History

Fact Explanation
Age at onset of symptoms [1] May present symptomatically at any age with majority of the patients presenting between ages 5 and 35. [1] Hepatic manifestations are more frequently presented in patients in the first decade of life. [2] After the age of 20 years, 75% of patients present with neurological manifestations and 25% with both hepatic and neuropsychiatric manifestations. [1]
Family and past history [1] Affected family members or newly diagnosed siblings with WD. Past history of jaundice, extrapyramidal features and neuropsychiatric disorders. Death of any premature siblings. Patients diagnosed with WD may have a history of recurrent episodes of jaundice, due to hemolysis. [1]
Weight gain/ anorexia, diffuse abdominal pain, nausea/ vomiting, hyporexia [1] Suggestive of hepatic disease. Patients may present with any type of liver disease and has been seen to clinically precede neurological manifestations. Presenting symptoms may be highly variable, ranging from asymptomatic, with only biochemical abnormalities, to overt cirrhosis with all its complications. WD has also been found to present as acute hepatic failure sometimes associated with Coombs-negative hemolytic anemia and acute renal failure.
Tremor, lack of motor coordination, speech changes, drooling, dysarthria, dystonia, spasticity [1] Neurologic manifestations. Neurological , behavioural or psychiatric disorders may be the first clinical presentation of WD, sometimes associated with hepatic signs simultaneously, or years later. Patients presenting with advanced liver disease, neurological symptoms can be misdiagnosed as signs of hepatic encephalopathy.
Declining school performance, personality changes, impulsiveness, labile mood, sexual exhibitionism, inappropriate behaviour, excessive fear, anxiety, depressio [1], excessive talkativeness, aggressive behavior, loss of interest, abusiveness [3] Psychiatric and behavioural manifestations. Neurological , behavioural or psychiatric disorders may be the first clinical presentation of WD, sometimes associated with hepatic signs simultaneously, or years later. These features usually go undiagnosed as due to WD for years .
Galactorrhea, menstrual abnormalities, hypoglycemia [4] These endocrine symptoms suggesting the presence of insulinoma and hyperprolactenemia, are found to be the initial clinical manifestations of WD in some patients. Zinc acetate has been found to be an effective treatment.
References
  1. EUROPEAN ASSOCIATION FOR STUDY OF LIVER. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol [online] 2012 Mar, 56(3):671-85 [viewed 26 July 2014] Available from: doi:10.1016/j.jhep.2011.11.007
  2. MANSOOR SUMREENA, NAVEED ABDULKHALIQ, MAJEED ASIFA. Analysis of clinical and biochemical spectrum of Wilson Disease patients. Indian J Pathol Microbiol [online] 2012 December [viewed 26 July 2014] Available from: doi:10.4103/0377-4929.101746
  3. VALE THIAGO CARDOSO, CARAMELLI PAULO, TEIXEIRA ANTôNIO LúCIO. Long-term mood disorder antedating the diagnosis of Wilson's disease. Rev. Bras. Psiquiatr. [online] 2011 March, 33(1):101-102 [viewed 28 July 2014] Available from: doi:10.1590/S1516-44462011000100021
  4. KRYSIAK R, HANDZLIK-ORLIK G, OKOPIEN B. Endocrine Symptoms as the Initial Manifestation of Wilson's Disease Yale J Biol Med [online] , 85(2):249-254 [viewed 28 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375662

Examination

Fact Explanation
Kayser–Fleischer rings [1] This characteristic ophthalmologic change is found by the slit-lamp examination and are caused due to the deposition of copper in Desçemet’s membrane of the cornea. Presents most commonly in patients with neurological symptoms and over half of those without neurological symptoms. But KF rings are not entirely specific for WD, since they may be found in patients with chronic cholestatic diseases including children with neonatal cholestasis. KF rings may be absent in 50% of patients with WD and are commonly absent in children. Another rare change observed is sunflower cataracts which is caused by deposits of copper in the center of the lens. [1]
Movement disorders (tremor, involuntary movements), Drooling, dysarthria, Rigid dystonia, Pseudobulbar palsy, Seizures, Migraine headaches ,Insomnia [1] Neurologic abnormalities of WD typically present later than liver disease but most patients with neurologic symptoms have been found to have some degree of liver disease at presentation. A coarse, irregular proximal tremulousness with a “wing beating” appearance (characteristic tremor). Dystonia (focal, segmental or very severe), involving all parts of the body, leading to severe contractures. Motor impairments: dysarthria (can be cerebellar or extrapyramidal leading to aphonia), drooling or oropharyngeal dystonia. Other characteristic manifestations: facial grimacing, open jaw, running saliva, and lip retraction. A tremor-rigidity syndrome (“juvenile Parkinsonism”) should raise suspicion of WD. [1]
Jaundice, anorexia, vomiting, ascites, edema, hepatomegala/ splenomegaly, variceal hemorrhage [1] [2] Seen in WD patients presenting with liver disease. [2]
Paranoia, schizophrenia, depression [1] These psychotic features have been seen in older persons, but behavioural and personality changes are also commonly seen. [1]
Lunulae ceruleae [2] Blue lunulae is seen as the cutaneous manifestation associated with WD.
Aminoaciduria, hypercalciuria, nephrocalcinosis, nephrolithiasis [3] Renal abnormalities are rare but may be the initial presentation of WD in the pediatric population without the appearance of any symptoms of neurological and hepatic involvement. Clinical features of renal involvement may remain as the only sign of WD even up to 10 years. Thus, in the presentation of these clinical features it is important to investigate for the presence of WD and start specific treatment to prevent irreversible damages and long term complications.
Premature osteoporosis and arthritis [4] Skeletal abnormalities have been found in rare cases of WD and the most common radiological abnormality was a generalized increase of radiolucency, interpreted as skeletal demineralization , followed by premature osteoarthrosis. Symptoms associated with these radiological abnormalities comprised back pain, stiffness with restricted movement, pain and stiffness of knees, hips, and wrists, and tenderness to pressure over margins of affected joints.
Cardiomyopathy, dysrhythmias, ventricular hypertrophy [5] Cardiac involvement is rare but it has been found that men are more susceptible to cardiac complications than women. Studies have found definite clinical and morphological abnormalities in some patients with WD consistent with a cardiomyopathy.
Hypoparathyroidism. [6] Menstrual irregularities; infertility, repeated miscarriages [1] Affected individuals with WD can get pregnant and are mostly fertile but rarely there may be infertility and and repeated miscarriages. Parathyroid insufficiency may be associated with Wilson's disease and could be due to deposition of copper in the parathyroid glands.
References
  1. EUROPEAN ASSOCIATION FOR STUDY OF LIVER. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol [online] 2012 Mar, 56(3):671-85 [viewed 26 July 2014] Available from: doi:10.1016/j.jhep.2011.11.007
  2. ROBERTS E. A practice guideline on Wilson disease. Hepatology [online] 2003 June, 37(6):1475-1492 [viewed 26 July 2014] Available from: doi:10.1053/jhep.2003.50252
  3. DI STEFANO VALERIA, LIONETTI ELENA, ROTOLO NOVELLA, LA ROSA MARIO, LEONARDI SALVATORE. Hypercalciuria and Nephrocalcinosis as Early Feature of Wilson Disease Onset: Description of a Pediatric Case and Literature Review. Hepat Mon [online] 2012 August [viewed 29 July 2014] Available from: doi:10.5812/hepatmon.6233
  4. Golding DN, Walshe JM. Arthropathy of Wilson’s disease. Study of clinical and radiological features in 32 patients. Ann Rheum Dis 1977;36:99–111 [viewed 29 July 2014] Available from: http://ard.bmj.com/content/36/2/99.full.pdf
  5. KUAN P. Cardiac Wilson's disease. Chest [online] 1987 Apr, 91(4):579-83 [viewed 29 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/3829752
  6. CARPENTER THOMAS O., CARNES DAVID L., ANAST CONSTANTINE S.. Hypoparathyroidism in Wilson's Disease. N Engl J Med [online] 1983 October, 309(15):873-877 [viewed 29 July 2014] Available from: doi:10.1056/NEJM198310133091501

Differential Diagnoses

Fact Explanation
Acute hepatitis of unknown etiology. Acute fulminant hepatic failure of unknown etiology. Chronic active hepatitis of unknown etiology. Cirrhosis of liver of unknown etiology. Autoimmune hepatitis [1] Acute hepatitis is suspected when there is a rapid onset of jaundice and hemolytic anemia. In a patient with unexplained liver disease, consider WD in the differential diagonisis and measure serum ceruloplasmin, 24-hour urinary copper; and perform a slit lamp examination to check for KF rings, but their absence does not excude WD. Normal serum ceruloplasmin, total serum copper levels and 24-hour urinary copper excretion would exclude WD.
Major psychosis. Attention deficit hyperactive disorder. Personality disorder. Mental retardation. [1] Psychiatric illness. A normal serum ceruloplasmin, total serum copper levels and 24-hour urinary copper excretion would exclude WD.
Degenerative cerebellar disease ,Demyelinating disease ,Essential tremor [3] Suspected when presents with titubation or tremor. The KF ring is an important marker in neurological WD, and in strongly suspected cases a slit lamp examination should be repeated by an experienced ophthalmologist if the initial result is negative. A normal serum ceruloplasmin, total serum copper levels and 24-hour urinary copper excretion would exclude WD.
Degenerative or metabolic cerebellar disease or demyelinating disease Craniovertebral anomaly [3] Suspect when a patient presents with ataxia. A normal serum ceruloplasmin, total serum copper levels and 24-hour urinary copper excretion would exclude WD.
Huntington's disease, Sydenham's chorea. Storage disorders, Drug-induced chorea. Neuroacanthocytosis. Vasculitis (particularly systemic lupus erythematosus) [3] Suspect in patients presenting with chorea. A normal serum ceruloplasmin, total serum copper levels and 24-hour urinary copper excretion would exclude WD.
References
  1. EUROPEAN ASSOCIATION FOR STUDY OF LIVER. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol [online] 2012 Mar, 56(3):671-85 [viewed 26 July 2014] Available from: doi:10.1016/j.jhep.2011.11.007
  2. DAS SHYAMAL K, RAY KUNAL. Wilson's disease: an update. Nat Clin Pract Neurol [online] 2006 September, 2(9):482-493 [viewed 28 July 2014] Available from: doi:10.1038/ncpneuro0291

Investigations - for Diagnosis

Fact Explanation
Serum caeruloplasmin and total serum copper concentrations Caeruloplasmin normal range: 200-600 mg/litre. Total serum copper normal range: 10–22 µmol/litre. [1] Low serum caeruloplasmin and copper concentrations can be seen in WD. [1] Ceruloplasmin levels are not always reliable in the diagnosis of WD because they may be low in diseases such as autoimmune hepatitis, severe hepatic insufficiency in advanced liver disease, celiac disease, familial aceruloplasminemia or in heterozygous carriers of ATP7B mutations who do not show copper overload disease. [2] Nephrotic syndrome can also cause a low serum copper and caeruloplasmin but it can be excluded in most cases in the clinical setting. [1] Not all patients with WD have low serum caeruloplasmin. [1] Serum "free" copper Hepatic copper
Serum non-ceruloplasmin-bound copper concentration Non-ceruloplasmin-bound copper (or “free copper”) can be calculated by subtracting ceruloplasmin-bound copper (3.15 × ceruloplasmin in mg/L equals the amount of ceruloplasmin-bound copper in μg/L) from the total serum copper concentration (in μg/L; serum copper in μmol/L × 63.5 equals serum copper in μg/L). This measurement has been proposed as a diagnostic test for WD. But its reliability is dependent on the adequacy of the methods for measuring both serum copper and ceruloplasmin. Serum non-ceruloplasmin-bound copper concentration is of more value in monitoring pharmacotherapy than in the diagnosis of WD. [2]
Hepatic copper concentration Hepatic copper content >4 μmol/g dry weight is considered as the best biochemical evidence for Wilson’s disease. But the major problem associated with hepatic parenchymal copper concentration is the inhomogeneous distribution of copper within the liver in later stages of WD. Thus, due to sampling error, the concentration can be underestimated. This test is unreliable in patients with cirrhosis, long-standing cholestatic disorders and idiopathic copper toxicosis syndromes such as Indian childhood cirrhosis. [2]
24hour urinary copper Urinary copper excretion: In healthy individual < 1.0 µmole of copper. In an adult with WD > 1.6 µmoles/24 hours. In a child with WD > 0.64 µmoles/24 hours. Contamination may give false positive result. [1]
Ophthalmic slit lamp eye examination Kayser–Fleischer rings may be seen. These are characteristic copper deposits in the cornea. Their presence with other signs and symptoms are characteristic of WD but their absence does not exclude the disease. It is found that KF rings to almost never been seen in children and are more typically associated with neurological presentations. KF rings may also be present in late stages of biliary cirrhosis but in these cases the clinical presentation will exclude WD. The combination of serum caeruloplasmin below 200 mg/litre and serum copper below 10 µmol/litre with KF rings is diagnostic for WD. If KF rings are present but caeruloplasmin and copper levels are normal or if KF rings are absent but caeruloplasmin and copper levels are low, then move on to other tests, such as liver function and urinary copper excretion tests. [1]
Coombs test Coombs-negative haemolytic anemia may be the only initial symptom of Wilson’s disease. There maybe decay of liver cells resulting in the release of large amounts of stored copper, which would further aggravate hemolysis. However, marked hemolysis is commonly associated with severe liver disease therefore WD may present as acute hepatic failure sometimes associated with Coombs-negative hemolytic anemia and acute renal failure. [2] Hemolytic anemia associated with acute liver failure is strongly suggestive of fulminant WD.
Liver function tests Abnormalities associated with WD are highly variable. In some cases, minor increase in AST and an increase in LDH can be seen which is either because of a low grade hemolysis (low serum haptoglobin) or hepatic cellular damage. Whereas in some other cases, severe cirrhosis w/ increased bilirubin and alkaline phosphatase, low serum albumin and prolonged prothrombin time can be seen. [1]
Penicillamine challenge test Penicillamine is found to increase urinary copper excretion in all subjects (healthy controls, patients with all forms of liver disease, heterozygote carriers of Wilson’s disease, and patients with Wilson’s disease). On administration of 1g dose of penicillamine, if urinary copper excretion is > 25µmoles/24 hours it is considered compatible with a diagnosis of WD. But this test is no longer recommended because of difficulties in its interpretation. However, it has been found useful in some laboratories. [1]
Liver biopsy The reference range for liver copper is 12–84 µg/g dry weight. Liver copper content > 250 µg/g dry weight is diagnostic for Wilson’s disease. Copper accumulates in the liver in cirrhotic obstructive liver disorders, such as primary biliary cirrhosis where the liver copper concentration can be as high as in WD but the clinical presentation will help to distinguish from WD. No characteristic feature of WD in its early stages is found in histomorphology liver studies hence are considered unhelpful. [1]
Copper isotope incorporation studies Copper isotope incorporation into serum components after oral dosage can be measured in ambiguous cases. A normal response excludes WD, whereas failure to produce serum enrichment by 3-4 days is indicative of WD or heterozygosity. Stable copper (65Cu) isotope studies have replaced radioisotope studies and can be used in making the diagnosis of WD and investigating copper metabolism because it is safer and suitable for use in children, and is continuously available as well unlike 64Cu and 67Cu. For adult studies, 3 mg of 65Cu in the form of copper nitrate is given orally. [1]
Genetic investigation Gene tracking: This is particularly useful and can be successfully applied in families where a newly diagnosed child has siblings who could be pre-symptomatic or unaffected. Mutation detection: There are three relatively common European mutations causing WD. If two mutant alleles are detected then WD is confirmed even without a family history. For any patient with WD the chances of this are approximately 36%. Any other result such as none or one mutant allele, it cannot be taken as non-diagnostic evidence for WD because the disease could be caused by a more rare mutation. DNA studies are unhelpful diagnostically because of the genetic heterogeneity of the condition but may be useful in family studies. [1]
MRI / CT Detects structural abnormalities in the basal ganglia. The most frequent findings are an increased density on CT or hyperintensity on T2 MRI in the region of the basal ganglia. MRI may be more sensitive in detecting these lesions. The “face of the giant panda” sign is a characteristic finding in WD, but it is found only in a minority of patients. Other pathognomonic features of WD are hyperintensities in tectal-plate and central pons (CPM-like), and simultaneous involvement of basal ganglia, thalamus, and brainstem Significant abnormalities on brain imaging may even be present in some individuals prior to the onset of symptoms. [2]
Magnetic resonance spectroscopy and single-photon emission computed tomography (SPECT) These might be useful in detecting early brain damage in WD. These can be used to assess and treat motor impairment and also better evaluate the less investigated disorders in the cognitive domain. [2]
Transcranial brain parenchyma sonography (TCS) TCS detects lenticular nucleus hyperechogenicity even when in MRI no abnormalities are observed, but further studies are required for confirmation. [2]
References
  1. GAFFNEY D, FELL G, O'REILLY D. Wilson's disease: acute and presymptomatic laboratory diagnosis and monitoring J Clin Pathol [online] 2000 Nov, 53(11):807-812 [viewed 28 July 2014] Available from: doi:10.1136/jcp.53.11.807
  2. EUROPEAN ASSOCIATION FOR STUDY OF LIVER. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol [online] 2012 Mar, 56(3):671-85 [viewed 26 July 2014] Available from: doi:10.1016/j.jhep.2011.11.007

Investigations - Followup

Fact Explanation
Serum copper and ceruloplasmin, 24 hour urinary copper excretion [1] Done to monitor adequacy of treatment.
Liver enzymes and international normalized ratio [1] For assessment of liver function and liver disease.
Complete blood count, urine analysis, physical and neurological examinations [1] To assess and examine for any hepatic, neurological; or any other complications.
References
  1. GAFFNEY D, FELL G, O'REILLY D. Wilson's disease: acute and presymptomatic laboratory diagnosis and monitoring J Clin Pathol [online] 2000 Nov, 53(11):807-812 [viewed 28 July 2014] Available from: doi:10.1136/jcp.53.11.807

Investigations - Screening/Staging

Fact Explanation
Genetic counselling and family screenings WD disease occurs with different clinical presentations: hepatic, neurological, psychiatric disorder or asymptomatic and the phenotype of WD varies considerably among patients with the same genotype without any correlations, even within a single family. WD may occur at any age, commonly seen in between 3 and 40 years of age; and may also have a late onset. Since, WD may be asymptomatic, have a late onset, and absent phenotype-genotype correlation, it is especially necessary to screen the parents of a new patient. First-degree relatives should be screened as well because WD occurs in 25% siblings and 0.5% offspring and also a 0.5% risk of inheriting WD in the previous generation. Screening can be done by taking a brief history (jaundice, liver disease and neurological features) and by performing liver tests, explorations of copper metabolism, and suitable genetic testing. [1] Family screenings and early treatment can prevent WD symptoms and potentially fatal disease progression. [2]
References
  1. BRUNET ANNE-SOPHIE, MAROTTE STéPHANIE, GUILLAUD OLIVIER, LACHAUX ALAIN. Familial screening in Wilson’s disease: Think at the previous generation!. Journal of Hepatology [online] 2012 December, 57(6):1394-1395 [viewed 28 July 2014] Available from: doi:10.1016/j.jhep.2012.07.011
  2. KLEINE RT, MENDES R, PUGLIESE R, MIURA I, DANESI V, PORTA G. Wilson's disease: an analysis of 28 Brazilian children. Clinics (Sao Paulo) [online] 2012, 67(3):231-5 [viewed 28 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22473403

Management - General Measures

Fact Explanation
Education [1] Educate the patient that treatment must continue for life. Importance on ensuring life long compliance must be highlighted and advice the patient to visit a specialist centre every six months for a clinical examination and to monitor for hepatic, neurological, and other complications.
Food and water [2] On commencement of treatment, advice patients to avoid the intake of food and water high in copper concentrations.
Contraception [2] Estrogen may interfere with biliary copper excretion. Increased serum copper and urinary copper excretion; and corneal copper depositions have been found in healthy women taking contraception. So in women with WD, it is advisable to only use spermicide and barrier contraception, and progesterone-only preparations.
References
  1. GAFFNEY D, FELL G, O'REILLY D. Wilson's disease: acute and presymptomatic laboratory diagnosis and monitoring J Clin Pathol [online] 2000 Nov, 53(11):807-812 [viewed 28 July 2014] Available from: doi:10.1136/jcp.53.11.807
  2. EUROPEAN ASSOCIATION FOR STUDY OF LIVER. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol [online] 2012 Mar, 56(3):671-85 [viewed 26 July 2014] Available from: doi:10.1016/j.jhep.2011.11.007

Management - Specific Treatments

Fact Explanation
D-Penicillamine It is a chelator that promotes urinary excretion of copper and is given to all symptomatic patients with WD. Adults: 750-1500mg/day divided into two or three doses. Children: 20 mg/kg/day rounded off to the nearest 250 mg and given in two or three divided doses. Administer D-Penicillamine 1 hour prior to meals because food inhibits its absorption. D-penicillamine tends to interfere with pyridoxine action, thus supplemental pyridoxine should be provided (25–50 mg/day). Monitor the adequacy of treatment by measuring 24-hour urinary copper excretion while on treatment. Reduce dosage during pregnancy. [1]
Trientine Trientine is a chelator and promotes urinary copper excretion. Used as an alternative drug for D-penicillamine. Given to patients intolerant of penicillamine and is also found effective as an initial therapy in patients with decompensated liver disease at the outset. Adults: 900–2700 mg/day divided into two or three doses. Children: 20 mg/kg/day rounded off to the nearest 250 mg, given in two or three divided doses. Administer trientine 1 hour before or 3 hours after meals. Avoid co-administration of trientine and iron because the complex with iron is toxic. Monitor the adequacy of treatment by measuring 24-hour urinary copper excretion (after 2 days of cessation of therapy) and non-ceruloplasmin bound copper. Reduce dosage during pregnancy. [1]
Ammonium tetrathiomolybdate (TM) A strong decoppering agent. Potential adverse effects include bone marrow depression, hepatotoxicity, and overly aggressive copper removal leading to neurological dysfunction. TM also has anti-angiogenic effects due to its extensive decoppering effect. It remains as an experimental therapy and is not commercially available, and the clinical experience with this drug is limited. [1]
Zinc Zinc interferes with the uptake of copper from the gastrointestinal tract. Different zinc salts (sulphate, acetate, gluconate) are used. Adult: 150 mg elemental zinc/day. Children: <50 kg in body weight 75 mg Administered in three divided doses, 30 minutes before meals. Most commonly for asymptomatic or presymptomatic patients and used as a first line therapy in neurological patients. Major side effect caused is gastric irritation. Other side effects include immunosuppressant effects and reduction in leukocyte chemotaxis. Elevations in serum lipase and/or amylase may also occur, without clinical or radiologic evidence of pancreatitis. Zinc monotherapy is effective and safe in neurologic WD and in asymptomatic siblings but should be very cautious in patients with hepatic WD due to reported fatal hepatic deterioration. [1] Zinc acetate has been found an effective treatment for the disappearance of endocrine symptoms caused in some patients with WD. [2]
Liver transplantation Indicated for patients presenting with acute liver failure or decompensated cirrhosis due to WD or those unresponsive to chelation treatment . [1]
References
  1. EUROPEAN ASSOCIATION FOR STUDY OF LIVER. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol [online] 2012 Mar, 56(3):671-85 [viewed 26 July 2014] Available from: doi:10.1016/j.jhep.2011.11.007
  2. KRYSIAK R, HANDZLIK-ORLIK G, OKOPIEN B. Endocrine Symptoms as the Initial Manifestation of Wilson's Disease Yale J Biol Med [online] , 85(2):249-254 [viewed 28 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375662