Wilson disease can begin at any age and from almost any organ, so it is the pattern of organ involvement, rather than a single pathognomonic sign, that makes the presentation recognisable. Most patients are between the ages of 3 and 55 years, and the first manifestation can be hepatic, neurological without any hepatic insufficiency, or psychiatric. The course can be chronic, or even very acute with a rapid onset.
Hepatic involvement
Hepatic involvement is more likely to be the primary manifestation in younger patients. Wilson disease should be considered in the differential diagnosis of any child with unexplained steatosis, persistently high liver enzymes or hepatomegaly, because these common findings may be its first sign. Patients who present this way usually have non-specific hepatic symptoms — anorexia, malaise, nausea, jaundice and abnormal coagulation tests — rather than a distinctive picture.
Two less common patterns are worth separating. Some patients have episodic, self-limiting jaundice, possibly due to hemolysis caused by the direct toxicity of copper on erythrocytes. Others present with severe hepatic involvement, with hepatosplenomegaly, a low serum albumin level, persistently abnormal coagulation tests and, rarely, isolated splenomegaly from the portal hypertension that Wilson disease produces.
In children and young adults the picture can be indistinguishable from autoimmune hepatitis, with interface hepatitis, a raised serum IgG and a positive ANA — a resemblance that delays the diagnosis because the two conditions look the same on serology.
Wilson disease can also present as acute liver failure (ALF), with severe coagulopathy and encephalopathy. Its classical laboratory presentation is distinctive: Coombs-negative hemolysis with extremely high unconjugated bilirubin and a low haptoglobin, and renal failure from the extensive hemolysis; a normal or even low alkaline phosphatase; and serum aminotransferases that are disproportionately low, mostly less than 2000 U/L, which does not reflect the severity of the liver disease. Urinary copper excretion is increased.
In children with hepatic involvement, neurological and psychiatric manifestations are common even when the liver is the obvious organ: low performance at school, clumsiness and hypophonia, a whispery voice, are early clues.
Because the disease mimics commoner conditions, two differential diagnoses matter most: fatty liver disease, because of the steatosis, and autoimmune hepatitis, because of the ANA positivity and the increase in IgG, especially in younger patients.
Neurological involvement
Neurological involvement as the primary manifestation tends to appear in the second and third decades of life, though it has also been reported in patients as young as 7 years. It is mainly motor, and takes one of two patterns depending on how far the disease has progressed. An earlier movement disorder produces tremor, poor coordination and loss of fine movement control. A later rigid dystonia produces mainly spastic movements, with a mask-like face, rigidity and pseudobulbar features such as drooling and dysphagia.
Psychiatric involvement
In about 20% of cases there is a pure psychiatric presentation, and its features are variable: depression, antisocial behaviour, aggressiveness and phobias.
Ocular involvement
Copper can be deposited in the peripheral region of the cornea, producing the Kayser-Fleischer ring. The ring is easier to see when copper deposition is heavy and iris pigmentation is light. More than 95% of patients with neurological or psychiatric involvement have a Kayser-Fleischer ring, whereas about 40–50% of patients with exclusive hepatic involvement do not have one. The ring is not specific to Wilson disease; it can also be seen in other liver disorders, such as primary biliary cirrhosis and chronic active hepatitis.
Other organs
Copper deposited outside the liver and brain produces a range of other problems: episodic hemolytic anemia from copper toxicity; renal involvement in the form of Fanconi syndrome; arthritis; cardiomyopathy and arrhythmia, which are rare but can lead to sudden death; and amenorrhea and infertility.