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].

• Splenomegaly

  She had no hepatomegaly and no splenomegaly. Breast and pubic hair development was concomitant with Tanner stage 4. There was performed laboratory and instrumental investigations. [ncbi.nlm.nih.gov]

  It is characterized by progressive degeneration of the basal ganglia of the brain, a brownish ring (Kayser-Fleischer ring) at the outer margin of the cornea caused by deposition of copper in the Descemet membrane, cirrhosis of the liver, splenomegaly, [whonamedit.com]

  Hypocupremia Wilson disease Wilsons disease Wilson's disease Clinical Information Rare autosomal recessive disease characterized by the deposition of copper in the brain, liver, cornea and other organs; clinical features include liver cirrhosis, liver failure, splenomegaly [icd9data.com]

  Kayser–Fleischer rings are a sign of Wilson's disease, which involves abnormal copper handling by the liver resulting in copper accumulation in the body and is characterised by abnormalities of the basal ganglia of the brain, liver cirrhosis, splenomegaly [en.wikipedia.org]

• Anemia

  Symptoms such as jaundice, anemia, ascites, and anorexia are most frequently reported. [symptoma.com]

  Although fulminant hepatitis with nonimmune hemolytic anemia is frequently reported, chronic mild hepatitis can occur with bouts of transient hemolytic anemia. [ncbi.nlm.nih.gov]

  Acute kidney failure and a type of anemia called hemolytic anemia often occur in people who have acute liver failure due to Wilson disease. [niddk.nih.gov]

• Fatigue

  We report a 16-year-old female who presented with fatigue, dizziness, and new onset jaundice. [ncbi.nlm.nih.gov]

  When to Call a Doctor Call a doctor if you or your child develops tremors, psychological changes, fatigue or jaundice, especially if there is a family history of Wilson’s disease. [healthcommunities.com]

  Symptoms can include: weakness and unusual fatigue weight loss stomach pain and/or bloating easy bruising or bleeding swelling in the legs, ankles or feet muscle cramps jaundice brown rings in the outer part of the eye known as Kayser-Fleischer rings [childrenshospital.org]

  The signs and symptoms of liver disease include yellowing of the skin or whites of the eyes (jaundice), fatigue, loss of appetite, and abdominal swelling. [ghr.nlm.nih.gov]

• Falling

  Slips & Falls Slips, trips & falls: standing height; construction sites; stairs and ladders; assisted falls from high cliffs and buildings; floor maintenance; foreign substances; sidewalk defects. [hayesassoc.com]

  I’d just randomly fall over or fall out of the shower. To me, the diagnosis was kind of a long process. It was frustrating because I went to a bunch of doctors. I was misdiagnosed and I had liver problems. Then the neurological symptoms started. [wilsontherapeutics.com]

  Complications may include: Anemia ( hemolytic anemia is rare) Central nervous system complications Cirrhosis Death of liver tissues Fatty liver Hepatitis Increased chances of bone fractures Increased number of infections Injury caused by falls Jaundice [nlm.nih.gov]

  Ogden and American Falls to the. Montana location. ' ' ' ' ' * ' ·. .. ' Th'e Great ·- Falls Tribune, · in quoting' *W. L. Wattis regarding the construction plans, says: "The .initial work- at the- dam cile. [newspapers.com]

• Weight Loss

  The most common symptoms are transient, but recurrent episodes of hemolytic anemia and jaundice, accompanied by weight loss and ascites in some cases. [symptoma.com]

  Symptoms can include: weakness and unusual fatigue weight loss stomach pain and/or bloating easy bruising or bleeding swelling in the legs, ankles or feet muscle cramps jaundice brown rings in the outer part of the eye known as Kayser-Fleischer rings [childrenshospital.org]

  Signs and symptoms of the disease may include: Abdominal pain and bloating Anxiety and depression Edema or fluid build up in legs and feet Fatigue Jaundice Kayser-Fleischer rings Loss of appetite Muscle stiffness Nausea and vomiting Tremor Weight loss [news-medical.net]

  Some common symptoms of Wilson’s disease include: Fatigue Clumsiness Bruising Joint pain Shaking Jaundice (Yellowing of the skin and eyes) Weight loss Nausea Difficulty speaking or swallowing Swelling of the limbs Depression Drooling Wilson’s disease [disability-benefits-help.org]

• Difficulty Walking

  Signs and symptoms of these problems can include clumsiness, tremors, difficulty walking, speech problems, impaired thinking ability, depression, anxiety, and mood swings. [ghr.nlm.nih.gov]

  I started having brain fog, chronic headaches, dizziness, difficulty walking, lots of food sensitivities, tinnitus, numbness in my hands and feet, cold intolerance, diarrhea, nausea, infertility, and joint pain (knees and elbows). [inspire.com]

• Vomiting

  These patients had clinical features such as numbness of hands and feet, vomiting, insomnia, palsy, liver failure and Kayser-Fleischer (K-F) rings and were diagnosed with Wilson disease in the Human Genetics Department, Vietnam National Children's Hospital [ncbi.nlm.nih.gov]

  Other symptoms may include: Jaundice Nausea, loss of appetite Vomiting blood Difficulty speaking, swallowing, walking Tremors in hands and arms Muscle rigidity Skin rash Enlarged liver and spleen Buildup of abdominal fluid Anemia Low platelet and white [columbiasurgery.org]

  These symptoms may include feeling tired nausea and vomiting poor appetite pain over the liver, in the upper part of the abdomen darkening of the color of urine lightening of the color of stool yellowish tint to the whites of the eyes and skin, called [niddk.nih.gov]

  Wilson Disease Liver Abdominal pain or distention Nausea, vomiting Yellowish skin or whites of eyes (jaundice) Easy bruising Swollen liver and spleen Behavioral changes Stiff muscles Uncontrollable tremors Slow or repeated movements Trouble swallowing [nm.org]

  In the tigecycline group, the median time to onset of nausea and/or vomiting was approximately 1.1 days. The total duration of nausea or vomiting occurred over a median of approximately 2.5 days while on tigecycline therapy. [bmcpulmmed.biomedcentral.com]

• Nausea

  Other symptoms may include: Jaundice Nausea, loss of appetite Vomiting blood Difficulty speaking, swallowing, walking Tremors in hands and arms Muscle rigidity Skin rash Enlarged liver and spleen Buildup of abdominal fluid Anemia Low platelet and white [columbiasurgery.org]

  These symptoms may include feeling tired nausea and vomiting poor appetite pain over the liver, in the upper part of the abdomen darkening of the color of urine lightening of the color of stool yellowish tint to the whites of the eyes and skin, called [niddk.nih.gov]

  In the tigecycline group, the median time to onset of nausea and/or vomiting was approximately 1.1 days. The total duration of nausea or vomiting occurred over a median of approximately 2.5 days while on tigecycline therapy. [bmcpulmmed.biomedcentral.com]

  Wilson Disease Liver Abdominal pain or distention Nausea, vomiting Yellowish skin or whites of eyes (jaundice) Easy bruising Swollen liver and spleen Behavioral changes Stiff muscles Uncontrollable tremors Slow or repeated movements Trouble swallowing [nm.org]

  Signs and symptoms of the disease may include: Abdominal pain and bloating Anxiety and depression Edema or fluid build up in legs and feet Fatigue Jaundice Kayser-Fleischer rings Loss of appetite Muscle stiffness Nausea and vomiting Tremor Weight loss [news-medical.net]

• Hematemesis

  Hematemesis – Vomiting of blood; may be red, appear as coffee grounds, brown or black. Hematuria – The presence of blood or blood cells in the urine. [wilsonsdisease.org]

  Physical Examination Hepatic symptoms Hepatic insufficiency and cirrhosis may slowly develop and can result in signs of fulminant hepatic failure, including the following: Ascites and prominent abdominal veins Spider nevi Palmar erythema Digital clubbing Hematemesis [emedicine.medscape.com]

  […] follows: Chronic active hepatitis Cirrhosis (the most common initial presentation) Fulminant hepatic failure Signs of fulminant hepatic failure include the following: Ascites and prominent abdominal veins Spider nevi Palmar erythema Digital clubbing Hematemesis [emedicine.com]

• Sialorrhea

  Initially, the patient presented with akathisia, sialorrhea, oromandibular dystonia (occasionally grimacing) and slight dysarthria. The patient's symptoms diminished after treatment with d-penicillamine was initiated. [ncbi.nlm.nih.gov]

  Drooling, or sialorrhea, is also an early feature of WD and is seen at the initial examination in up to 21% of neurologic cases (23). [atm.amegroups.com]

• Jaundice

  Subsequently, neurologic symptoms may lead to a correct diagnosis when such features as jaundice and ascites are attributed, in retrospect, to the cirrhosis of Wilson's disease. [dx.doi.org]

  Symptoms such as jaundice, anemia, ascites, and anorexia are most frequently reported. [symptoma.com]

  We report a 16-year-old female who presented with fatigue, dizziness, and new onset jaundice. [ncbi.nlm.nih.gov]

• Hepatomegaly

  CONCLUSIONS: Wilson disease can present with only significantly increased transaminases activity and hepatomegaly or liver failure, but neurological symptoms are very rare in children. [ncbi.nlm.nih.gov]

  Hepatic disease can be quite variable, ranging from hepatomegaly or other nonspecific symptoms that mimic viral hepatitis to severe liver damage, such as cirrhosis. [mayomedicallaboratories.com]

  […] exam may show signs of: Damage to the central nervous system, including loss of coordination, loss of muscle control, muscle tremors, loss of thinking and IQ, loss of memory, and confusion (delirium or dementia) Liver or spleen disorders (including hepatomegaly [nlm.nih.gov]

• Asterixis

  Palmar erythema Spider nevi (angiomata) Gynaecomastia Feminising hair distribution Testicular atrophy Small irregular shrunken liver Anaemia Caput medusae Decompensation[edit] Drowsiness (encephalopathy) Hyperventilation (encephalopathy) Metabolic flap/asterixis [en.wikipedia.org]

  Asterixis may be absent in the third and fourth stages. Etiology The cause of hepatic encephalopathy is undoubtedly multifactorial. [intranet.tdmu.edu.ua]

• Osteoporosis

  Wilson Disease Association Other symptoms and health problems Wilson disease can affect other parts of your body and cause symptoms or health problems, including a type of anemia called hemolytic anemia bone and joint problems, such as arthritis or osteoporosis [niddk.nih.gov]

  […] liver and spleen Behavioral changes Stiff muscles Uncontrollable tremors Slow or repeated movements Trouble swallowing Slurred speech Poor coordination Drooling Decreased fine motor abilities Feeling stressed and anxious Depression, suicidal thoughts Osteoporosis [nm.org]

  Other symptoms include heart problems, anemia, pancreatitis (inflamed pancreas ), repeated miscarriages (in females), and premature osteoporosis. Diagnosis If Wilson's disease runs in your family, you and your siblings should be screened as well. [health.ccm.net]

  Other symptoms and health problems Wilson disease can affect other parts of your body and cause symptoms or health problems, including a type of anemia called hemolytic anemia bone and joint problems, such as arthritis or osteoporosis heart problems, [my.clevelandclinic.org]

  […] anxiety, and/or psychosis.[5][1][2] Other signs and symptoms may include:[5][1][2] Menstrual period irregularities, increased risk of miscarriage and infertility in women Anemia Easy bruising and prolonged bleeding Kidney stones Early-onset arthritis Osteoporosis [rarediseases.info.nih.gov]

• Arthralgia

  The abnormalities include arthralgia of the knees in four patients, genu varum in two patients, arthralgia of hip joints in one patient, genu valgum in one patient and talipse equinovarus in one patient. [bmcneurol.biomedcentral.com]

  0000140 Acute hepatic failure Acute liver failure 0006554 Acute hepatitis Acute liver inflammation 0200119 Aggressive behavior Aggression Aggressive behaviour Aggressiveness [ more ] 0000718 Anemia Low number of red blood cells or hemoglobin 0001903 Arthralgia [rarediseases.info.nih.gov]

  Patients may have osteoporosis or osteomalacia, or they may have joint disorders such as arthritis or arthralgias. Female patients frequently have oligomenorrhea or amenorrhea. [clinicaladvisor.com]

  Other late-onset undesirable effects of the drug include a lupus-like syndrome characterized by hematuria, proteinuria, arthralgia, and appearance of antinuclear antibodies; bone marrow toxicity with severe thrombocytopenia and even aplasia may occur, [dx.doi.org]

• Kayser-Fleischer Ring

  Some copper is deposited around the rim of the cornea and edge of the iris, causing Kayser-Fleischer rings. The rings appear to encircle the iris. [msdmanuals.com]

  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. [symptoma.com]

  Annual slit-lamp examination of Kayser-Fleischer rings should document fading or disappearance if copper is being adequately removed. If the rings return, it suggests poor compliance with treatment. [patient.info]

  Interestingly, Kayser-Fleischer rings were initially described a decade earlier by German physicians Bernhard Kayser and Bruno Fleischer in 1902 and 1903 respectively 16,17. Promoted articles (advertising) [radiopaedia.org]

• Yellow Discoloration of the Skin

  […] disease".[11] Signs and symptoms[edit] The main sign of jaundice is a yellowish discoloration of the white area of the eye (sclera) and the skin. [en.wikipedia.org]

• Impulsivity

  Reduced academic performance, impulsive behavior, mood changes, and depression, as well as paranoia and schizophrenia, are recognized symptoms of WD. [symptoma.com]

  About 30% of Wilson disease patients will exhibit psychiatric disturbances that include changes in behavior, personality changes, depression, attention deficit hyperactivity disorder, paranoid psychosis, suicidal tendencies, and impulsivity. [themedicalbiochemistrypage.org]

  Patients in the choreic group (11%) - Predominantly characterized by choreoathetoid abnormal movements associated with dystonia Psychiatric features include emotional lability, impulsiveness, disinhibition, and self-injurious behavior. [emedicine.medscape.com]

  Behavioral and psychiatric manifestations of WD include depression, altered behavior and personality, impulsiveness and labile mood, sexual exhibitionism, and frank psychosis.7 When neurologic or psychiatric manifestations precede clinical liver disease [aasldpubs.onlinelibrary.wiley.com]

• Auditory Hallucination

  Jung An Lee, Nae-Yun Heo, Bong Ju Lee, Gyung-Mee Kim, Jung Goo Lee and Seon-Cheol Park, A case of Wilson’s disease presenting only with somatic preoccupation, suicidal tendencies and auditory hallucinations, Psychiatry and Clinical Psychopharmacology, [dx.doi.org]

• Tremor

  An isolated unilateral rest tremor is atypical in Wilson’s disease. When rest tremor is present it is usually accompanied by postural and kinetic tremor that is often more severe than the rest tremor. [clinicaladvisor.com]

  Tremor did not need treatment. CONCLUSIONS: In Wilson disease, neurologic complications can be severe. The most common complication seen in our patients was tremor. Early diagnosis and treatment may slow down neurologic disability. [ncbi.nlm.nih.gov]

  After her 25th birthday, Ann began to experience upper limb tremors. Within 4 months, the tremors progressed to all of Ann's limbs, followed by bouts of mania. [medicalbag.com]

  Secondly, impaired balance and gait, as well as tremor and rigidity of the body are main manifestations of the central nervous disease. [symptoma.com]

• Dystonia

  The authors diagnosed acute focal dystonia induced by clomipramine. Botulinum toxin and intensive rehabilitation was initiated; complete regression of hand dystonia was observed. [ncbi.nlm.nih.gov]

  Dystonia is chronic but the vast majority of dystonias do not affect other functions of the brain. Dystonia causes varying degrees of disability and pain, from mild to severe. [dystonia-europe.org]

  Patients have been classified as having focal dystonia (cervical dystonia, cranial dystonia, or writer's cramp); segmental dystonia (cranio-cervical dystonia or neck/arm dystonia), and multifocal dystonia (arm dystonia plus cranial involvement). 7 None [dx.doi.org]

• Personality Change

  People with Wilson disease may have tremors, difficulty speaking and swallowing, problems with coordination, personality changes, or hepatitis. Blood tests and eye examinations help confirm the diagnosis. [msdmanuals.com]

  In other patients the first symptoms are nervous system or psychiatric symptoms or both and include tremor, rigidity, drooling, difficulty with speech, abrupt personality change, grossly inappropriate behavior and inexplicable deterioration of school [medicinenet.com]

• Dysarthria

  Clinical presentation is non-specific and varied, typically manifesting by early adulthood 5,11,13,15 : weakening of hands and dysarthria are often the earliest symptoms 5 dystonia pseudoparkinsonian and cerebellar symptoms psychiatric symptoms liver [radiopaedia.org]

  Clinical manifestations of neurologic Wilson's disease include variable combinations of dysarthria, dystonia, tremor, and choreoathetosis. [ncbi.nlm.nih.gov]

• Neurologic Manifestation

  The patient had severe neurologic manifestations of Wilson disease pretransplant, including dysarthria, hyperreflexia, asymmetrical ataxia, tremor, bradyphrenia, and shuffling gait. [ncbi.nlm.nih.gov]

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].

• Nephrolithiasis

  Renal abnormalities include tubular dysfunction (e.g., renal tubular acidosis, aminoaciduria) and nephrolithiasis. Bone demineralization is a common manifestation in patients with WD. [ncbi.nlm.nih.gov]

  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). [symptoma.com]

  Nephrolithiasis - A condition marked by the presence of renal calculi (kidney stones). [wilsonsdisease.org]

  […] urine phosphate levels 0003109 Hypoparathyroidism Decreased parathyroid hormone secretion 0000829 Joint hypermobility Double-Jointed Flexible joints Increased mobility of joints [ more ] 0001382 Mixed demyelinating and axonal polyneuropathy 0007327 Nephrolithiasis [rarediseases.info.nih.gov]

  Other manifestations of disease may include renal abnormalities such as hypercalciuria, nephrocalcinosis, nephrolithiasis, and aminoaciduria, cardiomyopathy with arrhythmias, autonomous nervous alterations, gigantism, hyoparathyroidism, osteoarthritis [dx.doi.org]

• Glycosuria

  Dementia Dementia, progressive Progressive dementia [ more ] 0000726 Drooling Dribbling 0002307 Dysphagia Poor swallowing Swallowing difficulties Swallowing difficulty [ more ] 0002015 Dystonia 0001332 Esophageal varix Enlarged vein in esophagus 0002040 Glycosuria [rarediseases.info.nih.gov]

• Copper Decreased

  In Alzheimer's disease (AD), meta-analyses show that copper decreases in brain but increases in serum, due to the nCp Cu component increase. [ncbi.nlm.nih.gov]

  Diagnosis of Wilson disease is often based on decreased serum levels of copper, decreased serum levels of ceruloplasmin, and increased urine levels of copper. [britannica.com]

  Another lab test measures the ability of a patient's ceruloplasmin to bind with a form of copper (decreased in Wilson disease). [medical-dictionary.thefreedictionary.com]

• Prothrombin Time Prolonged

  time prolongation (seconds) < 4 4-8 9-12 13-20 >30 Prognosis after liver transplantation is relatively good. [emedicine.medscape.com]

• Hypouricemia

  […] laboratory testing includes elevated aminotransferase levels, decreased serum ceruloplasmin levels (in ∼95% with chronic presentations), decreased serum copper levels, elevated 24‐hour urine copper excretion (which is higher in symptomatic patients), and hypouricemia [aasldpubs.onlinelibrary.wiley.com]

• Liver Biopsy

  Wilson disease results in accumulation of copper in the liver and other organs. Hepatic or neurologic symptoms develop. Diagnosis is based on a low serum ceruloplasmin level, high urinary excretion of copper, and sometimes liver biopsy results. [msdmanuals.com]

  Additionally, patients with WD show decreased copper in serum, increased copper in urine, and significantly elevated copper on liver biopsy. [mayomedicallaboratories.com]

  Anti-smooth muscle antibody was positive 1:20, and liver biopsy showed micronodular cirrhosis with abundant Mallory hyaline and stainable copper deposits. [ncbi.nlm.nih.gov]

• Hepatocellular Carcinoma

  Here, we describe a 45-year-old woman who presented with an incidental hepatocellular carcinoma at the time of transplant. [ncbi.nlm.nih.gov]

  Our team works side by side with oncologists to care for patients with hepatocellular carcinoma (HCC) to increase treatment options and optimize survival. [northwell.edu]

  It consists of a wide range of liver pathologies which include inflammation (chronic hepatitis), liver cirrhosis, and hepatocellular carcinoma. The entire spectrum need not be experienced. [en.wikipedia.org]

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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