Dysfunction in copper metabolism consequently results in toxic copper accumulation in the blood, cornea, brain, and liver. This translates to a spectrum of expression ranging from completely asymptomatic to symptomatic, classically resulting in hepatic and neurological sequelae. The variable and at times incomplete penetrance of the WD gene is responsible for the range of presentation, including its hepatic, neurological, psychiatric, hematological, gastrointestinal, endocrinological, renal, cardiac, skeletal, and ocular symptoms (Fig. 21.1). Notably, neurological symptoms should prompt a neurological evaluation and radiographic imaging of the brain, preferably via magnetic resonance imaging (MRI). Specifically, proton-density MRI sequences remain sensitive in displaying the extent of neuropathology [7]. Histologically, astrocytes are increased within the gray matter associated with swollen glia, liquefaction, and spongiform degeneration. Clinically, in a case series of 25 patients with WD, 11 of the 25 patients, or 44 %, presented with neurological symptoms [8]. Specifically, movement abnormalities are categorized as akinetic–rigid syndromes , similar to Parkinson’s disease, pseudosclerosis dominated by tremor, ataxia, and dystonic syndrome [9]. Behavioral and psychiatric symptoms, particularly in children, consist of personality changes and unstable behavior resulting in deteriorating school performance. In reference to hematological symptoms, Coombs-negative hemolytic anemia is often neglected as a presenting symptom in WD. Marked hemolysis is often associated with severe liver disease. Clinicians should also be aware of ocular signs and symptoms, in particular Kayser–Fleischer rings (Fig. 21.2) and sunflower cataract s caused by copper deposition on Descemet’s membrane in the cornea and lens respectively, necessitating a slit lamp examination [10, 11]. Up to 95 % of patients with neuropsychiatric symptoms have Kayser–Fleischer rings, whereas they are less often encountered in those with a hepatic presentation. In a case series of 30 patients with WD, 14 out of 22 or 63 % of patients without fulminant hepatic failure (FHF) and 6 out of 8 patients or 75 % of patients with FHF presented with Kayser–Fleischer rings [12]. At the same time, the absence of Kayser–Fleischer rings does not exclude the diagnosis of WD and other cholestatic liver diseases (which may also result in excessive copper accumulation due to decreased biliary excretion) have been associated with the development of Kayser–Fleischer rings.

The natural history of WD is variable, with the most worrisome complication being FHF. It is important to recognize characteristic clinical findings in FHF (Table 21.2) [13–19]. Predominantly in young females (the female:male ratio is 4:1), FHF, if untreated, carries an almost 95 % risk of mortality [20]. Traditionally, a ratio of serum alkaline phosphatase to total bilirubin <1 has been believed to have 86 % sensitivity and 50 % specificity for a diagnosis of fulminant WD [21, 22], a more recent study by Korman et al. [23] reporting that an alkaline phosphatase to total bilirubin ratio of less than 4 yielded 94 % sensitivity and 96 % specificity for FHF due to WD. Thus, a proportionately low alkaline phosphatase level should be a clue to the clinician with regard to WD, particularly in the patient with FHF. A prognostic scoring system for WD (Table 21.3) was developed by Nazer et al. [24] with score of 7 and above suggestive of high mortality in a combined pediatric and adult WD population and subsequently, a modified version based on bilirubin, aspartate aminotransferase, albumin, white cell count, and international normalized ratio was prospectively validated in a pediatric population (Table 21.4). Based on the new index, a score greater than 11 predicts a high risk of mortality, a requisite for liver transplantation with sensitivity 93 %, specificity 97 %, positive predictive value 92 %, and negative predictive value 97 % [25]. Patients with advanced fibrosis and cirrhosis are susceptible to complications associated with cirrhosis, which are detailed elsewhere in this text. Although copper chelation therapy does not necessarily lead to regression of advanced fibrosis, disease stabilization with chelation therapy is the rule in those without a fulminant presentation, although a proportion of patients, 15–20 %, experience a worsening of their neurological symptoms with chelation. Lastly, in a retrospective case series of 363 patients with WD, the frequency of malignancy was 0, 4.2, 5.3, and 15 % in the <10 years age group, 10–19 years, 20–29 years, and 30–39 years respectively. In general, malignancy, and particularly hepatocellular carcinoma , is an uncommon complication of WD isolated to those with cirrhosis, who should be screened on a regular basis [26].

When the diagnosis of WD is suspected, initial testing should be pursued with serum ceruloplasmin , 24-h urinary copper excretion, and slit-lamp examination to assess for Kayser–Fleischer rings. When warranted based on this initial testing, further testing, including the serum free copper concentration, hepatic copper concentration based on biopsy, the d-penicillamine challenge test , and genetic testing are options that can be considered (Table 21.5) [13].