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 causes copper to accumulate in various tissues and organs, especially the liver, brain, and eyes.1 The excess copper results in cellular damage and hepatic, neurological, psychiatric, and hematological problems that include jaundice, extrapyramidal movement disorders, psychiatric problems, and anemia. The symptoms overlap with those of many other conditions, so that the differential diagnosis of Wilson disease is challenging.2
The onset of the symptoms of Wilson disease is variable, typically occurring in persons between 5 and 45 years old but occasionally as young as 1 or as old as 70 years. The symptoms are heterogeneous and vary both quantitatively and qualitatively. According to each patient’s unique presentation, several conditions with similar manifestations must be ruled out to confirm the diagnosis of Wilson disease unless definitive evidence of an ATP7B genetic mutation causing the formation of a dysfunctional ATP7B copper-transporter protein is available.2
No single laboratory test exclusively confirms the diagnosis of Wilson disease; a comprehensive workup is required to rule out conditions with similar features and accurately confirm the presence of Wilson disease on the basis of a combination of multiple biomarkers and tests. Multiple studies show that the cut-off for non-ceruloplasmin bound copper found in the 24 hour urinary excretion is too high in the pediatric setting.3
Other Conditions With Abnormal Copper Metabolism
Wilson disease must be differentiated from other disorders of copper metabolism, including Menkes disease, occipital horn syndrome, Indian childhood cirrhosis, ceruloplasmin deficiency, MEDNIK (mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratodermia) syndrome, Huppke-Brendel syndrome, and CCS (copper chaperone for superoxide dismutase) deficiency.2
Hepatic symptoms of Wilson disease, which typically appear first, include jaundice, elevated transaminases and bilirubin, and symptoms of acute hepatitis in the absence of a viral infection. Wilson disease may progress rapidly to acute liver failure, or more slowly to chronic cirrhosis or chronic decompensated liver disease. Haematologically, it can lead to the occurrence of leukopenia, thrombocytopenia, and Coombs-negative hemolytic anemia in addition to hepatosplenomegaly.2
Entities in the differential diagnosis with hepatic symptoms overlapping those of Wilson disease include hepatitis A through E, viral hepatitis, non-alcoholic fatty liver disease, alcoholic hepatitis, acute liver failure, hepatocellular adenoma, cirrhosis, autoimmune chronic active hepatitis, hemochromatosis, alpha-1 antitrypsin deficiency, and Indian childhood cirrhosis.2-4
The neuropsychiatric form of Wilson disease affects the central nervous system. The deposition of excess copper within astrocytes and oligodendrocytes in the brain disrupts the blood-brain barrier, leading to demyelination and neuronal damage.5 Commonly affected regions of the brain in Wilson disease include the putamen, other regions of the basal ganglia, the pons, and the thalamus. If these areas are affected, a patient with Wilson disease will present with pseudoparkinsonism, pseudosclerosis, or dystonia. Symptoms include rigidity, bradykinesia/hypokinesia, tremors (either resting, postural, or intention), hypomimia, hypersalivation, dysarthria, acroataxia, and cerebellar ataxia.6
When the midbrain and cortex are affected, which happens less frequently, symptoms of torsion spasm may develop. Rarely, patients with Wilson disease present with choreoathetosis, which suggests damage to the caudate nucleus. MR imaging scans of the brain show abnormal bilateral long T1 and T2 signals in the head of the caudate nucleus and putamen nucleus within the basal ganglia.6
Other entities to consider in the differential diagnosis when a patient presents with neurological or extrapyramidal symptoms include Parkinson disease, multiple sclerosis, Huntington disease, all neurodegenerative diseases, Leigh disease, aceruloplasminemia, central nervous system vasculitis, occipital horn syndrome, MEDNIK syndrome, and various glycogen-storage diseases (including types 0, I, II, III, IV, V, VI, and VII).2,4,7
Nearly 10% of patients with psychiatric manifestations of Wilson disease present with abnormal behavior, personality changes, depression, anxiety, and cognitive impairment, and rarely schizophrenia-like psychoses.2,8,9 Psychiatric symptoms more often accompany neurological symptoms than hepatic symptoms, but sometimes they may be the only manifestation of Wilson disease.2,9
Other entities to consider in the differential diagnosis if a patient with Wilson disease presents with psychiatric symptoms include depression, anxiety, schizophrenia, antisocial personality disorder, and various types of neuropathic glycogen-storage disorders causing psychiatric or behavioral symptoms.4,7
Hemolytic anemia, especially Coombs-negative acute intravascular hemolytic anemia, is a rare complication of Wilson disease, occurring in 10% to 15% of all cases. The deposition of copper in erythrocytes results in early hemolysis as a consequence of oxidative damage due to excess copper in the red blood cells. Anemia may be the initial clinical manifestation of Wilson disease.10 Other clinical hematological symptoms of Wilson disease may include thrombocytopenia and leukopenia.2
Other entities to consider in the differential diagnosis if a patient with Wilson disease presents with hematological symptoms include disorders causing coagulopathy, chronic anemia, and leukodystrophy.4
Read about other signs and symptoms of Wilson disease
- Wilson disease. Medline Plus. Accessed September 14, 2022.
- Hermann W. Classification and differential diagnosis of Wilson’s disease. Ann Transl Med. 2019;7(Suppl 2):S63. doi:10.21037/atm.2019.02.07
- Schroeder SM, Matsukuma KE, Medici V. Wilson disease and the differential diagnosis of its hepatic manifestations: a narrative review of clinical, laboratory, and liver histological features. Ann Transl Med. 2021;9(17):1394. doi:10.21037/atm-21-2264
- Gilroy RK. Wilson disease differential diagnoses. Medscape. Updated February 14, 2019. Accessed September 14, 2022.
- Dusek P, Litwin T, Członkowska A. Neurologic impairment in Wilson disease. Ann Transl Med. 2019;7(Suppl 2):S64. doi:10.21037/atm.2019.02.43
- Yu XE, Gao S, Yang RM, Han YZ. MR imaging of the brain in neurologic Wilson disease. AJNR Am J Neuroradiol. 2019;40(1):178-183. doi:10.3174/ajnr.A5936
- Pastores GM, Maegawa GHB. Neuropathic lysosomal storage disorders. Neurol Clin. 2013;31(4):1051-1071. doi:10.1016/j.ncl.2013.04.007
- Dening TR, Berrios GE. Wilson’s disease: psychiatric symptoms in 195 cases. Arch Gen Psychiatry. 1989;46(12):1126-1134. doi:10.1001/archpsyc.1989.01810120068011
- Rathbun JK. Neuropsychological aspects of Wilson’s disease. Int J Neurosci. 1996;85(3-4):221-229. doi:10.3109/00207459608986684
- Grudeva-Popova JG, Spasova MI, Chepileva KG, Zaprianov ZH. Acute hemolytic anemia as an initial clinical manifestation of Wilson’s disease. Folia Med (Plovdiv). 2000;42(2):42-46.
Reviewed by Debjyoti Talukdar, MD, on 9/25/2022.