Hepatic, neurologic and psychiatric manifestations of copper-mediated damage may be encountered in patients suffering from WD [2] [4]:

• Liver disease ranges from mild, asymptomatic elevations of transaminases to life-threatening fulminant liver disease. It is important to mention that WD is one of the most common causes of liver failure and children [9]. The most common symptoms are transient, but recurrent episodes of hemolytic anemia and jaundice, accompanied by weight loss and ascites in some cases.
• Neurologic disease may present in various forms - tremor, akinesia, ataxia, dystonia with severe contractures and rigidity similar to Parkinson's disease, whereas spasticity, myoclonus, chorea, hypomimia, and dysarthria can be reported as well [2].
• Reduced academic performance, impulsive behavior, mood changes, and depression, as well as paranoia and schizophrenia, are recognized symptoms of WD.

The deposition of copper in the cornea, known as Kayser-Fleischer rings, is a pathognomonic finding in WD [4]. It is seen in 95% of adult patients with neurologic symptoms and in little over 50% of individuals who do not exhibit CNS symptoms [4]. Kayser-Fleischer rings are rarely encountered in children suffering from liver disease, however, while additional ocular changes include sunflower cataracts, which reflect copper deposition in the center of the lens [8]. Other systems may also be affected by circulating copper - renal (hypercalciuria, nephrolithiasis), cardiac (rhythm abnormalities and myopathy), endocrine (hypoparathyroidism and gigantism may be seen), as well as hematologic (hemolytic anemia) [2]. The onset of symptoms may occur at virtually any age, but some studies determined a median age of approximately 15 years [7].

In some patients, clinical symptoms may be sufficient to make an initial diagnosis, whereas a confirmation may be obtained by any of the following laboratory procedures [2] [3]:

• Measurement of free serum copper, showing values of > 200 mcg/L in WD (normal values range from 100-150 mcg/L).
• Determination of serum ceruloplasmin, which is usually below 50% of its physiological value. However, it may be elevated in the setting of an ongoing infection (due to its role as an acute-phase reactant), thus it is advisable to interpret these results with caution.
• 24-hour evaluation of copper levels in urine.

In addition, a slit-lamp examination should be performed to visualize Kayser-Fleischer rings or sunflower cataracts that may not be seen macroscopically [4], while genetic testing may be performed to confirm ATP7B mutations [5]. Imaging studies such as MRI have shown to be of significant benefit in WD, as the exclusion of other diseases may be performed by this technique [9].

The principle of therapy is to potentiate elimination of copper through both renal and gastrointestinal routes by various chelating agents [2] [3] [4]:

• D-penicillamine - Because of its role in promoting urinary excretion of copper by binding to this heavy metal, but also reducing the capacity of intestinal absorption, D-penicillamine is considered to be one of the most important initial therapeutic strategies. It must be noted that food inhibits the absorption of this drug (but also all other chelating agents), which is why it must be taken one or two hours before meals [2]. Initial regimens are 250-500 mg q24h that are increased to 1000-1500 mg q24h, while maintenance dosages are 25-30% lower. Adverse effects are common and include fever, rash, lymphadenopathy and proteinuria in early stages of therapy, whereas bone marrow and nephrotoxicity may be reported with chronic use. In rare cases, abrupt elevation of free serum copper during d-penicillamine therapy may precipitate neurological damage and unfortunately, almost 20-30% of patients must switch to another drug because of adverse reaction.
• Trientine - Despite its relatively higher cost, trientine is shown to be an excellent alternative to D-penicillamine, primarily because of its safety. The dosages range between 750-1500 mg q12-24h for adults and 20 mg/kg/24h for children and maintenance doses are around 15 mg/kg/day. Caution must be present when using this drug, as concomitant administration of iron may cause toxic effects, whereas overtreatment can lead to sideroblastic anemia [2].
• Zinc - The administration of this heavy metal is considered to be vital in the long-term management of WD, primarily because of its safety and mechanism of action. Namely, zinc stimulates the activity of metallothionein in the small intestine and liver, which causes inhibition of intestinal copper absorption and facilitation of fecal excretion, thus allowing chelation therapy to reduce the levels of copper in blood more efficiently [10] [11]. In fact, some authors recommend zinc as the initial drug of choice, followed by the introduction of either trientine or d-penicillamine [2]. Gastric irritation is the only major adverse effect reported and doses are 75 and 150 mg/day in children and adults, respectively.
• Tetrathiomolybdate - Although it is still considered as an experimental drug, its ability to bind to copper and make it unabsorbable by the small intestine may be prudent in further clinical practice.

In addition to chelation therapy, appropriate dietary changes through restriction of copper rich foods (chocolate, mushrooms, nuts, soy, etc) are advised as well [2]. For patients who suffer from severe liver failure, transplantation may be the only solution. 10-survival rates are almost 80% in some studies, however, indicating that this procedure is considered to be safe, even from donors who are heterozygous for WD gene [12]. Moreover, improvement of neuropsychiatric symptoms was observed after liver transplantation [6], but a poorer prognosis was seen in these patients, unfortunately [13].

If the disease is discovered in asymptomatic or mild stages, proper therapy is highly effective, but if the diagnosis is made when extensive liver damage already occurred, the prognosis is much worse [7]. In fact, it is estimated that almost 50% of patients die from this disease due to failed diagnosis of the disease [7]. For these reasons, early recognition of the disease may be the most significant factor in the outcome of patients.

Mutations in the ATP7B gene located on chromosome 13, which codes for an intracellular copper-transporting P-type ATPase [5], is the cause of WD and so far, more than 500 mutations have been identified, including deletions/insertions in the coding region, missense mutations and various other [5] [8]. The disease exhibits both sporadic and autosomal recessive patterns of inheritance and various degrees of penetrance determine the severity of symptoms and long-term outcomes.

WD has shown to be a rare disease, as global prevalence rates are currently estimated at 0.5 per 100,000 individuals [2]. Significant differences exist from country to country, however, ranging from 2.5 per 100,000 in Germany and 3.3 per 100,000 in Japan, to 4.9 per 100,000 in Costa Rica [2]. Sardinia is considered as a highly prevlent area for WD as well, with estimated rates of 1 in 7,000-10,000 individuals [2]. Recent studies, however, have determined that up to 1 in 40 individuals are heterozygotes for the ATP7B gene and a predicted rate of 1 in 7,000 in the United Kingdom showed that this disease may be much more common that initially thought [8]. One of the reasons why such differences exist is the type of mutation encountered in these geographical areas and consequently, the degree of penetrance seen in patients with these mutations [2].

Under physiological circumstances, copper is a cofactor of numerous metabolic functions and in proper concentrations it is of significant benefit [3]. When copper needs to be excreted from the body, ceruloplasmin is mobilized, which will transport copper to the liver and bile, the principal site of its elimination [3]. In the setting of mutations that cause impaired function of intracellular pumps that should remove copper from the cell and subsequent prevention of its binding to ceruloplasmin, accumulation of free copper in blood and organs such as the brain, the liver, and the corneas occurs [8]. Mechanical accumulation is not the cause of organ damage and symptoms; however, the toxic effects of circulating copper result in the symptoms [2]. Lipid peroxidation, free radical mediated damage of mitochondria and DNA, but also inhibition of mechanisms that regulate apoptosis are documented modes of injury [2] [3].

Screening of first and second-degree relatives of patients with known WD is the single most important preventive strategy [2]. Isolated reports have shown the importance of wide-scale screening of children for WD [7] [9], and its implementation in general practice should be discussed. Several studies have emphasized the importance of compliance and adherence to therapy, as the cause of death was attributed to improper therapy in some patients [14].

Hepatolenticular degeneration, initially discovered during the study of brain injury associated with liver cirrhosis [1], is now known as Wilson disease (WD), a genetic disorder of defective copper metabolism. It is distinguished by mutations of intracellular copper-transporting ATPase, resulting in defective intracellular metabolism and insufficient binding of this heavy metal to ceruloplasmin, its extracellular transporter [2]. Specifically, mutations of the protein ATP7B on chromosome 13q14, either by sporadic or autosomal recessive patterns, is the underlying mechanism of disease [2]. As a result of these pathological events, the binding of copper to ceruloplasmin and their subsequent excretion into bile (in the form of holo-ceruloplasmin) is not achieved, leading to accumulation of free copper in the circulation [3]. In higher serum concentrations, copper is toxic to cells of various lineages by inducing oxidative stress and damage to lipid membranes, mitochondria, and DNA, but also by promoting apoptosis [2]. Overall prevalence rates are established at 0.5 per 100,000 individuals, suggesting that this disease is rarely encountered in clinical practice [2]. Patients of any age may be affected, but in most cases, the diagnosis is made in individuals between 5-35 years of age [4]. The clinical presentation encompasses three main forms - neurologic, psychiatric and hepatic, either appearing as isolated or in combination [4]. Ataxia, tremor, dyskinesia, rigidity and dysarthria are some of the most common findings in neurologic disease, while mood changes, depression, paranoia, schizophrenia and impulsive behavior are hallmarks of psychiatric disease [4]. When it comes to liver disease, the severity may range from asymptomatic elevations of liver transaminases to severe fulminant liver failure. Symptoms such as jaundice, anemia, ascites, and anorexia are most frequently reported [4]. The deposition of copper around the cornea, known as Kayser-Fleischer rings, are pathognomonic findings in WD patients and may be often seen during the regular physical examination. For this reason, the workup should start with a meticulous clinical examination and patient history that will obtain information regarding the onset of symptoms and presence of similar diseases in the family. To confirm WD, various laboratory tests may be performed - determination of free copper in blood and feces, 24-hour urine excretion of copper and detection of ceruloplasmin in serum [2], whereas genetic testing may be done as well [5]. Chelation therapy is the principle line of treatment in patients suffering from this disease. D-penicillamine, trientine, and zinc are used to promote excretion of copper from blood and are highly efficient if administered properly [2]. In patients with a fulminant liver disease, liver transplantation is recommended and good long-term results have been observed [6]. Because WD may be fatal if not recognized on time and because almost 50% of patients die due to lack of diagnosis [7], physicians must maintain a high dose of clinical suspicion in younger patients with unexplained hepatic, neurologic and/or psychiatric symptoms.

Wilson disease (WD) is a genetic condition characterized by improper metabolism of copper. Under physiological conditions, this heavy metal is an important constituent of numerous metabolic reactions in the body. In the setting of WD, mutations of proteins that form the transporter mechanisms from the cell to the external environment are the cause of this disease. The insufficient ability of the cells to excrete copper and insufficient production and formation of transporter - ceruloplasmin, leads to accumulation of free copper in the circulation. Normally, excess copper is excreted through bile and feces, but because it cannot be transported to these structures, it starts to deposit in various tissues, most notably the liver and the brain. Consequently, symptoms related to these organs are the main clinical manifestations of the disease and they may appear either in isolated forms or in combination. Firstly, liver symptoms may range from the asymptomatic elevations of liver enzymes to complete organ failure that necessitates rapid transplantation. The most common symptoms are anemia, jaundice, ascites and weight loss. Secondly, impaired balance and gait, as well as tremor and rigidity of the body are main manifestations of the central nervous disease. Additionally, psychiatric symptoms such as mood disorders, impulsiveness, depression and schizophrenia are not uncommon in these patients. One of the hallmarks of WD is the appearance of Kayser-Fleischer rings - deposits of copper around the cornea. This sign is more commonly seen in adults than in children. Although WD is considered to be a rare disease, with estimated rates of 0.5 per 100,000 individuals, a much higher rate is suspected based on wide-scale screening studies. To make the diagnosis, it is necessary to maintain a high dose of clinical suspicion, especially in children, as WD is shown to be one of the most common causes of liver failure in the pediatric population. To confirm WD, various laboratory tests may be performed, including evaluation of copper levels in the blood, urine, as well as the determination of ceruloplasmin levels in the blood. Treatment consists of drugs known as chelating agents, which bind to the heavy metal and are excreted in urine or feces. In patients with complete liver failure, transplantation may be the only treatment option. Hence, early recognition of this disease is detrimental in achieving better long-term outcomes.

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