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Wilson Disease

WD

Wilson disease is a genetic disorder characterized by the accumulation of copper due to mutations of ceruloplasmin, which is involved in its transport and excretion. Hepatic, neurologic and psychiatric symptoms may be encountered. The diagnosis is made by biochemical studies that determine values of copper in urine and ceruloplasmin in blood. Chelation therapy must be initiated as soon as possible.

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Presentation

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

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]
  • […] 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 and splenomegaly[medlineplus.gov]
Anemia
  • 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]
  • Excess copper chelating treatment-induced anemia and iron deposition in the liver was suspected. Proper monitoring of copper status is important for the management of Wilson disease.[ncbi.nlm.nih.gov]
  • Low values for serum alkaline phosphatase activity were observed early in the course of two patients with Wilson's disease presenting with the combination of severe liver disease and Coombs' negative acute hemolytic anemia.[ncbi.nlm.nih.gov]
  • The diagnosis of the later was based on the clinical presentation of hepatitis and severe Coomb's negative hemolytic anemia, coupled with laboratory evidence of WD. To our knowledge, this is the first report on the cooccurrence of EbetaT and WD.[ncbi.nlm.nih.gov]
  • Characteristic of acute hepatic failure in WD is concomitance of acute intravascular hemolytic anemia that in some patients may represent a first clinical symptom of WD.[ncbi.nlm.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: Jaundice Fluid buildup in the legs or abdomen Bruising easily Difficulty swallowing Drooling Involuntary shaking Fatigue DIAGNOSING WILSON'S DISEASE Symptoms often increase or change over time.[barnesjewish.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]
  • 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]
Falling
  • 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[medlineplus.gov]
  • […] symptoms of Parkinson's disease include: Muscle rigidity Tremors Bradykinesia (the slowing down of movement and the gradual loss of spontaneous activity) Changes in walking pattern and posture Changes in speech and handwriting Loss of balance and increased falls[webmd.com]
Weight Loss
  • 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]
  • 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]
  • Liver symptoms Liver symptoms may be those of long-lasting (chronic) liver disease such as: Extreme tiredness (fatigue) Muscle cramps Weakness Loss of appetite Nausea Vomiting Weight loss Fluid in your belly or legs Yellowish skin or whites of eyes (jaundice[hopkinsmedicine.org]
Collapse
  • […] acute or chronic viral hepatitis Chronic hepatitis may have Mallory bodies Cirrhosis develops late; usually no / minimal eosinophils or plasma cells Note: copper deposition is focal and may not be present on needle biopsies Fulminant hepatitis: liver collapse[pathologyoutlines.com]
  • In acute liver failure, degeneration of the liver cells and collapse of the liver tissue architecture is seen, typically on a background of cirrhotic changes.[en.wikipedia.org]
  • In some cases, there is fulminant hepatic failure with parenchymal necrosis and collapse of lobular architecture.[clevelandclinicmeded.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]
  • 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]
  • 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]
Hematemesis
  • 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]
  • 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]
  • […] 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]
Drooling
  • The proband, a 17-year-old boy, visited our hospital due to abnormal behaviors including generalized slow movement, dysphagia, drooling and ataxia.[ncbi.nlm.nih.gov]
  • 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]
  • Symptoms can include: Jaundice Fluid buildup in the legs or abdomen Bruising easily Difficulty swallowing Drooling Involuntary shaking Fatigue DIAGNOSING WILSON'S DISEASE Symptoms often increase or change over time.[barnesjewish.org]
  • […] 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 Slurred speech Poor coordination Drooling[nm.org]
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.[oadoi.org]
  • We report a 16-year-old female who presented with fatigue, dizziness, and new onset jaundice.[ncbi.nlm.nih.gov]
  • A 6-year-old boy presented with 2 months history of progressive abdominal distension and jaundice. He was deeply icteric with ascites, hepatosplenomegaly, hyperbilirubinemia, raised transaminases, and coagulopathy.[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]
  • 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]
  • Twenty patients were symptomatic, 19 were referred because of abnormal liver function test results and/or hepatomegaly, and 18 received their diagnoses after family screening.[ncbi.nlm.nih.gov]
  • […] 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[medlineplus.gov]
Kayser-Fleischer Ring
  • The key features of Wilson disease are liver disease and cirrhosis, neuropsychiatric disturbances, Kayser-Fleischer rings, and acute episodes of hemolysis, often in association with acute liver failure.[ncbi.nlm.nih.gov]
  • Abstract Wilson disease (WD) that manifests solely with acute and severe neurological damage in the absence of hepatic disease and Kayser-Fleischer ring of the cornea is rare and difficult to diagnose at the acute setting.[ncbi.nlm.nih.gov]
  • 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]
  • The diagnosis was based on the findings of 20 mg/dl ceruloplasmin serum level, Kayser-Fleischer ring and Coombs-negative haemolytic anaemia. Genetic testing revealed the presence of the H1069Q heterozygous mutation.[ncbi.nlm.nih.gov]
  • Viral markers and slit lamp examination for Kayser-Fleischer ring were negative. Serum ceruloplasmin and 24-h urinary copper post-D-pencillamine challenge were normal.[ncbi.nlm.nih.gov]
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]
  • This comes in two, not mutually exclusive, categories: frontal lobe disorder (may present as impulsivity, impaired judgement, promiscuity, apathy and executive dysfunction with poor planning and decision making) and subcortical dementia (may present as[en.wikipedia.org]
  • Late manifestations (now rare because of earlier diagnosis and treatment) include the following: Dystonia Spasticity Grand mal seizures Rigidity Flexion contractures Psychiatric features (10-20% of patients) include the following: Emotional lability Impulsiveness[emedicine.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
  • 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]
  • , rare genetic tremor disorder, rare metabolic liver disease, metal transport or utilization disorder with epilepsy, rare genetic epilepsy, neurometabolic disease, rare disorder with dystonia and other neurologic or systemic manifestation, nephropathy[commons.wikimedia.org]
  • KEYWORDS: Wilson disease; botulinum toxin; deep-brain stimulation; dopamine; dystonia; parkinsonism; tremor[ncbi.nlm.nih.gov]
  • RESULTS: Most patients (62.3%) exhibited tremor and ataxia, whereas 15.1% were dystonic, and 11.3% had parkinsonism. Discrete or unclassified signs only were observed in 11.3% of patients.[ncbi.nlm.nih.gov]
  • We report a WD patient who developed a unilateral wing-beating tremor 6years after OLT. New neurological symptoms develop immediately after OLT in most cases.[ncbi.nlm.nih.gov]
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]
  • All three patients responded well to gabapentin after failing to respond to other anti dystonia drugs.[ncbi.nlm.nih.gov]
  • KEYWORDS: Wilson disease; botulinum toxin; deep-brain stimulation; dopamine; dystonia; parkinsonism; tremor[ncbi.nlm.nih.gov]
  • Wilson disease (WD) is a neurodegenerative disorder, which presents as a spectrum of neurologic manifestations that includes tremor, bradykinesia, rigidity, dystonia, chorea, dysarthria, and dysphagia, together with a combination of neurologic symptoms[ncbi.nlm.nih.gov]
  • Clinical manifestations of neurologic Wilson's disease include variable combinations of dysarthria, dystonia, tremor, and choreoathetosis.[ncbi.nlm.nih.gov]
Ataxia
  • RESULTS: Most patients (62.3%) exhibited tremor and ataxia, whereas 15.1% were dystonic, and 11.3% had parkinsonism. Discrete or unclassified signs only were observed in 11.3% of patients.[ncbi.nlm.nih.gov]
  • The patient had severe neurologic manifestations of Wilson disease pretransplant, including dysarthria, hyperreflexia, asymmetrical ataxia, tremor, bradyphrenia, and shuffling gait.[ncbi.nlm.nih.gov]
  • The proband, a 17-year-old boy, visited our hospital due to abnormal behaviors including generalized slow movement, dysphagia, drooling and ataxia.[ncbi.nlm.nih.gov]
  • On the follow-up neurologic examination 1 year after the first evaluation, the patient showed slurred, somewhat hypokinetic, speech, blepharospasm, dystonic posturing, abnormal co-contraction of limb muscles, and limb ataxia.[jamanetwork.com]
  • The overload of copper inevitably leads to progressive liver and neurological dysfunction such as LIVER CIRRHOSIS; TREMOR; ATAXIA and intellectual deterioration. Hepatic dysfunction may precede neurologic dysfunction by several years.[fpnotebook.com]
Dysarthria
  • Wilson disease (WD) is a neurodegenerative disorder, which presents as a spectrum of neurologic manifestations that includes tremor, bradykinesia, rigidity, dystonia, chorea, dysarthria, and dysphagia, together with a combination of neurologic symptoms[ncbi.nlm.nih.gov]
  • Clinical manifestations of neurologic Wilson's disease include variable combinations of dysarthria, dystonia, tremor, and choreoathetosis.[ncbi.nlm.nih.gov]
  • 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]
  • The patient had severe neurologic manifestations of Wilson disease pretransplant, including dysarthria, hyperreflexia, asymmetrical ataxia, tremor, bradyphrenia, and shuffling gait.[ncbi.nlm.nih.gov]
  • The clinical manifestations of neurologic WD 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]
  • OBJECTIVE: To evaluate the sensitivity of different MRI sequences in Wilson disease (WD) with neurological manifestations and its correlation with clinical features and outcome.[ncbi.nlm.nih.gov]
  • CONCLUSIONS: The predominant neurological manifestations in this cohort of newly diagnosed Wilson disease patients were ataxia and tremor. Neurological impairment measured was highly correlated with the level of disability.[ncbi.nlm.nih.gov]
  • Here we report a case of Wilson disease with neurological manifestations in a 7-year-old girl with concurrent asymptomatic liver involvement and characteristic radiological findings of signal intensity alterations in bilateral striata and thalami along[ncbi.nlm.nih.gov]
  • Wilson disease (WD) is a neurodegenerative disorder, which presents as a spectrum of neurologic manifestations that includes tremor, bradykinesia, rigidity, dystonia, chorea, dysarthria, and dysphagia, together with a combination of neurologic symptoms[ncbi.nlm.nih.gov]

Workup

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 tubular acidosis, aminoaciduria) and nephrolithiasis. Bone demineralization is a common manifestation in patients with WD. Cardiac injury may include arrhythmia, cardiomyopathy, and autonomic dysfunction.[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]
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]
  • Twenty four-hour urinary copper decreased significantly at 6 months and usually remained under 75 μg/day and between 1 and 3 μg/kg/day for the remainder of the study. All patients continued to take zinc, and none became symptomatic.[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).[encyclopedia.com]
Liver Biopsy
  • 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]
  • Liver biopsy revealed pronounced bile ductular reaction, bridging fibrosis, and hepatocytic anisocytosis and anisonucleosis with degenerative enlarged eosinophilic hepatocytes, suggestive of Wilson disease.[ncbi.nlm.nih.gov]
  • In association with other clinical and biochemical tests, liver biopsy results and molecular genetic testing can also be used to generate a score for diagnosing Wilson disease.[ncbi.nlm.nih.gov]
  • Most liver biopsy specimens show moderate to severe steatosis, variable degree of portal and/or lobular inflammation, and fibrosis eventually progressing to cirrhosis.[ncbi.nlm.nih.gov]
  • Clinical data, serum ceruloplasmin, liver function tests, urinary copper and liver biopsy reports were all recorded where available. 1573 patients had a serum ceruloplasmin measurement during the 7-year study period. 96 patients (6.1%) had a ceruloplasmin[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]
  • LT is also used to treat hepatocellular carcinoma when it develops in patients with WD when tumor resection is not feasible. LT solely for neurologic or psychiatric WD remains controversial.[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]

Treatment

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].

Prognosis

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.

Etiology

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.

Epidemiology

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].

Sex distribution
Age distribution

Pathophysiology

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].

Prevention

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].

Summary

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.

Patient Information

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.

References

Article

  1. Rosencrantz R, Schilsky M. Wilson disease: pathogenesis and clinical considerations in diagnosis and treatment. Semin Liver Dis. 2011;31:245–259.
  2. Rodriguez-Castro KI, Hevia-Urrutia FJ, Sturniolo GC. Wilson's disease: A review of what we have learned.World J Hepatol. 2015;7(29):2859-2870.
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Last updated: 2018-06-22 11:16