Wilsons 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

1. Wilsons Disease By Divya

2. Introduction 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

3. Staging The natural history of Wilson disease may be considered in four stages, as follows: Stage I - The initial period of accumulation of copper within hepatic binding sites Stage II - The acute redistribution of copper within the liver and its release into the circulation Stage III - The chronic accumulation of copper in the brain and other extrahepatic tissue, with progressive and eventually fatal disease Stage IV - Restoration of copper balance by the use of long-term chelation therapy

4. Etiology In Wilson disease, the processes of incorporation of copper into ceruloplasmin and excretion of excess copper into bile are impaired.   The transport of copper by the copper-transporting P-type ATPase is defective in Wilson disease secondary to one of several mutations in the  ATP7B  gene.   By genetic linkage studies, Bowcock and colleagues narrowed the assignment of the Wilson disease locus to 13q14-q21. The excess copper resulting from Wilson disease promotes free radical formation that results in oxidation of lipids and proteins. Ultrastructural abnormalities in the earliest stages of hepatocellular injury, involving the endoplasmic reticulum, mitochondria, peroxisomes, and nuclei, have been identified. Initially, the excess copper accumulates in the liver, leading to damage to hepatocytes. Eventually, as liver copper levels increase, it increases in the circulation and is deposited in other organs

5. Signs and Syptoms Hepatic dysfunction is the presenting feature in more than half of patients. Although the condition may manifest as acute hepatitis, the three major patterns of hepatic involvement are as 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 Jaundice

6. Signs and Syptoms Musculoskeletal manifestations The arthropathy of Wilson disease is a degenerative process that resembles premature osteoarthritis Symptomatic joint disease usually arises late in the course of the disease, frequently after age 20 years The arthropathy generally involves the spine and large appendicular joints ( eg , knees, wrists, hips) Hematologic and renal manifestations Coombs-negative acute intravascular hemolysis (10%-15%) Urolithiasis Hematuria

7. 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 with an ophthalmoscope set at +40 When not visible to the unaided eye, the rings may be identified using slit-lamp examination or gonioscopy Observed in up to 90% of individuals with symptomatic Wilson disease and almost invariably present in those with neurologic manifestations No longer considered pathognomonic of Wilson disease unless accompanied by neurologic manifestations, as they may also be observed in patients with chronic cholestatic disorders

8. Signs and syptoms 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 Masklike facies Clumsiness with the hands Personality changes

9. Signs and Syptoms Psychiatric abnormalities associated with Wilson disease has been divided into the following four basic categories: Behavioral Affective Schizophrenic-like Cognitive Additional manifestations Skeletal abnormalities ( eg , osteoporosis, osteomalacia , rickets, spontaneous fractures, polyarthritis) Cardiac manifestations ( eg , rhythm abnormalities, increased autonomic tone) Skin pigmentation and a bluish discoloration at the base of the fingernails (azure lunulae )

10. Diagnosis - Considerations in the workup of Wilson disease are as follows: Serum ceruloplasmin levels are less than 20 mg/dL (reference range, 20-40 mg/dL) in approximately 90% of all patients with Wilson disease The urinary copper excretion rate is greater than 100 mcg/day (reference range, < 40 mcg/day) in most patients with symptomatic Wilson disease, but it may also be elevated in other cholestatic liver diseases In a patient with Kayser-Fleischer rings, a serum ceruloplasmin level < 20 mg/dL and 24-hour urine copper excretion >40 mcg/day establish the diagnosis of Wilson disease Hepatic copper concentration (criterion standard) on a liver biopsy specimen is >250 mcg/g of dry weight even in asymptomatic patients; a normal result (15-55 mcg/g) effectively excludes the diagnosis of untreated Wilson disease, but elevation may be found in other chronic hepatic disorders

11. Diagnosis Radiolabeled copper testing directly assays hepatic copper metabolism Genetic testing is limited to screening of family members for an identified mutation detected in the index patient Brain imaging shows characteristic findings; MRI appears to be more sensitive than CT in detecting early lesions Abdominal imaging findings are neither sensitive nor specific Resting ECG abnormalities include left ventricular or biventricular hypertrophy, early repolarization, ST segment depression, T-wave inversion, and various arrhythmias Electron microscopic detection of copper-containing hepatocytic lysosomes is helpful in the diagnosis of the early stages of Wilson disease, in addition to the quantification of hepatic copper by atomic absorption spectrophotometry

12. Treatment Management Features of treatment of Wilson disease are as follows: 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 unresponsive to standard conservative measures Orthotopic liver transplantation is curative

13. Treatment 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