Wilson disease is a rare, potentially lethal genetic disease that manifests in a wide range of phenotypic forms.1,2 The manifestations are mainly hepatic, neurological, or psychiatric and can vary from asymptomatic states to fatal fulminant liver failure.3 The inactivation of copper transporter ATP7B and resultant overload of copper in organs, particularly the liver, are the cause of Wilson disease. Nevertheless, neither specific mutations in the ATP7B gene nor elevated liver copper levels by themselves can account for the wide range of clinical manifestations.2 

In children and young adults with Wilson disease, liver disease usually develops as the first manifestation; individuals in whom the disease is diagnosed later in life typically do not have liver-related symptoms, although minimal liver disease may be present. Yellowing of the skin or whites of the eyes (jaundice), fatigue, appetite loss, and abdominal swelling are all indicators of liver disease. Liver-related symptoms also include ascites, swelling of the legs, itchiness, weakness, and vomiting.1,4

Nervous system or psychiatric abnormalities are frequently the initial symptoms in adults in whom the condition is diagnosed, and they are common in young adults with Wilson disease. Clumsiness, tremors, trouble walking, speech issues, diminished thinking capacity, depression, anxiety, and mood swings are some of the clinical manifestations.1

Homeostasis of Copper in the Liver

A protein network that includes transmembrane copper transporters (CTR1 and ATP7B), cytosolic copper carriers (chaperones), copper storage proteins (metallothioneins), and copper-requiring enzymes maintain copper homeostasis in the liver. The body requires copper mainly as a cofactor for various enzymes: ferroxidase ceruloplasmin (an abundant copper-binding protein secreted by hepatocytes into the blood), cytochrome c oxidase (mitochondrial respiration), superoxide dismutase (free radical defense), factor VIII (blood clotting), tyrosinase, and others.2 Copper membrane transporter 1 protein (CTR1), found in the cells of the small bowel, aids in the absorption of copper into the body through the digestive tract and helps carry copper inside cells, where some of it is linked to metallothionein and some is transported by antioxidant 1 copper chaperone (ATOX1) to an organelle known as the trans-Golgi network (TGN). ATP7A enzyme (Menkes ATPase) releases copper into the hepatic portal vein in response to an increase in copper levels. CMT1 protein and metallothionein are transported by liver cells, after which ATOX1 binds them inside the cells. Subsequently, the copper is linked to ceruloplasmin by ATP7B, which then releases it into the bloodstream while secreting any extra copper into bile.4

Pathophysiology of Wilson Disease

Nearly 800 different mutations of the ATP7B gene have been identified in Wilson disease, and these functionally impair copper transport to the TGN. The results of these mutations include an absence of ATP7B in the TGN (mutation H1069Q in exon 14), an inability of ATOX1 to bind to this transporter, and impaired transmembrane translocation or release at the luminal side of the TGN. The residual, non-transportable cytoplasmic copper accumulates and is linked to metallothionein, whose synthesis is stimulated by copper. When the ability of metallothionein to bind copper reaches its limit, extra copper is deposited within lysosomes, where because of the acidic environment amorphous copper complexes build up and induce free radical damage.5 Because copper belongs to a transition metal group, an excess of copper results in toxic hydroxyl group formation and a rise in oxidative stress in the cells. This oxidative stress can cause damage to the cells that can lead to clinical manifestations like movement disorders, behavioural problems, liver failure, and the formation of Kayser-Fleischer rings in the cornea.4 Reduced copper transport via ATP7B to the TGN also leads to a loss of biliary copper excretion and an overload of copper in the liver.5

The pathophysiology of Wilson disease involves the production of free radicals and oxidative damage, which is probably mediated by copper buildup in the mitochondria. The origin of liver disease in Wilson disease is a direct result of copper buildup in the hepatocytes.6 The malfunctioning copper excretory system in Wilson disease causes copper to accumulate in the liver and seep into the blood, after which it accumulates in other organs and tissues, including the subthalamus, putamen, cortex, kidneys, and cornea. The oxidative damage in the liver results in chronic active hepatitis, fibrosis, cirrhosis, and liver failure. Unbound copper that has not been linked to ceruloplasmin is released by the liver into the bloodstream. The free copper accumulates throughout the body, mainly in the eyes, brain, and kidneys. Kayser-Fleischer rings appear in the cornea of the eye. The basal ganglia, putamen, and globus pallidus (also known as the lenticular nucleus) are regions of the brain that play a role in coordinating movement and neurocognitive activities, such as mood regulation. The neuropsychiatric symptoms of Wilson disease are caused by damage to these regions.4


  1. Wilson disease. MedlinePlus. Accessed October 3, 2022. 
  2. Dev S, Kruse RL, Hamilton JP, Lutsenko S. Wilson disease: update on pathophysiology and treatment. Front Cell Dev Biol. 2022;10:871877. doi:10.3389/fcell.2022.871877
  3. Rodriguez-Castro KI, Hevia-Urrutia FJ, Sturniolo GC. Wilson’s disease: a review of what we have learned. World J Hepatol. 2015;7(29):2859-2870. doi:10.4254/wjh.v7.i29.2859
  4. Chaudhry HS, Anilkumar AC. Wilson disease. StatPearls [Internet]. May 8, 2022. Accessed October 3, 2022.
  5. Stremmel W, Weiskirchen R. Therapeutic strategies in Wilson disease: pathophysiology and mode of action. Ann Transl Med. 2021;9(8):732. doi:10.21037/atm-20-3090
  6. Ferenci P. Pathophysiology and clinical features of Wilson disease. Metab Brain Dis. 2004;19(3-4):229-239. doi:10.1023/b:mebr.0000043973.10494.85

Reviewed by Debjyoti Talukdar, MD, on 10/4/2022.