EASL Clinical Practice Guidelines

Clinical presentation

The most common presentations are with liver disease or neuropsychiatric disturbances. Asymptomatic patients are most often detected by family screening.

Age at onset of symptoms

Wilson's disease may present symptomatically at any age, although the majority presents between ages 5 and 35. The youngest patient reported with cirrhosis due to Wilson's disease was 3-years-old [9]. About 3% of patients present beyond the fourth decade, either with hepatic or neurologic disease [5]. The oldest patients diagnosed were in their eighth decade [[10], [11]].

Physical signs

The clinical hallmark of Wilson's disease is the Kayser–Fleischer ring, which is present in 95% of patients with neurologic symptoms and somewhat over half of those without neurologic symptoms [[12], [13]]. In children presenting with liver disease, Kayser–Fleischer rings are usually absent [14]. Kayser–Fleischer rings are caused by deposition of copper in Desçemet's membrane of the cornea. A slit-lamp examination by an experienced observer is required to identify Kayser–Fleischer rings. They are not entirely specific for Wilson's disease, since they may be found in patients with chronic cholestatic diseases including children with neonatal cholestasis. Other ophthalmologic changes are rare and include sunflower cataracts, which are caused by deposits of copper in the center of the lens. They can also be found by slit-lamp examination [15].

Neurologic signs are variable, most often tremor, ataxia, and dystonia. Signs of liver disease are nonspecific, but any liver disease of unknown origin should be considered as Wilson's disease until proved otherwise. Diagnostic vigilance is important because Kayser–Fleischer rings may be absent in up to 50% of patients with Wilson's disease affecting the liver [12].

Liver disease

Any type of liver disease may be encountered in patients with Wilson's disease. Clinically evident liver disease may precede neurologic manifestations by as much as 10 years and most patients with neurologic symptoms have some degree of liver disease at presentation. Presenting symptoms of liver disease can be highly variable, ranging from asymptomatic, with only biochemical abnormalities, to overt cirrhosis with all its complications. Wilson's disease may also present as acute hepatic failure sometimes associated with Coombs-negative hemolytic anemia and acute renal failure. Patients diagnosed with Wilson's disease who have a history of jaundice may have previously experienced an episode of hemolysis. Clinical symptoms are summarized in Table 2.

Table 2
Clinical symptoms in Wilson's disease patients presenting with liver diseas[157], [158].



∗Only cases with chronic active hepatitis.
$Elevated ALT at routine testing, or accidental finding of cirrhosis or of Kayser–Fleischer rings.
Acute liver failure due to Wilson’s disease (former: “fulminant Wilson’s disease”)

Wilson's disease enters into the differential diagnosis of any young patient presenting with acute hepatitis. Its clinical presentation may be indistinguishable from that of acute viral hepatitis, with jaundice and abdominal discomfort. In some patients symptoms resolve spontaneously, but once the diagnosis is made, lifelong treatment is necessary. On the other hand, rapid deterioration can occur with acute liver failure.

Wilson's disease accounts for 6–12% of all patients with acute liver failure who are referred for emergency transplantation [[16], [17]]. Although cirrhosis is already present in most cases, the clinical presentation is acute and progresses rapidly to hepatic and renal failure and, when untreated, carries an almost 95% mortality. Acute liver failure due to Wilson's disease occurs predominantly in young females (female:male ratio 4:1) [18]. An acute presentation with rapid deterioration may also occur in patients who were previously treated but stopped their medications [16]. Suspicion for acute Wilson's disease should be particularly high in patients with deep jaundice, low haemoglobin, low cholinesterase [17], only mildly increased transaminases, and low alkaline phosphatase.

Chronic hepatitis and cirrhosis

Many patients present with signs of chronic liver disease and evidence of cirrhosis, either compensated or decompensated. Patients may present with isolated splenomegaly due to clinically inapparent cirrhosis with portal hypertension. The presentation may be indistinguishable from other forms of chronic active hepatitis, with symptoms including jaundice, malaise, and vague abdominal complaints.

Hemolysis

Coombs-negative haemolytic anemia may be the only initial symptom of Wilson's disease. However, marked hemolysis is commonly associated with severe liver disease. Decay of liver cells may result in the release of large amounts of stored copper, which further aggravates hemolysis. In one series, hemolysis was a presenting feature in 25 out of 220 cases (12%); in these patients hemolysis occurred either as a single acute episode or recurrently or was low-grade and chronic [18]. In a series of 283 Japanese patients with Wilson's disease, only three presented with acute hemolysis alone [19]. One quarter of the patients presenting with jaundice also had hemolysis. Acute liver disease and hemolysis as a presenting symptom can occur during delivery, mimicking HELLP syndrome [20]. Low-grade hemolysis may be associated with Wilson's disease even when liver disease is not clinically evident. Some patients presenting with neurologic symptoms report that they have experienced transient episodes of jaundice previously, probably due to hemolysis [21]. On the other hand, rapid deterioration can occur with acute liver failure.

Neurologic disease

Wilson's disease can manifest with an impressive spectrum of neurological, behavioral or psychiatric disorders, which may be its first clinical manifestation, appearing simultaneously with hepatic signs, or some years later.

Neurological presentation can be extremely subtle, and intermitted for many years, but may also develop very rapidly, leading within a few months to complete disability. The neurological abnormalities can be classified as: (1) Akinetic-rigid syndrome similar to Parkinson's disease; (2) Pseudosclerosis dominated by tremor; (3) Ataxia; and (4) Dystonic syndrome. In many cases, neurological signs are very difficult to classify as patients can have more than one abnormality, each with different levels of severity.

The characteristic tremor is a coarse, irregular proximal tremulousness with a “wing beating” appearance. Dystonia can be focal, segmental or very severe, involving all parts of the body, leading to severe contractures. Very common motor impairments involve the cranial region, and manifest clinically as dysarthria (can be cerebellar or extrapyramidal leading to aphonia), drooling or oropharyngeal dystonia. Facial grimacing, open jaw, running saliva, and lip retraction are characteristic manifestations. Speech changes and drooling are often early neurologic symptoms. A tremor-rigidity syndrome (“juvenile Parkinsonism”) should raise suspicion of Wilson's disease [[22], [23], [24]].

Because of an increasing difficulty in controlling movement or progressive dystonia, patients become bedridden and unable to care for themselves. Ultimately, the patient becomes severely disabled, usually alert, but unable to talk. In patients presenting with advanced liver disease, neurologic symptoms can be mistaken for signs of hepatic encephalopathy.

Psychiatric symptoms

Behavioral and psychiatric symptoms are common and some of them may precede neurologic or hepatic signs and symptoms. About one-third of patients initially present with psychiatric abnormalities. In children with Wilson's disease, declining school performance, personality changes, impulsiveness, labile mood, sexual exhibitionism, and inappropriate behavior are observed [[24], [25]]. The initial symptoms are frequently misdiagnosed as behavioral problems associated with puberty. In older persons, psychotic features resembling paranoia, schizophrenia or depression can be observed but behavioral changes are also common. Severe cognitive deterioration is observed in patients with advanced neurological disease, but in general, cognitive function is not markedly impaired [26].

A delay in diagnosing Wilson's disease in patients with neuropsychiatric presentations is frequent and was in one case as long as 12 years [27]. Patients presenting with neuropsychiatric symptoms may have concurrent symptomatic liver disease, but in most patients liver disease can only be detected by laboratory evaluation, imaging studies of the liver or by liver histology. About half of the patients have advanced fibrosis or frank cirrhosis. On the other hand, signs of liver disease may be even completely absent at biopsy [28].

Other clinical manifestations

Less common presentations include gigantism, lunulae, renal abnormalities including aminoaciduria and nephrolithiasis, hypercalciuria and nephrocalcinosis [[29], [30]], cardiomyopathy [31], myopathy [32], chondrocalcinosis and osteoarthritis [33], hypoparathyroidism [34], pancreatitis [35], infertility or repeated miscarriages [[36], [37]].