Wilson disease is a rare genetic disorder in which abnormal copper metabolism results in the deposition of copper throughout the tissues, including those of the liver, brain, and eyes.1 

Mutations in the ATP7B gene result in the synthesis of abnormal ATP7B protein. Normally, ATP7B transports excess copper from the liver into the biliary system for excretion. ATP7B protein located in the trans-Golgi network loads copper onto apoceruloplasmin, converting it to ceruloplasmin. Ceruloplasmin is then secreted into the bloodstream and transported to other organs and tissues that require copper for normal function. In Wilson disease, the disruption of copper metabolism leads to an accumulation of excess copper, first within the liver and eventually in other organs and tissues.2,3  The deposition of excess copper in tissues and organs can result in several complications, some of them life-threatening. If left untreated, Wilson disease can be fatal.

Hepatic Complications

Damage to hepatocytes is caused by oxidative stress secondary to the accumulation of excess copper within lysosomes. The rate of progression of liver damage in individuals with Wilson disease varies. Acute hepatic failure (the fulminant form of Wilson disease) as the initial manifestation is usually seen in female patients younger than 22 years, who present with deep jaundice, a tendency to bleed easily, a discrete tremor, and an unremarkable medical history.4 Patients with acute hepatic failure require a liver transplant to resolve the symptoms of Wilson disease.

In most people, liver damage progresses more slowly, with the development of chronic active hepatitis, fibrosis, and cirrhosis. Complications of liver disease include ascites, lower-extremity edema, splenomegaly, hepatorenal syndrome, variceal bleeding, and in severe cases hepatic encephalopathy.4,5  

Neurological Complications

Wilson disease can result in damage to various regions of the brain, including the basal ganglia and cerebellum. Neurological complications may manifest as pseudoparkinsonism, pseudosclerosis, or arrhythmia-hyperkinesia.4  

When Wilson disease affects the central nervous system, problems with movement and neuromuscular control develop, such as hypokinesia or bradykinesia, choreoathetosis, dystonia, tremors, clumsiness, difficulty swallowing or speaking, gait disturbances, cerebellar ataxia, muscle rigidity, and rarely epilepsy.4,5  

Psychiatric Complications

Psychiatric complications of Wilson disease include depression, schizophrenia-like behavior, cognitive impairment, mood disorders, behavioral disorders, impulsiveness, disinhibition, and self-harming behaviors. Psychotic episodes are rare but possible.4,6

Hematological Complications

Excess copper that spills into the bloodstream attaches to erythrocytes, which lyse prematurely as a consequence of oxidative stress. This process results in the development of Coombs-negative hemolytic anemia. Often accompanying acute hepatic failure, Coombs-negative hemolytic anemia causes extreme fatigue and may progress to a hematological crisis; high-dose glucocorticoids can be used for managing acute hemolysis. If liver disease is severe or hemolytic anemia accompanies fulminant acute hepatic failure, a liver transplant is often required to resolve symptoms.4,7.8 Another hematological complication that accompanies hepatic disease is thrombocytopenia, which leads to easy bruising and bleeding.9

Musculoskeletal Complications

Chronic liver disease affects bone mineral density.10 Metabolic bone diseases associated with Wilson disease include osteoporosis/osteopenia, osteomalacia, renal tubular acidosis, and rickets, which increases the risk for spontaneous fractures and delayed growth.6,11  

Cartilage degeneration and symptomatic joint disease occur in 20% to 50% of people with Wilson disease at relatively young ages, particularly in the spine, hips, knees, and wrists. Patients with Wilson disease may present with polyarthritis, osteochondritis dissecans, chondromalacia patellae, or chondrocalcinosis.6

Renal Complications

Renal complications of Wilson disease include urolithiasis, proteinuria, peptiduria, and impairment of the proximal or distal renal tubules leading to aminoaciduria, hypercalciuria, hyperphosphaturia, glucosuria, hyperuricosuria, and loss of bicarbonate and potassium.4 

A rare complication of Wilson disease is renal tubular acidosis, which correlates with metabolic bone disease. In Fanconi syndrome, a specific type of renal tubular acidosis,4,12,13 defects in the proximal renal tubules impair the absorption of electrolytes and other substances, leading to severe rickets and growth delay in children.11,14,15 

References

  1. Wilson disease. Medline Plus. Accessed September 14, 2022.
  2. Linder MC. Apoceruloplasmin: abundance, detection, formation, and metabolism. Biomedicines. 2021;9(3):233. doi:10.3390/biomedicines9030233
  3. Gilroy RK. Wilson disease: etiology. Medscape. Updated February 14, 2019. Accessed September 14, 2022.
  4. Stremmel W, Merle U, Weiskirchen R. Clinical features of Wilson disease. Ann Transl Med. 2019;7(Suppl 2):S61. doi:10.21037/atm.2019.01.20  
  5. Chaudhry HS, Anilkumar AC. Wilson disease. StatPearls [Internet]. Updated May 8, 2022. Accessed September 14, 2022.
  6. Gilroy RK. Wilson disease clinical presentation. Medscape. Updated February 14, 2019. Accessed September 14, 2022.
  7. Ye XN, Mao LP, Lou YJ, Tong HY. Hemolytic anemia as first presentation of Wilson’s disease with uncommon ATP7B mutation. Int J Clin Exp Med. 2015;8(3):4708-4711. 
  8. Walshe JM. The acute haemolytic syndrome in Wilson’s disease—a review of 22 patients. QJM. 2013;106(11):1003-1008. doi:10.1093/qjmed/hct137
  9. Ma TJ, Sun GL, Yao F, Yang ZL. Wilson disease associated with immune thrombocytopenia: a case report and review of the literature. World J Clin Cases. 2019;7(17):2630-2636. doi:10.12998/wjcc.v7.i17.2630
  10. Selimoglu MA, Ertekin V, Doneray H, Yildirim M. Bone mineral density of children with Wilson disease: efficacy of penicillamine and zinc therapy. J Clin Gastroenterol. 2008;42(2):194-198. doi:10.1097/MCG.0b013e318032388d
  11. Kapoor N, Shetty S, Thomas N, Paul TV. Wilson’s disease: an endocrine revelation. Indian J Endocrinol Metab. 2014;18(6):855-857. doi:10.4103/2230-8210.141383
  12. Palkar AV, Shrivastava MS, Padwal NJ, Padhiyar RN, Moulick N. Renal tubular acidosis due to Wilson’s disease presenting as metabolic bone disease. BMJ Case Rep. 2011;2011:bcr0420114121. doi:10.1136/bcr.04.2011.4121
  13. Dzieżyc-Jaworska K, Litwin T, Członkowska A. Clinical manifestations of Wilson disease in organs other than the liver and brain. Ann Transl Med. 2019;7(Suppl 2):S62. doi:10.21037/atm.2019.03.30
  14. Fathallah-Shaykh S. Fanconi syndrome: background. Medscape. Updated February 9, 2018. Accessed September 14, 2022.
  15. Keefe P, Bokhari SRA. Fanconi syndrome. StatPearls [Internet]. Updated July 4, 2022. Accessed September 14, 2022.

Reviewed by Harshi Dhingra, MD, on 9/15/2022.