Management of Wilsons Disease Hepatic Disease

Patients with liver disease may be asymptomatic or they may experience symptoms of chronic liver disease, such as fatigue or jaundice, or manifest signs or symptoms ofpor-tal hypertension, such as ascites and varices without or with bleeding. Some may have chronic hepatitis with features indistinguishable from autoimmune hepatitis. In about 5%, the sudden onset of jaundice or ascites with associated hemolysis heralds the onset of acute FHF.

Patients that are asymptomatic with compensated liver disease may be treated with zinc monotherapy or with a chelating agent, typically trientine or penicillamine (see Table 124-2). Tetrathiomolybdate is a very potent chelator that may be useful for initial therapy for patients with Wilson's disease, however it is still undergoing further testing and is not commercially available in the United States. Patients with active disease should be treated initially with a chelator or a chelator with zinc supplementation. Chelation therapy must be begun slowly and with careful monitoring for side effects. Specific concerns for penicil-lamine are hypersensitivity reactions and marrow suppression. For patients with complications of the chronic liver disease due to Wilson's disease additional therapy is the same as that for other chronic liver diseases. The most common problems are that associated with portal hypertension or with portosystemic shunting. Patients with ascites are treated with diuretics; those with variceal bleeding are treated with p-blockers, somatostatin infusion, endoscopic band ligation, and portosystemic shunting, or liver transplantation. Encephalopathy is present in the acute fulminant setting, or in patients with end-stage liver disease. In this latter group, encephalopathy may exacerbate neu-ropsychological symptoms due to the Wilson's disease, and should be considered and treated separately.

For Wilson's disease patients with liver disease, the initial period of treatment with a chelator should range from 2 to 12 months, with close monitoring maintained during this initial period of treatment. For most patients, there is a general trend towards stabilization of hepatic function over the first 8 weeks of therapy. Biochemical parameters of hepatic inflammation and insufficiency should show a trend towards gradual improvement over the next 6 to 12 months, though may improve further for up to about 4 years after the initiation of treatment in some individuals. For those with ascites and edema that respond to the primary treatment of the Wilson's disease, requirements for diuretics decrease with time. Similarly, the need for treatment of encephalopathy, if necessary, may also improve with primary treatment for Wilson's disease. Once stabilization is achieved, then either the chelator can be continued at a reduced dosage, or patients can be maintained on zinc therapy. For those individuals with severe hepatic insufficiency but not fulminant liver failure due to Wilson's disease, a trial of medical therapy is warranted. However these individuals should also be followed by a liver transplantation center because some may fail to respond to therapy or suffer serious complications of their liver disease before stabilization.

Patients presenting with FHF due to Wilson's disease typically have a nonimmune hemolytic anemia, relatively low

TABLE 124-2. Therapies for Wilson's Disease

Medication Mode of Action Dosages (total/24 h) Adverse Effects d-Penicillamine (Cuprimine) Chelating agent, 750 to 2000 mg in 2 to 3 divided doses apart Worsening of neurologic symptoms in 10 to 50% after induces cupriuresis from meals; maintenance 750 to 1000 mg; initiation of treatment; initial hypersensitivity reactions;

requires supplemental pyridoxine marrow suppression; lupus-like syndrome; nephrosis;

dermatologic toxicity; rare Goodpastures syndrome

Trientine (Syprine) Chelating agent, 750 to 1500 mg in 2 to 3 divided doses apart Lupus-like syndrome; nephrosis; marrow suppression induces cupriuresis from meals; maintenance 750 to 1000 mg

Zinc (Galzin) Blocks intestinal 75 to 150 mg in 2 to 3 divided doses apart Gastric irritation copper uptake by from meals enterocytes alkaline phosphatase level compared to total bilirubin (ratio < 4), aminotransferases less than 500 IU/L and significant hypoalbuminemia and coagulopathy. In this setting, urine and hepatic copper concentrations are markedly elevated. Liver transplantation is lifesaving for these individuals, and most have good long term survival. While awaiting a donor liver, the use of albumin dialysis, plasma exchange or plasmapheresis, or other devices equipped for these functions will acutely lower serum copper that was released into the serum by the severe hepatocellular injury. Although these treatments may help decrease hemolysis and the continued insult to the liver and other organs, specifically the kidneys, they have not been shown to eliminate the need for transplantation. Wilson's disease accounts for approximately 5% of all patients presenting with acute liver failure (ALF) worldwide.

Special consideration must be made for patients who become pregnant or are contemplating pregnancy while being treated for their Wilson's disease, and for those Wilson's disease patients who are undergoing elective surgical procedures. Treatment of Wilson's disease must continue through pregnancy. Successful pregnancies have been reported with patients using penicillamine, trientine, and zinc. FHF has occurred following discontinuation of therapy during pregnancy. No dosage reduction is needed for zinc therapy, whereas the smallest effective dosage of penicillamine or trientine should be administered during pregnancy and afterward in those who undergo cesarean section to promote wound healing. A separate issue is the potential problem of portal hypertension and varices and the risk of variceal bleeding in pregnancy, a state where vascular volume typically increases. If varices are detected, patients should be treated with a p-blocker with the consent of the obstetrician. In Wilson's disease patients undergoing elective surgical procedures, dosages of chelating agents should be minimized until wound healing is achieved. Zinc dosages should remain unaltered for those undergoing elective surgery.

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