Ophthalmologic

o Kayser-Fleischer rings are from greenish gold to brown; when well developed, rings may be readily visible to the naked eye or with an ophthalmoscope set at +40. When not visible to the unaided eye, the rings may be identified using slit-lamp examination [169].
o Kayser-Fleischer rings are observed in up to 90% of individuals with symptomatic Wilson disease and are almost invariably present in those with neurologic manifestations [169].
o Although Kayser-Fleischer rings are a useful diagnostic sign, they are no longer considered pathognomonic of Wilson disease unless accompanied by neurologic manifestations. They may also be observed in patients with chronic cholestatic disorders such as partial biliary atresia, primary biliary cirrhosis, primary sclerosing cholangitis, and cryptogenic cirrhosis.
o The rings form bilaterally, initially appearing at the superior pole of the cornea, then the inferior pole, and, ultimately, circumferentially.
o Sunflower cataracts (which represent copper deposits in the lens) may also be seen by slit-lamp examination [184,185]. Their prevalence in Wilson's disease is not well-established. Like Kayser-Fleischer rings, the cataracts gradually disappear with treatment of the Wilson's disease.
Musculoskeletal
o Skeletal involvement is a common feature of Wilson disease, with more than half of patients exhibiting osteopenia on conventional radiologic examination.
o The arthropathy of Wilson disease is a degenerative process that resembles premature osteoarthritis. Symptomatic joint disease, which occurs in 20-50% of patients, usually arises late in the course of the disease, frequently after age 20 years. The arthropathy generally involves the spine and large appendicular joints such as knees, wrists, and hips. Osteochondritis dissecans, chondromalacia patellae, and chondrocalcinosis have also been described [178].
Hematologic
o Hemolytic anemia is a recognized but rare (10-15%) complication of the disease.
o Coombs-negative acute intravascular hemolysis most often occurs as a consequence of oxidative damage to the erythrocytes by the higher copper concentration.
Renal
o The Wilson disease gene is expressed in kidney tissue; therefore, any renal manifestations may be primary or secondary to release of copper from the liver.
o Clinically, patients may resemble those with Fanconi syndrome, demonstrating defective renal acidification and excess renal losses of amino acids, glucose, fructose, galactose, pentose, uric acid, phosphate, and calcium. The frequency of renal manifestations is variable [179].
o Urolithiasis, found in up to 16% of patients with Wilson disease, may be the result of hypercalciuria or poor acidification [180].
192. Hematuria and nephrocalcinosis are reported, and proteinuria and peptiduria can occur both before treatment as part of the disease process and after therapy as adverse effects of D-penicillamine.
Cancer risk
• Whether patients with Wilson's disease are at increased risk for hepatocellular carcinoma or other malignancies is unclear.
• Occasional reports have described hepatocellular carcinoma and cholangiocarcinoma occurring in the setting of Wilson's disease [181,182,183].

SIGNS
Physical findings are consistent with liver disease, to include jaundice, varices, spider angiomas, and palmar erythema.
DIFFRENTIAL DIAGNOSIS
As a consequence of the varied clinical manifestations of WD, the condition is commonly underdiagnosed. Following is a list of disorders for which WD should always be considered in the differential diagnosis []
Parkinsonian features
• Juvenile Parkinson's disease
• Neurodegeneration with brain iron accumulation (NBIA
Dystonia
• Dopa-responsive dystonia
• Idiopathic torsion dystonia
• Lipid storage disease
• Post-encephalitic dystonia
• Dystonic cerebral palsy
• Focal dystonias such as writer's cramp


Ataxia
• Degenerative or metabolic cerebellar disease
• Demyelinating disease
• Craniovertebral anomaly

Titubation or tremor
• Degenerative cerebellar disease
• Demyelinating disease
• Essential tremor
Myoclonus and cognitive deterioration
• Mitochondrial disease
• Neuronal ceroid lipofuscinosis
• Lafora's bodies disease
• Baltic myoclonus
• Subacute sclerosing panencephalitis (SSPE)

Chorea
• Huntington's disease
• Sydenham's chorea
• Storage disorders
• Drug-induced chorea
• Neuroacanthocytosis
• Vasculitis (particularly systemic lupus erythematosus)

Psychiatric illness
• Major psychosis
• Attention deficit hyperactive disorder
• Personality disorder
• Mental retardation

Proximal muscle weakness
• Muscular dystrophy
• Metabolic myopathy
• Inflammatory myopathy

Liver disease

• Acute hepatitis of unknown etiology
• Acute fulminant hepatic failure of unknown etiology
• Chronic active hepatitis of unknown etiology
• Cirrhosis of liver of unknown etiology
INVESTIGATIONS [187]


• WD should be considered in any individual between the ages of 3 and 45 years with liver abnormalities of uncertain cause.

• In a patient in whom WD is suspected Kayser-Fleischer rings should be sought by slit-lamp examination by a skilled examiner. The absence of Kayser-Fleischer rings does not exclude the diagnosis of WD, even in patients with predominantly neurologic disease

• Serum ceruloplasmin should be routinely measured during the evaluation of unexplained hepatic, neurologic, or psychiatric abnormalities in children and adults through middle age.

• An extremely low serum ceruloplasmin level (<50 mg/L or <5 mg/dL) should be taken as strong evidence for the diagnosis of WD.

• Modestly subnormal levels suggest that further evaluation is necessary. Serum ceruloplasmin within the normal range does not exclude the diagnosis

• Serum uric acid may be decreased at presentation with symptomatic hepatic or neurologic disease because of associated renal tubular dysfunction (Fanconi syndrome). Insufficient evidence is available to determine the predictive value of this finding

• The basal 24-hour urinary copper excretion should be measured as an aid to the diagnosis of WD and monitoring treatment. Basal 24-hour urinary excretion of copper in WD is typically greater than 100 µg (1.6 µmoles) in symptomatic patients, but a finding greater than 40 µg (>0.6 µmoles or >600 nmoles) may indicate WD and requires further investigation.
• In children, penicillamine challenge studies may provide evidence for the diagnosis of WD if urinary excretion of greater than 1,600 µg copper per 24 hours (>25 µmoles per 24 hours) is found following the administration of 500 mg of d-penicillamine at the beginning and again 12 hours later during the 24-hour urine collection. The predictive value of this test in adults is unknown
• Although a disease of copper overload, the total serum copper (which includes copper incorporated in ceruloplasmin) in WD is usually decreased in proportion to the decreased ceruloplasmin in the circulation.
• In patients with severe liver injury, serum copper may be within the normal range despite a decreased serum ceruloplasmin level. In the setting of acute fulminant hepatic failure due to WD, levels of serum copper may be markedly elevated due to the sudden release of the metal from tissue stores. Normal or elevated serum copper levels in the face of decreased levels of ceruloplasmin indicate an increase in the concentration of copper not bound to ceruloplasmin in the blood (nonceruloplasmin-bound copper).
• The serum nonceruloplasmin-bound copper concentration has been proposed as a diagnostic test for WD. It is elevated above 25 µg/dL in most untreated patients (normal <15 µg/dL). Nonceruloplasmin-bound copper is usually estimated from the serum copper and ceruloplasmin. The amount of copper associated with ceruloplasmin is approximately 3.15 µg of copper per milligram of ceruloplasmin.
• The serum nonceruloplasmin copper concentration may be elevated in acute liver failure of any etiology, not only WD, and it may be elevated in chronic cholestasis and in cases of copper intoxication from ingestion or poisoning.
• Hepatic parenchymal copper content greater than 250 µg/g dry weight provides critical diagnostic information and should be obtained in cases where the diagnosis is not straightforward and in younger patients.
• Liver biopsy should be obtained in following situations:
1. If patient has normal ceruloplasmin but KF ring is present and patient has abnormal LFT’s
2. If patient has decreased ceruloplasmin, absent KF ring, normal LFT’s and has persisting significant symptoms including hemolysis, unexplained splenomegaly, extrahepatic manifestations of WD and neurologic or psychiatric disorders.
3. If patient has decreased ceruloplasmin, absent KF ring, abnormal LFT’s or 24 hr urinary Cu > 40 microgm/day or > 600 nmol/day

• For patients under 18 years, a penicillamine challenge test may be performed prior to liver biopsy.
• In untreated patients, normal hepatic copper content (<40 to 50 µg/g dry weight) excludes a diagnosis of WD
• Neurologic evaluation and radiologic imaging of the brain, preferably by MR, should be considered prior to treatment in all patients with neurologic WD and should be part of the evaluation of any patient presenting with neurologic symptoms consistent with WD
• When possible, genetic diagnosis based on haplotype analysis should be used for family screening of first-degree relatives of patients with WD
• First-degree relatives of any patient newly diagnosed with WD must be screened for WD. Assessment should include history and physical examination, serum aminotransferases and biochemical tests of hepatic synthetic function, complete blood count, and ceruloplasmin. Kayser-Fleischer rings should be sought by slit-lamp examination. The basal 24-hour urinary copper excretion should be measured. Genotype or haplotype studies based on findings in the proband should be performed
TREATMENT [169,187]

• The aim of medical treatment for WD is to remove the toxic deposit of copper from the body to produce a negative copper balance, and to prevent its reaccumulation. Successful therapy is measured in terms of a restoration of normal levels of free serum copper and its excretion in the urine.
NON PHARMACOLOGICAL TREATMENT
• Foods with very high concentrations of copper (shellfish, nuts, chocolate, mushrooms, nuts and organ meats) generally should be avoided, at least in the first year of treatment.
• Diets deficient in copper may delay the onset of the disease and control disease progression, but dietary management is not recommended as sole therapy [188].
• Consultation with a dietitian is advisable for practicing vegetarians.
• Well water or water brought into the household through copper pipes should be checked for copper content, but in general, municipal water supplies do not have to be checked.
• A water purifying system may be advisable if the copper content of the water is high. For those with copper pipes, it is important to flush the system of stagnant water before using water for cooking or consumption.

PHARMACOLOGICAL TREATMENT

• Copper chelating agents are the first-line therapy for WD
• In the initial phase of treatment, toxic levels of copper are controlled, and dietary copper is restricted.
• Chelating agents are prescribed to promote 24-hour excretion of approximately 2 mg of copper in the urine, to induce a negative copper balance.
• In the maintenance phase, the dosage can be reduced and zinc salt added to prevent the systemic absorption of copper.
• Studies have demonstrated that the majority of presymptomatic WD patients treated indefinitely with either zinc or copper chelators achieve a successful outcome
• D-penicillamine is the most commonly used chelating agent
• Other chelating agents that can be used include triethylene tetramine dihydrochloride (trientine).
• In addition, zinc salt (sulfate or acetate) helps in the prevention of copper absorption from the gut
• If patient has WD treatment is lifelong and should not be discontinued, unless a liver transplantation has been performed

D- PENICILLAMINE
• Since 1955, D-penicillamine has been the most commonly used chelating agent
• D-penicillamine not only chelates copper from tissue, but also detoxifies tissue copper by promoting the synthesis of metallothionein, which forms a non-toxic combination with copper.
• Dose is 0.75-1.5 g/day (children: 20 mg/kg/body weight)
• If penicillamine is given, it can be ascertained by measuring 24-hour urinary copper excretion or determining the presence of D-penicillamine in urine by amino acid analysis.The initial goal is urinary copper excretion of 2000 µg/day. The rate of copper excretion falls as copper stores become depleted. Values usually fall to below 500 µg/day at four to six months.
• Regular measurement of the 24-hour urinary excretion of copper provides an important index of copper removal from the body. If the excretion level in a compliant patient decreases to less than 0.5 mg daily, the dose can be lowered.
• At this point, a zinc salt should be added to the treatment regimen, preferably before meals.
• D-penicillamine should be taken 2 hours after meals to avoid any interaction with the zinc.
• Side effects from D-penicillamine can occur both early and late in the treatment period.
• Early side effects include a hypersensitivity reaction characterized by fever, skin rash and lymphadenopathy that commonly occurs within 3 weeks of commencing medication. In 20-30% of cases, an exacerbation of the neurological symptoms occurs over a period of 2 weeks to 12 months (commonly after 6 weeks).
• An early hypersensitivity reaction can be managed by temporary withdrawal of the drug, followed by its reintroduction after a course of oral steroids. Neurological deterioration can be attenuated by withdrawing the drug, and then reinstituting it at a smaller dosage with a slow escalation to the optimum dosage.
• If neurological deterioration recurs, D-penicillamine should be withdrawn and substituted with other chelators or zinc salt alone.
• Pyridoxine (vitamin B6) is added routinely to the treatment regimen in a dosage of 25-50 mg daily, as its deficiency has been documented during D-penicillamine therapy.
• Delayed side effects occur in about 5% of cases, and can be caused by immunological factors, interference with collagen and elastin synthesis, or idiopathic factors.
• In cases in which the patient cannot tolerate treatment with D-penicillamine, trientine can be used as a substitute, which is usually effective except in cases with systemic lupus erythematosus or elastosis perforans.
• Treatment should be withdrawn if the total WBC falls below 3000 per cu mm, neutrophils fall below 2000 or platelets below 120,000, or if a steady decline over three successive tests is observed, even though the counts remain within the normal range.
• Penicillamine should also be withheld (and trientine begun) if proteinuria exceeds 2+ on a dipstick, if red cell or white casts are observed at microscopic examination of the urine, or if more than 10 red cells are seen per hpf.
• Some authors would continue penicillamine if quantitative proteinuria does not exceed 1 g/day and is stable. However, penicillamine should be permanently discontinued if proteinuria exceeds 2 g/day, the glomerular filtration rate falls, or red blood cell casts are seen.

TRIENTINE AND AMMONIUM TETRATHIOMOLYBDATE
• Trientine and ammonium tetrathiomolybdate are considered to be safer alternatives to D-penicillamine.
• Trientine is a less potent copper remover than D-penicillamine, and its toxic profile is similar to that of D-penicillamine, although side effects are less frequent and generally milder.
• Dose of trientine is 1 g/day in three divided doses (range 750-2,000 mg)
• If zinc and trientine are combined, combination of these two drugs may increase the risk for development of sideroblastic anemia (an uncommon complication); thus, monitor hemoglobin levels closely. Zinc is discontinued in those whose hemoglobin levels decline.
• Ammonium tetrathiomolybdate, an agent previously used to treat copper toxicosis in animals, has been advocated because of its lower toxic profile, but it is still an experimental drug that is not routinely available, and its long-term safety and efficacy is unknown.
• Dose of ammonium tetrathiomolybdate is 2-3 mg/kg/body weight given in six doses along with meal and in the interval between meals

ZINC
• Dose of zinc is 150 mg/day of elemental zinc in three divided doses
• Mild abdominal discomfort occurs in 10% of patients