoms, with or without liver involvement.

Hepatic Manifestation

Hepatic symptoms in WD range from asymptomatic or incidentally discovered abnormal liver tests to complications like acute liver failure [1]. Early stages may show no symptoms but could include elevated liver enzymes or abnormal ultrasound findings. As the disease progresses, patients may display signs of chronic liver disease or cirrhosis complications. WD should always be considered when a child or young adult presents with abnormal liver tests or clinical features resembling non-alcoholic fatty liver disease or autoimmune liver disease [24,25].

Acute liver failure in WD is a severe form marked by jaundice, hepatitis, hepatomegaly, and coagulopathy, with or without encephalopathy. Acute liver failure is defined as international normalized ratio (INR) ≥1.5 with encephalopathy or INR ≥2.0 regardless of encephalopathy [26]. Some children may have a history of acute self-limited hepatitis-like illness, recurrent jaundice, hemolytic anemia, or elevated transaminases. Some clinicians consider this presentation as acute-on-chronic liver failure, often showing preexisting chronic liver damage on histology. Acute-on-chronic liver failure is defined as acute hepatitis causing jaundice (total bilirubin >5 mg/dL or 85 µmol/L) and coagulopathy (INR>1.5) with ascites and/or hepatic encephalopathy within 4 weeks [27].

Differentiating WD from other causes of hepatic failure involves relatively milder elevation of liver enzymes, high total bilirubin, and low alkaline phosphatase [20,28]. Associated hemolysis due to free copper can contribute to elevated total bilirubin.

Neurological Manifestation

Neuropsychiatric symptoms in children are rare, especially in those under 10 years old, but about 5% to 15% of children with liver issues may experience neurological symptoms [17,29]. These symptoms include incoordination, declining school performance, mild cognitive impairment, language difficulties, or movement disorders like tremors. Psychiatric symptoms can range from behavioral and personality problems to mood disorders, and even psychosis. Brain magnetic resonance imaging is a valuable diagnostic tool for patients with neurological signs/symptoms, revealing hyperintensity lesions in the basal ganglia, thalamus, midbrain, and pontine white matter [30,31]. These findings indicate cerebral involvement in WD. Conversely, high signal intensity lesions in the basal ganglia on T1-weighted images may result from chronic liver disease and may suggest WD with hepatic involvement [17,20].

DIAGNOSIS

WD diagnosis relies on clinical features and lab tests. A WD diagnostic score (Table 1) created in 2001 is widely adopted for its diagnostic accuracy and incorporated into the European Association for Study of Liver guidelines [32,33]. Validation studies in children and young adults by Koppikar and Dhawan [34] confirmed its diagnostic value.

Table 1 . The scoring system for the diagnosis of Wilson disease (WD) [32,43].

Score−10124
Kayser-Fleischer ringsAbsentPresent
Neuropsychiatric symptoms suggestive of WD (or typical brain MRI)AbsentPresent
Coombs-negative hemolytic anemia+high serum copperAbsentPresent
Urinary copper (in the absence of acute hepatitis)Normal1-2 ULN>2×ULN or normal, but >5 ×ULN day after challenge with 2×0.5 g D-penicillamine
Liver copper quantitativeNormal<5×ULN (<250 µg/g)>5×ULN (>250 µg/g)
Rhodanine positive hepatocytes (only if quantitative Cu measurement is not available)AbsentPresent
Serum ceruloplasmin (nephelometric assay)>0.2 g/L0.1–0.2 g/L<0.1 g/L
Disease-causing mutations detectedNone12

Assessment of the WD diagnostic score: 0–1, unlikely; 2–3, probable; 4 or more, highly likely..

ULN, upper limit of normal..



Mutational analysis is crucial for WD diagnosis, distinguishing carriers from affected presymptomatic patients [7]. However, accessibility and time for genetic tests can vary. Some cases may need additional analysis for large gene defects. Approximately 900 ATP7B mutations have been identified, and most patients have compound heterozygous mutations [20,35]. If only one mutation is found, it could indicate either a carrier or a WD patient awaiting a second mutation. Comprehensive genetic analysis can yield detection rates of 77% to 98% [36,37], allowing for cases with one or no ATP7B variants [35]. In such cases, diagnosis may rely on suggestive laboratory tests and the WD diagnostic score. A recent study proposed measuring ATP7B peptides for direct evidence of variant consequences, even without a second mutation [38].

LIVER TRANSPLANTATION

Indications for liver transplantation (LT) in WD include acute liver failure with severe hepatic insufficiency, coagulopathy, and hepatic encephalopathy, as well as acute-on-chronic liver failure [1,17,39]. LT in neurologic WD cases remains controversial. Children with acute liver failure but without hepatic encephalopathy can be treated with chelation agents, but response may be delayed, taking at least 1 month for prothrombin time improvement and 3 to 12 months for normalization [40]. Deciding when to opt for LT can be challenging. The revised King’s prognostic WD Index helps identify those at risk of failing chelation or facing mortality without LT (Table 2). An index score of ≥11 strongly predicts mortality without LT, with high sensitivity and specificity (93% and 97%, respectively), along with high positive and negative predictive values (92% and 97%, respectively) [41].

Table 2 . The revised King’s prognostic Wilson Index [41,43].

ScoreBilirubin (µmol/L)INRAST (IU/L)WBC (×109/L)Albumin (g/L)
01–1000–1.290–1000–6.7>45
1101–1501.3–1.6101–1506.8–8.332–44
2151–2001.7–1.9151–3008.4–10.325–33
3201–3002.0–2.4301–40010.4–15.321–24
4>301>2.5>401>15.4<20

INR, international normalized ratio; AST, aspartate transaminase; WBC, white blood cell..



In patients without advanced liver or brain damage, liver function can improve in over 90% of cases within 2 to 6 months. Neurological improvement occurs in 50% to 60% of patients over 1 to 3 years with early and proper pharmacological treatment [39]. Adherence to therapy is crucial for long-term success, and 24-hour urinary copper excretion has been proposed as a monitoring tool in children with WD [42].

DISCUSSION

In WD, LT is primarily indicated for two conditions: acute liver failure and chronic liver disease. There is also emerging consideration for LT in cases of uncontrolled neurological disease without liver deficiency [43-45]. While acute liver failure is the initial presentation in 5% of WD patients, the rate has been reported as 4% to 6% in the United States [46]. It has been suggested that mortality in these acute liver failure cases reaches 100% without LT [45,46].

Diagnosing WD in cases of acute liver failure remains challenging due to associated difficulties. Key diagnostic tools include 24-hour urine copper levels, hepatic copper concentration, ATP7B gene mutations, the presence of Kayser–Fleischer rings, neurological symptoms, cranial magnetic resonance imaging findings, serum ceruloplasmin and copper levels, and the presence of hemolytic anemia. However, it is important to note that Kayser–Fleischer rings are only observed in about 50% of patients [23]. Serum and urine copper levels are unreliable markers, as they can fluctuate not only in WD but also in other acute liver failure cases [47,48]. These complexities underscore the importance of a thorough and precise differential diagnosis.

Supportive treatments play a crucial role in patients diagnosed with acute liver failure, particularly when there is severe encephalopathy, during living donor preparation, or while waiting for a deceased donor. These treatments encompass various approaches, including exchange transfusion, plasmapheresis, the molecular adsorbent recycling system, therapeutic plasma exchange, and renal replacement therapies [49,50]. Plasma exchange treatments have shown a beneficial effect, particularly in improving serum copper levels, liver function, and kidney function [51].

The decision for LT in cases of chronic liver disease related to WD have received limited attention. It is worth considering that in countries primarily reliant on deceased donor operations, LT decisions are typically based on the Model for End-Stage Liver Disease score, allowing patients to become eligible only as their Model for End-Stage Liver Disease score increases. On the contrary, living donor LT offers an opportunity for WD patients with chronic liver disease in better clinical condition to access LT by preparing suitable living donors under elective circumstances.

Lately, there have been documented cases of central nervous system involvement without concurrent liver failure as a potential third indication for LT in WD [52]. The topic of LT in the context of central nervous system involvement remains a subject of debate, particularly in patients with advanced neurological complications. Nevertheless, reports indicate that LT can either ameliorate or halt the progression of neurological issues [46,53]. Survival rates are notably poor in patients with chronic liver disease and severe neurological involvement [46,54].

In conclusion, LT is an effective treatment approach with a high rate of success in addressing WD-related acute or chronic liver failure.

FUNDING

There was no funding related to this study.

CONFLICT OF INTEREST

All authors have no conflicts of interest to declare.

AUTHORS’ CONTRIBUTIONS

Conceptualization: All. Data curation: JIP. Investigation: BHJ. Methodology: JIP. Project administration: JIP. Resources: JIP. Writing – original draft: All. Writing – review & editing: All.

Table 1 The scoring system for the diagnosis of Wilson disease (WD) [32,43]

Score−10124
Kayser-Fleischer ringsAbsentPresent
Neuropsychiatric symptoms suggestive of WD (or typical brain MRI)AbsentPresent
Coombs-negative hemolytic anemia+high serum copperAbsentPresent
Urinary copper (in the absence of acute hepatitis)Normal1-2 ULN>2×ULN or normal, but >5 ×ULN day after challenge with 2×0.5 g D-penicillamine
Liver copper quantitativeNormal<5×ULN (<250 µg/g)>5×ULN (>250 µg/g)
Rhodanine positive hepatocytes (only if quantitative Cu measurement is not available)AbsentPresent
Serum ceruloplasmin (nephelometric assay)>0.2 g/L0.1–0.2 g/L<0.1 g/L
Disease-causing mutations detectedNone12

Assessment of the WD diagnostic score: 0–1, unlikely; 2–3, probable; 4 or more, highly likely.

ULN, upper limit of normal.


Table 2 The revised King’s prognostic Wilson Index [41,43]

ScoreBilirubin (µmol/L)INRAST (IU/L)WBC (×109/L)Albumin (g/L)
01–1000–1.290–1000–6.7>45
1101–1501.3–1.6101–1506.8–8.332–44
2151–2001.7–1.9151–3008.4–10.325–33
3201–3002.0–2.4301–40010.4–15.321–24
4>301>2.5>401>15.4<20

INR, international normalized ratio; AST, aspartate transaminase; WBC, white blood cell.


References

  1. Socha P, Janczyk W, Dhawan A, Baumann U, D'Antiga L, Tanner S, et al. Wilson's disease in children: a position paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018;66:334-344.
    Pubmed CrossRef
  2. Reilly M, Daly L, Hutchinson M. An epidemiological study of Wilson's disease in the Republic of Ireland. J Neurol Neurosurg Psychiatry 1993;56:298-300.
    Pubmed KoreaMed CrossRef
  3. Poujois A, Woimant F, Samson S, Chaine P, Girardot-Tinant N, Tuppin P. Characteristics and prevalence of Wilson's disease: a 2013 observational population-based study in France. Clin Res Hepatol Gastroenterol 2018;42:57-63.
    Pubmed CrossRef
  4. Cheung KS, Seto WK, Fung J, Mak LY, Lai CL, Yuen MF. Epidemiology and natural history of Wilson's disease in the Chinese: a territory-based study in Hong Kong between 2000 and 2016. World J Gastroenterol 2017;23:7716-7726.
    Pubmed KoreaMed CrossRef
  5. Gao J, Brackley S, Mann JP. The global prevalence of Wilson disease from next-generation sequencing data. Genet Med 2019;21:1155-1163.
    Pubmed CrossRef
  6. Steindl P, Ferenci P, Dienes HP, Grimm G, Pabinger I, Madl C, et al. Wilson's disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology 1997;113:212-218.
    Pubmed CrossRef
  7. Seo JK. Diagnosis of Wilson disease in young children: molecular genetic testing and a paradigm shift from the laboratory diagnosis. Pediatr Gastroenterol Hepatol Nutr 2012;15:197-209.
    Pubmed KoreaMed CrossRef
  8. Kluska A, Kulecka M, Litwin T, Dziezyc K, Balabas A, Piatkowska M, et al. Whole-exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson's disease phenotype. Liver Int 2019;39:177-186.
    Pubmed CrossRef
  9. Ferenci P. Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing. Hum Genet 2006;120:151-159.
    Pubmed CrossRef
  10. Gomes A, Dedoussis GV. Geographic distribution of ATP7B mutations in Wilson disease. Ann Hum Biol 2016;43:1-8.
    Pubmed CrossRef
  11. Huster D, Kühne A, Bhattacharjee A, Raines L, Jantsch V, Noe J, et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology 2012;142:947-956.e5.
    Pubmed KoreaMed CrossRef
  12. Ferenci P, Roberts EA. Defining Wilson disease phenotypes: from the patient to the bench and back again. Gastroenterology 2012;142:692-696.
    Pubmed CrossRef
  13. Caca K, Ferenci P, Kühn HJ, Polli C, Willgerodt H, Kunath B, 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;35:575-581.
    Pubmed CrossRef
  14. Ferenci P. Phenotype-genotype correlations in patients with Wilson's disease. Ann N Y Acad Sci 2014;1315:1-5.
    Pubmed CrossRef
  15. Merle U, Weiss KH, Eisenbach C, Tuma S, Ferenci P, Stremmel W. Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease. BMC Gastroenterol 2010;10:8.
    Pubmed KoreaMed CrossRef
  16. Okada T, Shiono Y, Kaneko Y, Miwa K, Hasatani K, Hayashi Y, et al. High prevalence of fulminant hepatic failure among patients with mutant alleles for truncation of ATP7B in Wilson's disease. Scand J Gastroenterol 2010;45:1232-1237.
    Pubmed CrossRef
  17. Członkowska A, Litwin T, Dusek P, Ferenci P, Lutsenko S, Medici V, et al. Wilson disease. Nat Rev Dis Primers 2018;4:21.
    Pubmed KoreaMed CrossRef
  18. Gitlin D, Janeway CA. Turnover of the copper and protein moieties of ceruloplasmin. Nature 1960;185:693.
    Pubmed CrossRef
  19. Mounajjed T, Oxentenko AS, Qureshi H, Smyrk TC. Revisiting the topic of histochemically detectable copper in various liver diseases with special focus on venous outflow impairment. Am J Clin Pathol 2013;139:79-86.
    Pubmed CrossRef
  20. Fernando M, van Mourik I, Wassmer E, Kelly D. Wilson disease in children and adolescents. Arch Dis Child 2020;105:499-505.
    Pubmed CrossRef
  21. Walshe JM. The acute haemolytic syndrome in Wilson's disease--a review of 22 patients. QJM 2013;106:1003-1008.
    Pubmed CrossRef
  22. Lin LJ, Wang DX, Ding NN, Lin Y, Jin Y, Zheng CQ. Comprehensive analysis on clinical features of Wilson's disease: an experience over 28 years with 133 cases. Neurol Res 2014;36:157-163.
    Pubmed CrossRef
  23. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology 2008;47:2089-2111.
    Pubmed CrossRef
  24. Roberts EA, Yap J. Nonalcoholic Fatty Liver Disease (NAFLD): approach in the adolescent patient. Curr Treat Options Gastroenterol 2006;9:423-431.
    Pubmed CrossRef
  25. Yener S, Akarsu M, Karacanci C, Sengul B, Topalak O, Biberoglu K, et al. Wilson's disease with coexisting autoimmune hepatitis. J Gastroenterol Hepatol 2004;19:114-116.
    Pubmed CrossRef
  26. Squires RH Jr, Shneider BL, Bucuvalas J, Alonso E, Sokol RJ, Narkewicz MR, et al. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr 2006;148:652-658.
    Pubmed KoreaMed CrossRef
  27. Zaccherini G, Weiss E, Moreau R. Acute-on-chronic liver failure: definitions, pathophysiology and principles of treatment. JHEP Rep 2020;3:100176.
    Pubmed KoreaMed CrossRef
  28. Berman DH, Leventhal RI, Gavaler JS, Cadoff EM, Van Thiel DH. Clinical differentiation of fulminant Wilsonian hepatitis from other causes of hepatic failure. Gastroenterology 1991;100:1129-1134.
    Pubmed CrossRef
  29. Rukunuzzaman M. Wilson's disease in Bangladeshi children: analysis of 100 cases. Pediatr Gastroenterol Hepatol Nutr 2015;18:121-127.
    Pubmed KoreaMed CrossRef
  30. Kim TJ, Kim IO, Kim WS, Cheon JE, Moon SG, Kwon JW, et al. MR imaging of the brain in Wilson disease of childhood: findings before and after treatment with clinical correlation. AJNR Am J Neuroradiol 2006;27:1373-1378.
  31. Zhong W, Huang Z, Tang X. A study of brain MRI characteristics and clinical features in 76 cases of Wilson's disease. J Clin Neurosci 2019;59:167-174.
    Pubmed CrossRef
  32. Ferenci P, Caca K, Loudianos G, Mieli-Vergani G, Tanner S, Sternlieb I, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int 2003;23:139-142.
    Pubmed CrossRef
  33. Nicastro E, Ranucci G, Vajro P, Vegnente A, Iorio R. Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease. Hepatology 2010;52:1948-1956.
    Pubmed CrossRef
  34. Koppikar S, Dhawan A. Evaluation of the scoring system for the diagnosis of Wilson's disease in children. Liver Int 2005;25:680-681. Erratum in: Liver Int 2005;25:1078.
    Pubmed CrossRef
  35. Espinós C, Ferenci P. Are the new genetic tools for diagnosis of Wilson disease helpful in clinical practice? JHEP Rep 2020;2:100114.
    Pubmed KoreaMed CrossRef
  36. Ferenci P, Stremmel W, Członkowska A, Szalay F, Viveiros A, Stättermayer AF, et al. Age and sex but not ATP7B genotype effectively influence the clinical phenotype of Wilson disease. Hepatology 2019;69:1464-1476.
    Pubmed CrossRef
  37. Mukherjee S, Dutta S, Majumdar S, Biswas T, Jaiswal P, Sengupta M, et al. Genetic defects in Indian Wilson disease patients and genotype-phenotype correlation. Parkinsonism Relat Disord 2014;20:75-81.
    Pubmed CrossRef
  38. Collins CJ, Yi F, Dayuha R, Duong P, Horslen S, Camarata M, et al. Direct measurement of ATP7B peptides is highly effective in the diagnosis of Wilson disease. Gastroenterology 2021;160:2367-2382.e1.
    Pubmed KoreaMed CrossRef
  39. European Association for Study of Liver. EASL clinical practice guidelines: Wilson's disease. J Hepatol 2012;56:671-685.
    Pubmed CrossRef
  40. Santos Silva EE, Sarles J, Buts JP, Sokal EM. Successful medical treatment of severely decompensated Wilson disease. J Pediatr 1996;128:285-287.
    Pubmed CrossRef
  41. Dhawan A, Taylor RM, Cheeseman P, De Silva P, Katsiyiannakis L, Mieli-Vergani G. Wilson's disease in children: 37-year experience and revised King's score for liver transplantation. Liver Transpl 2005;11:441-448.
    Pubmed CrossRef
  42. Chanpong A, Dhawan A. Long-term urinary copper excretion on chelation therapy in children with Wilson disease. J Pediatr Gastroenterol Nutr 2021;72:210-215.
    Pubmed CrossRef
  43. Chanpong A, Dhawan A. Wilson disease in children and young adults - state of the art. Saudi J Gastroenterol 2022;28:21-31.
    Pubmed KoreaMed CrossRef
  44. Dal MB, Alim A, Acarli K. The advantage of early liver transplantation for Wilson's disease using living donors. Prz Gastroenterol 2021;16:213-218.
    Pubmed KoreaMed CrossRef
  45. Catana AM, Medici V. Liver transplantation for Wilson disease. World J Hepatol 2012;4:5-10.
    Pubmed KoreaMed CrossRef
  46. Guillaud O, Dumortier J, Sobesky R, Debray D, Wolf P, Vanlemmens C, et al. Long term results of liver transplantation for Wilson's disease: experience in France. J Hepatol 2014;60:579-589.
    Pubmed CrossRef
  47. McCullough AJ, Fleming CR, Thistle JL, Baldus WP, Ludwig J, McCall JT, et al. Diagnosis of Wilson's disease presenting as fulminant hepatic failure. Gastroenterology 1983;84:161-167.
    Pubmed CrossRef
  48. Schilsky ML, Sternlieb I. Overcoming obstacles to the diagnosis of Wilson's disease. Gastroenterology 1997;113:350-353.
  49. Sen S, Felldin M, Steiner C, Larsson B, Gillett GT, Olausson M, et al. Albumin dialysis and Molecular Adsorbents Recirculating System (MARS) for acute Wilson's disease. Liver Transpl 2002;8:962-967.
    Pubmed CrossRef
  50. Collins KL, Roberts EA, Adeli K, Bohn D, Harvey EA. Single pass albumin dialysis (SPAD) in fulminant Wilsonian liver failure: a case report. Pediatr Nephrol 2008;23:1013-1016.
    Pubmed CrossRef
  51. Jhang JS, Schilsky ML, Lefkowitch JH, Schwartz J. Therapeutic plasmapheresis as a bridge to liver transplantation in fulminant Wilson disease. J Clin Apher 2007;22:10-14.
    Pubmed CrossRef
  52. Walker G, Hussaini T, Stowe R, Cresswell S, Yoshida EM. Liver transplant can resolve severe neuropsychiatric manifestations of Wilson disease: a case report. Exp Clin Transplant 2018;16:620-624.
  53. Stracciari A, Tempestini A, Borghi A, Guarino M. Effect of liver transplantation on neurological manifestations in Wilson disease. Arch Neurol 2000;57:384-386.
    Pubmed CrossRef
  54. Ostapowicz G, Fontana RJ, Schiødt FV, Larson A, Davern TJ, Han SH, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137:947-954.
    Pubmed CrossRef
The Korean Liver Transplantation Society

Vol.4 No.1
May 2024

pISSN 2765-5121
eISSN 2765-6098

Stats or Metrics

Share this article on :

  • line