The hepatic symptoms of Wilson’s disease may precede the onset of neuropsychiatric disorders by up to 10 years. About 50% of patients with WD present with liver disease. Hepatic steatosis is the earliest histological feature in WD and may reflect copper-induced impairment in the function of mitochondria ^[1][2][16,17]. It may be indistinguishable from non-alcoholic fatty liver disease (NAFLD). Mitochondrial changes, increased peroxisomes’ fat droplets, lipolysosomes, and intranuclear glycogen inclusions have been described as the most frequent hepatic ultrastructural changes in WD patients ^[3][18]. As the copper content of hepatic tissue is not measured in every case, electron microscopic examination seems to be a valuable diagnostic tool for the early detection of the disease. Moreover, ultrastructural evaluation may be helpful to distinguish between heterozygous carriers and WD patients ^[4][19]. Liver histology may have several different patterns, i.e., mild non-specific changes, steatosis or steatohepatitis, chronic hepatitis, and acute hepatitis with submassive or massive necrosis ^[5][20]. None of these are specific to WD. Similarly, variable clinical manifestations of liver disease have been described in WD patients. They include (1) clinically asymptomatic liver disease that can only be confirmed by biochemical abnormalities, imaging, or histopathological changes, which still occurs only in rare WD cases as even a liver biopsy may not show any organ alterations; (2) chronic hepatitis; (3) cirrhosis of the liver (compensated or decompensated), which is the most common liver disorder at WD diagnosis; and (4) acute liver failure, which usually occurs in young women (assessed female to male ratio is 4:1) or in previously diagnosed patients who have stopped their treatment ^[5][6][7][20,21,22]. The acute liver failure in the course of Wilson’s disease should be suspected in every patient with intense jaundice and only a slight elevation of the activity of transaminases, low alkaline phosphatase, and cholinesterase levels, and low hemoglobin concentrations may occur. Occasionally, the condition may be associated with Coombs-negative hemolytic anemia and acute renal failure. Moreover, the retrospective multicenter cohort study of 1186 patients revealed that the rate of hepatobiliary malignancies in WD is very low, even in cirrhotic patients ^[8][23]. Similar results were obtained from a Dutch retrospective cohort study in 130 patients with WD who were followed during a median follow-up of 15 years (range of 0.1–51.2). Although data do not support regular HCC surveillance in patients with WD ^[9][24], the risk of carcinogenesis is increased in these patients. HCC occurrence has been reported both in cirrhotic ^[10][11][25,26] and non-cirrhotic WD patients ^[12][27]. Furthermore, some reports highlight the need for consideration of liver cancer development, even in young patients with WD ^[13][28]. Moreover, the American and European Association for the Study of Liver Diseases (AASL and EASL) recommend HCC screening in patients with liver cirrhosis regardless of etiology ^[14][15][29,30].

Neurological disorders are the second most frequent clinical symptoms of WD after liver disease. They may appear early in the course of this disease, through parallel hepatic disorders, or several years after its onset. Prominent neuropsychiatric symptoms can confuse the initial diagnosis and delay treatment ^[16][17][14,15]. However, most patients with neurologic manifestations are already diagnosed with liver cirrhosis. The basal ganglia and brainstem are regions with the highest susceptibility to copper toxicity and their injury leads to various combinations of movement and psychiatric disorders ^[2][17]. The severity of neurologic disorders in the course of WD may differ from subtle symptoms recurring from time to time for several years to rapid and acute disorders that lead to complete disability in a short time. The most common early signs of WD include ataxia, clumsiness of the face, dysarthria, hypersalivation, and personality changes. Late manifestations, which are less prevalent with appropriate WD treatment, include dystonia, tremors, parkinsonism, seizures, and choreoathetosis ^[16][18][14,31]. Based on the most common neurologic disorders, WD is classified into four types of clinical syndromes: (1) Parkinson-like syndrome (45%) with face masking, speaking problems, involuntary hand movements, and muscle stiffness, and, in particular, the diagnosis of the so-called “Juvenile Parkinsonism” should lead to WD suspicion; (2) multiple sclerosis-like syndrome (pseudosclerosis) (24%), with predominantly tremors; (3) ataxic syndrome (15%), wherein excessive muscle tension with abnormal limb movements dominate; and (4) chore-like syndrome (11%), with predominantly abnormal movements and dystonia ^[16][14]. However, a large number of patients present more than one type of neurologic disorder, therefore sometimes it is difficult to categorize them unambiguously into one of the aforementioned subgroups. Additionally, in patients with end-stage liver disease, the neurologic manifestations of WD may be incorrectly recognized as hepatic encephalopathy.

At the time of diagnosis, about 10 to 20% of patients with WD present psychiatric disorders ^[19][32]. They mainly include emotional lability, increased impulsivity, sexual exhibitionism, and self-harm tendencies. More than one psychiatric disorder may be present. Depression is quite common and worthy of mentioning ^[19][32]. Children may present with isolated psychiatric symptoms as the first WD sign ^[20][33]. Sometimes, these disorders may be mistaken for adolescence-period problems. Regarding neurologic signs, psychiatric disorders are classified into four groups: (1) behavioral disorders; (2) affective disorders; (3) schizophrenia-like type disorders; and (4) cognitive disorders.

Kayser–Fleischer rings, which correspond to copper deposits in the descement membrane around the cornea, are observed in about 95% of WD patients presenting with neurologic signs and symptoms, and may be absent in up to 50% of both WD patients with isolated hepatic disease and most asymptomatic individuals. Moreover, Kayser–Fleisher rings may be observed in other liver diseases, e.g., in primary biliary cholangitis (PBC) ^[21][34]. The rings can be visualized in a non-invasive ophthalmological examination using a slit lamp ^[22][35]. Kayser–Fleischer rings are considered to be relevant criteria for confirmation of Wilson’s disease ^[23][36]. Furthermore, their disappearance can be observed as a result of favorable therapy. Patients with Wilson’s disease may present with another eye disorder called the sunflower cataract. The special pattern of copper deposition in the middle point of the lens forms a disc with radial strands that resemble a sunflower, hence the name of the disorder ^[24][37]. Reports on the incidence of sunflower cataract (SC) in WD patients are limited and inconsistent. Results of two small ophthalmological studies, in which 52 and 53 heterogeneous patients with WD were assessed, confirmed SC presence in 1.9 and 17% of patients ^[21][34]. However, a more recent study carried out in Polish patients found SC in only one (1.2%) of the newly diagnosed WD individuals. It completely disappeared after one year of treatment for WD. The authors concluded that SC might be a rare and reversible ophthalmological manifestation of WD and observed only at the time of the disease diagnosis, disappearing with chelation therapy ^[25][38].

Acute hemolytic anemia may occur as a rare complication of Wilson’s disease ^[26][39]. It appears in about 10–15% of WD cases. In most patients, it is Coombs-negative and occurs as a result of toxic intravascular damage to erythrocytes caused by high blood copper concentrations. This type of anemia may be associated with acute liver failure. Therefore, any patient with acute hepatic failure and Coombs-negative hemolytic anemia, together with low levels of transaminases and alkaline phosphatase, as well as an alkaline phosphatase to bilirubin ratio of below 2, should be checked for Wilson’s disease. Other hematologic alterations, including thrombocytopenia and leukopenia, may result from hypersplenism due to liver cirrhosis or may be side effects of WD therapy ^[27][7][3,22].

The incidence of renal complications in Wilson’s disease varies greatly. The expression of the gene causing Wilson’s disease has been confirmed in the kidneys, therefore dysfunction may be a primary or secondary phenomenon in the release of copper from the liver ^[28][40]. Damage to the renal tubules caused by copper deposits leads to symptoms that may resemble Fanconi syndrome and may be associated with both the presence of renal acidosis and excessive excretion of amino acids, glucose, fructose, galactose, uric acid, phosphorus, and calcium in the urine. Approximately 16% of patients have urolithiasis, which is usually related to excessive excretion of calcium in the urine and the impaired acidification process. Hematuria and nephrolithiasis were also observed in the course of the disease. Proteinuria in this disease may appear isolated or secondary as a side effect of D-penicillamine treatment ^[29][2].

Symptoms and signs of the joint disease occur in 20–50% of patients with Wilson’s disease in its late stage, most often after the age of 20, and may resemble osteoarthritis ^[28][40]. Arthropathies and joint pains usually affect the joints of the spine and large joints of the limbs, wrists, knees, and hips. Aseptic arthritis, chondromalacia, and chondrocalcinosis have also been described, as well as a case of acute rhabdomyolysis. Osteopenia is found in more than half of the patients in radiographs. Osteoporosis, rickets, and spontaneous bone fractures have also been reported in the course of the disease ^[16][14]. Sometimes, the clinical and radiological symptoms of the osteoarticular disease are the first harbingers of metabolic disorders in Wilson’s disease and lead to its diagnosis.

In Wilson’s disease, cardiovascular involvement can be also observed as arrhythmias, cardiac myopathy, and small vessel disease. Recent reports have confirmed that signs and symptoms associated with cardiovascular complications are frequent indications for hospitalization in WD patients ^[30][31][41,42]. Additionally, altered skin pigmentation and a bluish color at the base of the nails (so-called azure nipples) have been described. Dermatoses may follow therapy, e.g., with D-penicillamine ^[28][40].