Wilson disease

wilson

1. WILSON DISEASE DR ANVESH NARIMETI

2. Progressive lenticular degeneration, a familial nervous disase associated with cirrhosis of the liver. SAK Wilson Thesis, Univ. of Edinburgh, 1911

3. Epidemology Occurs worldwide Incidence of one in 30,000 The age at onset of symptoms ranges from 6 to about 40 years.

4. THE COPPER PATHWAY Copper is a micro nutrient and an essential cofactor for many enzymes , Daily copper intake is 1-4 mg

5. Cu Metabolism

6. WD – Genetic Link Autosomal recessive disorder The WD gene, ATP7B is located on the long arm of chrom . 13q14.1 The WD gene encodes a Hepatocyte canalicular copper-transporting atpase

7. WD – Genetic Link Autosomal recessive disorder The WD gene, ATP7B is located on the long arm of chrom. 13q14.1 The WD gene encodes a copper-transporting P-Type ATPase) which is expressed predominantly in the liver

8. Molecular Mechanism The Wilson Disease Protein (WNDP) has two functions: Export of copper from the cell and Incorporation into copper-dependent enzymes

9. Copper Metabolism - Normal

10. Copper Metabolism – WD Mutations

11. PATHOGENESIS ATP7B protein deficiency impairs biliary copper excretion, resulting in positive copper balance, hepatic copper accumulation, and copper toxicity from oxidant damage. Excess hepatic copper is initially bound to metallothionein , but as this storage capacity is exceeded, liver damage begins Defective copper incorporation into apoceruloplasmin leads to excess catabolism and low blood levels of ceruloplasmin . Serum copper levels are usually lower than normal because of low blood ceruloplasmin , which normally binds >90% of serum copper. As the disease progresses, nonceruloplasmin serum copper ("free" copper) levels increase, resulting in copper buildup in other parts of the body, such as the brain, leading to neurologic and psychiatric disease.

12. CLINICAL PRESENTATION HEPATIC Wilson's disease may present as hepatitis, cirrhosis, or as hepatic decompensation An episode of hepatitis may occur, with elevated blood transaminase enzymes, with or without jaundice, and then spontaneously regress. Hepatitis often reoccurs, and most of these patients eventually develop cirrhosis. Hepatic decompensation is associated with elevated serum bilirubin , reduced serum albumin and coagulation factors, ascites , peripheral edema , and hepatic encephalopathy. In severe hepatic failure, hemolytic anemia may occur because large amounts of copper derived from hepatocellular necrosis are released into the bloodstream. The association of hemolysis and liver disease makes Wilson's disease a likely diagnosis

13. Neurologic The neurologic manifestations of Wilson's disease typically occur in patients in their early twenties, although the age of onset extends into the sixth decade of life. MRI and CT scans reveal damage in the basal ganglia and occasionally in the pons , medulla, thalamus, cerebellum, and subcortical areas. The three main movement disorders include dystonia , incoordination , and tremor. Dysarthria and dysphagia are common. In some patients, the clinical picture closely resembles that of Parkinson's disease. Dystonia can involve any part of the body and eventually leads to grotesque positions of the limbs, neck, and trunk. Autonomic disturbances may include orthostatic hypotension and sweating abnormalities as well as bowel, bladder, and sexual dysfunction. Memory loss, migraine-type headaches, and seizures may occur. Patients have difficulties focusing on tasks, but cognition is not usually grossly impaired. Sensory abnormalities and muscular weakness are not features of the disease.

14. Psychiatric behavioral disturbances, with onset in the five years before diagnosis, is present in half of patients with neurologic disease. The features are diverse and may include loss of emotional control (temper tantrums, crying bouts), depression, hyperactivity, or loss of sexual inhibition. Other Manifestations female patients have repeated spontaneous abortions, and most become amenorrheic prior to diagnosis . Cholelithiasis and nephrolithiasis occur with increased frequency. Some patients have osteoarthritis, particularly of the knee. Microscopic hematuria is common, increased urinary excretion of phosphates, amino acids, glucose, or urates may occur; however, a full-blown Fanconi syndrome is rare. Sunflower cataracts and Kayser -Fleischer rings (copper deposits in the outer rim of the cornea) may be seen

15. DIAGNOSIS

16. TREATMENT ANTI COPPER DRUGS. Penicillamine was previously the primary anticopper treatment but now plays a minor role because of its toxicity and because it often worsens existing neurologic disease if used as initial therapy. If penicillamine is given, it should always be accompanied by 25 mg/d of pyridoxine. 500mg bd ½ hr before or 2hrs after the food Trientine is a less toxic chelator and is supplanting penicillamine when a chelator is indicated

17. patients with hepatitis or cirrhosis, but without evidence of hepatic decompensation or neurologic/psychiatric symptoms, zinc is the therapy of choice, although some advocate therapy with trientine . Zinc has proven efficacy in Wilson's disease and is essentially nontoxic. It produces a negative copper balance by blocking intestinal absorption of copper , and it induces hepatic metallothionein synthesis, which sequesters additional toxic copper . All presymptomatic patients should be treated prophylactically , because the disease is close to 100% penetrant 50mg elemental zinc tid ,each separated from food and trientene or pencillamine by atleast 1hr

18. Hepatic decompensation The first step in evaluating patients presenting with hepatic decompensation is to establish disease severity, which can be estimated using the Nazer prognostic index . Patients with scores < 7 can usually be managed with medical therapy. Patients with scores > 9 should be considered immediately for liver transplantation. Those with scores between 7 and 9 require clinical judgment as to whether to recommend transplantation or medical therapy. A combination of trientine and zinc has been used to treat patients with Nazer scores as high as 9, but such patients should be watched carefully for indications of hepatic deterioration, which mandates transplantation. For initial medical therapy of patients with hepatic decompensation , a chelator ( trientine is preferred) plus zinc is recommended . Zinc should not, however, be ingested simultaneously with trientine , because it will chelate zinc and form therapeutically ineffective complexes; administration of the two drugs should be separated by at least one hour.

19. Neurologic presentation For initial neurologic therapy, tetrathiomolybdate is emerging as the drug of choice because of its rapid control of free copper, preservation of neurologic function, and low toxicity. Penicillamine and trientine should be avoided because they each have a high risk of worsening the neurologic condition. Until tetrathiomolybdate is commercially available, zinc therapy is recommended. Although it is relatively slow-acting, zinc itself does not cause neurologic worsening. Although hepatic transplantation may improve neurologic symptoms, it does so only by removing copper, which can be done more safely and inexpensively with anticopper drugs. Pregnant patients should be treated with zinc or trientine throughout pregnancy, but without tight copper control, because copper deficiency can be teratogenic .

20. How long the treatment ? LIFE LONG With treatment, liver function usually recovers after about a year, although residual liver damage is usually present. Neurologic and psychiatric symptoms usually improve after 6 to 24 months of treatment.

21. MONITORING When first using trientine or penicillamine , it is necessary to monitor for drug toxicity—particularly bone marrow suppression and proteinuria . Complete blood counts, standard biochemical profiles, and a urinalysis should be performed at weekly intervals for a month, then at twice-weekly intervals for two to three months, then at monthly intervals for three or four months, and at four- to six-month intervals thereafter

22. The anticopper effects of trientine and penicillamine can be monitored by following 24-h "free" serum copper. Changes in urine copper are more difficult to interpret because excretion reflects the effect of the drug, as well as body loading with copper. Free serum copper is calculated by subtracting the ceruloplasmin copper from the total serum copper. The normal free copper value is 1.6–2.4 mmol /L (10–15 mg/ dL ), and it is often as high as 7.9 mmol /L (50 mg/ dL ) in untreated Wilson's disease. With treatment, free copper should be <3.9 mmol /L (<25 mg/ dL ).

23. Zinc treatment does not require blood or urine monitoring for toxicity. Its only significant side effect is gastric burning or nausea in 10% of patients, usually with the first morning dose. This can be mitigated by taking the first dose an hour after breakfast or taking the zinc with a small amount of protein Because zinc mainly affects stool copper , 24-h urine copper can be used to reflect body loading. The typical value in untreated symptomatic patients is >3.1 mmol (>200 micro g) per 24 h. This level should decrease during the first 1–2 years of therapy to <2.0 mmol (<125 mg) per 24 h. A normal value [0.3 to 0.8 mmol (20 to 50 mg)] is rarely reached during the first decade of therapy and should raise concern about overtreatment (copper deficiency ), the first sign of which is anemia and/or leukopenia .

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