Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.
Wilson disease is a rare genetic disorder with autosomal-recessive inheritance in which abnormal copper metabolism results in the deposition of copper throughout the tissues, particularly those of the liver, brain, and eyes. Patients with a diagnosis of Wilson disease may be asymptomatic, or a wide variety of clinical features, including hepatic, neurologic, psychiatric, ophthalmic, musculoskeletal, hematologic, and renal symptoms, may be present.1,2
Approximately 30% of patients with Wilson disease are asymptomatic, and in these cases, the disease is identified primarily through family screening. Most patients with Wilson disease present with either hepatic or neurologic symptoms.3
Copper metabolism takes place primarily in the liver. At first, excess copper is stored within the hepatocytes, resulting in progressive damage to the liver; however, liver damage occurs at different rates in patients with Wilson disease. Liver symptoms typically exhibit 1 of 3 patterns: chronic active hepatitis, cirrhosis, or fulminant hepatic failure. The most common initial clinical feature is cirrhosis of the liver.2
In most patients (>90%) with Wilson disease, the development of liver fibrosis or cirrhosis is relatively slow, often manifesting as splenomegaly, thrombocytopenia, liver cirrhosis with portal hypertension, chronic active hepatitis, steatosis, or elevated liver function test values.3 Common clinical features indicative of liver failure include jaundice, lower-extremity edema, and ascites.4,5
Occurring in approximately 5% of cases of Wilson disease, fulminant hepatic failure 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.3,5
The signs and symptoms of hepatic encephalopathy occur in the later stages of hepatic decompensation. Fulminant hepatic failure may lead to death, and immediate liver transplant is required for optimal outcomes.3
The suspected cause of fulminant hepatic failure in Wilson disease is the rupture of lysosomes overloaded with excess copper, followed by the release of free copper into the bloodstream. Copper-loaded erythrocytes also rupture prematurely, resulting in the concomitant development of Coombs-negative hemolytic anemia.2,3
It is estimated that between 30% and 60% of patients who have Wilson disease present with neuropsychiatric symptoms.2,3 The neurological manifestations of Wilson disease generally take 1 of 3 courses: pseudosclerotic, pseudoparkinsonic, or arrhythmic-hyperkinetic. Clinical features of the pseudosclerotic course include tremors (either resting, intention, or postural), dysarthria, cerebellar ataxia, and nystagmus.3 Clinical features of pseudoparkinsonism include rigidity, hypokinesia or bradykinesia, hypomimia, clumsiness, resting tremor, and dysarthria.2,3 Clinical features of the arrhythmic-hyperkinetic course include dystonia and choreoathetoid dyskinesia.3 Other neurological manifestations include micrographia, dysphagia with pseudohypersalivation, gait disorders, and rarely epilepsy or grand mal seizures.2,3
Sources differ in their estimates of the percentage of patients with Wilson disease who present with psychiatric clinical features; these range between 10% to 20% and 30% to 60%.2,3 Psychiatric features are divided into 4 main categories: behavioral, affective, cognitive, and schizophrenic-like.2 Psychiatric clinical features include depression, mood swings, personality changes, impulsiveness, disinhibition, self-harming behaviors, and cognitive impairment. Psychotic episodes occur rarely.2,3
Up to 98% of patients with untreated Wilson disease who present with neurologic symptoms have Kayser-Fleischer rings. Approximately 50% of patients with a hepatic form of Wilson disease present with Kayser-Fleischer rings, although some studies have described higher rates (93%) among patients with primarily hepatic manifestations.2,3,6
Kayser-Fleischer rings are yellowish, greenish-gold, or brownish rings surrounding the iris that are caused by the deposition of copper in the Descemet membrane in the limbus of the cornea.2,3 These ophthalmic features are often visible to the naked eye, but in some cases, a slit-lamp examination or gonioscopy may be necessary to identify them.2
Less frequently, sunflower cataracts occur, also visible on slit-lamp examination with particular attention given to lens transparency. Sunflower cataracts are thin, centralized opacifications arranged in ray-like formations that are located directly under the anterior capsule of the eye.2,7
Some patients with Wilson disease present with musculoskeletal abnormalities, such as osteoporosis, osteomalacia, rickets, polyarthritis, and a history of spontaneous fractures. More than half of patients with Wilson disease present with osteopenia on conventional bone density scans.2
Approximately 20% to 50% of patients with Wilson disease present with arthropathy in multiple joints; this often resembles premature osteoarthritis, which typically occurs after age 20. Frequently involved joints include the spine, hips, knees, and wrists. Progressive joint degeneration also manifests as osteochondritis dissecans, chondromalacia patellae, and chrondrocalcinosis.2
Coombs-negative hemolytic anemia develops in approximately 10% to 15% of patients with Wilson disease. Younger patients with acute liver failure often present with concomitant Coombs-negative hemolytic anemia. Oxidative damage due to excess copper deposition in erythrocytes causes premature lysis of the red blood cells and may progress to hemolytic crisis.2,3
Renal clinical features include urolithiasis, proteinuria, peptiduria, renal tubular acidosis (including Fanconi syndrome), and symptoms of proximal or distal tubular dysfunction, such as loss of bicarbonate and potassium, hyperuricosuria, glucosuria, hypercalciuria, hyperphosphaturia, and amido-aciduria. Damage to the kidneys can result from excessive copper excretion.2,3
Approximately 16% of patients with Wilson disease have urolithiasis secondary to hypercalciuria or poor acidification. Both the disease process and the adverse effects of treatment with d-penicillamine may cause hematuria, nephrocalcinosis, proteinuria, and peptiduria.2
- Wilson disease. Medline Plus. Accessed September 13, 2022.
- Gilroy, RK. Wilson disease clinical presentation. Updated February 14, 2019. Accessed September 13, 2022.
- 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
- Wilson’s disease – symptoms and causes. Mayo Clinic. Accessed September 13, 2022.
- Schilsky ML. Wilson disease: clinical manifestations, diagnosis, and natural history. UpToDate. Accessed September 13, 2022.
- 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(2):157-163. doi:10.1179/1743132813Y.0000000262
- Langwińska-Wośko E, Litwin T, Dzieżyc K, Członkowska A. The sunflower cataract in Wilson’s disease: pathognomonic sign or rare finding? Acta Neurol Belg. 2016;116:325-328. doi:10.1007/s13760-015-0566-1
Reviewed by Hashi Dhingra, MD, on 9/22/2022.