Dr. M. SOFI MD; FRCP (London); FRCPEdin; FRCSEdIn WILSON’S DISEASE Dr. M. SOFI MD; FRCP (London); FRCPEdin; FRCSEdIn

WILSON’S DISEASE Wilson disease is a rare autosomal recessive inherited disorder of copper metabolism that is characterized by excessive deposition of copper in the liver, brain, and other tissues. Wilson disease is often fatal if not recognized and treated when symptomatic. Wilson disease biopsy specimen with rhodanine stain (stain specific for copper deposition).

Signs and symptoms May lead to fulminant liver failure Encephalopathy Hepatic dysfunction is the presenting feature in more than half of patients. 3 major patterns of hepatic involvement are as follows: Chronic active hepatitis Cirrhosis (the most common initial presentation) Fulminant hepatic failure May lead to fulminant liver failure Encephalopathy Cerebral edema: Signs of increased intracranial pressure(eg, papilledema, hypertension, bradycardia) Jaundice: Often present but not always Ascites: Potential for hepatic vein thrombosis with rapid development of fulminant hepatic failure Change in liver span: May be small due to hepatic necrosis 

Signs and symptoms Neuropsychiatric features Most patients who present with neuropsychiatric manifestations have cirrhosis. The most common presenting neurologic feature is asymmetric tremor, which is variable in character and may be predominantly resting, postural, or kinetic. Frequent early symptoms include the following: Difficulty speaking Excessive salivation Ataxia Mask like facies Clumsiness with the hands Personality changes

Signs and symptoms Late manifestations: Dystonia Spasticity Grand mal seizures Rigidity Flexion contractures Psychiatric features (10-20% of patients) include: Emotional lability Impulsiveness Disinhibition Self-injurious behavior Psychiatric abnormalities associated with Wilson disease has been divided into the following 4 basic categories: Behavioral Affective Schizophrenic-like Cognitive

Signs and symptoms Musculoskeletal manifestations The arthropathy of Wilson disease resembles premature osteoarthritis Symptomatic joint disease late in the course of the disease, frequently after age 20 years The arthropathy generally involves the spine and large appendicular joints (e.g., knees, wrists, hips) Osteochondritis dissecans, chondromalacia patellae, and chondrocalcinosis have also been described Hematologic and renal manifestations Coombs-negative acute intravascular hemolysis (10-15%) Urolithiasis Hematuria

Signs and symptoms Kidneys: renal tubular acidosis (Type 2), a disorder of bicarbonate handling by the proximal tubules leads to: Nephrocalcinosis (calcium accumulation in the kidneys) Weakening of bones (due to calcium and phosphate loss), Aminoaciduria Heart: cardiomyopathy is a rare but recognized problem in Wilson's disease; it may lead to:  Heart failure Cardiac arrhythmias Endocrine: Hypoparathyroidism  leading to low calcium levels)  Infertility  Habitual abortion

Signs and symptoms Kayser-Fleischer rings Formed by the deposition of copper in the Descemet membrane in the limbus of the cornea The color may range from greenish gold to brown Well-developed rings may be readily visible to the naked eye or an ophthalmoscope set at +40 Kayser-Fleischer rings Identified using slit-lamp examination or gonioscopy Present in 90% of individuals with symptomatic WD invariably present in those with neurologic manifestations Not pathognomonic of WD unless accompanied by neurologic manifestations, as may observed in patients with chronic cholestatic disorders

Ophthalmologic examination revealed the presence of bilateral Kayser–Fleischer rings, most prominently seen laterally (arrows).

Wilson’s disease: Diagnosis Serum ceruloplasmin levels are less than 20 mg/dL (NR: 20-40 mg/dL) approximately 90% of all patients with WD The urinary copper excretion rate is greater than 100 mcg/day (NR: < 40 mcg/day) but it may be elevated in other cholestatic liver diseases Patient with Kayser-Fleischer rings, a serum ceruloplasmin level < 10 mg/dL and 24-hour urine copper excretion >40 mcg/day establish the diagnosis of Wilson disease Hepatic copper on a liver biopsy specimen is >250 mcg/g of dry weight even in asymptomatic patients Normal result (15-55 mcg/g) effectively excludes the diagnosis of untreated WD Genetic testing is limited to screening of family members for an identified mutation detected in the index patient

MRI Brain: Wilson disease Hyperintensity in lentiform nuclei and mesencephalic regions on T1 have been described as most common initial MRI abnormality   T2 hyperintensity is also seen typically involving basal ganglia: Putamen Globus pallidus Caudate nucleus Thalamus: ventrolateral aspect

T2-weighted axial MRI demonstrates the “face of the giant panda” in the midbrain (arrow).

Wilson’s disease: Diagnostic evaluation WD should be considered in any individual between the ages of 3 and 55 years with liver abnormalities of uncertain cause. WD must be excluded in any patient with unexplained liver disease along with neurological or neuropsychiatric disorder In a patient in whom WD is suspected, KayserFleischer rings should be sought by slit-lamp examination by a skilled examiner. The absence of KayserFleischer rings does not exclude the diagnosis of WD, even in patients with predominantly neurological disease

Wilson’s disease: Management The mainstay of therapy is lifelong use of chelating agents (eg, penicillamine, trientine) Symptoms, particularly neurologic ones, may worsen with initiation of chelation Surgical decompression or transjugular intrahepatic shunting (TIPS) is reserved for recurrent or uncontrolled variceal bleeding Orthotopic liver transplantation is curative Other treatments for Wilson disease include the following: Anticholinergics, baclofen, GABA antagonists, and levodopa to treat parkinsonism and dystonia Antiepileptics to treat seizures Neuroleptics to treat psychiatric symptoms Protein restriction, lactulose, or both to treat hepatic encephalopathy

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